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Anticoagulant Management of Cancer-Associated Thrombosis and Thrombocytopenia: A Retrospective Chart Review
Umaima Abbas1, Ushra Khan1, Robin Mackenzie1, Rija Fatima2, Tzu-Fei Wang3, Caroline Hamm1,4,5, Andrea Cervi1,4,5
1Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada, 2Department of Translational Health Science, University of Windsor, Windsor, ON, Canada, 3Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada, 5Windsor Regional Hospital, Windsor, ON, Canada

BACKGROUND: Patients with cancer-associated thrombosis (CAT) are at an increased risk of recurrent thrombosis and bleeding for several reasons, including treatment- and disease-related thrombocytopenia. While the direct oral anticoagulants (DOACs) are increasingly used in the management of CAT based on data from multiple randomized controlled trials, patients with thrombocytopenia have been largely excluded from these studies. As a result, low-molecular-weight heparin (LMWH) continues to be recommended for patients with CAT and thrombocytopenia, with significant heterogeneity in LMWH dosing and platelet transfusion. In clinical practice, the DOACs are variably used to treat patients with CAT and thrombocytopenia despite a lack of evidence demonstrating their safety, or efficacy in preventing thrombosis recurrence. OBJECTIVES: Identify rates of recurrent venous thromboembolism (VTE) and bleeding in patients with CAT and thrombocytopenia treated with DOACs compared to LMWH. METHODS: We performed a retrospective chart review of adult patients at a large community hospital with CAT and thrombocytopenia treated with a DOAC or LMWH between 2016-2023. Thrombocytopenia was defined as a platelet count below 100,000/mcL within 14 days of diagnosis of CAT. Data were collected for the first 100 days following VTE diagnosis for each patient. Primary outcomes included: (1) rates of recurrent VTE, and (2) bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). RESULTS: Forty-two patients met our inclusion criteria. Twenty-two patients (52.4%) were female, mean patient age at VTE diagnosis was 64 years. Twenty patients (47.6%) had a solid organ malignancy, most commonly lung cancer (n=5; 11.9%) while 22 (52.4%) had a hematologic malignancy, with myeloma as the most frequent subtype (n=6; 14.3%). The number of patients with correlating platelet count range within the first 7 days of VTE diagnosis was: <25,000/mcL: n=3 (7.1%,), 25,000-50,000/mcL: n=9 (21.4%), and 50,000-100,000/mcL: 19 (45.2%). Sixteen patients (38.1%) were initially treated with a DOAC, 19 (45.2%) were treated with LMWH, and 6 (14.3%) were treated with unfractionated heparin (UFH). One patient did not receive anticoagulant within the first 7 days of VTE diagnosis due to concurrent bleeding. Apixaban (n=12; 28.6%) was the most common type of DOAC used, while dalteparin (n=18; 42.9%) was the most common type of LMWH. Among individuals initially treated with LMWH, 13 patients later switched to a DOAC owing to patient preference for an oral anticoagulant. None of the patients initially treated with a DOAC switched to LMWH. Among patients treated with DOACs, there were no recurrent VTEs and 2 clinically relevant non-major (CRNM) bleeding events (12.5%), while those treated with LMWH had 1 recurrent VTE (5.3%) and 2 CRNM bleeding events (10.5%). CONCLUSIONS: Rates of recurrent thrombosis and major bleeding were similar among thrombocytopenic patients with CAT treated with DOACs and LMWH, although variation in baseline patient characteristics remains a limitation. Further prospective research is needed to determine whether the DOACs represent a suitable option for patients with cancer-associated VTE and thrombocytopenia.
Session: Posters/Exhibits/Break
Safety and Efficacy of the Anti-Tissue Factor Pathway Inhibitor Marstacimab in Participants With Severe Hemophilia Without Inhibitors: Results From the Phase 3 Basis Trial and Ongoing Long-Term Extension Study
Suchitra S. Acharya1, Davide Matino2, Andrew Palladino3, Eunhee Hwang3, Regina McDonald4, Carrie Turich Taylor5, John Teeter5
1Cohen Children's Medical Center, Northwell Hemostasis and Thrombosis Center, Northwell Health, New Hyde Park, NY, USA, 2McMaster University, 237 Barton St. East, Hamilton, ON, Canada, 3Pfizer Inc, Collegeville, PA, USA, 4Pfizer Inc, New York, NY, USA, 5Pfizer Inc, Groton, CT, USA

Background: Marstacimab (PF-06741086) is a monoclonal antibody targeted to the tissue factor pathway inhibitor protein to improve hemostasis via the extrinsic coagulation pathway. BASIS (NCT03938792) is an open-label, pivotal phase 3 study of marstacimab in participants with severe (factor [F]VIII ˂1%) hemophilia A (HA) or moderately severe to severe (FIX ≤2%) hemophilia B (HB), with or without inhibitors. Objective: To evaluate the safety and efficacy of marstacimab in participants without inhibitors compared with previous factor replacement therapy.

Methods: Screened males aged ≥12-<75 years with severe HA or moderately severe to severe HB entered a 6-month observational phase (OP) and received on demand (OD) or routine prophylaxis (RP) therapy. Participants then entered a 12-month active treatment phase (ATP) and received a single loading dose of 300 mg subcutaneous marstacimab followed by 150 mg once/week. Primary endpoints were annualized bleeding rate (ABR) for treated bleeds and safety outcomes. Secondary endpoints included ABR of bleed categories. Participants could enroll in the long-term extension (LTE) study (NCT05145127).

Results: In total, 128 participants (median age, 30 [range 13-66] years) entered the OP (OD: HA n=29, HB n=8; RP: HA n=72, HB n=19), 116 (OD, n=33; RP, n=83) were dosed in the ATP, and 107 continued in the LTE (data cut: OD, n=32; RP, n=75; duration: 36-693 days). At baseline, 89 participants (69.5%; OD: n=36; RP: n=53) had ≥1 target joint. Mean (range) duration of marstacimab treatment was 12.1 (11.5-13.1) months for OD and 11.6 (0.9-12.8) months for RP in the ATP, and 14.0 (1.2-21.8) months for OD and 11.9 (4.9-23.1) months for RP in the LTE. Over the ATP, the OD group reported no serious adverse events (SAEs) vs 1 (2.7%) in the OP; the RP group reported 7 (8.4%) SAEs, of which 1 (1.2%) was treatment-related, vs 2 (2.2%) in the OP. One RP participant discontinued the ATP due to a non-treatment-related SAE. No treatment-related SAEs were reported during the LTE. Antidrug antibodies developed in 23/116 participants (19.8% incidence), of which titers were low and resolved in 22 participants by end of BASIS. No deaths or thromboembolic events were recorded during the ATP or LTE (Table 1). Marstacimab reduced the mean (95% CI) ABR for treated bleeds vs OD (91.6% [88.1-94.1%]) and RP (35.2% [5.6-55.6%]) during the ATP and demonstrated superiority vs OD (P<0.001) and superiority/non-inferiority vs RP (P=0.0376). Overall, mean ABR declined over the first 6 months and continued to decline during the second 6 months of the ATP. The ABR up to 16 months during the LTE was consistent with the ATP for the OD group and reductions continued for the RP group (Table 2). Marstacimab significantly reduced ABR across all secondary bleed categories vs OD and numerically reduced vs RP (non-inferiority).

Conclusions: Once-weekly subcutaneous marstacimab was safe and effective for reducing bleeding events in participants with severe HA or moderately severe to severe HB without inhibitors for 12 months in BASIS, and in an additional 16 months in the LTE study.
Session: Posters/Exhibits/Break
Discovering novel pro-coagulant agents from snake venom
Raymond Adili

Novel Snake Venom Hemocoagulase Restores in Vivo Hemostasis and Limits Bleeding Associated with Coagulation Disorders

Reheman Adili M.D

Bloodworks Research Institute, Seattle, WA

Background: Activation of platelets and coagulation at vascular injury sites are crucial for hemostasis and limiting excessive bleeding. Coagulation defects can lead to severe bleeding, which requires urgent restoration of hemostasis. However, there is an unmet medical need for novel therapeutic agents that restore hemostasis in vivo. We recently reported slounase, a novel hemocoagulase containing a snake venom-derived batroxobin (a thrombin-like enzyme that converts fibrinogen to fibrin independent of thrombin) and a Factor X activator, restores hemostatic clot formation in heparin-anticoagulated mice suggesting slounase may circumvent FXa inhibition and restore coagulation.

Objectives: To investigate the hemostatic effect of slounase in severe bleeding disorders associated with hemophilia and treatment with Factor Xa Inhibitors.

Methods: The effect of slounase on hemostasis and bleeding was determined in FVIII-/- mice, with and without inhibitors, and wild-type mice that were pretreated with apixaban or rivaroxaban (via oral gavage), using intravital microscopy hemostatic models, and a tail-bleeding assay. The effect of slounase on clot formation in whole human blood was studied using reconstituted Factor FVIII-/- deficient blood or whole human blood pretreated with apixaban or rivaroxaban in vitro determined by thromboelastography (TEG).

Results: Hemostatic clot formation in response to vascular injury is severely defective in FVIII-/- mice and WT mice pretreated with FXa inhibitors examined under intravital microscopy. Prophylactic intravenous treatment of 1U/kg slounase in FVIII-/- mice significantly enhanced platelet activation, accumulation, and fibrin formation in response to vascular injury, resulting in stable hemostatic clot formation in the cremaster artery and saphenous vein laser ablation hemostasis models and by ferric chloride injury to the carotid artery. Importantly, in vivo, hemostatic enhancement persisted in FVIII-/- mice intravenously treated with anti-FVIII antibodies and slounase in vivo. Slounase treatment dose-dependently restored clot formation in FVIII-/- mice whole blood and FVIII-/- deficient reconstituted human whole blood examined by TEG. Slounase intervention (1U/kg) reversed the anticoagulant effect of apixaban or rivaroxaban in vivo and significantly enhanced platelet-fibrin hemostatic clot formation in response to vascular injury. Rivaroxaban or apixaban treatment in human whole blood dose-dependently inhibited clot formation in vitro on TEG. Slounase treatment dose-dependently restored clot formation and clot strength to the normal range. Lastly, Slounase treatment significantly corrected prolonged tail bleeding time and decreased blood loss in FVIII-/- mice and WT mice treated with FXa inhibitors in tail clip assays.

Conclusion: Slounase treatment restores hemostasis and limits bleeding hemophilia A, with and without inhibitors. Slounase treatment reverses the anticoagulant effect of FXa inhibitors rivaroxaban and apixaban in vitro and in vivo. Our results demonstrate that slounase is a potential bypassing agent to restore hemostasis in bleeding associated with inherited coagulation disorders and as a rapid reversal agent for anticoagulation by FXa inhibitors to decrease bleeding and blood loss.

Session: Take a hike Mickey- novel T&H insights from non-murine animals
Benefit of albumin infusion in an elderly cirrhotic patient on DOAC: about a case.
LAMIA AIT OUALI1, FARID SLIMANI2, SAMIA OULARBI1, SAMIR TINE1,3
1APHP René Muret , Sevran, France, 2APHP Jean Verdier , Bondy, France, 3APHP Avicenne, Bobigny, France

Introduction : Hypoalbuminemia is frequently observed in patients with decompensation of cirrhosis, which is aggravated by nutritional status, renal insufficiency which are frequent complications in the elderly, leading to infectious, hemodynamic, hydroelectrolyte complications, and the increase in the bioavailability of certain drugs such as DOACs.Albumin infusion, alone or in combination with other drugs, has been proposed for the treatment of various complications of cirrhosis. We propose to look at the case of our cirrhotic patient Child-Pugh A on DOAC who was infused with Albumin. Observation: This is an 89-year-old patient with a history of type II diabetes, moderate chronic kidney disease, cirrhosis on DOAC for atrial fibrillation. Admitted to geriatric SSR for reautomonization following oedematoascitic decompensation on urinary sepsis. Clinically upon arrival: Infectious: urinary sepsis with ESBL germs Klebsiella pneumoniae. Hepatic: oedematoascitic decompensation on cirrhosis. In terms of haemostasis: Persistent gross haematuria and epistaxis, on Dabigatran with a haemorrhagic score of 4.right posterior tibial DVT. Renal: Hepatorenal syndrome. Pulmonary: PNP at SARSCOV2. Nutritionally severe undernutrition with albuminemia at 19.9mg/l prealbuminemia 0.06mg/l. The infusion of 1g/kg of albumin improved the clinical picture of our patient. Discussion: The perfusion of albumin during cirrhosis is interesting in the correction of hemodynamic complications by increasing oncotic pressure, infectious by decreasing the bioavailability of prostaglandin, but also by decreasing the bioavailability of DOACs thus limiting the risk of overdose, increased by renal failure and hypoalbuminemia. Conclusion: Our observation allows us to deduce that albumin infusion improves the clinical condition of cirrhotic patients with severe hypoalbuminemia under DOAC, but no study has demonstrated its interest in limiting the risk of bleeding in these patients.
Session: Posters/Exhibits/Break
Fixed-dosing of 4-factor prothrombin complex concentrate for reversal of anticoagulation: evaluating the effectiveness, safety, and cost savings
Amer Al Homssi1, Ryan Lokkesmoe1, Ryan Powers1, Benjamin Jung2, Lisa Baumann Kreuziger3
1Medical College of Wisconsin, Milwaukee, WI, USA, 2Froedtert Health, Milwaukee, WI, USA, 3Versiti Blood Research Institute, Milwaukee, WI, USA

Background: Reversal of anticoagulation is required in bleeding or emergent surgical procedures. Four-factor prothrombin complex concentrate (4F-PCC) is a common medication used to reverse warfarin or off-label management of bleeding in patients taking direct oral anticoagulants (DOACs). The ability to quickly mix and administer 4F-PCC is advantageous over other reversal agents, however, dosing strategies that optimize anticoagulant reversal and cost, such as fixed dosing of 4F-PCC, are still under evaluation. Objective: The primary objective of this study is to evaluate the effectiveness, safety, and cost savings of fixed dosing of 4F-PCC at 1500 units for warfarin reversal and 2000 units for DOAC reversal in urgent and emergent situations.

Methods: Three hospitals of Froedtert and the Medical College of Wisconsin transitioned to fixed 4F-PCC (Kcentra) dosing in October 2018. We retrospectively reviewed patients from 10/1/2018-4/30/2021 who received fixed dosing. Cost-savings were defined as the difference in the cost between the administration of fixed dosing and the projected weight-based dosing based on the package insert for warfarin reversal or 50 units/kg in patients treated with DOACs.

Results: 592 patients received Kcentra during the prespecified period, of whom 541 received Kcentra for warfarin reversal (n=414) or DOAC (n=127) management in emergency settings. The mean age was 71, 57% were males, and the mean weight was 86 kg. More than half of the patients were treated with anticoagulation for atrial fibrillation and 24% had venous thromboembolism. Reversal in patients on warfarin was needed in 32% of cases pre-procedure and 65% of cases for bleeding of which 42% was for intracranial hemorrhage (ICH) and 30% for gastrointestinal bleeding. Whereas for patients treated with DOAC, 87% of cases were reversed for bleeding of which 63% were for ICH. More than half of the patients on warfarin had a pre-reversal INR between 2 and 4 and almost a quarter over 6. Post-reversal INR below 2 and 1.5 was achieved in 89% and 56% of patients, respectively. The mean doses for warfarin and DOAC reversals were 1,636 and 2,106 units, respectively. Less than 5% in either group required repeat doses. 82% of patients treated with warfarin also received vitamin K. Within 30 days, both groups had similar bleeding (12%) and thrombotic (5%) events. All-cause 30-day mortality rates in patients treated with warfarin and DOAC, including patients who suffered from ICH, were 24% and 30%, respectively. The median cost savings of fix dosing per patient on warfarin and DOAC were $1,567 (IQR $455 - $2,947) and $3,936 ($2,716 - $5,632), respectively. The annualized median hospital cost savings for warfarin and DOAC were $176,239 and $146,733, respectively.

Conclusions: Based on our real-world data over more than two years, fixed-dosing of 4F-PCC (Kcentra) for warfarin and DOAC hemorrhage management had significantly less cost than adjusted dose and is associated with similar rates of thrombosis and death compared to other studies.
Session: Posters/Exhibits/Break
A Retrospective Study of Acquired Von Willebrand Syndrome in Myeloproliferative Neoplasms
Mohammed Al Sharif 1 ,2, Brian Harnett 3, Subia Tasneem 1, Brian Leber 4 ,5, Christopher Hillis 5, Catherine P.M. Hayward 1 ,3 ,4
1Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada, 2 Department of Pathology and Laboratory Medicine, King Abdullah Bin Abdulaziz University Hospital, Princess Nourah University, Riyadh, Saudi Arabia, 3 Department of Medicine, McMaster University, Hamilton, ON, Canada, 4 Hamilton Regional Laboratory Medicine Program, Hamilton, ON, Canada, 5 Hematology/Oncology, Juravinski Cancer Center, Hamilton, ON, Canada

Background: Myeloproliferative Neoplasms (MPN) cause overproduction of red cells, platelets, and/or white cells and can manifest with bleeding, thrombosis, bone marrow scarring/fibrosis, and transformation to acute leukemia. Bleeding in MPN can reflect acquired von Willebrand syndrome (AVWS), with loss of high molecular weight (HMW) von Willebrand factor (VWF) multimers and extreme platelet elevation, and decisions on aspirin therapy. Nonetheless, there are uncertainties about the prevalence of AVWS in MPN and its association to high platelet counts and bleeding. Objectives: Assess AVWS clinical-laboratory correlations for a cohort of MPN patients who had VWF screens performed. Method: Clinical and laboratory data were evaluated for retrospective cohort of MPN patients, seen at the Juravinski Cancer Clinic in Hamilton from January 2019 until February 2023, with research ethics approval. VWF screens included: activity by VWF:GPIbR or VWF:GPIbM; VWF antigen (Ag) by Liatest; VWF activity/antigen ratio; FVIIIC; multimers for some. Data were assessed for: evidence of AVWS and if AVWS had influenced aspirin therapy (documented in records), associations between VWF and other clinical and laboratory findings, including platelet counts and bleeding. Result: During the four year period, 27 MPN patients (59.3% female, 40.7% male; median age 60 years, IQR: 60-70) had VWF screens (96% with multimer analysis). MPN diagnoses included: Essential Thrombocythemia, n=18 (66.7%); Polycythemia Vera, n=4 (14.8%); Primary Myelofibrosis, n=2 (7.4%); Pre-fibrotic Primary Myelofibrosis, n=2 (7.4%); and Chronic Myeloid Leukemia, n=1 (3.7%). MPN driver mutations were: JAK2 (V617F) n=13 (48.1%), CALR n=6 (22.2%), triple negative n=4 (14.9%), JAK2 negative n=3 (11.1%), and BCR-ABL1 n=1 (3.7%). Most had thrombocytosis (96.3%, platelet counts X109/L: median=839, IQR=839 - 1155, range 166-2,572). Many (24/27, 88.8%) had evidence of AVWS, defined as a VWF activity/VWF:Ag ratio below the local cutoff of 0.63 (ratios: median=0.40, range: 0.02-0.99, IQR=0.4 - 0.56), with low VWF activity (<0.50 U/mL) in 16/24 (66.7% ) of AVWS cases (median activity=0.22 U/mL, range: 0.04-0.44; IQR=0.22-0.26). Three patients developed AVWS during follow-up whereas five had their AVWS resolve with MPN treatment. Among AVWS cases, VWF activity/antigen ratios showed weak association to platelet counts (R2=0.22, p=0.013) and stronger association to VWF activity (R2=0.73, p<0.0001). With a few exceptions (3/24, 12.5%, all with high VWF:Ag), most (21/24, 87%) MPN patients with AVWS had loss, or relative loss, of high molecular weight multimers (HMW), indicating that VWF activity/antigen ratios were sensitive to multimer changes. Only 5 (21%) MPN patients with AVWS had documented bleeding (nasal n=3, vaginal n=1, oral n=1), which was mild (n=1 needing aspirin discontinuation) and without relationships to VWF activity (p=0.26) or platelet counts (p=0.68). Conclusion: Most patients with MPN who had VWF screens at our center had AVWS with low VWF activity/antigen ratios (due to loss of HMW VWF), more commonly with VWF deficiency, with only a few having mild bleeding. A larger prospective study of VWF screens in unselected patients with MPN would help define the overall prevalence of VWF abnormalities in MPN and their significance and relationship to platelet counts.
Session: Online Poster Session
Safety and cost-effectiveness analysis of anticoagulation therapy in adult patients undergoing extracorporeal membrane oxygenation
Amanda Arenella1, Michael Calloway1, Joshua Oh2
1Department of Health Economics and Outcomes Research, Grifols SSNA, Research Triangle Park, NC, USA, 2University of North Carolina at Charlotte, College of Health and Human Services, Department of Public Health Sciences , Charlotte, NC, USA

Background: Unfractionated heparin (UFH) is currently the gold standard of treatment for anticoagulation in patients undergoing extracorporeal membrane oxygenation (ECMO). Recent Extracorporeal Life Support Organization (ELSO) guidelines also recommend the use of direct thrombin inhibitors (DTIs), bivalirudin and argatroban, in patients with diagnosed heparin-induced thrombocytopenia (HIT) undergoing extracorporeal membrane oxygenation (ECMO). However, DTIs are becoming increasingly utilized as alternative anticoagulants for patients with and without HIT requiring ECMO support. Antithrombin III (AT3) is a plasma-derived agent that can be used in adjunct with UFH to supplement low AT3 levels in response to heparin resistance in this patient population. Objectives: The purpose of this study is to investigate safety and cost outcome differences between AT3 supplementation and direct thrombin inhibitor treatment for anticoagulation in patients undergoing ECMO.

Methods: A retrospective review of adult patients undergoing ECMO using the Premier Perspective® Hospital dataset (2018-2021) was conducted. Patients receiving coronary artery bypass graft (CABG) surgery were excluded due to the difference in treatment decisions for anticoagulation. It is suspected that severity of illness plays a role in treatment patterns when a patient is receiving both CABG and ECMO, which would bias outcomes in the study. Patients were stratified into AT3 only and DTI only treatment groups. Prior to the comparisons, and to make the comparisons more robust, the two groups were balanced amongst patient demographics, hospital characteristics, and comorbidities using propensity score matching (PSM). Examples of these characteristics include age, gender, and race of the patients as well as urban versus rural hospital type, hospital bed number, and teaching hospital status. Charlson Comorbidity Index was also used to measure and match baseline clinical status. The use of PSM adjusts for any differences in significant health issues. Logistic regression, quantile regression, and negative binomial regression were utilized to assess clinical outcomes.

Results: 2,625 patients undergoing ECMO met study requirements. After propensity score matching, 357 patients in each treatment arm were included in the analysis. Higher rates of thrombosis were found in the DTI group compared to AT3 (OR: 1.97; 95% CI: 1.35-2.88). No difference was seen between bleed events (OR: 0.98; 95% CI: 0.68-1.40). There was a significantly longer median length of stay found in the DTI group compared to the AT group (DTI: 30 days; AT: 22 days; p <0.0001). However, median patient cost did not significantly differ (DTI: $233,245; AT3: $211,478; p = 0.116).

Conclusions: Anticoagulation with DTIs in patients undergoing extracorporeal membrane oxygenation showed a statistically significantly higher rate of thrombosis and a longer median length of stay compared to treatment with AT3. No difference in cost and bleed events were identified. Further studies are needed to validate the clinical and economic differences between these two therapies for anticoagulation in ECMO.
Session: Posters/Exhibits/Break
In vivo volume electron microscopy analysis at the single cell level reveals regional increases in platelet shape dispersity across a mouse, jugular vein puncture wound thrombus
Madhavi A. Ariyarathne1, Irina D. Pokrovskaya1, Oliver S. Zhao2, Richard D. Leapman2, Maria A. Aronova2, Brian Storrie1
1University of Arkansas for Medical Sciences, Little Rock, AR, USA, 2National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA

Background: Platelet ultrastructure analysis using high-resolution 3D imaging is crucial for understanding various stages of platelet activation. Traditional microscopy techniques like light microscopy and transmission electron microscopy (TEM) lack the ability to provide detailed 3D image sets. However, recent advances, particularly in serial block-face scanning electron microscopy (SBF-SEM), offer the potential to generate high-resolution 3D images within in vivo thrombi in experimental models such as mice. To date, quantitative and detailed 3D ultrastructural analyses of in vivo activation stages of platelets at the individual cell level have been lacking. Objective: The primary goal of this study was to conduct an in vivo comparative analysis of platelet activation stages in puncture wound thrombi using SBF-SEM. The study aimed to bridge the gap in understanding platelet activation stages by in situ 3D analysis in mouse models. The research sought to provide the first in vivo 3D census of platelet ultrastructure across different activation stages and different subregions within a wound thrombus. Method: The research utilized SBF-SEM to capture images of platelets within various subregions in a 5-minute puncture wound thrombus in a mouse. Four specific regions of interest (ROIs) within the thrombus were selected to represent different stages of thrombus formation, namely ROI_01 - loosely adherent platelets, ROI_02 - transition to tightly adherent platelets, ROI_03 - hole exposed platelet surface and ROI_04 - collagen associated platelets surface) (Figure 1). We used Amira software for processing SBF-SEM images from ROIs. Amira software was utilized to identify, render, and quantify condensed alpha granules, decondensed alpha granules, mitochondria, and identify different platelet structures (Figure 2).

Results: Preliminary findings revealed that ~80% of platelets in ROI_01 maintained a discoid cell shape, while ROI_02 displayed significant variation in cell shape, notably with the presence of pseudopods (Figure 2). These pseudopods arise due to platelet activation-induced cellular reorganization and potentially aid in mediating platelet aggregation. Moreover, analysis of the surface area to volume ratio plot in ROI_01 revealed a clustered pattern, indicating uniform platelet shapes with minimal variation compared to the dispersed distribution observed in ROI_02 (Figure 2). Interestingly, both surface area and surface area to volume ratio were significantly higher (p <0.05) in ROI_02 compared to ROI_01 (Figure 2). Furthermore, our analysis highlighted distinctive characteristics of mouse condensed alpha granules and mitochondria emphasizing their variable, elongated, rod-like shapes (Figure 2). Conclusion: The observations initiate the detailed characterization and comparison of different platelet activation stages at the level of individual platelets under in vivo conditions using advanced imaging techniques. These insights will significantly contribute to understanding platelet behavior and function in physiological contexts, especially in response to activation triggers like puncture wounds in experimental mouse models. The behavior of pseudopods suggests a potential role in platelet aggregation, indicating avenues for further exploration into platelet activation mechanisms.
Session: Posters/Exhibits/Break
The impact of a high-risk anticoagulation prescribing stewardship scoring tool implementation in an inpatient setting
Emma Baker1, John Lindsley1, Ian Watt1, Rakhi Naik2, Michael Streiff2, Jennifer Yui2, Kathryn Dane1
1The Johns Hopkins Hospital Department of Pharmacy, Baltimore, MD, USA, 2Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

Background: A Hemostatic and Antithrombotic Stewardship Program was created at The Johns Hopkins Hospital in August of 2017. As part of stewardship program implementation, an electronic medical record (EMR) based scoring tool was developed to identify patients with high-risk combinations of individual patient characteristics and active anticoagulant orders which impact the safety or efficacy of anticoagulant therapy. The scoring tool evaluates a combination of patient demographics, medical history, and active medication orders to generate a score which flags high-risk patients for review by antithrombotic stewardship pharmacists. Through these reviews, the stewardship pharmacists identify opportunities for optimization of therapy. Patient reviews and recommendations are documented and stored in the EMR. This project will evaluate the clinical impact of this initiative, identify educational opportunities, and illustrate areas for improvement in the build specifications of the scoring tool. Objectives: The objective of this study was to evaluate the impact of implementation of an EMR-based high-risk anticoagulation prescribing stewardship scoring tool at a large academic medical center.

Methods: A single-center, retrospective, observational cohort study was conducted from January 26, 2022, to September 23, 2022. Admitted adult patients with documented antithrombotic stewardship scoring tool reviews by stewardship pharmacists or trainees during the study period were included. Patients with missing data were excluded. The details of eligible high-risk anticoagulation scoring tool reviews were collected, including the medication and high-risk criteria involved, recommended therapy changes, and recommendation acceptance. The endpoints for this study were to quantify and categorize recommendations made through use of the scoring tool, evaluate the rate of accepted recommendations, and characterize scoring tool reviews which did not result in a recommended change in therapy.

Results: A total of 643 patients were reviewed by stewardship pharmacists and trainees during the study period and included in the final analysis predominantly from medicine or surgical services (Table 1). The scoring tool identified 824 medication and high-risk patient characteristics (triggers) which generated a score for review (Table 2). Overall, direct oral anticoagulants (DOACs) made up the majority of reviews (n=419, 65%). The most common high-risk characteristics prompting review were obesity (n=151, 18.3%), apixaban 2.5 mg BID orders (n=138, 16.7%), and low body weight (n=120, 14.6%). Scoring tool use resulted in 125 recommendations (19%), with 91 recommendations implemented (73%). The most common recommended change in therapy was apixaban dose adjustment (n=27, 22%).

Conclusions: Utilization of a high-risk anticoagulation prescribing stewardship scoring tool by anticoagulation stewardship pharmacists resulted in improvements in anticoagulation management at a large academic medical center. The use of stewardship scoring tools can help focus efforts of stewardship team members to more efficiently to review high-risk anticoagulant prescribing. Future directions will include refining scoring tool workflows to improve efficiency and provider education for commonly encountered high-risk prescribing practices.
Session: Posters/Exhibits/Break
Investigating inter-assay variability between DOAC calibrated anti-factor Xa assays: A substudy of the PAUSE trial
Ryan Baker1, Rita Selby2,3, Karen A. Moffat4,5, Melanie St John5, Alex C. Spyropoulos6,7,8, Sam Schulman9, James Douketis9
1Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada, 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, 3Department of Medicine, University of Toronto, Toronto, ON, Canada, 4Hamilton Regional Laboratory Medicine Program, Hamilton, ON, Canada, 5Department of Medicine, McMaster University, Hamilton, ON, Canada, 6The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA, 7Institute of Health System Science - The Feinstein Institutes for Medical Research, Manhasset, NY, USA, 8Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA, 9Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada

BACKGROUND: Direct oral anticoagulants (DOACs), especially factor Xa inhibitors are first-line therapy for most indications due to their efficacy, safety and no requirement for routine monitoring. DOAC calibrated anti-Xa assays can accurately assess the residual anticoagulant level in patients requiring urgent procedures or surgery. However, previous studies have shown variability between anti-Xa levels determined by different reagent-instrument combinations. These studies had limitations such as using lyophilized plasma, DOAC-spiked plasma, or assayed at various laboratories which may explain the inter-assay variability. The PAUSE trial examined perioperative DOAC management for patients on chronic anticoagulation who had interrupted factor-Xa inhibitor therapy before undergoing elective surgery.[1] We conducted a substudy on frozen plasma samples from previously consented PAUSE trial patients. OBJECTIVES: 1. To describe the inter-assay variability in apixaban and rivaroxaban anti-Xa levels using three common coagulation reagent-instrument platforms. 2. To determine if any differences in anti-Xa levels between the reagent-instrument combinations would be clinically relevant. METHODS: We analyzed apixaban (n=76) and rivaroxaban (n=61) anti-Xa levels on 3 different reagent-instrument combinations using manufacturer specific reagents, calibrators and quality control material (STA® reagents on the STA CompactMAX (Diagnostica Stago), HemosIL on the ACL TOP 300 (Werfen) and Biophen (Hyphen Biomed) on the BCS XP (Siemens)). We analyzed inter-assay correlation as a group and at two pre-determined cut-offs (<30 ng/mL and >30 ng/mL). We also compared median anti-Xa levels across reagent-instrument combinations using analysis of variance. RESULTS: Both apixaban and rivaroxaban anti-Xa levels showed good to excellent correlation between the 3 reagent-instrument groups, with correlation coefficients (r) ranging from 0.74 - 0.95 for apixaban, and 0.64 - 0.92 for rivaroxaban in both the <30 ng/mL and >30 ng/mL groups. In a 3-way comparison of median anti-Xa levels there was no significant difference between the reagent-instrument combinations for either apixaban or rivaroxaban in the >30 ng/mL group (Figure 1). For anti-Xa activity levels <30 ng/mL, there was a significant difference between Biophen/BCS XP and HemosIL/ACL TOP for apixaban anti-Xa levels, and for rivaroxaban when comparing HemosIL/ACL TOP to both Biophen/BCS XP and Stago/STA CompactMAX (Figure 1). These differences were small and not clinically relevant. In 7.3% (10/136) samples, the three reagent-instrument combinations discrepantly classified anti-Xa levels across the 30 ng/mL threshold. CONCLUSIONS: Using plasma from patients who had interrupted factor-Xa inhibitor DOAC therapy we were able to demonstrate that anti-Xa levels determined by three of the most common reagent-instrument combinations correlate well with each other, when anti-Xa activity is <30 and >30 ng/mL. Although there are statistically significant differences between median anti-Xa levels in the <30 ng/mL group, particularly for rivaroxaban, these differences are small and not clinically significant and result in discrepant classification across the 30 ng/mL threshold in only 7.3% of samples. REFERENCES: 1. Douketis, J.D., et al., Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med, 2019. 179(11): p.1469-1478.
Session: Online Poster Session
Structured Education for Newly Diagnosed Persons with von Willebrand Disease: A Hemophilia Treatment Center Quality Improvement Project Abstract
Dominique N. Barclay, Sarah E. Gonzales, Marsha Hurn, Amanda Kilgore, Jesla Ryan, Jonathan C. Roberts, Michael D. Tarantino
Bleeding and Clotting Disorders Institute, Peoria, IL, USA

Background: At Comprehensive Care Clinic visits following the new diagnosis of von Willebrand disease (VWD) patients verbalized lack of understanding of their diagnosis, treatment, and the different types of clinics provided at BCDI a federally recognized treatment center for persons with bleeding disorders. BCDI staff noted inconsistencies in patients and families receiving education, documentation of education and the new diagnosis in the electronic medical record (EMR). Without consistent, comprehensive education, patients are unable to self-advocate, receive optimal care or improve their health outcomes. To address this process, BCDI developed a quality improvement project. VWD was the pilot disorder to implement the structured education program. Project Aims: 1) Improve patients' understanding of the diagnosis, treatment options and services offered by BCDI. 2) Develop a standardized method to deliver education to patients and families utilizing BCDI approved educational materials. 3) Improve documentation of diagnosis and education materials provided within the EMR.

Methods: Data was collected by reviewing newly diagnosed patients at BCDI from January 2022 to September 2022. Focusing on new VWD diagnoses, data included diagnosis date and when documented, patient notificaton date, documentation of education materials provided, whether a school in-service was scheduled, type of follow-up visits, personnel who entered diagnosis in problem list. The team developed an education visit plan, reviewed available education materials and ensured they were up-to-date and available for patient use, developed an education visit checklist outlining the visit, and created pre- and post-visit questionnaires to evaluate project effectiveness. Questions utilized a 0-4 scale with 4 being the best rating, other questions were in multiple choice format.

Results: Ten newly diagnosed VWD patients participated in the pilot educational program. A pre-visit questionnaire was completed by each patient and then the education nurse reviewed diagnosis, laboratory results, educational materials, inheritance of VWD, signs & symptoms, and treatment options with each patient. The Medical Social Worker reviewed assistance programs, travel letters, medical jewelry, school in-services, BCDI's patient advisory board and BCDI's website. The Physical Therapist reviewed the Comprehensive Care model and the NHF "Play It Safe" booklet. Patients then completed the post-visit questionnaires. Two weeks after the education visit the Education Nurse completed a follow-up phone call to answer any additional questions. Analysis of the pre- and post-visit questionnaires revealed that patient's familiarity with the VWD diagnosis, using 0-4 scale, improved from pre-visit educaton score of 0.8 (0-2) to 3.6. (3-4). Fig 1a. Patient understanding of medications to avoid improved with 9/10 correct answers to multiple choice question, compaired to 2/10. Of fifteen services, patients chose which they believed BCDI provided before and after the education visit. Improvement was seen after education visit. Fig 3a, 3b. Conclusion: Analysis demonstrated marked improvement in the patients understanding of diagnosis, treatment and services provided by BCDI. We plan to use the data from VWD and expand this process for other disorders of hemostasis and thrombosis managed at BCDI.
Session: Posters/Exhibits/Break
The Role of Fibrinogen in Changing the Hemostasis of Patients with Neoplasia and Their Influence on the Microcirculatory Bed of the Lungs and Control by Anticoagulants
Vira A. Barilka, Volodymyr L. Matlan, Sofia V. Prymak, Olha O. Shalay, Vasyl L. Novak
SI "Institute of Blood Pathology and Transfusion Medicine of NAMS of Ukraine" Lviv Ukraine, Lviv, Ukrenia

Introduction: Fibrinogen (Fib) is the first coagulation factor with a half-life of 4-5 days in peripheral blood, an important indicator for the assessment of hemostasis and inflammation. Proinflammatory cytokine tumor necrosis factor (TNF), antiinflammatory transforming growth factor beta 1 (TGFβ1), which are secreted by the tumor can stimulate the synthesis of procoagulants and fibrinogen. Elevated Fib are life-threatening in oncohematological patients (pts) due to thrombosis within 1-12 days after surgical removal of tumors without the use of low molecular weight heparin (LMWH). The LMWH pharmacokinetics determined by indicators of anti-Xa-factor activity of plasma, which is not always available, and the efficacy of treatment with LMWH is insufficiently studied. The aim of this study was to evaluate the Fib level in plasma of 81 patients (pts) with uterine, cervical, ovarian, lung cancer and non- Hodgkin's lymphoma (NHL) before and after surgical removal/treatment and to select the doses of LMWH to prevent thrombosis.

Methods: The hemostatic parametrs were investigated in tumors outflowing blood, peripheral arterial and venous citrate blood by the hemostatic methods. TNF and TGFβ1 were detected by biological methods. The mediana age 52 (range 40 - 68 years). Pts had no signs of thrombosis at the time of examination. The median Fib before surgery - 6.4 mg / ml (range 5.69 - 13.02 ), after surgery - 8.4 mg / ml (range 4.1 - 14.97). Fib content was determined on the 3rd day before treatment and up to 10 days after surgery/treatment. The use of LMWH was performed according to the level of Fib.

Results: We administered LMWH subcutaneously once a day in 10,000 anti-Xa IU / ml in the preoperative period when Fib was ≥ 5.0 to 7,8 mg/ml. In cases of Fib ≥ 7,8 mg / ml used LMWH 2 times a day in the concentration above. In the postoperative period (Fib ≥ 5.0 to 7.8 mg / ml) we used subcutaneous administration of LMWH once a day at a dose of 10,000 anti-Xa IU / ml for 3 days, followed by pentoxifylline, aspirin for 60 days. If the level of Fib exceeded 8 mg / ml (in 40.5% of pts) in the postoperative period we used LMWH two times a day at a dose 10,000 anti-Xa IU / ml for 3 to 10 days, for the reduction of Fib. A significant decrease in TNF, TGFβ1 in plasma was observed in pts on the 10-th day after treatment with LMWH (p˂0, 005; in both cases) . However, the level of TNF, TGFβ1 in pts plasma was significantly higher before and after treatment than in healthy individuals.

Conclusions: The determination of Fib and the use of LMWH according to the level of Fib allows to avoid mortality in the postoperative period and after the first line treatments of NHL. The cytokines from the tumors microenvironment determine the high procoagulant activity of the blood flowing from the tumor.
Session: Online Poster Session
Correlation Between ABO Blood Types and Disease Severity in Sickle Cell Anemia: Implications for Thrombosis and Hemostasis.
George M Bassey1, Titilope A Adeyemo1,2, Ann A Ogbenna1,2, Abiola B Bolarinwa1, Ademola S Adewoyin2, Emmanuel Iyere1
1Lagos University Teaching Hospital , Lagos, Nigeria, 2College of Medicine University of Lagos, Lagos, Nigeria

Background: Hemoglobin S (HbS), arising from a single nucleotide substitution in the gene encoding β-globin, leads to pathological hemolysis and concurrent endothelial dysfunction. This process induces a prothrombotic state characterized by elevated markers such as VCAM and VWF. Hemolysis, along with other mechanisms also contributes to an increased platelet count, exacerbating adhesion molecule expression, thus intensifying the prothrombotic state and worsening the vaso-occlusive complications associated with sickle cell disease (SCD) e.g. pulmonary hypertension, non-hemorrhagic stroke, priapism, and cutaneous leg ulcers. While the scientific relevance of ABO blood types in various diseases, including thrombosis, is well-established in non-SCD populations, this is yet to be examined in SCD population. Aim: Our study seeks to explore the correlation between disease severity, markers of endothelial dysfunction, thrombosis, and ABO phenotypes in individuals with sickle cell anemia. Materials and

Methods: We enrolled seventy-three participants with SCD in this investigation. We evaluated their clinical attributes, disease severity, ABO blood phenotypes, markers of hemolysis (Hbfree, lactate dehydrogenase - LDH, total and conjugated bilirubin, corrected reticulocyte count, and reticulocyte production index), as well as markers for endothelial dysfunction and thrombosis (VCAM, von Willebrand Factor - vWF, platelet count, and nitric oxide - NO). Hbfree, VCAM, vWF, and NO levels were quantified using enzyme-linked immunoassay techniques. LDH and bilirubin (total, conjugated, and unconjugated) were assessed using a COBAS C311 chemistry auto-analyzer. Full blood count and reticulocyte count were determined through automated procedures. Blood group phenotypes were determined using the tile method. Our analyses involved ANOVA and logistic regression to establish associations between hemolysis markers, blood group phenotypes, and disease severity, with a statistical significance level set at 5%.

Results: Our findings indicated that individuals with sickle cell anemia (SCA) and non-group O blood phenotypes demonstrated elevated levels of VCAM, vWF, platelet count, and reduced levels of nitric oxide compared to SCA individuals with group O blood types (P <0.05 in all cases). Disease severity was notably higher in SCA individuals with non-group O blood types. Conclusion: The combined effects of non-group O blood type and SCA appear to independently contribute to a prothrombotic state, heightening the severity of the disease and increasing the risk of developing severe complications associated with sickle cell disease. These findings have significant implications for understanding the pathophysiology of thrombosis and hemostasis in individuals with SCD.
Session: Online Poster Session
DNA Damage Repair Inhibition: A Catalyst for Enhanced Megakaryopoiesis and Thrombopoiesis
Roelof H Bekendam1,2, Andrew Stone1, Clementine Payne1, Virginia Camacho1, Isabelle Becker1, Estelle Carminita1, Maria Barrachina1, Kellie Machlus1, Joseph Italiano1
1Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA, 2Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Background: Megakaryocytes are large hematopoietic cells that can reach polyploid states greater than 64n. This is notable, as cancer cells with a polyploid DNA complement of even 4n are more susceptible to DNA damage accumulation. Poly-ADP-ribose-polymerase (PARP) inhibitors exhibit their anti-tumor effects in solid tumors through inducing DNA damage by interfering with DNA repair mechanisms. The bone marrow compartment is extremely susceptible to PARP inhibition. Clinically, higher dose PARP inhibitors have led to thrombocytopenia as a major dose-limiting toxicity. However, DNA damage accumulation can also induce stress hematopoiesis. To date, the role of low amounts of DNA damage accumulation on megakaryopoiesis has not been investigated. Objectives: To investigate the role of DNA damage repair inhibition on megakaryocyte development and platelet production. We hypothesize that low dose PARP inhibition stimulates megakaryopoiesis through accumulation of DNA damage.

Methods:
PARP inhibitors were administered to C57BL/6J or vWF-GFP reporter mice using intraperitoneal injection. Murine long bones and bone marrow were harvested for evaluation of hematopoietic stem and progenitor cell (HSPC) and megakaryocyte populations, megakaryocyte differentiation, polyploidization, and platelet formation. DNA damage was measured using antibodies against γH2AX - a marker of DNA strand breaks. Platelets were washed, followed by counting and analysis using flow cytometry.

Results:
To assess DNA damage in megakaryocytes, immunofluorescence staining of γH2AX in femurs of C57BL/6J mice was performed in situ, showing a significant number of γH2AX foci in mature megakaryocytes. Flow cytometry revealed that γH2AX intensity increased with increasing ploidy in both murine and human megakaryocytes. To examine the effect of increasing DNA damage in megakaryocytes, C57BL/6J mice were treated with high and low doses of FDA-approved PARP inhibitors for both 3- and 11-day intervals. High dose PARP inhibition led to severe pancytopenia - consistent with the clinical phenotype. After 3 days of lower dose PARP inhibitor treatment, there was a significant expansion in CD41+-biased HSCs, the multipotent progenitor 2 cell population (MPP-2) and mature (CD41+ CD42d+) megakaryocytes. This correlated with increased γH2AX in long term HSCs and CD41+ HSCs, confirming accumulation of DNA damage. However, platelet counts were not changed. After 11 days, there was a significant decrease in CD41+ HSCs and MPP-2 cells in the PARP inhibitor treated group. Further, both megakaryocytes and (immature) platelets were elevated ~2-fold. Strikingly, there was a significant increase in >32n megakaryocytes in the PARP inhibitor treated group, suggesting enhanced DNA damage led to an increase in megakaryocyte maturation. To observe live platelet production by megakaryocytes in vivo, vWF-GFP reporter mice underwent 2-photon intravital microscopy in their calvaria after treatment with lower dose PARP inhibitors for 7 days. These mice showed increased megakaryocyte number, proplatelet production, and platelet counts. To test whether PARP inhibitors alter platelet structure/function we performed platelet activation assays, which confirmed normal functionality of platelets in the PARP inhibitor-treated group.

Conclusions:
Our data suggest that DNA damage repair inhibition using PARP inhibitors increases murine thrombopoiesis via enhanced megakaryopoiesis. Further, the resulting megakaryocytes and platelets are functionally active. Targeting DNA damage repair pathways may represent a novel therapeutic strategy in thrombocytopenic states.
Session: Short Talks - Insights on Platelet Biology
Development of a Patient Reported Outcome Measure to Study Quality of Life in Bleeding Disorder of Unknown Cause
Callie Berkowitz1, Supreet Goraya2, Alice Ma1, Nigel Key1, Angela Stover3
1Division of Hematology and Blood Research Center, University of North Carolina, Chapel Hill, NC, USA, 2Department of Maternal, Child, and Family Health, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, USA, 3Department of Health Policy and Management, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, USA

Background: Bleeding of Disorder Unknown Cause (BDUC) is an increasingly recognized diagnostic category encompassing patients with a clear bleeding tendency but without identifiable abnormality on hemostatic testing. Phenotypically, BDUC resembles other mucocutaneous bleeding disorders including von Willebrand's disease (vWD) and platelet function defects, and the National Hemophilia Foundation guidelines now recommend that patients with BDUC be followed in Hemophilia Treatment Centers. However, little is known about the Quality of Life (QoL) impact of the disorder and patient-specific needs. Existing validated bleeding disorder-specific patient reported outcome measures (PROMs) may fail to capture the social, emotional, and reproductive health impact of this disorder. Objective: The objective of this study is to develop a disease-specific QoL measure for patients with BDUC.

Methods: We conducted a literature review of existing PROMs used in the study of bleeding disorders, with focus on vWD, hemophilia, and menorrhagia. Using results of the literature review and our clinical expertise in caring for BDUC patients, we drafted an initial set of candidate items and elicited expert feedback. Semi-structured interviews of patients with BDUC were conducted for purposes of both concept elicitation and cognitive debriefing on candidate items. Items were iteratively revised with a trained group of PRO researchers, and a literacy review was performed using Lexile Analyzer. Candidate items were subsequently piloted in an adult undiagnosed bleeding disorder clinic with endpoints of acceptability and feasibility, jointly administered with other validated questionnaires (PROMIS-29, Self-BAT, and the Menstrual Impact Questionnaire).

Results: Review of existing PROMs in hemophilia showed emphasis on activity limitation due to joint disease limiting generalizability to BDUC. We identified 7 studies of QoL in vWD using disease-specific measures, however each study relied on ad-hoc questionnaires without validation procedure. While multiple validated questionnaires for menorrhagia exist, heavy menses is not a universal symptom in BDUC and may not drive QoL impact in an individual patient. Informed by literature review, an initial set of candidate items was developed including the following symptom domains: daily function, emotional health, sexual & reproductive health, and healthcare impact. Seven semi-structured interviews with BDUC patients were conducted, which included one male patient and one person of color. Iterative revisions throughout content validation procedure were systematically tracked. Reading level analysis of the PROM was consistent with 3rd-4th grade reading level. Thirty-two patients completed pilot testing in the clinic setting: 88% of patients found the items relevant to them and 84% of patients found the questions easily comprehensible. Conclusion: We developed and performed content validation of a novel PROM to study QoL in BDUC with further validation studies ongoing. Our work highlights the need for validated PROMs in the study of mucocutaneous bleeding disorders given limitations of existing tools.
Session: Online Poster Session
Evaluating Diagnostic Algorithms for Heparin-Induced Thrombocytopenia Using Two Combined Rapid Automated Assays
Anna-Lise Bissola1,2, Yi Zhang1,3, Madison Cranstone2,4, Donald Arnold1,2, Ishac Nazy1,2
11. Faculty of Medicine, Michael DeGroote School of Medicine, McMaster University, 2. Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada, 2Faculty of Medicine, Michael DeGroote School of Medicine, McMaster University, 3. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, 32. Michael G. DeGroote Centre for Transfusion Research, McMaster University, 4. Department of Statistics and Actuarial Science, University of Waterloo,, Hamilton, ON, Canada, 41. Faculty of Medicine, Michael DeGroote School of Medicine, McMaster University, 2. Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada, 51. Faculty of Medicine, Michael DeGroote School of Medicine, McMaster University, 2. Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada

Background: Most diagnostic laboratory enzyme immunoassays (EIA) for heparin-induced thrombocytopenia (HIT) are excellent for 'ruling-out' HIT but suffer from reduced specificities. Alternatively, functional platelet-activation assays, including the 14C-serotonin release assay (SRA), offer higher specificity and sensitivity, but are technically challenging and require healthy donor platelets. Rapid automated assays may offer a solution to these diagnostic challenges. However, further practical evaluations of these assays are required. Aims: This study compared the performances of latex immunoturbidimetric assay (LIA) and chemiluminescence immunoassay (CLIA), either alone or in combination, to identify the presence of platelet-activating anti-PF4/heparin antibodies in a prospective cohort of clinically suspected HIT patients. Moreover, we compared the performance of two algorithmic approaches developed in previous retrospective studies that evaluate the combined performance of both automated assays.

Methods: A total of 1144 unique patient serum or plasma samples were collected between December 2018 and August 2020 based on a clinical suspicion of HIT. Based on sample availability, patients were tested in a commercial Immucor IgG/A/M PF4-enhanced EIA (IgG/A/M EIA, n=914), LIA (HemosIL®HIT-Ab(PF4-H)], n=1012), CLIA ([HemosIL®AcuStarHIT-Ab(PF4-H)], n=1128), or both LIA and CLIA (n=996) according to manufacturer's instructions. The combined performance of the LIA and CLIA (n=996) was determined by using two previously evaluated test algorithms 1) the Simultaneous approach adapted from Warkentin et al.1 and 2) the Sequential approach adapted from Rittener-Ruff et al.2 Using the Simultaneous algorithm, patients are tested in both rapid assays and a positive result is obtained where CLIA and/or LIA results are ≥ 1.0 U/mL. Using the Sequential algorithm, LIA testing combined with an "assumed" high (6-8) or intermediate (4-5) 4T scores was used to predict or exclude HIT, followed by CLIA testing where results were inconclusive. Following CLIA testing, HIT was again predicted or excluded using 4T scores. Patients who remain inconclusive when using 4Ts scores and LIA/CLIA results are resolved with additional testing in a functional platelet-activation assay (SRA).

Results: Using the standard SRA as a surrogate reference for the confirmation of HIT, we determined the performance characteristics of the IgG/A/M EIA (sensitivity 100%, specificity 48.6%), LIA (sensitivity 91.7%, specificity 68.4%), CLIA (sensitivity 92.4%, specificity 85.8%), and combined CLIA-LIA using the Simultaneous algorithm1 (sensitivity 99.0%, specificity 64.3%). The Sequential algorithm2 assuming intermediate (4-5) or high (6-8) 4T scores correctly predicted HIT in 94.5% and 96.0% of patients and correctly excluded HIT in 82.6% and 80.1% of patients, respectively. Conclusion: Compared to individual LIA or CLIA testing, both combined algorithms improved diagnostic performance, supporting the use of these assays together for HIT diagnosis to supplement platelet-activation assays if both instruments are available. Evaluating two diagnostic strategies using a single cohort of prospective patients revealed the Simultaneous algorithm to have a lower number of false HIT predictions (7.9%) than the Sequential algorithm (37.6% and 41.6%). We also found the Simultaneous algorithm more practical because it does not rely on 4T scores. Our work also highlights that prospective studies accounting for clinician and interlaboratory variability can more accurately evaluate the real-world performance of HIT diagnostic tests.
Session: Short Talks - Insights on Platelet Biology
Effect on stem cell research
Paul Blumenthal

Abstract: Unforeseen Consequences of "Dobbs": Clinical, Social and Professional Perspectives

On June 24 2022, the United States Supreme Court issued its decision in Dobbs v Jackson Women's Health Organization, revoking the almost 50-year old precedent that pregnancy termination is a constitutional right. Overturning Roe v Wade had immediate and swift consequences on many levels. To date, fourteen states have enforced total bans on abortion, with seven more restricting abortion access at levels not seen since before Roe. Per the Guttmacher Institute, nearly 18 million patients of reproductive age live in states where abortion access is limited or completely inaccessible. Since "Dobbs" much has been postulated in the scientific literature and lay media about a post-Dobbs world. In this presentation, we examine theorized and now increasingly proven outcomes of Dobbs, through three lenses: clinical, social, and professional. We analyze the expected as well as the unforeseen sequelae of revoking a patient's right to abortion on clinical and research endeavors.

Session: Abortion/Reproductive Health - When the law and healthcare collide - How laws that restrict access to reproductive care are affecting hemostasis and thrombosis patients
Iron deficiency has generally not been considered when defining sex-based hemoglobin reference intervals: A systematic review
Ingrid Blydt-Hansen1, Vidushi Swarup2, Teruko Kishibe3, Carine Bekdache2, Vanessa Giuliano4, Rebecca Sampat2, Rowan Thillaye-Kerr2, Angela Weyand5, Mark Crowther6, Miranda Wozniak7, Grace H Tang8, Michelle Sholzberg8
1Department of Internal Medicine, University of British Columbia, Vancouver, BC, Canada, 2Hematology-Oncology Clinical Research Group, Division of Hematology-Oncology, St. Michael's Hospital, Toronto, Canada , Toronto, ON, Canada, 3Health Sciences Library, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON, Canada, 4Department of Medicine, University of Toronto, Toronto, ON, Canada, 5Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA, 6Department of Medicine, McMaster University, Hamilton, ON, Canada, 7Department of Laboratory Medicine & Pathobiology, Hematological Pathology, University of Toronto,, Toronto, ON, Canada, 8Departments of Medicine, and Laboratory Medicine and Pathobiology, St Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada

Background: The World Health Organization defines anemia as a hemoglobin below 120 g/L for females and below 130 g/L for males. Historically, this discrepancy has been attributed to physiological differences between biological sexes. However, there is increasing evidence to suggest that sampled 'healthy' females for the establishment of hemoglobin reference intervals (RIs) included those with untreated iron deficiency. In fact, iron deficiency anemia is the most common presenting manifestation of bleeding disorders in females. Applying appropriate definitions of anemia are therefore of great importance to individuals with disorders of hemostasis and those on antithrombotic therapies given the prevalence of anemia and its association with morbidity and mortality. To address this, we conducted a systematic review to evaluate the literature to date on sex-based hemoglobin RIs. Objectives: To determine if healthy females without evidence of or risk factors for iron deficiency have a lower baseline hemoglobin than healthy males.

Methods: A systematic review was conducted using a comprehensive search of MEDLINE, EMBASE, CINAHL and Web of Science from inception to November 2022. Two reviewers independently screened and performed data extraction. A third reviewer adjudicated decisions when a consensus was not reached. Studies that evaluated hemoglobin RIs in a state of known pathophysiology (e.g. untreated iron deficiency, bone marrow pathology, inherited red blood cell disorders, chronic diseases) were excluded. A priori defined quality assessment of all manuscripts was performed and included the following criteria: the manner in which "health" was defined in the sampled population, whether there was adherence to Clinical and Laboratory Standards (CLSI) guidelines for RI establishment studies, methodological rigour applied and transparent reporting of results.

Results: 6411 articles were generated for title/abstract review, 909 articles were selected for full-text analysis. 313 articles met inclusion criteria and were extracted for analysis. 139 articles sought to establish a hemoglobin RI. The remainder (174/313) established a mean hemoglobin within the designated study population. Of the studies that sought to establish a RI, 66 adhered to CLSI guidelines (47%). 209/313 studies considered iron deficiency status and/or risk factors in study design (e.g. MCV, ferritin, bleeding history). 63/313 (20%) studies excluded individuals with laboratory evidence of and/or at least one risk factor for iron deficiency. Of the studies that used ferritin as the screening laboratory test for iron deficiency, the ranges of the lower limit of normal (LLN) for ferritin were as follows: 0-12.1 ug/L (31 studies), 13-15 ug/L (18 studies), 16-30 ug/L (14 studies) and 50 ug/L in 1. In the remaining 250 (80%) studies, individuals with iron deficiency and/or iron deficiency risk factors may have been included. Conclusion: Only 20% of studies evaluated explicitly excluded individuals with iron deficiency or its risk factors when establishing a hemoglobin RI or mean. Furthermore, in studies that measured ferritin, the majority used a ferritin LLN below established standards to define iron deficiency. This systematic review identifies that risk of iron deficiency and iron status are not routinely considered when establishing a hemoglobin RI, despite the extremely high prevalence of iron deficiency in females.
Session: Posters/Exhibits/Break
Coagulation profile and clot stiffness analysis from COVID-19-positive patients using a novel viscoelasticity testing technology
Dimitria Bonizol Camasao1,2+, Jose G. Munguia-Lopez1+, Anna Perez5, José A. Correa3, Cedric Schmitt2, Anis Hadj Henni2, Chantal Séguin4, Donald C. Vinh5, Showan N. Nazhat1*
1Department of Mining and Materials Engineering, McGill University, Montreal, QC, Canada, 2Rheolution Inc., Montreal, QC, Canada, 3Department of Mathematics and Statistics, McGill University, Montreal, QC, Canada, 4Department of Medicine, Division of Hematology, McGill University Health Centre, McGill University, Montreal, QC, Canada, 5Department of Experimental Medicine, Division of Infectious Diseases, McGill University Health Centre, McGill University, Montreal, QC, Canada

Background COVID-19-associated coagulopathy represents a serious complication from the SARS-CoV-2 infection that can lead to thromboembolic events. A personalized patient-oriented treatment is sought given the large diversity of patient cohorts, with the analysis of different biomarkers and coagulation profiles. The viscoelasticity testing of bilayered materials (VeTBiM) technology has been recently introduced as a precise method to measure the real-time viscoelasticity of coagulating blood. In this work, this technology was used to obtain the coagulation profile and the clot stiffness of plasma samples from hospitalized patients in the general COVID-19 ward (non-ICU) and in the intensive care unit (ICU). Methods Eighteen plasma samples from eleven hospitalized patients, collected at various times relative to the first positive SARS-CoV-2 PCR result (Dec 2020 - Jun 2021), were obtained from the McGill University Health Centre COVID-19 Biobank (Montreal, Canada). Activated partial thromboplastin time reagents (Thermo Fisher Scientific) induced the coagulation of plasma samples. The final solution was immediately tested in the ElastoSensTM Bio (VeTBiM technology, Rheolution, Canada) at 37 °C (figure 1). Shear storage modulus (G' in Pascals [Pa], physical property that represents the stiffness of the forming clot) as a function of time was obtained for each sample. Four descriptors were extracted from the G'-vs-time curves: clotting initiation time (time at which G' reached 15 Pa), clotting time (time at which G' reached 90% of final G'), maximum clotting rate (Pa/s) and final clot stiffness (final G'). Multiple linear regression analyses were performed to examine the effects of ICU admission, sampling time, among others, on these descriptors. Results Figure 2 displays the four descriptors extracted from the coagulation profiles. Clotting initiation time did not show a trend over time with values ranging from 20 to 120 s. Clotting time slightly decreased over time, in line with a slight increase in the maximum clotting rate. This tendency implies that clotting occurs more rapidly as time advances from the onset of the disease, however, a larger number of samples especially from each individual should be analyzed to confirm this trend. Clot stiffness underwent a significant decrease over time. For this descriptor only, statistical analysis showed an interaction effect between ICU admission (i.e., non-ICU vs ICU) and blood sampling time (p<0.0001). In the presence of other covariates, the results showed a more rapid decrease in the clot stiffness for the non-ICU patients compared to those in the ICU. Previous studies suggest that clot stiffness is directly related to the occurrence of thromboembolic complications, and therefore the monitoring of this parameter could help in optimizing anticoagulant therapies. Conclusions The VeTBiM technology has demonstrated potential in providing precise information on the coagulation profile and clot stiffness from plasma samples. The clot stiffness decreased with time post COVID-19 infection, and at a slower rate for patients in the ICU when compared to those in the general ward. This type of analysis can be valuable in research for the fundamental study of coagulopathies as well as in clinics to help establish personalized and more effective treatments for this life-threatening complication.
Session: Posters/Exhibits/Break
IL-6-Induced Potentiation of Platelet Activity and Glycosylation in Venous Thromboembolism
Michelle K. Brenner1, Karin Hoffmeister2, Brian Branchford1
1Pediatric Hematology/Oncology/Bone Marrow Transplant, Children’s Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA, 2Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, USA

Background: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), affects nearly 1 of every 100 hospitalized children in the US each year and is associated with both increased mortality (up to 2%) and morbidity. While development of VTE is multifactorial, emerging data indicate that inflammatory cytokines, such as IL-6, contribute significantly to thrombosis. Thromboinflammation, the interplay of thrombosis and inflammation, causes profound alterations in vascular homeostasis. It is known that thromboinflammation leads to pathologic platelet activation and increased recruitment of immune cells in the vasculature. The full extent of platelets in inflammatory-driven VTE, however, has yet to be fully elucidated. It is well known that post-translational modification (such as glycosylation) of surface adhesion receptors affects platelet activity, localization, and adhesion. The investigation of thromboinflammation-associated glycan alterations on platelets themselves, and their role in VTE development has not been previously studied, thus representing a novel approach to exploring the mechanistic underpinnings of this pathologic event. IL-6 is a cytokine synthesized in response to inflammation, such as trauma, malignancy, or infection. IL-6 signaling requires formation of a 3-part complex including IL-6, one of two types of IL-6 receptor (membrane-bound for classical signaling or soluble for trans-signaling), and the receptor gp130 that is expressed on all cells and acts as the signal transducer. Platelets can release soluble IL-6 receptor from their granules and use IL-6 for trans-signaling. Prior data have demonstrated that stimulation of platelet rich plasma (PRP) with physiologic concentrations of IL-6 enhances agonist-induced platelet aggregation and secretion. Objective: We hypothesized that platelet activation, in the presence of IL-6, leads to specific glycoprotein changes that result in hyperreactivity, heightening the risk of pathologic thrombosis.

Methods:
Platelets were isolated from platelet-rich plasma, which was derived by differential centrifugation of whole blood from healthy human donors and incubated with various concentrations of human recombinant IL-6 ranging from doses comparable to patients receiving IL-6 immunotherapy (lower dose) up to those with meningococcal septic shock (higher dose). Agonist-induced platelet granule release and integrin activation, as well aggregation responses were then assessed with flow cytometry and light transmission aggregometry, respectively. Glycan changes were assessed via flow cytometry. Results: IL-6 alone does not stimulate platelet aggregation or activation. In PRP, addition of lower dose IL-6 inhibits platelet aggregation in response to collagen and TRAP (thrombin receptor activated peptide), but there is no difference with the addition of higher dose IL-6. In isolated platelets, higher dose IL-6 may increase platelet aggregation and activation with certain platelet agonists. Finally, addition of IL-6 to washed platelets induces changes in O-glycosylation both with and without platelet agonists and induces Neuraminidase-1 exposure on platelet surfaces, indicative of sialic acid loss (Figure 1).

Conclusions:
IL-6 modulates activation and aggregation of platelets in the presence of additional agonists. The increased presence of Neuraminidase-1 on platelets incubated with IL-6 may demonstrate desialyation of platelets that impact the role of platelets in thromboinflammation. Future studies will investigate the action of neuraminidase inhibitors, such as oseltamivir, on this process.
Session: Posters/Exhibits/Break
T-hlper Cytokine Interactions with BAFF in the Factor VIII Immune Response
Tammi L. Briscoe1, Mostafa A. Shaheen1, Bhavya S. Doshi1,2
1Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA

Background: Inhibitor development to factor VIII (FVIII) remains the most challenging complication of replacement therapy in hemophilia A (HA). The antibody (Ab) response is dependent on CD4+ T helper cell mediated B cell activation to drive Ab affinity and neutralizing capacity. The mechanisms driving maturation of the Ab response are not understood but may rely on immune signals that regulate B cell affinity maturation. We recently identified the BAFF (B cell activating factor) cytokine as a modulator of FVIII immune responses. BAFF levels correlated with inhibitors, anti-FVIII IgG4 Ab, and immune tolerance induction (ITI) response in HA patients. Further, anti-BAFF Ab therapy decreased inhibitor responses in HA mice. Whether BAFF exerts this effect via direct regulation of B cells or via interaction with other cytokine signaling is unknown. Objectives: We aimed to analyze the correlation between BAFF and T-helper cytokine levels in HA patients with and without inhibitors.

Methods:
Plasma from 97 HA patients were collected and analyzed for ten T-helper cytokines (IFNγ, IL10, IL-12, IL17, IL-2, IL-4, IL-5, IL-6, IL-21 and TNFα) via Luminex assay and BAFF levels via ELISA. Data was analyzed with Prism using Pearson correlation of BAFF versus T-helper cytokines, p-values <0.005 (Bonferroni correction) were considered significant. The Fisher z-transformation was used to compare correlation coefficients between inhibitor positive and negative groups.

Results:
Of the 105 HA patients, 30 had active or transient inhibitors and 75 were inhibitor free. BAFF levels were higher in the inhibitor cohort (1.04 ± 0.40 ng/ml) versus non-inhibitor cohort (0.76 ± 0.31 ng/ml), p<0.001 by t-test. In the inhibitor cohort, significant correlation was noted between BAFF and IL-4 (r = 0.536, p = 0.002) and IL-6 (r = 0.529, p = 0.002). There was no correlation between BAFF and IL-4 and IL-6 levels in the non-inhibitor cohort at r = 0.148 (p=0.204) and r = 0.177 (p=0.127), respectively. In the non-inhibitor cohort, BAFF levels correlated modestly with IFNγ at r = 0.455 (p <0.001) and IL-10 with r = 0.441 (p <0.001). The inhibitor positive groups had correlation coefficients of 0.3751 (p=0.04) and 0.307 (p=0.098) for IFNg and IL-10, respectively. Fisher's z-transformation identified significant difference in correlation coefficients for BAFF and IL-6 and IL-4 between inhibitor positive and negative groups with p <0.05.

Conclusions:
Our data suggest that BAFF, IL-4, and IL-6 may have synergistic effects in regulating humoral immune responses to FVIII in HA patients. In autoimmune disorders, IL-6 secreted from myeloid cells is regulated by BAFF and drives autoantibody production (Yoshimoto K et al 2011). IL-6 is a potent B cell stimulator and promotes IgG production. IL-4 can have pleiotropic roles in regulating inflammation and immunity but is thought to promote B cell differentiation. Future studies with cellular subsets from patient samples and combinatorial approaches in animal models will help delineate mechanistic pathways of BAFF's role in FVIII immunogenicity.
Session: Posters/Exhibits/Break
Child Hemo-TEM Observer-Reported Outcome Measure: Understanding and Assessing Treatment Burden in Children With Hemophilia
Meryl Brod1, Donald M. Bushnell2, Jesper Skov Neergaard3, Anne Kirstine Busk3, Vlady Ostrow4
1The Brod Group, Mill Valley, CA, USA, 2Evidera|PPD, Bethesda, MD, USA, 3Novo Nordisk A/S, Søborg, Denmark, 4Novo Nordisk Inc., Plainsboro, NJ, USA

Background: Treatment advancements have improved quality of life for patients with hemophilia. However, children with hemophilia (CwH) may still experience treatment burden, leading to adherence problems, due to factors related to administration of intravenous infusions. Objectives: This study aimed to develop and validate the Child Hemo-TEM observer-reported outcome (ObsRO) measure to assess treatment experiences of CwH based on caregiver-reported observations.

Methods: Concept elicitation (CE) was performed using data gathered from a review of the current hemophilia literature and interviews with 4 clinical experts (hematologists or nurses with a 50% hemophilia patient load and ≥5 years' experience providing care to CwH), 25 CwH (males aged 8 to 12 years with hemophilia A or B with or without inhibitors who were currently self-administering on-demand or prophylactic treatment for hemophilia), and 25 caregivers of CwH (adult parents or guardians of a male CwH aged 2 to <12 years with hemophilia A or B with or without inhibitors). Interview transcripts were analyzed for themes using Dedoose software, and emerging concepts were coded and grouped into domains. Validation was performed by collecting data from caregivers of CwH aged 2 to <12 years in the US via a web-based survey. Recruitment quotas for this phase were designed to capture input from a diverse population with a variety of prophylactic treatment frequencies and treatment administration types.

Results: In the CE phase, child participants were, on average, aged 9.6 years with 8.9 years of factor treatment experience. Most participants were White (n=16; 64%) and had hemophilia A (n=23, 92%). Caregivers' CwH were, on average, aged 6.3 years with 6.0 years of factor treatment experience. Most were White (n=11; 44%) and had hemophilia A (n=22; 88%). All CwH and caregivers' CwH had severe hemophilia. The most frequently reported treatment experience concepts reported by CwH were self-treatment; child adherence; emotional impacts and treatment concerns; treatment-related physical impacts; interference with daily life; treatment satisfaction; and treatment experience differences based on age, regimen, and disease characteristics. The most frequently reported treatment experience concepts reported by caregivers of CwH were self-treatment, caregiver ease of use, caregiver adherence, caregiver emotional impacts and treatment concerns, interference with caregiver's daily life, and treatment satisfaction. At the end of the CE phase, a 19-item, validation-ready version of the Child Hemo-TEM was finalized. During the validation phase, in which 187 caregivers of CwH were surveyed, 12 items were dropped from the measure due to factors such as high ceiling effects at baseline and high correlation with retained items. The final 7-item measure covered domains of treatment concerns (3 items), adherence (1 item), physical impact (1 item), and interference with daily life (2 items). The Child Hemo-TEM was found to be internally consistent (Cronbach's α=0.855). A priori hypothesized associations were predominantly confirmed.

Conclusions: This study identified key treatment-related experiences encountered by CwH, supporting development of the Child Hemo-TEM ObsRO measure. Validation found adequate evidence supporting the measure's reliability and validity. The Child Hemo-TEM ObsRO measure may be useful to clinicians and researchers assessing treatment experience in CwH.
Session: Posters/Exhibits/Break
A Survey of Clinician Practice Patterns on the Use of Inferior Vena Cava Filters for Venous Thromboembolism
Jillian Calandra1, Rahman Ladak2, Massimo Sementilli3, Alejandro Lazo-Langner2,4, Deborah Siegal5,6, Tzu-Fei Wang5,6, Rong Luo7, Andrea Cervi7
1WE-SPARK Health Institute, Windsor, ON, Canada, 2Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, 3Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada, 4Lawson Health Research Institute, London, ON, Canada, 5Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada, 6Ottawa Hospital Research Institute, Ottawa, ON, Canada, 7Windsor Regional Hospital, Windsor, ON, Canada

Background: While anticoagulation remains the first line of treatment for acute deep vein thrombosis (DVT) and pulmonary embolism (PE), use of inferior vena cava filters (IVCFs) has increased in recent decades. IVCFs were designed to trap thrombus originating in lower extremity veins to prevent the development of clinically-significant PE. Data demonstrating the effectiveness of IVCFs in reducing thrombosis-related morbidity are lacking, however. While current guidelines agree that IVCFs should be considered in instances of acute venous thromboembolism (VTE) and an absolute contraindication to anticoagulation, details surrounding indiciations for their use vary among guideline societies which contributes to the heterogeneity in use of IVCFs in practice. Given that IVCFs may be associated with significant harm and costs, further efforts toward defining clear indications for IVCF use are needed. Objectives: As a first step toward defining best practices, we developed a survey of clinicians to characterize current IVCF use in various VTE scenarios. Specifically, we aimed to evaluate clinician use of IVCFs according to (1) acuity of VTE and absolute contraindication to anticoagulation; (2) isolaed PE without concurrent lower extremity DVT; and (3) anticoagulation failure.

Methods: We conducted an online, cross-sectional survey of clinicians using Qualtrics software. The survey was publicized via emails to international organizations of hematologists, thrombosis specialists and interventional radiologists, including the Anticoagualtion Forum, Thrombosis Canada, Canadian Hematology Society (CHS), International Society on Thrombosis and Hematosis (ISTH), and the Society of Interventional Radiology (SIR).

Results: We received 188 survey responses in total. The majority of respondents specialize in interventional radiology (38.7%) and hematology/thrombosis (34.1%), with half practicing in an academic facility (49.6%) versus community setting. Approzimately half (53.4%) of respondents indicated having established protocols for IVCF removal post-insertion. When provided with a case of acute PE with contraindication to anticoagulation but no concurrent leg DVT, 44% responded that they would proceed with a filter as opposed to observation with serial leg ultrasounds. Most (61%) respondents would consider filter placement for a proximal leg DVT diagnosed 2-days before an absolute contraindication to anticoagulation, but only 24% would proceed with a filter if the DVT was diagnosed 3-weeks earlier. In the setting of recurrent PE and acute proximal leg DVT despite therapeutic anticoagulation, 44% of clinicians would advocate for IVCF insertion. Across fictional case scenarios, thrombosis specialists/hematologists were less likely to proceed with filter insertion compared to other specialists (p=0.024). There was no impact of practice setting (i.e. academic versus community) on responses (p=0.512).

Conclusions: Our survey highlights the heterogeneity in the use of IVCFs in clinical practice, particularly in instances of acute PE without lower extremity DVT and anticoagulation failure. The variability in survey responses is reflective of the discrepancy that exists among current practice guidelines which contradict one another in certain settings relating to filter use, or lack clarity in other indications. Moreover, most clinical guidelines do not provide recommendation on monitoring post-IVCF insertion to optimize filter removal rates and minimize risk of complications. Futher prospective data relating to the use of IVCFs in controversial settings is warranted.
Session: Posters/Exhibits/Break
Thrombosis Rates and Use of Thromboprophylaxis after Discharge from Gynecologic Cancer-Related Surgery
Leticia Campoverde, Alyssa Mercadel, Dan Morgenster, Asaad Trabolsi, Thomas Plate IV, Rachel Kronenfeld, Wei Zhao, Matthew Schlumbrecht , Gerald Soff
University of Miami, Miami, FL, USA

BACKGROUND: Cancer and major abdominopelvic surgeries each pose significant thrombosis risks, making cancer-related surgery highly susceptible to venous thromboembolism (VTE). Without post-operative thromboprophylaxis (TPX), VTE risk can reach 29% in the weeks following major cancer surgeries. National Comprehensive Cancer Network (NCCN) guidelines recommend anticoagulation for up to 4 weeks after such surgeries, primarily using low molecular weight heparin (LMWH). As a Quality Assessment/Quality Improvement (QA/QI) project, we assessed the VTE rates linked to various gynecologic cancer-related surgeries and the compliance with TPX in a large cancer-center cohort. Additionally, we sought to further characterize the thrombosis risk as a function of surgical procedure and cancer type. METHODS: Patients (pts) diagnosed with gynecologic cancer between January 1st, 2012, through September 15th, 2022, at our institution were identified through our tumor registry. Using an in-house automated text search tool from our electronic medical record (Epic®), combined with natural language processing review, venous thromboembolism (VTE) events were identified, with secondary adjudication by the study leader (GAS). VTE was defined as either lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE) diagnosed from the day of surgery until 90 days after surgery. Logistic regression was performed on binary outcomes for the presence of VTE and TPX use at discharge. Kaplan-Meier curves and Cox regression were used for overall survival analysis. RESULTS: 801 pts were identified who underwent gynecologic cancer-related surgery. The overall VTE rate was 1.9% (n=15) but the events were not equally distributed. Minimally invasive surgery (MIS), vulvovaginal surgery, and biopsies collectively were associated with VTE rate of 0.57% (n=3), even when considering that only 11.1% of those pts received TPX at discharge. VTE was more commonly diagnosed in patients who underwent open surgery (4.3%, n=12), with 5 pts (1.8%) having VTE events before discharge and 7 (2.5%) after discharge. In multivariable logistic regression analysis, open procedures were associated with a higher risk of thrombosis (RR 7.5, p <0.001). Notably, only 50% (139 of 279) of pts who underwent open surgery received TPX at the time of discharge. Within the open surgery cohort, there was an inverse correlation between the incidence of post-discharge VTE and the utilization of post-discharge TPX. Of the 139 patients who received post-discharge TPX, 1 (0.7%) developed VTE, compared with 6 (4.3%) of the 140 patients who did not receive post-discharge TPX. (RR 0.17, p= 0.12). There was no difference in overall survival in pts who received TPX and those who did not, up to 36 months after open surgery. CONCLUSIONS: Our findings suggest a tiered risk of post-operative VTE after gynecologic cancer surgery, with a clinically relevant risk observed only in women undergoing open surgery. In patients who underwent open surgery, TPX at discharge showed a trend towards a protective effect, although this result did not reach statistical significance, probably due to sample size. This supports the need for improved targeted thrombosis prophylaxis.
Session: Posters/Exhibits/Break
Platelet immunophenotype induced by the Spike (S) protein and the RBD domain of SARS-CoV-2 virus.
Alan Cano-Mendez, Nallely Garcia-Larragoiti, Yesenia Ambriz-Murillo, Patricia Guzman-Cansino, Alejandra Ochoa-Zarzosa, Martha Eva Viveros-Sandoval
Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Mexico

Background: COVID-19 caused by SARS-CoV-2 has affected millions of people worldwide. This viral agent uses the Spike (S) protein to infect target cells. An active immunothrombotic state has been described in severe stages of infection. Platelets are cells involved in the inflammatory and thrombotic process and have been positioned as immune system sentinel cells due to their unique characteristics. Aim: To study the platelet immunophenotype induced by the complete Spike protein and the RBD domain of SARS-CoV-2 virus. Methodology: Blood samples were obtained from healthy volunteers by venipuncture after signing an informed consent form. 3.2% sodium citrate was used as anticoagulant. Platelet-rich plasma (PRP) was obtained by slow centrifugation (100 g x 10 minutes). PRP was separated and resuspended in Tyrodes. Stimulation of PRP (1X107 cells/ml) with protein S and protein S receptor binding domain (RBD) [2 ug/ml] was performed for different times, 37°C. A panel of inflammatory biomarkers was analyzed by flow cytometry using the LEGENDplex Kit TM Human Thrombosis Panel Standard BioLegend® and the LEGENDplex Kit TM Human Innflammation Panel 1 Standard BioLegend® (San Diego, CA, USA) following the instructions suggested by the supplier.

Results: The complete Spike protein and the RBD domain induce platelet expression of factors that contribute to the inflammatory process. We observed that cells treated with the protein secrete concentrations of IL-6, IL-8, INF- α2, IL-1B and IL-10 when compared to the expression of these factors in untreated PRP or upon stimulation with vehicle (p<0.05) and with procoagulant agonists such as ADP, epinephrine and collagen. Conclusion: Protein S and the RBD domain induce a proinflammatory phenotype in platelets, favoring the perpetuation of the immunothrombotic environment.
Session: Online Poster Session
Pitfalls and Considerations for Thrombophilia Testing--how can laboratories support patients? (purpura fulminans, acute DIC, APAS, interferences etc.)
Donna Castellone

Pitfalls in Thrombophilia Testing: How can laboratories support patients?

Donna D Castellone, MS, MASCP, MLS(ASCP)SH

Hereditary thrombophilia is rare, most cases are acquired. Thrombophilia testing is complex, expensive and several tests must be performed to make a diagnosis. Testing should be performed when it supports outcomes for treatment. Using testing algorithms and adhering to guidelines can guide initial testing that is best for patients. Genetic testing may also be utilized however patients should be aware of the ramifications of having that information. It is the responsibility of the laboratory to provide robust and quality testing to aid in the diagnosis and treatment of these disorders. Testing methodology should be chosen to best reflect the patient population being evaluated. Implementing quality indicators to minimize preanalytical, analytical and post analytical issues will provide the most accurate patient results. Understanding what risks the laboratory is willing to accept with testing can also be important in implementing and maintaining these tests. Participating and understanding the information provided by proficiency testing is a tool in quality practices. All this information can aid in supporting patients in the diagnosis of thrombophilia.

Session: Dissolving the Clot of Thrombilia Testing: Current Diagnostic Updates and Challenges
The Severe Von Willebrand Disease Patient Registry: A Longitudinal Natural History and Patient Outcomes Study
Johnna Cesta1, Mrinal Gounder1, Christopher Walsh 2, Alice Araphsian1, Jeanette Cesta1, Christina Morgenthaler1
1VWD Connect Foundation , Wellington , FL, USA, 2Icahn School of Medicine Mount Sinai Hospital, New York , NY, USA

Background: Severe von Willebrand Disease (sVWD) is a rare bleeding disorder with a natural history poorly defined in literature. VWD Connect Foundation (VCF) is a U.S. National non-profit patient advocacy organization serving the sVWD patient community. To address the research gaps, VCF initiated a prospective study titled "The Severe Von Willebrand Disease Patient Registry: A Longitudinal Natural History and Patient Outcomes Study" (IRB VWD-001). Objectives: The primary objective is to characterize the sVWD patient population through the use of an online portal where patient demographics, medical history, self-reported bleeding history and impact on quality of life are investigated. This data will provide researchers and other stakeholders with natural history data on the sVWD population to set as benchmarks to develop guidelines and guide treatment and clinical trial design.

Methods: Enrollment criteria include a patient diagnosis of Type 3 VWD or Severe Types 1, 1C, 2A, 2B, 2M, and 2N, excluding acquired vWD. Patients with unknown/other types may be considered severe if they have von Willebrand factor levels <20%. Following informed consent and screening, participants complete online modules, with continued participation as new modules are released. Current modules include Demographics and the Self-Administered Bleeding Assessment Tool (Self-BAT; Deforest et al, 2015). Additionally, current medications and medical history data are collected and updated by the participant as needed over time. Future modules planned include: quality of life, family history, laboratory data, genetic data, reproductive bleeding, joints, treatments, prophylaxis and inhibitors.

Results: From December 2021 to December 2023, 44 participants have enrolled, and recruitment is ongoing. 40 of the 44 participants are diagnosed Type 3 VWD. Select participant data on demographics, Self-BAT responses, treatment, and medical and medication history will be presented at the meeting.

Conclusions: To advance the understanding of severe von Willebrand Disease, robust data describing patients' medical history and lived experiences must be collected. By gathering broad data from those with sVWD from all over the United States, this Registry is beginning to address this research gap. The Registry's collection of further information on diagnosis, phenotype, genetic and laboratory data will accelerate this mission.
Session: Posters/Exhibits/Break
Anti-Factor XI Antibodies Targeting the Apple 2 Domain and the Catalytic Domain Exert Distinct In Vitro Inhibitory Profiles on Coagulation Function
Dan Chalothorn, KehDih Lai, Weizhen Wu, Holly Sorenson, George Ehrlich, Ashique Rafique, Ishita Chatterjee, Kei Saotome, Matthew Franklin, Lori Morton
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

Background: Acute venous and arterial thromboses (i.e., abnormal clotting of blood within vessels) are common causes of morbidity and mortality in developed countries. Although several classes of antithrombotic agents are currently approved, an unmet medical need exists for antithrombotics that do not increase bleeding risk. A combination of genetic and pharmacological evidence from human and animal studies suggests that inhibition of coagulation factor XI (FXI) can be effective at preventing thrombosis with little-to-no increased bleeding risk. We have generated two monoclonal antibodies (mAbs) that bind to different domains on FXI/FXIa and exert distinct inhibitory profiles on coagulation function. Objectives: To characterize epitope binding sites, affinities for FXI and FXIa, and inhibitory effects on coagulation pathway function for each anti-FXI/FXIa mAb.

Methods: Epitope binding sites on FXI/FXIa were mapped using cryogenic electron microscopy (cryo-EM), and binding affinities were determined using surface plasmon resonance techniques. Functional effects on coagulation activities were assessed using the clinical method of activated partial thromboplastin time (aPTT), which reflects factor function in both intrinsic and common pathways. Prothrombin time (PT), which reflects factor function in both extrinsic and common pathways, was also assessed. Functional effects on thrombin generation, which is mediated by intrinsic or extrinsic pathway activators, were assessed using a thrombin generation assay.

Results: High resolution cryo-EM revealed that one mAb is an Apple 2 domain binder (A2-mAb) and the other a catalytic domain binder (Cat-mAb), which interfere with FXI/FXIa interactions with high-molecular-weight kininogen and coagulation factor IX, respectively. Both mAbs have sub-nanomolar binding affinities for FXI and FXIa (A2-mAb: 23.0 pM and 150 pM, respectively; Cat-mAb: 4.0 pM and 7.0 pM, respectively) at 37°C. In functional dose-response analyses, A2-mAb had an aPTT ratio of 2.0 at 32 nM and a maximum aPTT ratio of 3.0 at 320 nM; Cat-mAb had an aPTT ratio of 2.0 at 24 nM and a maximum aPTT ratio of 4.3 at 75 nM. Neither mAb affected PT up to the maximum tested concentration of 25 µM. In the thrombin generation assay using pooled healthy human plasma, A2-mAb reduced intrinsic pathway-triggered thrombin generation in a dose-dependent manner and completely abolished thrombin generation at doses 250 nM, without affecting extrinsic pathway-triggered thrombin generation. Cat-mAb reduced intrinsic pathway-triggered thrombin generation to 38% of baseline at a dose of 16 nM and completely abolished thrombin generation at doses 31 nM; extrinsic pathway-triggered thrombin generation was reduced by 40-50% of baseline at doses 16 nM, likely due to the mAb interfering with the thrombin-FXI feed-forward loop. Both mAbs reduced thrombin generation in a contact-mediated thrombosis setting when plasma was incubated with non-biological surfaces (hemodialysis fibers or mechanical heart valve components).

Conclusions: A2-mAb and Cat-mAb bind to different domains of FXI/FXIa and consequently exert distinct inhibitory profiles on coagulation function. A2-mAb is a moderately potent inhibitor of intrinsic, but not extrinsic, pathway-triggered activity. Cat-mAb is a more potent/efficacious inhibitor of intrinsic pathway-triggered activity, with moderate effects on propagation/amplification of the thrombin-FXI feed-forward loop, as evidenced by alterations in extrinsic pathway-triggered thrombin generation.
Session: Posters/Exhibits/Break
Chimeric Antigen Receptor (CAR) T Cell Treatment in Very High Titer Inhibitor Murine Model Requires CD19 and BCMA Targeting
Julia Q. Chau2, Caroline Markmann1, Zheng Zhang1, Michael C. Milone1, Bhavya S. Doshi2,3, Vijay G. Bhoj1, Benjamin J. Samelson-Jones2,3
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 2The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA, 3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Background: The development of anti-factor VIII (FVIII) antibodies is the major complication of FVIII replacement therapy in hemophilia A (HA). Though the consequences of neutralizing anti-FVIII antibodies for HA patients has been improved by the development of non-factor therapies for HA, inhibitors remain a challenging clinical problem. The anti-FVIII immune response continues to be incompletely understood. Immunosuppression has historically been used as second-line therapy if inhibitors are resistant to ITI regimens, with anti-CD20 monoclonal antibody being the recommended agent (Valentino et al. Haemophilia 2015). As it is an antibody-mediated process, B and plasma cells must participate in the inhibitor response. We hypothesized that targeting CD19+ cells is advantageous to selective depletion of CD20+ B cells, as the former is expressed on plasmablasts and some plasma cell populations that may contribute to FVIII antibody production. Objective: We tested if administration of murine (m) T cells expressing chimeric antigen receptors (CARs) composed of an anti-mCD19 single-chain variable fragment (scFv) extracellular targeting domain (CART-19) or a B-cell maturation antigen (BCMA) ligand (mAPRIL) extracellular targeting domain (CART-BCMA) could eradicate very high-titer inhibitors in HA mice. Methods: HA mice on the C57BL/6-129 background were immunized with 1.5 IU of intravenous recombinant human FVIII protein weekly for 4-6 weeks to achieve very high-titer inhibitors. After lymphodepletion with 5 Gray total-body radiation, 4 x 106 unmodified (NTD negative control) or CAR T cells per mouse were intravenously administered. This degree of lymphodepletion is necessary for sustained T cell engraftment in immunocompetent animals and does not by itself eradicate FVIII inhibitors. Results: We initially compared administration of unmodified T cells and CART-19 in inhibitor mice (5-9/cohort) with median and interquartile range (IQR) of 340 (280-750) BU and 310 (140-370) BU, respectively. At 2 weeks, both cohorts had peripheral B cell depletion, though the CART-19 cohort was lower at 3.5 (0-6.9) compared to 14 (55-180) cells/μL for NTD (p <0.005). However, by 6 weeks, the NTD cohort had recovered (2,600 (1,600-3,900) cells/μL), while the CART-19 cohort had sustained B cell aplasia (4.4 (1.4-5.5) cells/μL). Despite this sustained B cell aplasia, the NTD and CART-19 mice retained similar persistent very high-titer inhibitors: 250 (220-320) and 240 (0-300). These results suggest that very high-titer FVIII inhibitors in the HA mice model are resistant to sustained CD19+ B cell depletion. We then compared administration of unmodified T cells, CART-BCMA, and concomitant CART-BCMA and CART-19 (CART-COMBO) in inhibitor mice (5-14 cohort) with 310 (150-440) BU, 250 (170-260) BU, and 440 (120-510) BU respectively. At 7 weeks, the mice that received CART-COMBO had a significantly lower inhibitor titer of 0 (0-3) BU compared to either the CART-BCMA (12 (2-62) BU, p <0.05) and NTD (50 (6-120) BU, p <0.005), as shown in Figure 1. Conclusions: These results indicate that very high-titer neutralizing antibodies to FVIII requires the elimination of both mature B cells and plasma cells, which can be accomplished by concomitant treatment with CART-19 and/or CART-BCMA; CD19+ B cell depletion alone is likely insufficient for eradication of very high-titer inhibitors.
Session: Posters/Exhibits/Break
Efficacy and Safety of Eptacog Beta for Bleed Treatment in Adults and Adolescents with Hemophilia B and Inhibitors During PERSEPT 1
Meera Chitlur1, Yasmina Abajas2, Suchitra Acharya3, Sanjay Ahuja4, Jonathan Bernstein5, Elizabeth Bowhay-Carnes6, Brandon Hardesty7, Jonathan C. Roberts8,9, Vanessa Salinas10, Craig Seaman11, Robert Sidonio Jr.12, Daniel Bonzo13, Jim Phipps14, Thomas Wilkinson15, Guy Young16
1Central Michigan University College of Medicine/Children’s Hospital of Michigan, Carmen and Ann Adams Department of Pediatrics, Division of Hematology/Oncology, Detroit, NY, USA, 2Hemophilia and Thrombosis Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 3Cohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, USA, 4Rainbow Babies & Children’s Hospital, Cleveland, OH, USA, 5Hemophilia Center of Central Pennsylvania, Hershey Medical Center, Hershey, PA, USA, 6UT Health San Antonio, San Antonio, TX, USA, 7Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA, 8Bleeding & Clotting Disorders Institute, Peoria, IL, USA, 9Departments of Pediatrics and Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA, 10Center for Inherited Blood Disorders, Orange, CA, USA, 11Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA, 12Aflac Cancer and Blood Disorders Center and Emory University, Atlanta, GA, USA, 13LFB-USA, Inc., Framingham, MA, USA, 14HEMA Biologics, LLC, Louisville, KY, USA, 15GLOVAL LLC, Broomfield, CO, USA, 16Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Background: Hemophilia B (HB) prevalence has been estimated to be 3.8 cases per 100,000 males, with inhibitors developing in 5-10% of patients receiving factor IX replacement therapy. Given the small proportion of persons with HB and inhibitors (PwHBI), data describing bleeding episode (BE) treatment and outcomes in PwHBI are scarce. Eptacog beta (Sevenfact®) is a recombinant activated human factor VII that is FDA-approved for the treatment and control of BEs in patients with hemophilia A or B with inhibitors (age ≥12 years) using an initial dose regimen (IDR) of 75 or 225µg/kg. The pivotal PERSEPT 1 trial (NCT20202369) included 2 PwHBI subjects and 25 hemophilia A subjects with inhibitors. Objective: To evaluate the efficacy and safety of 75 and 225µg/kg eptacog beta IDRs for mild or moderate BE treatment in PwHBI from PERSEPT 1 at 12 and 24 h post-initial dose.

Methods:
Subjects treated BEs with either the 75 or the 225µg/kg IDR in a randomized crossover trial design. Subjects using the 75µg/kg IDR received an initial 75µg/kg eptacog beta dose followed by 75µg/kg q3h as needed until BE treatment success, while subjects in the 225µg/kg IDR received 225µg/kg eptacog beta followed 9 h later by 75µg/kg q3h as needed. Mild or moderate BE treatment success was determined by patients or caregivers, and defined as obtaining a hemostasis evaluation of "good" or "excellent" with no use of additional eptacog beta, alternative hemostatic agents or blood products, and no increase in pain following the first "good" or "excellent" assessment.

Results:
Two PwHBI treated 24 BEs (all of mild or moderate severity) in PERSEPT 1. One PwHBI (Subject 1; age 12) experienced 16 joint BEs (including 5 target joint BEs). The other PwHBI (Subject 2; age 34) treated 8 BEs, 6 of which were joint BEs (including 3 target joint BEs). At 12 h post-initial infusion, treatment success proportions for BEs treated using 75 and 225µg/kg IDRs in PwHBI were 90.0% and 81.8%, respectively (Figure 1). At 24 h, the treatment success proportions were 90.9% for the 75µg/kg IDR and 100% for the 225µg/kg IDR. Treatment success proportions seen for PwHBI treating BEs with either IDR were consistent with those seen in the PERSEPT 1 trial overall (Figure 1). While assigned to the 225µg/kg IDR, Subject 1 experienced a treatment-related adverse event (increased body temperature) of moderate severity, which resolved following administration of ibuprofen and other non-steroidal anti-inflammatory medications. No neutralizing anti-drug antibodies were found in PwHBI (or in any PERSEPT 1 subject), and no thrombotic, allergic, hypersensitivity, or anaphylactic events occurred.

Conclusions:
Both eptacog beta IDRs provided safe and effective control of mild or moderate BEs in PwHBI during PERSEPT 1. Most BEs experienced by PwHBI were successfully treated at 12 h post-initial eptacog beta infusion, and all BEs in PwHBI treated with the 225µg/kg IDR had resolved at 24 h. These results support the efficacy and safety of eptacog beta for BE treatment in adult and adolescent PwHBI.
Session: Posters/Exhibits/Break
Insight Into ATHN 16: Treatment of Bleeding Events in Patients with Congenital Hemophilia A or B with Inhibitors to Evaluate the Safety of Coagulation Factor VIIa (recombinant)-jncw
Tammuella Chrisentery-Singleton1, SUCHITRA ACHARYA2, SANJAY AHUJA3, LAUREN AMOS4, MEERA CHITLUR5, MIGUEL ESCOBAR6, ASHLEY EASON7, SHVETA GUPTA8, PHILLIP KURIAKOSE9, SHARON PENNINGTON10, RAJIV PRUTHI11, MICHAEL RECHT12, SPENCER SULLIVAN13, DORIS QUON14, ALLISON WHEELER15, MARK REDING16
1American Thrombosis and Hemostasis Network, Rochester, NY, USA, 2Northwell Health Hemostasis and Thrombosis Center, New Hyde Park, NY, USA, 3University Hospitals Health System Cleveland, Cleveland, OH, USA, 4Children’s Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA, 5Central Michigan University/Children’s Hospital of Michigan, Detroit, MI, USA, 6University of Texas Health Science Center, Houston, TX, USA, 7Willett Children's Hemophilia Treatment Center at Memorial Health, Savannah, GA, USA, 8Arnold Palmer Hospital for Children, Orlando, FL, USA, 9Henry Ford Health System, Detroit, MI, USA, 10Louisiana Center for Advanced Medicine, Slidell, LA, USA, 11Mayo Clinic, Rochester, MN, USA, 12National Blood Disorders Foundation, New York, NY, USA, 13Mississippi Center for Advanced Medicine, Madison, MS, USA, 14Orthopaedic Hemophilia Treatment Center, Los Angeles, CA, USA, 15Vanderbilt University Medical Center, Nashville, TN, USA, 16University of Minnesota Medical Center, Minneapolis, MN, USA

Background: Eptacog beta (rFVIIa-jncw, SEVENFACT®) was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of bleeding events (BEs) in individuals 12 years of age and older with hemophilia A or B complicated by inhibitors. The ATHN 16 study: Treatment of Bleeding Events in Patients with Congenital Hemophilia A or B with Inhibitors to Evaluate the Safety of Coagulation Factor VIIa (recombinant)-jncw was designed to collect real-world evidence on the safety of eptacog beta. Objective: To provide an evaluation of the safety of eptacog beta when used to treat BEs in persons with hemophilia A or B and inhibitors (PwHABI) with or without FDA-approved prophylactic treatment.

Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric, multicenter, open-label, safety study enrolling PwHABI, aged 12 years and older, who are either on an FDA-approved prophylaxis therapy and at risk of experiencing a breakthrough BE or who are not on prophylactic treatment and may need to control a BE. Safety is evaluated according to European Haemophilia Safety Surveillance (EUHASS) criteria, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor (FVII) development, thrombosis, cardiovascular events, malignancies, neurological events, and deaths. After informed consent was obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history were recorded. Each participant is provided nine (9) 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta was administered by the participant or by study staff at the time of a BE. The doses and duration of treatment were determined at the discretion of the treating physician and participant. BE details including timing of BE, any treatments associated with the BE (including eptacog beta) and timing of resolution of the BE, were collected as well as surgical procedures, EUHASS events, adverse events of special interest (AESIs), and serious adverse events (SAEs).

Results: Between August 2021 and October 2023, 17 participants were enrolled at 19 ATHN-affiliated sites. All study participants with severe hemophilia received prophylactic emicizumab with one starting emicizumab prophylaxis during the trial. To date, 72 BEs have been treated with eptacog beta. Of these bleeds, 29 were classified as spontaneous, 31 were traumatic, 11 were after activity or exercise, and 1 was classified as other (medical procedure). No adverse events (AEs) related to eptacog beta use were reported. Two AEs, unrelated to the study product, were reported and resolved. Three SAEs, unrelated to the study product were reported and resolved.

Conclusions: To date, the safety profile of eptacog beta for the treatment of BEs in the ATHN 16 participants is consistent with previously published reports.
Session: Posters/Exhibits/Break
ATHN Transcends: Natural History Cohort Study of Bleeding Symptoms and Treatment Outcomes in Patients with Glanzmann Thrombasthenia
Divyaswathi Citla Sridhar1, Sanjay Ahuja2, Tammuella Chrisentery-Singleton3, Carrie O'Neil3, Catherine Rea4, Jigar Amin4, Mike Recht5,6, Meera Chitlur7
1Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 2Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland , OH, USA, 3American Thrombosis and Hemostasis Network, Rochester, NY, USA, 4Hemab Therapeutics, Cambridge, MA, USA, 5National Bleeding Disorders Foundation, New York, NY, USA, 6Yale University School of Medicine, New Haven, CT, USA, 7Central Michigan University/Children’s Hospital of Michigan, Detroit, MI, USA

Background ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment in People with Non-Neo-plastic Hematologic Disorders is a multi-institutional, observational cohort study assessing the safety and effectiveness of various interventions for people affected by bleeding and clotting disorders. ATHN Transcends is carried out through the American Thrombosis and Hemostasis Network (ATHN) Affiliate Network. The ATHN Transcends: Congenital Platelet Disorders Natural History Arm is investigating the natural history of the safety and effectiveness of hemostatic therapies in the prevention or treatment of bleeding events (on-demand, surgery, prophylaxis) in adults and children with congenital platelet disorders. It is a longitudinal, prospective, retrospective, observational cohort arm of ATHN Transcends following participants for 15 years from the time of enrollment. The ATHN Transcends: Glanzmann Thrombasthenia (GT) Module is a registry in the Congenital Platelet Disorders Natural History Arm specific to patients with GT. GT is a rare, inherited, qualitative platelet disorder due to deficiency of one or both platelet surface proteins alpha IIb beta 3. Reports of the impact of living with GT are lacking. Platelet transfusions, which have been the mainstay of treatment for severe bleeding in people with GT, carry a number of risks including allergic reactions (anaphylaxis, acute lung injury), pathogen transmission, and the formation of allo-antibodies. As potential new therapies emerge, this registry allows unbiased, long-term data collection on the safety and effectiveness of both current and new therapies, in addition to information on the bleeding rate and phenotype, as well as lived experience. Aims and Objectives This is a multi-institutional, observational cohort study. The aim of this study is to provide genotype-phenotype correlation and treatment efficacy of new and old therapeutic modalities in GT. The objectives of the GT Module are to describe the bleeding phenotype in GT including: Frequency and site of bleeds Patient-reported outcomes Healthcare and treatment utilization Real-world effectiveness of GT therapies Adverse events related to currently utilized therapies, e.g., allo-antibody formation Creating a database for future research Study Design This study is a longitudinal, natural history, observational cohort study. Approximately 50 participants with GT will be enrolled at 16 ATHN-affiliated treatment centers in the United States and one international ATHN Affiliate. ATHN Transcends has received central IRB approval and is currently being rolled out across participating ATHN Affiliates in the United States. The minimum planned duration of study participation for participants is approximately 18 months. Up to 10 pediatric subjects aged 2 years to <10 years, 10 to <18 years, and a minimum of 30 adults aged >18 years with GT are expected to be enrolled. Each participant will complete a daily record for 3 months with treatment details, in addition to the lived experience of being impacted by GT. Conclusion The GT Module of ATHN Transcends will allow collection of data that will lead to a better understanding of the phenotype and treatment efficacy of the various treatment modalities, which will facilitate creation of better treatment guidelines for these patients.
Session: Posters/Exhibits/Break
Osteoporosis and Fragility Fractures in Hemophilia and von Willebrand disease - a large national claims database study
Divyaswathi Citla Sridhar1, Brandi Dupervil2, Laura Schieve2, Sanjay Ahuja3, Marilyn Manco-Johnson4, Roshni Kulkarni5, Suchitra Acharya6, Meera Chitlur7, Patricia Tobase8, Anjali Sharathkumar9, Binh Le2, Mike Soucie2
1University of Arkansas for Medical Sciences/ Arkansas Children's hospital, Little Rock, AR, USA, 2Centers for Disease Control and Prevention, Atlanta, GA, USA, 3Case Western Reserve University, Cleveland, OH, USA, 4Hemophilia & Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 5Centers for Bleeding and Clotting Disorders, Department of Pediatrics, Michigan State University, Lansing, MI, USA, 6Cohen Children's Medical Center, Northwell Hemostasis and Thrombosis Center, New Hyde Park, NY, USA, 7Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA, 8University of California San Francisco, San Francisco, CA, USA, 9Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa Health Care, Iowa City, IA, USA

Background: Osteoporosis is characterized by qualitative skeletal changes and reduction in bone mass resulting in bone fragility and higher risk of fractures. The risk of reduced bone mineral density in persons with hemophilia (PwH) has been described in several small single center and multi-center studies. Data on bone health outcomes in persons with von Willebrand disease [PwvWD] is very limited. Our study compares the prevalence of osteoporosis and bone fragility fractures in hemophilia and von Willebrand disease [vWD] with the general population in the US.

Methods: This retrospective study analyzed data from 2 large datasets: the MarketScan Multi-State Medicaid Database [MD] and MarketScan Commercial and Medicare Supplemental Claims Database CD. Cases were individuals between 11-64 years of age in 2021 with at least 1 inpatient diagnosis code ICD-9 or ICD-10 or ≥ 2 non rule-out outpatient diagnosis codes > 30 days apart of hemophilia A or B, or vWD between 2015-2021, and who were continuously enrolled in a health plan for 12 months during 2021. Controls were individuals that met age and continuous enrollment criteria with no bleeding disorder diagnostic codes between 2015-2021. We compared prevalence of osteoporosis and fragility fractures, among cases and controls, overall and within age and sex subgroups. Additionally, prevalence of fragility fractures was assessed according to whether the patient also had another clinical risk factor for poor bone health MD dataset only. Individuals with disorders associated with risk of fragility fracture e.g., malignant neoplasm were excluded.

Results: Fragility fractures[Table 1]: Hemophilia: Prevalence of fractures among PwH was significantly higher than controls, 3.7% vs 1.9%, [p <0.05] in CD and 8.1% vs 2.7%, [p <0.05] in MD. When categorized by age, prevalence of fractures was significantly higher among 31-45y and 46-64y in both CD and MD. Hypertension and vitamin D deficiency rates were significantly higher among PwH with fractures compared to controls with fractures in the MD. vWD: Prevalence of fractures among PwvWD was significantly higher than controls 4.0% vs 1.9%, [p <0.05] in CD and 4.3% vs 2.7%, [p <0.05] in MD. When categorized by age, prevalence of fractures was significantly higher in all three age groups, in both databases. Osteoporosis [Table 2]: Hemophilia: Prevalence of osteoporosis in PwH was significantly higher than controls 1.1% vs 0.3%, [p<0.05] in the MD. When categorized by age, prevalence of osteoporosis was significantly higher in 46-64y in the MD 8.4% vs 1.4%, [p<0.05]. vWD: Prevalence of osteoporosis in PwvWD was significantly higher than controls 1.1% vs 0.6%, [p <0.05] in CD and 0.6% vs 0.3%, [p <0.05] in MD. When categorized by age, prevalence of osteoporosis was significantly higher in 46-64y in the MD 4.7% vs 1.4%, [p<0.05] and 31-45y in the CD 4.1% vs 0.1%, [p<0.05].

Conclusions: The prevalence of fragility fractures and osteoporosis is significantly higher among PwH and PwvWD. These data highlight the importance of screening patients with these bleeding disorders for reduced bone mineral density, identifying additional risk factors for poor bone health, and providing education to prevent fractures.
Session: Short Talks - Complications of Disease and Therapy in H&T
Access to Factor VIII and Factor IX to Persons with Hemophilia in Arkansas: A Quality Improvement Study
Divyaswathi Citla-Sridhar1, 2, Kara Burge2, Jean Aroom3, Justine Kaplan3, Shelley Crary1, 2
1University of Arkansas for Medical Sciences, Little Rock, AR, USA, 2Arkansas Children’s Hospital, Little Rock, AR, USA, 3American Thrombosis and Hemostasis Network , Rochester, NY, USA

Introduction and objectives: Arkansas is ranked 48th in the United States for health, with only one federally supported hemophilia treatment center (HTC) where persons with hemophilia A and hemophilia B (PwH) can get specialized care: the Arkansas Center for Bleeding Disorders at Arkansas Children's Hospital ("our center"). Within Arkansas, there are a total of 57 designated trauma centers (DTC) for emergency treatment. With several PwH reporting that the emergency room they went to did not have factor available to treat their bleeding episode, this study aimed to identify factor VIII (F8) and factor IX (F9) availability at each of the 57 DTCs across the state of Arkansas and assess the time taken for a PwH to travel to the nearest center with factor availability.

Methods: This is a quality improvement (QI) study in collaboration with the National Hemophilia Program Coordinating Center (NHPCC). Using the list of DTCs available from the Arkansas Department of Health, our center's social worker contacted each center and compiled a list of F8 and F9 products available at each DTC. Using ZIP code information of PwH from a de-identified patient dataset at our center and using geographic information system (GIS), all PwH were mapped and their travel time to a DTC with factor availability was determined.

Results: Out of 57 DTCs, F8 was available at 18 centers (Table 1) - 6 Level 1 DTC (100%), 4 level II DTC (100%), 7 level III DTC (38.8%), 1 level IV DTC (3.4%). F9 was available at 10 centers - 6 Level 1 DTC (100%), 1 level II DTC (25%), 2 level III DTC (11.1%), 1 level IV DTC (3.4%). GIS map below (Figure 1) depicts PwH and their distribution in the state of Arkansas in relation to a DTC with factor availability. 30% of hemophilia A and 63.4% of hemophilia B patients lived greater than 1 hour from nearest DTC with factor availability.

Conclusions: With less than half of Arkansas' trauma centers carrying factor replacement therapies, PwH have especially limited access to life-saving factor replacement. By educating community emergency centers, improved health outcomes are possible for PwH through increased access to local emergency treatment centers. As the next step in QI, we have started an education program for DTCs, and we will re-assess factor availability upon completion of this educational effort.
Session: Posters/Exhibits/Break
Burden of disease and impact on quality of life in hereditary factor X deficiency patients who were diagnosed at birth: Findings from the Hereditary Factor X Deficiency in America Survey
Kim Clark1, Amy Wu2, Denise A. Garner2, Lorie Mody2, Jaymin Patel2, Brian Branchford3
1Kedrion Biopharma, INC., Fort Lee, NJ, USA, 2AESARA, INC., Chapel Hill, NC, USA, 3Versiti Blood Research Institute, Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI, USA

Background: Hereditary factor X deficiency (HFXD) is a rare genetic coagulation disorder leading to delayed hemostasis and potentially life-threatening bleeding. Disease burden is variable, possibly related to how early HFXD is diagnosed. Differences in burden and quality of life (QoL) related to diagnosis timing have not been well characterized. Objectives: Examine disease burden and patient-level QoL based on HFXD diagnosis timing.

Methods: A prospective cross-sectional web-based survey of patients with HFXD and their caregivers was conducted. Eligible individuals were identified by Hemophilia Treatment Centers, physicians, specialty pharmacies, social media, and patient advocacy groups. The survey assessed treatment patterns, patient satisfaction with diagnostic process, bleeding events, and QoL. Patient-level disease burden was measured using the Hemophilia Well-being Index (HWBI) and Short-Form Health Survey 12 (SF-12). HWBI has a maximum score of 32 with higher scores indicating better well-being. The SF-12 is an overall QoL measure with scores ranging from 0-100 for each component (physical and mental) with lower scores related to worse QoL. Patients were stratified into groups by time of diagnosis—at birth and not at birth. Diagnosed at birth was identified based on survey response stating diagnosed at birth. Descriptive results are presented.

Results: Thirty total HFXD patients were included: 13 (43.3%) were diagnosed at birth and 17 (56.7%) were diagnosed later (Table 1). Mean age at time of survey of those diagnosed a birth was 20.9 years (46.2% female, 66.7% White, and 25.0% Asian). Of those not diagnosed at birth, mean age at time of survey was 27.6 years (70.6% female, 29.4% White and 29.4% Asian); median age at diagnosis was 4.0 years (range: 4 days to 21 years). A majority of patients in the diagnosed at birth and not diagnosed at birth cohorts were on regular prophylaxis: 75.0% (n=9) and 68.8% (n=11), respectively. Of those diagnosed at birth, 38.5% (n=5) were receiving single-factor replacement (SFR) treatment while 64.7% (n=11) not diagnosed at birth were receiving SFR. However, of those diagnosed at birth and receiving SFR treatment, 80.0% (n=4) were also receiving other treatments while only 27.3% (n=3) of those not diagnosed at birth and receiving SFR treatment were also receiving other treatments. Patients diagnosed at birth (n=10) had similar overall well-being per HWBI (21, SD: 7.3) to patients diagnosed later in life (n=17) (20, SD: 10). Ten patients diagnosed at birth and 17 not diagnosed at birth completed the SF-12. Patients diagnosed at birth recorded lower mean physical and mental component scores (Table 1). Bleeding in the joints, in the muscles, and within the skull or brain were reported at a higher frequency in the diagnosed at birth cohort (Table 2).

Conclusions: Burden is high in patients with HFXD. Patients diagnosed at birth tended to have lower overall QoL, higher reported episodes of joint, muscle, and brain bleeding, and were more likely to be currently on multiple therapies including SFR relative to those who were not diagnosed at birth.
Session: Posters/Exhibits/Break
Disease burden, quality of life, and treatment patterns in patients with hereditary factor X deficiency: Analysis of data from the Hereditary Factor X Deficiency in America Survey
Kim Clark1, Denise A. Garner2, Amy Wu2, Lorie Mody2, Jaymin Patel2, Brian Branchford3
1Kedrion Biopharma, INC., Fort Lee, NJ, USA, 2AESARA, INC., Chapel Hill, NC, USA, 3Versiti Blood Research Institute, Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI, USA

Background: Hereditary factor X deficiency (HFXD) is a rare genetic coagulation disorder leading to delayed hemostasis and potentially life-threatening bleeding symptoms. Variability in disease burden may be associated with the number of HXFD treatments a patient has ever received. However, burden of disease and quality of life (QoL) may differ in patients who receive different types of treatments throughout their lifetime. Objectives: Examine disease burden, QoL, and treatment patterns among HFXD patients that have used different numbers and forms of treatments over their lifetime.

Methods: A prospective cross-sectional web-based survey of patients with HFXD and their caregivers was conducted. The survey assessed disease burden, QoL, and treatment patterns. Patient-level disease burden was measured using the Hemophilia Well-being Index (HWBI) and Short-Form Health Survey 12 (SF-12). HWBI has a maximum score of 32; lower scores indicate worse well-being. The SF-12 is an overall QoL measure; scores range from 0-100 for each component (physical and mental) with lower scores representing worse QoL. This analysis stratified individuals by number of treatments ever received: 1-2, 3-4, and 5+. Descriptive results are presented.

Results: Thirty HXFD patients were included: 10 (33.3%), 14 (46.7%), and 6 (20.0%) patients had ever received 1-2, 3-4, and 5+ treatments, with mean ages of 16 years (40.0% female, 55.6% Asian, and median age at diagnosis 0 years), 24.1 years (71.4% female, 21.4% Asian; median age at diagnosis 1.25 years), and 40.5 years (66.7% female, 33.3% White, 33.3% Black/African-American; median age at diagnosis 2 years), respectively (Table 1). The 1-2 treatment cohort reported an HWBI score of 24 (SD: 11.1). In contrast, the cohorts of 3-4 and 5+ treatments reported lower well-being scores of 20.5 (SD: 7.7) and 14.6 (SD: 5.9), respectively (Table 1). Patients who reported 5+ treatments had lower physical function mean (SD) scores for the SF-12, 36.1 (8.8) relative to 1-2 and 3-4 treatments (47.2 [13.0] and 47.5 [10.6], respectively). Mean (SD) mental function scores were also lower for 5+ treatments, 42.2 (6.7), relative to 1-2 treatments 52.3 (10.3) and 3-4 treatments 49.5 (11.5). Most (≥70%) patients in each treatment cohort reported ever receiving fresh frozen plasma (FFP). The 5+ cohort had the lowest proportion (16.7%) currently receiving FFP; 40% and 21.4% of the 1-2 and 3-4 treatments cohorts, respectively, were currently receiving FFP. All patients in the 5+ cohort had ever received prothrombin complex concentrate (PCC) and single-factor replacement (SFR). In contrast, in the 1-2 treatments cohort, 20% and 50% had ever received PCC and SFR, respectively; however, in the 3-4 treatments cohort, it was 50% and 64.3%, respectively. Few (0-10%) patients in the 1-2 and 3-4 cohorts were currently receiving PCC while 30-57.1% were currently receiving SFR (Table 2). Conclusion: Increased patient burden and lower QoL were more likely in HFXD patients that have received multiple treatments over their lifetime. In addition, more patients who ever received SFR were still on SFR treatment while FFP and PCC were less likely to be continued as current treatment.
Session: Posters/Exhibits/Break
Post-Roe's Downstream Effects - Impacting Patients, Personnel & Trainees
Alyssa Colwill

Access to reproductive health care suffered a major setback when Roe vs Wade was overturned in June 2022, rolling back 50 years of protections for pregnancy capable individuals. This presentation will describe how reggressive abortion laws have shaped access to reproductive health care in United States. After this presentation, you should be able to:

1. Understand the epidemiology of abortion

2. Understand abortion care delivery models in the US, and how they support safe provision for individuals with bleeding and thrombotic disorders

3. Describe the Post-Roe effects on abortion access, patient experience, personnel and education

Session: Abortion/Reproductive Health - When the law and healthcare collide - How laws that restrict access to reproductive care are affecting hemostasis and thrombosis patients
Initial Report of Part B Phase 1/2 Efficacy and Safety Results for Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia
Nichola Cooper1, A. J. Gerard Jansen2, Jiri Mayer3, Michael D Tarantino4, Remco Diab5, Brad Ward6, Ahmed Daak6, David J Kuter7
1Hammersmith Hospital, London, United Kingdom, 2Erasmus MC, University Medical Center, Rotterdam, Netherlands, 3Masaryk University Hospital, Brno, Czech Republic, 4The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine-Peoria, Peoria, IL, USA, 5Sanofi, Rotkreuz, LU, Switzerland, 6Sanofi, Cambridge, MA, USA, 7Hematology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Introduction: Rilzabrutinib, a potent oral reversible inhibitor of Bruton tyrosine kinase, could potentially play a role in treating immune thrombocytopenia (ITP) due to its activities in both B cells and macrophages that would reduce production of anti-platelet autoantibodies and destruction of opsonized platelets, respectively. Preliminary data indicated that rilzabrutinib treatment in patients previously treated for ITP resulted rapid and durable platelet responses with a favorable safety profile: part A of phase 1/2 clinical study (LUNA 2, NCT03395210). Objective: To investigate rilzabrutinib effects on a more refractory ITP population.

Methods: Part B of multicenter, open-label, phase 1/2 study assessed safety and effectiveness of rilzabrutinib 400 mg bid. Eligible patients were aged 18-80 years, with ≥2 baseline platelet counts <30x109/L not <7 days apart in 15 days before first dose, have past response (reached platelet count ≥50x109/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained and failed ≥1 other ITP therapy (not IVIg or CS). Consistent concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed. Primary endpoints were safety and durable platelet response (platelet counts ≥50x109/L on ≥8 of last 12 weeks of rilzabrutinib without rescue medication). Patients with platelet counts of at least 50x109/L or 30x109/L and double from baseline ≥4 of final 8 weeks of treatment without rescue medication could continue receiving rilzabrutinib for a long-term extension (LTE) period following a 24-week course of treatment.

Results: Enrolled patients (N=26) had median age (range) of 57 years (20-75), females (62%), and median baseline platelet count (range) was 13 (2-24)x109/L. Patients had median duration of ITP (range) of 10.3 years (0.7-48.2) and received prior unique median ITP therapies (range), 6 (3-19; 46% splenectomy). Seventeen patients (65%) received TPO-RA and/or concurrent non-rescue CS. Nine patients (35%; 95% CI, 17%-56%) achieved primary endpoint. By day 15 of rilzabrutinib treatment, 25% of patients had platelet counts ≥50x109/L (Figure 1A). The median time to reach a platelet count of at least 50x109/L was 15 days (range, 7-134) for 16 patients who attained this level of platelet count. Over time, median platelet counts of both responders and non-responders increased, surpassing 30x109/L platelet count threshold at day 57 and 50x109/L threshold at day 120 (Figure 1B). Mean (SD) number of weeks with platelet counts ≥50x109/L and/or ≥30x109/L and doubling from baseline was both 9.3 (10.1) weeks. During main treatment, three patients (12%) received rescue medications. Fifteen patients (58%) finished 24 weeks of rilzabrutinib and 11 (42%) entered LTE. Over the main treatment period, median treatment duration (range) was 167 days (7-169). Sixteen patients (62%) had ≥1 related treatment-emergent adverse event (rTEAE), including 35% diarrhea, 23% headache, and 15% nausea. Most rTEAEs were grade 1/2, except 1 Grade 3 rTEAE (blood creatinine phosphokinase increase) was observed. No serious rTEAEs, fatalities, or grade 2 bleeding/thrombotic rTEAEs were reported. Conclusion: Part B study results were consistent with part A despite the more refractory population. Rilzabrutinib provided quick, safe, and durable platelet responses in patients with relapsed ITP, with a favorable safety profile.
Session: Short Talks - Industry Bleeding - No CME
Deciphering platelet cold storage lesion in hibernating rodents
Scott Cooper

Natural hibernators such as the 13-lined ground squirrel undergo extensive physiological changes during hibernation while alternating between periods of torpor and brief interbout arousals. During torpor, their heart rate and body temperature decrease, they have decreased circulating platelet counts, and these platelets undergo structural changes resulting in a rod confirmation. Furthermore, the cooling of ground squirrel platelets does not impact their clearance rate from circulation post-transfusion, whereas chilled human platelets are rapidly cleared from circulation. Since cold-stored human platelets are rapidly cleared from circulation post-transfusion, they must be stored at room temperature, limiting their shelf-life to 5 days due to microbial contamination. To investigate the mechanisms involved in the clearance of cold-stored human platelets, human and ground squirrel platelets were stored at room-temperature or 4oC before being analyzed for changes in apoptosis, phagocytosis rates by HepG2 cells, and surface receptor desialylation. As expected, human platelets stored at 4oC displayed progressive increases in phosphatidylserine surface exposure and caspase activation, indicative of apoptosis, while ground squirrel platelets showed minimal change. Additionally, while cold storage caused increased rates of phagocytosis by HepG2 cells of human platelets, ground squirrel platelets showed lower rates of phagocytosis, with taxol treated ground squirrel platelets showing the lowest phagocytosis rates between both species and all treatments. Furthermore, following cold storage, sialic acid residues on human platelets were being removed, while the terminal sialic acid residues on ground squirrel platelets remained unaffected. These results suggest that ground squirrel platelets may be resistant to apoptosis, capable of avoiding phagocytosis by hepatocytes, and resist cold storage lesions by avoiding sialic acid removal. Although these experiments were in vitro, they do provide possible explanations as to how platelets can survive hibernation and can function following arousal.

Session: Take a hike Mickey- novel T&H insights from non-murine animals
Recombinant ADAMTS13 prophylaxis in patients with congenital thrombotic thrombocytopenic purpura: interim analysis from the phase 3b continuation study
Paul Coppo1, Parth Patwari2, Björn Mellgård2, Hong Li2, Marie Scully3, Masanori Matsumoto4, Jerzy Windyga5, Thomas L Ortel6, Spero Cataland7, Paul Knöbl8, Ziqiang Yu9, Ana Antun10, Sami Ibrahimi11, Doug Criger2, Linda T Wang2
1APHP.6�"Reference Center for Thrombotic Microangiopathies (CNR-MAT), Hôpital St Antoine, Paris, France, 2Takeda Development Center Americas, Inc., Cambridge, MA, USA, 3University College London Hospitals NHS Foundation Trust, London, United Kingdom, 4Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara, Japan, 5Department of Hemostasis Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland, 6Duke University, Durham, NC, USA, 7Department of Internal Medicine, Ohio State University, Columbus, OH, USA, 8Department of Medicine 1, Division of Hematology and Hemostasis, Medical University of Vienna, Vienna, Austria, 9National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, 10Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA, 11Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, potentially life-threatening disease resulting from severe ADAMTS13 deficiency. Burdensome prophylaxis with plasma infusions can be required to prevent acute TTP and chronic end-organ damage. Long-term prophylaxis with recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is being investigated in a phase 3b continuation study. Objectives: To evaluate the safety and efficacy of long-term rADAMTS13 prophylaxis in patients with cTTP.

Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT04683003) enrolled patients with cTTP ages 0 to 70 years. Patients had previously received prophylaxis with rADAMTS13 for 12 months and standard-of-care plasma infusion for 6 months in a randomized, crossover, pivotal trial (NCT03393975; rollover cohort) or had not participated in the pivotal study (non-rollover cohort). Rollover cohort data from a preplanned interim analysis (data cutoff, August 12, 2022) are presented. Patients received intravenous rADAMTS13 40 IU/kg prophylaxis every other week or weekly. The primary outcome was long-term safety and tolerability as assessed by incidence of adverse events (AEs) and serious AEs (SAEs) that were considered related to rADAMTS13. Secondary outcomes included incidences of acute and subacute TTP events and nonacute TTP manifestations.

Results: Data from 29 rollover patients were analyzed (mean ± SD age: 40.4 ± 12.1 years; 62% were female). The median (range) duration of rADAMTS13 treatment during the rollover period was 0.7 (0-1.4) years. No acute TTP events occurred during rADAMTS13 prophylaxis, and the incidence rates of subacute TTP events and TTP manifestations were comparable to those with rADAMTS13 prophylaxis in the pivotal study, which was lower than the previous standard of care (Table 1). With approximately 5 months of additional exposure to rADAMTS13 since the interim analysis (February 15, 2023) and data for an additional 7 rollover patients (n=36), there continued to be no related SAEs observed, no treatment interruptions or discontinuation due to AEs (Table 2), and no neutralizing antibodies observed.

Conclusions: In the rollover cohort of this continuation study, no adverse drug reactions were identified with rADAMTS13 prophylaxis, and no neutralizing antibodies developed. rADAMTS13 treatment that continued for up to 3.9 years prevented acute TTP events and reduced subacute events and TTP manifestations.
Session: Short Talks - Industry Bleeding - No CME
Clinical Outcomes of Congenital Thrombotic Thrombocytopenic Purpura with and without Prophylaxis Therapy: a Multinational Chart Review Study
Paul Coppo1, Marie Scully2, Johanna A Kremer Hovinga3, Maria Jose Aragon4, Parth Patwari5, Linda T Wang5, Björn Mellgård5, Ragy Saad5
1APHP.6�"Reference Center for Thrombotic Microangiopathies (CNR-MAT), Hôpital St Antoine, Paris, France, 2University College London Hospitals NHS Foundation Trust, London, United Kingdom, 3Department of Hematology and Central Hematology Laboratory, Bern University Hospital, Bern, Switzerland, 4HCD Economics, Knutsford, United Kingdom, 5Takeda Development Center Americas, Inc., Cambridge, MA, USA

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening genetic disorder characterized by severe deficiency of ADAMTS13, the von Willebrand factor-cleaving protease. This results in the formation of platelet-rich microthrombi, leading to platelet consumption and thrombocytopenia. Current treatment strategies focus on replenishing ADAMTS13 through plasma-based therapy. Objectives: The primary study objectives were to describe the characteristics of patients with cTTP, as well as the prevalence and incidence of clinical manifestations of cTTP and its complications. The secondary objectives were to explain the treatment patterns, treatment-related outcomes, and healthcare resource utilization in patients with cTTP. Treatment patterns and treatment-related outcomes are reported here.

Methods: This retrospective chart review was conducted in nine sites across Europe, the United Kingdom, and the United States. Patient-level data were abstracted from medical records from January 1, 2009, through December 31, 2020. Patients with cTTP were included if they experienced any of the following events from January 1, 2009, through December 31, 2017 (index identification period): cTTP diagnosis, prophylactic or on-demand treatment for cTTP, or another cTTP-related major clinical event. Patients were followed from the date of the first qualifying event (study index date) until loss to follow-up, enrollment in a clinical trial, end of the study period, or death. Results were summarized descriptively and stratified by follow-up time periods with and without prophylaxis exposure; patients may contribute patient-time to both periods, but never concurrently. Ethics approval and informed consent were obtained where applicable.

Results: The study included 78 patients, with a mean (SD) follow-up of 8.1 (3.1) years. Most patients were female (78.2%), including 45 with ≥1 reported pregnancy at any time. The mean (SD) age at initial cTTP diagnosis and study index was 26.2 (17.3) years and 29.5 (15.7) years, respectively. Prophylaxis was initiated 65 times in 47 (60.3%) patients. The most common reasons for initiation were clinical symptoms and pregnancy (both n=13/47; 27.7%). The mean (SD) duration of therapy was 3.9 (4.3) years; 41 (63.1%) treatments were stopped or interrupted (Table 1). A total of 92 acute events were reported by 55 (70.5%) patients during the study (0.145 episodes per person-year [PPY]). Fewer acute events occurred during prophylaxis treatment (n=12/92; 0.050 events PPY) than when patients were not receiving prophylaxis (n=80/92; 0.202 events PPY). Most events (11/12; 91.7%) occurring during prophylaxis exposure resolved without complications, and 50% (6/12) resolved in ≤7 days. Proportionally fewer events occurring outside prophylaxis exposure periods resolved without complications (59/80; 73.8%) and resolved in ≤7 days (25/80; 31.3%). Two patients died during an acute event, one each during prophylaxis exposure and non-exposure periods.

Conclusions: There were fewer acute events and improved event resolution without complications during prophylaxis exposure periods. While these findings suggest the benefit of and support the use of prophylactic therapies to mitigate the substantial clinical burden of cTTP, persistent disease manifestations, despite plasma-based prophylaxis, suggest that challenges with existing treatments persist (Schraner, 2023, Blood), highlighting the need for novel therapies with demonstrated clinical safety and efficacy.
Session: Posters/Exhibits/Break
Does unfractionated heparin versus low molecular weight heparin for thromboprophylaxis reduce complications near delivery?
Sophia A. Cordes, Hani Faysal, Joaquin A. Calderon, Renxi Li, Sonya T. Gelfand, Mina Felfeli, Haeun Kim, Homa K. Ahmadzia
Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Introduction: To analyze whether the conversion of pregnant patients from low molecular weight heparin (LMWH) to unfractionated heparin (UFH) prior to delivery results in improved outcomes and harm reduction.

Methods: A retrospective chart review of was conducted using data from 141 pregnant patients who delivered at a single university-affiliated hospital from January 2015 to September 2022 and were on LMWH or UFH during their pregnancy up until delivery. The primary outcome was the prevalence of hemorrhage associated morbidity in patients who were switched from LMWH to UFH prior to delivery. Secondary outcomes included neuraxial (NA) anesthesia complications, specifically related to anticoagulant use.

Results: Out of a total of 141 patients, 38 were converted from LMWH to UFH prior to delivery. The conversion and non-conversion groups had comparable rates of postpartum hemorrhage during delivery (5.3% vs 14.6% respectively, aOR = 0.42, 95% CI 0.09-2.05, p=0.29). Conversion and non-conversion groups have no difference in estimated blood loss (406.7 ± 53.0 vs 562.6 ± 73.1 mL, p=0.98) or quantitative blood loss (655.9 ± 296.6 vs 667.4 ± 62.3 mL, p=0.89). Only two patients in the LMWH group experienced NA anesthesia complications, but these were unrelated to anticoagulant use (headaches). Conclusion: Our findings demonstrate that there is not a significant difference in postpartum hemorrhage in pregnant patients who were switched from LMWH to UFH prior to delivery compared to those who were not switched. The prevalence of NA anesthesia complications was not high enough to be comparable and unrelated to a bleeding complication.
Session: Posters/Exhibits/Break
Managing medical challenges of gene therapy
Stacy Croteau

Integration of commercial gene therapy into routine clinical care is complex. This presentation will explore peri-infusion clinical considerations and practices for the currently licensed hemophilia A and B gene therapy products.

Session: Not your mom's jeans: Updates on Gene therapy for Hemophilia patients
Effect of Acute Deep Vein Thrombosis in Patients with lung cancer in Acute Deep Vein Thrombosis (DVT): A study of the Nation Inpatient Sample
Maria Cristina Cuartas- Mesa, Nana Yaa Ampaw, Edwin Gwira- Tamattey, Enrique Martinez- Trevino, Alejandro Nieto- Dominguez , Ekrem Turk
John H. Stroger, Jr. Hospital of Cook County, Chicago , IL, USA

BACKGROUND: Lung cancer, like most cancers, is a high-risk condition for developing deep vein thrombosis; however, little is known about the effects of deep vein thrombosis on the outcomes of patients with lung cancer. OBJECTIVES To identify the possible effects associated with the development of deep vein thrombosis in patients with lung cancer. METHODS The National Inpatient Sample database was utilized to obtain pertinent data. Using ICD-10 codes, total hospitalizations with lung cancer were extracted from the 2016 to 2020 database out of which adult patients with a secondary diagnosis of Acute DVT were determined. Statistical analysis was performed on STATA, using multivariable logistic regression to compare the odds of all-cause mortality, the length of stay, total hospital charges, and various comorbidities in lung cancer patients with acute DVT to those without. RESULTS Most patients were male (50.4%) and White (72.7%), followed by black (14.8%) and other races (7.4%) patients. The mean age was 68.6 years; most of the population was elderly (65.2%). There was a statistically significant increase in the proportion of patients with a Charlson score > 3 (p <0.01), which reflects an overall rise in the comorbidity burden in the study population. In hospitals, mortality accounted for 1.6% of admissions; when adjusted for age and gender, outcomes did not differ significantly between sex and income quartiles. Interestingly, there was a statistically significant increase in the rate of comorbidities such as myocardial infarction (MI) OR of 2 p <0.001, CVA with OR 1.66 p <0.001, intracranial bleeding with OR 2.2 p <0.001, intubation OR 1.3 p <0.001, AKI 1.3 p <0.001, PE OR 16 p <0.001, Red blood cell transfusion OR 1.49 p <0.001 and cardiogenic shock with OR 1.6 p=0.021. This was opposed to a reduced rate of requirements of Hemodialysis with OR 0.35 p <0.001 and respiratory complications with OR 0.77 p= 0.021. CONCLUSIONS Lung cancer carries significant morbimortality in patients, and deep vein thrombosis seems to be associated with a higher burden of comorbidities in this population, as mentioned above. Further research is needed to understand this pathophysiology further to prevent episodes and improve patients' quality of life.
Session: Online Poster Session
Machine learning for HIT
Adam Cuker

Heparin-induced thrombocytopenia is a high-stakes diagnosis. Without appropriate treatment (suspension of heparin and initiation of a non-heparin anticoagulant), there is a ~6% daily risk of thromboembolism, amputation, and death. Conversely, treatment for HIT is expensive and associated with a ~1% daily risk of major bleeding. Guidelines recommend a diagnostic algorithm involving calculation of the 4Ts score and immunoassay testing. However, current diagnosis is plagued by both under- and over-diagnosis. Underdiagnosis occurs primarily because clinicians do not recognize the signs and symptoms of HIT. Information technology (IT) can be used to curb underdiagnosis through automated monitoring for HIT in the electronic health record (EHR). A validated tool for this purpose is the HIT-CR score. IT, including artificial intelligence, can also be used to reduce overdiagnosis. Strategies include the addition of a 4Ts score calculator to the EHR HIT immunoassay orderset, a pop-up advisory to the EHR HIT immunoassay orderset based on the HIT-CR score, and the TORADI-HIT score, a novel diagnostic score developed with machine learning that outperformed the guideline recommended-diagnostic algorithm in an internal validation study.

Session: Immunothrombotic Syndromes
The Burden of Hemophilia in the US: Methods and Results from the Cost of Hemophilia: a Socioeconomic Survey (CHESS) US (2022)
Randall Curtis1, Maria Elisa Mancuso2,3, Enrico Ferri Grazzi4, Donna Coffin5, Brian O'Mahony6,7, Clive Smith8, Daniél Anibal García Diego9, Matteo Arzenton10, Thomas Sannié11, Fiona Brennan12, Tom Burke4,13, Sarah Brighton4
1Hematology Utilization Group Study (HUGS), Walnut Creek, CA, USA, 2Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Italy, 3Humanitas University, Pieve Emanuele, Milan, Italy, 4HCD Economics, Knutsford, United Kingdom, 5World Federation of Hemophilia, Montreal, QC, Canada, 6Irish Haemophilia Society Ltd, Dublin, Ireland, 7Trinity College, Dublin, Ireland, 8The Haemophilia Society, London, United Kingdom, 9Federación Española de Hemofilia (FedHemo), Madrid, Spain, 10Italian Federation of Haemophilia Associations (FedEmo), Rome, Italy, 11Association Française des Hémophiles (AFH), Paris, France, 12Faculty of Health and Social Care, University of Chester, Chester, United Kingdom

Background: Hemophilia is known to result in considerable clinical and socioeconomic burden in the United States (US). As such, it is important to further the generation of up-to-date information, consistent with current standard of care for the condition. CHESS III US aimed to assess the socio-economic burden of hemophilia in adult male patients of all severities in the US. Objectives The primary objective of the study was to quantify hemophilia-related costs, by disease severity, encompassing direct medical costs (i.e. treatment costs, hospital visits, tests and procedures performed) direct non-medical costs (i.e. health aids/devices, alternative and complementary therapy, travel costs) and indirect costs (i.e. work productivity impact, caregiver burden). Clinical burden by disease severity was also assessed.

Methods:
CHESS III US employed a retrospective, cross-sectional methodology, recruiting a sample of hematologists to complete an electronic case report form (CRF) covering demographic, clinical and healthcare resource use data for the 12 months prior to the date of extraction. Data collection took place from Apr-Nov 2022. The study was conducted with ethical approval from the University of Chester (UK) and with guidance from an Expert Reference Group. Total costs were quantified by summing the costs across all aspects of direct medical and non-medical, as well as indirect, costs using quantities collected in CHESS III US and unit costs sourced from the literature to enable estimation. Total cost (per-patient) was extrapolated using prevalence estimates from the 2021 WFH Annual Global Survey to estimate US population cost. Reported results focus on the clinical burden of hemophilia and related direct medical costs and are presented by clinical severity (based on baseline factor level): mild (>5-40%), moderate (1-5%), and severe (<1%).

Results:
The final sample consisted of 467 CRFs. Patients with severe hemophilia comprised 29% of the cohort, while mild and moderate condition represented 25% and 46% respectively. In the mild cohort, mean (SD) ABR was reported as 0.4 (0.9), increasing to 1.3 (2.0) and 1.6 (3.4) for moderate and severe respectively (Table 1). Joint damage was also observed, with mean (SD) problem joints reported as 0.5 (0.6), 1.1 (1.3) and 1.1 (1.8) for the mild, moderate and severe cohorts respectively. A similar pattern was observed in target joints (Table 1). Overall, levels of chronic pain increased with condition severity, with markedly higher levels in patients with moderate or severe hemophilia. Moderate or severe chronic pain was reported in 4% of mild, 18% of moderate, and 23% of severe hemophilia cohorts respectively (Table 1). The highest per-patient cost component was factor treatment cost, averaging at approximately $78,000 for mild, $226,500 for moderate and $636,500 for severe condition, respectively (estimated $462mn, $892mn and $5,457mn for the US hemophilia population). Excluding factor, direct medical costs for the US population were estimated to be highest for severe hemophilia ($41mn) decreasing for moderate ($14mn) and mild ($12mn) condition (Table 2).

Conclusions:
These findings demonstrate the significant clinical and financial burden of hemophilia to patients and the healthcare system in the US, with greater burden in more severe forms of the condition.
Session: Posters/Exhibits/Break
Describing the risks for bleeding and thrombosis unique to patients with renal impairment
William Dager

Describing the risks for bleeding and thrombosis unique to patients with renal impairment

William E Dager

The presence of severe renal impairment can create challenges in implementing and following safe and effective antithrombosis management plans. Multiple unique drivers for both thrombosis and bleeding that is unique to this setting exists creating a higher incidence of both in this setting. Understanding the drivers for bleeding and thrombosis and adapting to either acute or chronic renal impairment can be critical in developing and sustaining an optimal management plan and avoiding potential complications. Assessment of the nature of renal failure, potential factors for thrombosis and bleeding along with available literature can facilitate the assessment of the risk factors present and development of a management plan. Drivers for thrombosis and bleeding unique to either acute or chronic renal impairment, in addition to the challenges in pharmacokinetic assessment of the available anticoagulants and the influence of renal impairment along with dosing considerations and follow up assessment tools will be discussed. Potential challenges and shortcomings in the available literature for this population including limitations of how pharmacokinetic assessments were undertaken, impact of the type of renal dysfunction, assessment of elimination, adapting to a patient specific dosing regimen with follow-up plans, available literature, guidelines, and pending trials will be reviewed.

Session: Anticoagulation for patients with bleeding related conditions
Multispecies analysis of the ERAD pathway in platelet function
Anna Dahlgren

Atypical Equine Thrombasthenia (AET) is a heritable platelet disorder found in horses due to aberrant platelet signaling after thrombin stimulation, preventing platelets from fully activating or efficiently binding to fibrinogen, leading to prolonged bleeding. Despite the negative effects on horse health and racing performance, the underlying etiology of this disorder is unknown. The utilization of horse, zebrafish, mouse, and human cell culture models to identify the endoplasmic reticulum - associated protein degradation (ERAD) gene involved in the mechanism of AET will be discussed.

Session: Take a hike Mickey- novel T&H insights from non-murine animals
Rivaroxaban in Older Adults with Nonvalvular Atrial Fibrillation: Population-based Analysis in Response to Updated Beers Criteria
Ghadeer Dawwas1, Adam Cuker2
1Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA, 2Department of Medicine, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia , PA, USA

BACKGROUND Concerns have been raised regarding the updated Beers Criteria that recommended avoiding rivaroxaban use for long-term treatment of older adults with nonvalvular atrial fibrillation. We sought to compare the effectiveness and safety of rivaroxaban with other oral anticoagulants in elderly patients with nonvalvular atrial fibrillation. METHODS This was a retrospective new-user cohort study using MarketScan IBM commercial healthcare data in the United States from 1 January 2013 to 31 December 2021. We included patients 65 years or older at cohort entry, who had 12 months of continuous enrollment in medical and pharmacy benefits prior to their first eligible prescription and a diagnosis of atrial fibrillation prior to treatment initiation. We created three pairwise comparisons: a) rivaroxaban vs. warfarin; b) rivaroxaban vs. dabigatran; and c) rivaroxaban vs. apixaban. Our primary effectiveness outcome was a composite of ischemic stroke or systemic embolism defined using the principal position code of the International Classification of Diseases, Ninth and Tenth Revision. Our primary safety outcome was a composite of gastrointestinal or intracranial bleeding defined based on primary inpatient discharge diagnosis codes. Patients in the cohort were followed until the earliest of treatment discontinuation, switch to the comparator drug, outcome, last day of enrollment in health care benefits, or end of the study period. To adjust for potential baseline differences, we calculated propensity scores using logistic regression. Cox proportional hazards regression with a robust variance estimator was used to estimate hazard ratios [HRs] and 95% confidence intervals [CIs]. RESULTS We identified 70,678 patients who had received a prescription for rivaroxaban or warfarin (35,399 for each, comparison 1). In the matched sample, there was no difference between users of rivaroxaban and warfarin in the risk of stroke or systemic embolism (HR 0.89; 95% CI 0.79, 1.01) and bleeding (HR 1.07; 95% CI 0.98, 1.16). We identified 26,910 patients who had received a prescription for rivaroxaban or dabigatran (13,445 each, comparison 2). In the matched sample, there was no difference between users of rivaroxaban and dabigatran in the risk of stroke or systemic embolism (HR 0.92; 95% CI 0.80, 1.06). However, use of rivaroxaban was associated with a higher risk of bleeding compared with dabigatran (HR 1.20; 95% CI 1.06, 1.36). We identified 55,118 patients who had received a prescription for rivaroxaban or apixaban (27,559 each, comparison 3). In the matched sample, use of rivaroxaban compared with apixaban was associated with a higher risk of stroke or systemic embolism (HR 1.32; 95% CI 1.15, 1.52) and bleeding (HR 1.63; 95% CI 1.47, 1.80). CONCLUSION In this comparative effectiveness and safety study, older patients with nonvalvular atrial fibrillation who were new users of rivaroxaban had a higher risk of stroke or systemic embolism when compared with apixaban and bleeding when compared with apixaban or dabigatran. Although our results did not show potential benefits for rivaroxaban over other oral anticoagulants, the atrial fibrillation population is heterogeneous, and certain subgroups may potentially benefit from rivaroxaban.
Session: Posters/Exhibits/Break
Efficacy and Safety Is Maintained in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Receiving Pegcetacoplan for Up to 3 Years
Carlos de Castro1, Brian Mulherin2,3, Christopher J. Patriquin4, Veena Selvaratnam5, Raymond Siu Ming Wong6, Richard J. Kelly7, Lisa Tan8,9, Peter Hillmen10, Dale Zhang10, Regis Peffault de Latour11,12
1Duke University, Durham, NC, USA, 2Hematology Oncology of Indiana, Indianapolis, IN, USA, 3Ascension St. Vincent Carmel, Carmel, IN, USA, 4University Health Network, Toronto, ON, Canada, 5Ampang Hospital, Ampang, Malaysia, 6The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong, 7Department of Haematology, St. James’s University Hospital, Leeds, United Kingdom, 8Swedish Orphan Biovitrum AB, Stockholm, Sweden, 9Lisa Tan Pharma Consulting Ltd., Cambridge, United Kingdom, 10Apellis Pharmaceuticals, Inc., Waltham, MA, USA, 11French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France, 12Université Paris Cité, Paris, France

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease of complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first complement component 3-targeted therapy for PNH, increased hemoglobin (Hb) in adult patients with PNH from phase 3 trials who were either complement component 5 inhibitor (C5i)-experienced (PEGASUS [NCT03500549]) or -naive (PRINCE [NCT04085601]). Objectives: We evaluated long-term efficacy and safety of pegcetacoplan for PNH via an integrated analysis of data from PEGASUS, PRINCE, and the subsequent open-label extension study 307 (NCT03531255).

Methods: Patients received pegcetacoplan 1080 mg subcutaneously twice weekly, with dose escalations as permitted (e.g., once every 3 days or 3 times weekly). Efficacy was evaluated: Hb concentration, lactate dehydrogenase (LDH) concentration (upper limit of normal [ULN] 226 IU/L), absolute reticulocyte count (ARC), indirect bilirubin concentration, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and rates of transfusion avoidance (patients did not require a transfusion during treatment) from baseline (pegcetacoplan initiation) through Weeks 156 (3 years, PEGASUS) or 132 (2.5 years, PRINCE). Safety was assessed during pegcetacoplan monotherapy for up to 3 years and included adverse events (AEs), serious AEs (SAEs), and breakthrough hemolysis (BTH) (defined as reporting an AE of hemolytic disorder, LDH >2 × ULN, any prior LDH <1.5 × ULN, and median Hb decline of ≥2 g/dL).

Results: Of 133 patients (PEGASUS, n=80; PRINCE, n=53), 114 enrolled in study 307 (PEGASUS, n=64; PRINCE, n=50), of whom ≥75% had a transfusion in the year before initial enrollment. Prior to pegcetacoplan initiation, mean (standard deviation [SD]) Hb concentrations were 8.95 (1.09) g/dL (PEGASUS) and 9.27 (1.44) g/dL (PRINCE), median (interquartile range) LDH concentrations were 217.0 (184.8, 276.5) IU/L (PEGASUS) and 1964.0 (1409.0, 2503.3) IU/L (PRINCE), and mean (SD) FACIT-Fatigue scores were 31.6 (11.7) (PEGASUS) and 36.6 (10.0) (PRINCE). After pegcetacoplan initiation, mean Hb and median LDH concentrations (Figure 1) markedly improved and remained stable through Weeks 156 (PEGASUS) or 132 (PRINCE). Improvements in ARC and indirect bilirubin were similarly maintained. FACIT-Fatigue scores increased (indicating less fatigue) and were maintained near the population norm (43.6). Annual transfusion avoidance rates ranged from 71%-79% (PEGASUS) and 80%-86% (PRINCE) (Figure 2), with 52% avoiding transfusions for up to 3 years in PEGASUS and 67% for up to 2.5 years in PRINCE. Overall, >92% of patients had ≥95% compliance. Over 3 years, most patients experienced an AE, with SAEs reported in 50.0% of patients (deemed pegcetacoplan-related in 4.5%). Overall, 17 patients discontinued pegcetacoplan due to an AE: 9 due to a hemolytic disorder which occurred for most within 1 year (n=7). Over 3 years, 4 (3.0%) deaths occurred (none deemed pegcetacoplan-related) and 3 (2.3%) patients experienced a thrombotic event (in the context of multiple comorbidities or pegcetacoplan discontinuation); no meningitis cases were reported. Overall, 39 of 132 (29.5%) patients experienced BTH (PEGASUS, n=23/80 [28.8%]; PRINCE, n=16/52 [30.8%]). No new or unexpected safety findings were identified.

Conclusions: This analysis demonstrates rapid and sustained efficacy, reduced transfusion burden, and continued safety with long-term pegcetacoplan treatment of patients with PNH, regardless of prior C5i treatment.
Session: Short Talks - Industry Thrombosis - No CME
Reclassification of Antiphospholipid Antibody Syndrome According to the 2023 ACR/EULAR Guidance in a Pharmacist Directed Anticoagulation Clinic
Catherine DeFazio1, Lara Horvath1, Jennifer Morgan1, Meaghan Murphy1, Ashley Shtoyko1, Elizabeth Phillips2
1SUNY Upstate Medical University, Syracuse, NY, USA, 2St. John Fisher University, Wegmans School of Pharmacy, Rochester, NY, USA

Background: Antiphospholipid antibody syndrome (APS) is a complex medical condition that places patients at high risk for thrombosis and associated outcomes. Identifying patients with APS can be challenging as the diagnostic criteria includes clinical and laboratory components that have various nuances. Additionally, anticoagulation management in patients with APS is limited to warfarin, a high-risk medication that requires frequent monitoring and dose adjustments. In 2023, ACR/EULAR published updated APS classification criteria. These criteria highlight new considerations in the clinical and laboratory domains for classification of APS. A weighted value is assigned to each domain in order to classify a patient based on their lab results and clinical scenario, warranting review of current patient panels. Objectives: The primary objective was to determine the number of patients that met classification criteria for APS after applying the 2023 ACR/EULAR guidelines. The secondary objectives were to identify the reason patients did not meet criteria for APS according to the new guidance and to determine the number of patients who were single, double, or triple positive based on lab criteria.

Methods: This was a single center, retrospective chart review of patients with APS on anticoagulation actively managed by the ambulatory care clinical pharmacy team via collaborative drug therapy management agreements as of October 1st, 2023. The study was deemed exempt from the Upstate University Hospital Institutional Review Board. Data collected included patient demographics, type of anticoagulation, and clinical and laboratory criteria for APS as defined by the 2023 ACR/EULAR guidance. Data is presented using descriptive statistics.

Results: A total of 51 patients previously diagnosed with APS were included in the study. Of the 51 patients, 22 were male (43.1%) and 29 were female (56.8%). Ages ranged from 26 to 79 years old with an average age of 51 years old. There were 42 patients on warfarin (82.3%), four patients on direct oral anticoagulants (19%), three patients on low molecular weight heparin (5.8%), and two patients on fondaparinux (3.9%). Of the 51 patients, 11 (21.5%) met reclassification criteria, 27 did not meet reclassification criteria and 13 had insufficient data. Of the 27 patients that did not meet criteria, 12 patients did not meet the lab criteria (44.4%), five patients did not meet the clinical criteria (18.5%) and 10 patients did not meet both laboratory and clinical criteria (37%). Of the 11 patients that met reclassification criteria, one patient was triple positive (9%), three patients were double positive (27.2%), and seven patients were single positive (63.6%).

Conclusions: Results from this study indicate that APS continues to be a complex disease state with challenges in diagnosis and classification. Since only a small number of patients at our institution continued to meet the updated classification criteria for APS, opportunities for patient re-evaluation at other institutions should be considered. Based on the outcomes of this study, future directions include updating laboratory results to aid in interpretation and offering provider education series on the new APS classification criteria.
Session: Short Talks - Thrombosis - Special Populations
The anticoagulated trauma patient in the wilderness
Emma DeLoughery, Thomas DeLoughery
Oregon Health & Science University, Portland, OR, USA

Background: Anticoagulants carry the natural risk of bleeding, leading many patients to have questions about activity limitations, particularly recreational or wilderness activities. Although it would seem that such patients would be at higher risk for poor outcome there is little data to support this theory. Therefore, this study used data from the National Trauma Data Bank (NTDB), which provides trauma registry data from a variety of trauma centers around the United States, to analyze outcomes in the anticoagulated patient in the wilderness as compared to both their non-anticoagulated counterpart as well as the anticoagulated patient not in the wilderness.

Methods: Data was obtained from the NTDB. Cohorts were identified by a 'yes' to the comorbidity of anticoagulant therapy with the trauma taking place in a wilderness/recreational setting as defined by ICD-10 codes. Two separate groups were identified - one with controls composed of non-anticoagulated patients injured in a recreational/wilderness setting (A), and one with controls of anticoagulated patients injured in a non-recreational/wilderness setting (B). Both control groups were matched on age, sex, injury severity score (ISS), and several comorbidities. Outcome measures included emergency department (ED) and hospital disposition and length of stay.

Results: A total of 6411 anticoagulated trauma patients in the wilderness were found, along with 3152 in each A group and 3026 in each B group (Table 1). Cohort A had a lower ED mortality (0.1% cohort vs 0.3% control, P = 0.03) (Table 2). There was no difference in length of stay (4.9 vs 4.8 days, P = 0.4). There was no difference in hospital mortality (1.3% vs 1.1%, P = 0.38), discharge home from the hospital among survivors (73.1% vs 75.0%, P = 0.06), or discharge home from the ED (10.3% vs 9.0%, P = 0.09). Control B had increased ED mortality (0.1% vs 0.5%, P = 0.01) and increased hospital mortality (1.8% vs 5.1%, P <0.001). Cohort B had a shorter length of stay (5.0 vs 5.5 days, P <0.001). Cohort B had a higher rate of discharge home from the hospital (67.2% vs 52.6%, P <0.001). There was no difference in discharge home from the ED (10.1% vs 11.4%, P = 0.1).

Conclusions: This study showed similar mortality rates among anticoagulated and non-anticoagulated trauma patients in the wilderness, and lower mortality in anticoagulated patients in the wilderness compared with anticoagulated patients in other settings. Despite efforts to match for comorbidities, anticoagulated patients in the wilderness may be healthier than their non-wilderness counterparts. Limitations include use of registry data that may be incomplete, limited data availability, particularly in regards to transfusion and lab data, as well as inability to identify specific anticoagulants and possibility of inclusion of patients on anti-platelets as well as those not on anticoagulants but with bleeding disorders. Additionally, patients taking anticoagulants may avoid situations where injury is likely to occur. This study suggests that persons on anticoagulation are not at higher risk of mortality when engaging in wilderness or recreational activities though further studies are needed in this population to help better inform risk.
Session: Short Talks - Thrombosis - Innovations in AC
Efficacy of radiotherapy for hemostasis in tumor-related bleeding
Emma P. DeLoughery, Byron Wilson, Aaron Grossberg
Oregon Health & Science University, Portland, OR, USA

Introduction: Hemorrhage is a common complication of malignancy. Through invasion and angiogenesis, malignancies can produce highly vascular lesions with friable and disorganized vessels that are prone to bleeding. Bleeding symptoms are relatively common among patients with advanced cancer, and this can impact both the quality and quantity of life. Palliative radiotherapy (RT) has been associated with achieving hemostasis in a variety of bleeding malignancies, including gastric, bladder, lung, and gynecologic cancers. The goal of this study was to better determine the efficacy of radiotherapy in reducing transfusion requirements.

Methods: A retrospective chart review of patients was performed after IRB approval. Patients who received palliative radiation for controlling malignancy-associated hemorrhage were included in this study. The outcome measure was change in pRBC transfusion requirements from the month prior to the month following palliative RT. Data was obtained from the institution's electronic medical record. Change in pRBCs was analyzed using Welch's t-test and bleeding recurrence was analyzed using the exact test of goodness-of-fit.

Results: A total of 6002 patients were screened and 30 cases (63.3% female, average age at radiation treatment 62 years) were included in the study with RT treatment dates 2019-2023. Sixteen malignancy types were represented, with pancreatic adenocarcinoma and endometrial adenocarcinoma being the most common (both 4, 13.3%). Median radiation dose was 13 Gy (range 3-30) delivered over a median of 3.5 fractions (range 1-10). Bleeding was not noted to recur in 73.3% of the cases (P = 0.02). For those patients with recurrent bleeding, median time from RT to recurrent bleeding was 58 days (range 11-544). Transfusion requirements decreased from an average of 2.7 pRBC units over one month prior to completion of RT to 1.1 units for the month following completion of RT (P = 0.03). Median survival after completion of RT was 132 days (range 3-698). Conclusion: This study showed that radiation therapy resulted in apparent cessation of hemorrhage in over 70% of cases of hemorrhagic malignancies with a significant decrease in pRBC transfusion requirements over one month. This suggests that RT is effective in stopping hemorrhage in a variety of malignancies as well as reducing transfusion requirements. More work is needed to test this hypothesis on larger populations, as well as investigation on the mechanism by which RT results in hemostasis.
Session: Short Talks - Complications of Disease and Therapy in H&T
Platelet indices in healthy pregnancies
Laura M. Dionisio, Giovani M. Favero
State University of Ponta Grossa, Ponta Grossa, Brazil

Background: Platelet abnormalities can affect its hemostatic and non-hemostatic roles, and lead to complications during pregnancy and postpartum. Platelet indices are easily measured by hematology analyzers from a wide number of manufacturers. These indices have been studied in numerous pregnancy-related conditions like premature delivery, gestational diabetes, preeclampsia, ectopic pregnancy, and intrauterine growth restriction Considering the physiological changes in platelets during healthy and pathologic pregnancies, and the potential clinical use of these parameters, it is needed to fully comprehend how these changes affect the platelet indices in pregnant patients. Objectives: This study aimed to establish reference values for platelet indices in healthy pregnant and non-pregnant Brazilian women and to evaluate the differences between the trimesters and between pregnant and non-pregnant women.

Methods: 2mL of venous blood samples were collected into EDTA-K-2 tubes and tested for whole blood count using the Sysmex XN1000 hematology analyzer. All healthy pregnant women with no adverse medical or obstetric history were recruited. The non-pregnant women were healthy adult volunteers. The parameters included were: impedance platelet count (PLT-I), fluorescence platelet count (PLT-F), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR) and immature platelet fraction (IPF%). All statistical calculations were performed with R (3.6.1). As the data showed a non-normal distribution, reference intervals were calculated using a nonparametric method for lower and upper reference limits as 2.5% and 97.5% of the reference distribution. The significance of between-group differences was tested by Mann-Whitney and Kruskal-Wallis tests. Statistical significance was set to P <0.05.

Results: 240 women (120 non-pregnant and 120 pregnant) were enrolled in this study. For the pregnant group, there were 25 patients in the first trimester, 49 in the second, and 46 in the third. We obtained reference intervals for the platelet indices for pregnant and non-pregnant women. (Figure 1). The platelet count (PLT-I and PLT-F) and PCT were lower (p<0.001) for the pregnant women. Between-trimesters comparison showed significant differences only for PLT-I (p= 0.0134) and PLT-F (p=0.0271). Discussion: Both healthy and pathologic pregnancies are characterized by marked modifications of physiological functions, including hemostasis and therefore platelets. The reduced platelet counts in pregnant women are some of the most frequent alterations in hemostasis during normal pregnancies, mainly in the third trimester. These modifications in hemostasis are consequences of physiological hormonal changes as a part of an adaptation process. Also, the lower platelet counts in pregnancy are attributed to increased platelet turnover and hemodilution. Our study reported a gradual reduction in platelet count from the first to the third trimester, which was described previously. Although normal pregnancy is associated with increased platelet turnover, the parameters associated with platelet activation and production MPV, PDW, P-LCR, IPF % were not increased in the pregnant group. Indeed, platelet activation in normal pregnancies remains controversial, possibly due to the diversity of biomarkers to assess platelet activation. Conclusion: Considering the differences between pregnant and non-pregnant and the physiological changes in hemostasis during pregnancy, pregnancy-specific reference ranges for platelet parameters are essential for adequate clinical interpretation.
Session: Posters/Exhibits/Break
The Prevalence of Thrombotic Events Reported Following SARS-Cov2 Vaccine Receipt: Data from The ITP Natural History Study Registry
Jennifer DiRaimo1, Caroline Kruse1, Kate Foster1, Alexandra Kruse1,2, Howard Liebman3, Craig Kessler4
1Platelet Disorder Support Association, Cleveland, OH, USA, 2Tulane University School of Medicine, New Orleans, LA, USA, 3Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 4Vincent Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

Background: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder that affects all races and ages causing a low platelet count with increased bleeding risks, and an increased risk for thrombosis. The use of thrombopoietin receptor agonists (TPO-RA) for the treatment of ITP has also been associated with a risk of thrombosis due to stimulation of platelets and other hemostatic agents. Thrombotic events have also been reported following SARS-CoV2 infection and administration of related vaccines. Objectives: We sought to understand the prevalence of thrombotic events reported in the ITP Natural History Study Registry following a COVID-19 vaccine dose.

Methods: Prospective data was collected using responses from three surveys within the ITP Natural History Study Registry up to September 27, 2023. Children and adults with ITP were included upon completion of all three registry surveys. This cohort was divided into clotting and non-clotting patients and was analyzed with descriptive statistics and Fischer's exact test.

Results: The study included 695 participants; 667 were adults (ages 18-87 years), and 28 were children (ages 1-17 years). 8 adults (1%) reported a thrombotic event following administration of a COVID-19 vaccine. Three participants reporting a thrombotic event disclosed the dose and vaccine manufacturer associated with the event: Pfizer vaccine (3rd dose), Moderna (2nd dose, and Pfizer (4th dose). Three of the eight participants who reported thrombosis reported having a personal history of blood clots. One participant in the clotting group reported having surgery three months before developing a thrombosis. Participants were an average age of 56 years in the clotting group (n=8) vs. 47 years in the non-clotting group (n=687). Most of the cohort was female (62% and 75%), with a primary diagnosis of ITP (87% and 99%). The clotting group mostly had a BMI greater than 35 (75%) vs. 21% in the non-clotting group. None of the clotting patients had another autoimmune disease; 9% of the non-clotting patients did, the most common being lupus. Half the clotting patients were asplenic vs. 27% of the non-clotting group. The clotting group had a higher splenectomy rate (p=0.071) and was more likely to have a BMI of 35 or greater (p=0.0325). Regarding treatment, 37% of the clotting group received a TPO-RA within the last 6 months vs. 18% in the non-clotting group. Conclusion: Thrombotic events reported following receipt of a SARS-CoV2 vaccine dose are uncommon among individuals with ITP in our registry. Some participants who reported thrombosis also had a history of thrombosis or other risk factors. Future studies should look into the impact of other vaccinations and medications (such as statins) that could be impacting thrombotic risk, not assessed in this study. Particularly, whether receiving more than one vaccine at once impacts thrombotic risk. These results should serve as an additional reassurance to the ITP community that COVID-19 vaccines are safe, and the risk for a thrombotic event is greater for ITP patients who struggle with obesity and had a splenectomy. Such individuals should be monitored more closely with newly updated vaccines as their thrombotic potential is unknown.
Session: Online Poster Session
Engineering devices to measure and/or enhance fibrinolysis
Dante Disharoon

Detection of Hemostatic Impairment Caused by Platelet Number and Function Defects using Platelet-specific Dielectric Coagulometry

Dante Disharoon1 PhD, Sina Pourang2 MS, Christopher A. Delianides2 MS, Sanjay P. Ahuja3 MD, Michael A. Suster2 PhD, Matthew D. Neal4 MD, Pedram Mohseni1,2 PhD, Anirban Sen Gupta1 PhD

1Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH

2Department of Electrical, Computer, and Systems Engineering, Case Western Reserve University, Cleveland, OH

3Division of Pediatric Hematology/Oncology, Rainbow Babies and Children's Hospital, Cleveland, OH

4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA

Background: Platelets play a central role in hemostasis. Deficiencies in platelet number or function are associated with significant bleeding risk. Platelet transfusions are used to mitigate such risks, but current transfusion is guided only by platelet count, with no correlation to hemostatic function. Methods like aggregometry can only assess platelet aggregation capability, but is not predictive of hemostasis. Viscoelastometry can characterize overall clot kinetics and stability, but has low sensitivity to platelet-specific defects. Technologies that can provide distinct correlation of hemostatic status associated with platelet defects can be clinically important.

Aims: We investigated a dielectric coagulometer with sensitivity to platelet number and function defects that is predictive of compromised hemostasis.

Methods: We manufactured microfluidic coagulometers with gold electrodes to characterize whole blood coagulability using dielectric spectroscopy. For platelet-sensitivity, the electrodes were coated with thrombin receptor activating peptide 6 (TRAP-6). Healthy donor blood was modified in vitro to recapitulate platelet number defects (by depleting platelets) or platelet function defects (using platelet inhibitors), and tested on TRAP-6-coated electrodes to establish coagulometry readout signatures. Finally, clinical samples obtained through an IRB-approved protocol were used to validate the platelet-relevant signatures.



Results:
The coagulometer provides two parameters, Tpeak (clotting kinetics), and Δεr,max (clot firmness). Compared to healthy control, Tpeak was prolonged in blood with <50,000 platelets/µL, and Δεr,max was reduced at 100,000 platelets/µL. Δεr,max was also compromised with platelet GPIIb/IIIa inhibition and Tpeak was impaired with platelet PAR-1 inhibition. In patient samples, coagulometry showed impairment in both Tpeak and Δεr,max in severe thrombocytopenia, but only Δεr,max was significantly affected in moderate thrombocytopenia.

Conclusion: We developed a dielectric coagulometry assay sensitive to platelet number and function defects that can inform on functional hemostatic status. Translational advancement of this technology could provide a unique diagnostic modality to guide platelet transfusions.

Session: Cutting to the chase- Fibrinolysis
Apixaban and Rivaroxaban Versus Warfarin as Atrial Fibrillation or Venous Thromboembolism Treatment in Severely Obese Patients: A Multicenter Retrospective Analysis
Paul Dobry1,2, Stephanie Edwin1, Susan Szpunar3, Christopher Giuliano1,2
1Department of Pharmacy, Ascension St. John Hospital, Detroit, MI, USA, 2Department of Pharmacy Practice, Wayne State University, Detroit, MI, USA, 3Department of Medical Education, Ascension St. John Hospital, Detroit, MI, USA

Background: Factor Xa inhibitors such as apixaban and rivaroxaban have emerged as first line agents to treat both non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Obesity is an independent risk factor for both NVAF and VTE, and as the prevalence of obesity continues to rise, the need for data corroborating the safe and effective use of factor Xa inhibitors in this population persists. In particular, there are a paucity of data surrounding the use of factor Xa inhibitors in severely obese patients with a weight ≥ 150kg or BMI ≥ 50 kg/m2. Objectives: The purpose of this study is to evaluate whether factor Xa inhibitors are as safe and effective as warfarin for the treatment of NVAF and/or VTE in individuals with a BMI ≥ 50 kg/m2 and/or weight ≥ 150 kg.

Methods:
This was a multicenter retrospective cohort study of severely obese adult patients diagnosed with NVAF and/or VTE and treated with a factor Xa inhibitor (apixaban or rivaroxaban) or warfarin between January 1, 2012 and December 31, 2022. Patients were identified through two pre-existing databases collectively comprised of data from 7 different health systems. The primary efficacy outcome was odds of stroke / systemic embolism within 12 months and the primary safety outcome was odds of major bleeding within 12 months. Secondary outcomes included incidence of stroke / systemic embolism, major bleeding, VTE, clinically relevant non-major bleeding, all-cause mortality, change in anticoagulation and total number of hospital encounters.

Results:
A total of 1,736 patients were included in the final analysis; 1,073 in the warfarin group and 663 in the factor Xa inhibitor group (349 apixaban and 314 rivaroxaban). The mean weight and BMI of the overall cohort was 164.4 kg and 54.6 kg/m2, respectively. There was no difference in odds of stroke or systemic embolism (OR 0.79, 95% CI 0.37 - 1.67) or major bleeding (OR 0.9, 95% CI 0.47 - 1.7) with warfarin compared to factor Xa inhibitors after controlling for covariates. Similar results were observed in the propensity matched sensitivity analysis.

Conclusions:
This analysis of real-world data suggests that apixaban and rivaroxaban are safe and effective alternatives to warfarin for the treatment of NVAF and/or VTE in individuals with a BMI ≥ 50 kg/m2 and/or weight ≥ 150 kg.
Session: Short Talks - Thrombosis - Innovations in AC
Perioperative considerations for anticoagulation with mechanical devices and heart valves
James Douketis

Summary of Presentation Objectives

After this presentation, the audience will be able to:

1. Understand the essential components in the overall management of anticoagulated patients who need a surgery/procedure,

2. Have a guideline-informed approach to managing patients who are receiving a VKA for a mechanical heart valve and need an elective surgery/procedure,

3. Have a guideline-informed approach to managing patients who are receiving a VKA of DOAC and need a cardiac device procedure.

Session: Clinical Challenges for Antithrombotic Management in the Ambulatory Care setting
Platelet-nucleic acid receptor promotes pulmonary thrombo-inflammation in sickle cell disease
Rikesh K. Dubey1, Omika Katoch1, Prithu Sundd1,2
1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA, 2Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

Background: Acute chest syndrome (ACS), a type of acute lung injury is one of the primary reasons for mortality among Sickle Cell Disease (SCD) patients. Although new evidence suggests that circulating neutrophil extracellular traps (cNETs) promote lung injury in SCD by triggering occlusion of pulmonary arterioles by neutrophil-platelet thrombo-inflammatory aggregates, the molecular mechanism underlying cNETs-dependent lung vaso-occlusion remains unknown. Objective: Platelets are one of the few cell types that express Toll-like receptor 9 (TLR9), a receptor for double-stranded DNA on the surface (rather than in endosomes), however, the role of platelet-TLR9 in promoting pulmonary thrombo-inflammation in SCD has never been studied.

Methods:
Intravital (in vivo) lung microscopy in live SCD mice and imaging flow cytometry (in vitro) of SCD mice plasma were done for measuring lung vaso-occlusion and expression of TLR9 on platelets respectively. Function blocking TLR9 antibody were administered in SCD mice via IV route and performed intravital lung imaging to measure lung vaso-occlusion size and number and its percentage. Western blotting of TLR9, TBK1 and IRF3 were performed on human SCD platelets.

Results:
Using intravital (in vivo) lung microscopy in live SCD mice and imaging flow cytometry (in vitro) of SCD mice plasma, we show for the first time that lung vaso-occlusion and elevated levels of cNETs in knock-in humanized SCD mice challenged with 10 μmol/kg oxy-hemoglobin (oxy-Hb) is associated with significant upregulation of TLR9 surface expression in platelets. Importantly, TLR9 inhibition using a function blocking Ab led to significant reduction by ~6 and ~4 fold in the frequency and size of lung vaso-occlusions in SCD mice challenged with IV oxy-Hb. Identical to SCD mice, TLR9 surface expression was also significantly higher in SCD than control human platelets, and the expression was further upregulated following treatment of SCD patient platelet-rich-plasma (PRP) with oxy-Hb. Remarkably, elevated TLR9 expression in SCD patient platelets was concomitant to increased phosphorylation of both downstream TLR9 pathway effector tank-binding-kinase-1 (TBK-1) and the TBK-1 substrate interferon regulatory factor-3 (IRF3), which is the major transcription factor driving IFN-1 response.

Conclusions:
Our current findings suggest for the first time that activation of nucleic acid receptor TLR9 on the surface of platelets by cNETs contributes to lung vaso-occlusion and acute chest syndrome in SCD.
Session: Posters/Exhibits/Break
Long-term evaluation of liver health in participants who received fidanacogene elaparvovec: Data from a phase 1/2a study with up to 6 years of follow up
Jonathan Ducore1, Lindsey A George2, Ben J Samelson-Jones2, John Rasko3, Catherine McGuinn4, Adam Giermasz1, Jerome Teitel5, Katherine High6, Jeremy Rupon7, Annie Fang7, Lynne Smith7, Priya Patel7, Amit Chhabra7, Frank Plonski7, Matko Kalac7
1UC David Comprehensive Cancer Center, Sacramento, CA, USA, 2Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 3Centenary Institute, Sydney, Australia, 4Weill Cornell Medical Center, New York, NY, USA, 5University of Toronto, Toronto, ON, Canada, 6University of Pennsylvania, Philadelphia, PA, USA, 7Pfizer Inc, New York, NY, USA

Background: Fidanacogene elaparvovec is an adeno-associated virus (AAV) gene therapy for the treatment of hemophilia B (HB) (1, 2). The bioengineered capsid targets hepatocytes necessitating long-term assessment of liver health. Objectives: To evaluate the liver health of recipients of fidancogene elaparvovec as part of the 1-year ph1/2a study (NCT02484092) and 5-year long-term follow-up (LTFU) study (NCT03307980). Methods: Adult male (≥18 years) hemophilia B (FIX activity ≤2%) participants received fidanacogene elaparvovec at a dose of 5 × 1011 vector genomes vg/kg. Participants with a history of hepatitis C (HCV) and/or hepatitis B (HBV) virus infections, or HIV were eligible if health parameters were met. Liver health assessments included periodic liver ultrasound and laboratory evaluations including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alpha fetoprotein assessed at baseline and at scheduled intervals. The cutoff date for the current analysis was August 15, 2023. Results: Fifteen participants were dosed and completed 1 year of follow-up with fourteen entering the LTFU. At data cutoff, individual participant follow-up ranged from 3-6 years and 7 participants completed 6 years following vector administration. In the LTFU study 7 out of 14 participants (50%) have a history of HBV, 10 (71%) have a history of HCV, and 7 (50%) have a history of both HBV and HCV; 2 participants (14%) have HIV. Fidanacogene elaparvovec has been generally well tolerated and the safety profile observed in the LTFU study was consistent with that in the phase 1/2a study (1). Serious Adverse Events (SAEs) were reported in 4 participants; none were considered to be treatment related. Asymptomatic liver abnormalities were noted by liver US in 6 individuals with the most common finding of steatosis in 4 participants, all with BMI >25. Mean ALT for the group remained in the normal range though as shown in Figure 1a, some values >ULN occurred predominantly in participants developing steatosis. There was no clear relationship between HCV, HBV and HIV status with ALT elevation. LFTs of the 3 participants treated with corticosteroids for ALT elevations during the first year (Figure 1b) were within normal limit over time with the exception of participant 7 who notably developed steatosis during the study. No liver masses were detected. Despite the appearance of asymptomatic changes in ALT and liver ultrasound over time, FIX levels and ABR remained stable throughout the duration of follow-up. Conclusions: Fidanacogene elaparvovec was generally well tolerated in HB participants on these studies. Long-term follow-up (up to 6 years) suggests stable long-term liver health. The finding of hepatic steatosis was unexpected and relationship to treatment is not known at this time. As assessed by FIX levels and ABR, participants have had clinical benefit throughout the duration of the study. The phase 3 study (NCT03861273) is ongoing to assess safety and efficacy in a larger cohort of participants. References 1. George LA, et al. N Engl J Med. 2017;377:2215-27. 2. Peyvandi F, Garagiola I. Haemophilia. 2019;25:738-46.
Session: Posters/Exhibits/Break
Using a thrombodynamics test for diagnostics of hypercoagulation in cancer patients and prediction of thromboembolic complications: preliminary research results.
Irina Dudina1, Ekaterina Koltsova2,3, Irina Nigmatullina1, Yana Akhmadiyarova1, Olga Kostash1, Anna Chankina1, Daniil Stroyakovskiy1
1State Budgetary Healthcare Institution Moscow City Oncology Hospital No. 62 of the Moscow City Health Department, Russian Federation, Moscow, 143515, Moskovskaya area, Krasnogorsk urban district, Istra village, building 27, Moscow, Russia, 2Federal State Budgetary Institution Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Health of the Russian Federation, Russian Federation, Moscow, 117198, Samory Machel street, building 1, Moscow, Russia, 3Federal State Budgetary Institution of Science Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Russian Federation, Moscow, 109029, Srednyaya Kalitnikovskaya street, building 30, Moscow, Russia

Background. Venous thromboembolism complications (VTE) are the second most common cause of death in cancer patients. The Khorana score is used for risk stratification of VTE complications, although its sensitivity, according to world literature, is only 22% while its specificity is 82%. Objectives. This article presents preliminary results of a monocentric observational study which was aimed at the assessment of the effectiveness of a global hemostasis test, thrombodynamics, for the diagnostics of hypercoagulation in cancer patients and prediction of VTE complications. Methods. The interim analysis included 269 patients. The observation median value was 4.3 months. Blood tests for thrombodynamics were conducted using a thrombodynamics analyser (ООО HemaCore, Russia). The statistical analysis was conducted using the Mann-Whitney U test (unconjugated samples) and the Wilcoxon signed-rank test (conjugated samples). The results were considered significant with р<0.05. ROC analysis was used to assess the sensitivity of the thrombodynamics test results. Results. Blood coagulation in oncological patients was characterised by the presence of pronounced hypercoagulation in 90% of the patients, according to the test results. The median number of study points (blood sampling for thrombodynamics analysis) was 6 (1-38), the median follow-up period was 4.3 months. According to the parameters of thrombodynamics it was concluded that the parameter Tlag, characterizing the starting phase of clot growth, was within the normal range in the majority of patients, while the velocity parameters of thrombodynamics Vi and V were shifted towards hypercoagulation in 80-90% of patients included in the study. Moreover, the severity of hypercoagulability by Vi and V parameters statistically significantly decreased from 1 blood collection, which corresponded to the 1st course of chemotherapy, to the 5th blood collection - in 2.5-3 months from the beginning of chemotherapy. Also, 36-61% of the observed hypercoagulability was accompanied by the formation of spontaneous clots. Once the antineoplastic therapy was initiated, hypercoagulation tended to decrease. With a median value of 4.3 months, hypercoagulation resulted in VTE complications in 14% of patients. The Khorana score points were not reliable in this patient cohort. ROC analysis of the thrombodynamics data showed that the parameter value of V higher than 40.7 µm/min is an accurate predictor of a thromboembolic event allowing to classify groups with sensitivity of 60% and specificity of 78%. A relative risk of thrombosis calculated using this cut-off was 2.7 (95%CI 1.6-4.7; p<0.001). Conclusion. Thrombodynamics is a promising method for predicting VTE complications. This method has demonstrated higher sensitivity (60%) and almost similar specificity (78%) as compared to the Khorana score. Using this test in clinical practice allows identifying a group of patients who have a high risk of VTE complications and are in need of a preventive anticoagulant therapy while their Khorana score points are not high. Key words: thromboembolism complications, cancer, thrombodynamics, Khorana score
Session: Online Poster Session
Rebleed Incidence with Eptacog Beta Treatment through 24 and 48 Hours in Children (under 12 years) with Hemophilia A or B with Inhibitors
Amy L. Dunn1, Manuel Carcao2, Meera Chitlur3, Joanna Davis4, Nina Hwang5, Craig Kessler6, Catherine McGuinn7, Danielle Nance8, Robert Sidonio Jr.9, Tammuella Chrisentery-Singleton10, Courtney D. Thornburg11,12, Michael Wang13, Steven Pipe14
1Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH, USA, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Central Michigan University College of Medicine/Children’s Hospital of Michigan, Carmen and Ann Adams Department of Pediatrics, Division of Hematology/Oncology, Detroit, MI, USA, 4Pediatric Hemophilia Treatment Center, University of Miami, Miami, FL, USA, 5Center for Inherited Blood Disorders, Orange, CA, USA, 6Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA, 7Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA, 8Banner MD Anderson Cancer Center, Gilbert, AZ, USA, 9Aflac Cancer and Blood Disorders Center and Emory University, Atlanta, GA, USA, 10American Thrombosis and Hemostasis Network, Rochester, NY, USA, 11Hemophilia and Thrombosis Treatment Center, Rady Children's Hospital-San Diego, San Diego, CA, USA, 12Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA, 13Hemophilia and Thrombosis Center, University of Colorado, Aurora, CO, USA, 14University of Michigan, Ann Arbor, MI, USA

Background: Following a period of initial bleed control, persons with hemophilia A or B and inhibitors (PwHABI) may experience rebleeding and continued treatment. Eptacog beta is a recombinant activated human factor VII approved in the US and Mexico (SEVENFACT®), as well as in the EU and UK (CEVENFACTA®) for the treatment of bleeding episodes (BEs) in PwHABI ≥12 years using two initial dose regimens (IDRs) of 75 or 225µg/kg. In the EU and UK, eptacog beta is also indicated for preventing bleeding in the setting of surgery and invasive procedures. Eptacog beta has not been approved for the treatment of pediatric patients (<12 years) by both the FDA and EMA/UK. The pivotal PERSEPT1 trial (NCT02020369) with 27 adolescent and adult PwHABI experiencing 465 mild or moderate (M/M) BEs, not limb- or life-threatening, demonstrated bleed resolution of 96.7% and 99.5% in the 75 and 225µg/kg IDRs, respectively, at 24 hours post-initial infusion. In PERSEPT1, a single bleed recurrence was observed before 24 hours. PERSEPT2 (NCT02448680) demonstrated bleed resolutions at 24 hours of 97.4% and 98.0% for 75 and 225µg/kg IDRs, respectively, in 25 PwHABI 1-11 years of age (median age: 5 years) who treated 546 M/M BEs. Objective: To evaluate rebleed incidence in PwHABI <12 years in PERSEPT2 when treating M/M BEs with eptacog beta at 24 and 48 hours post-initial dose. Methods: PwHABI in PERSEPT2 were randomized upon enrollment to treat M/M BEs using either 75µg/kg IDR (an initial 75µg/kg eptacog beta dose followed by 75µg/kg q3h as needed) or 225µg/kg IDR (an initial 225µg/kg dose followed after 9 hours by 75µg/kg q3h as needed), and crossed over to the alternate IDR every 3 months. No PERSEPT2 subjects were using prophylaxis. BE treatment success at a given timepoint was assessed by the patient or caregiver and defined by a hemostasis evaluation of "excellent" or "good" (on a 4-point scale), no additional eptacog beta being infused, no alternative hemostatic agents or blood products being used, and no increase in pain following the first "excellent" or "good" assessment. A BE was considered a rebleed if occurring at the same anatomical location as an original bleed for which all treatment success criteria had been initially met, and occurring within 24 or 48 hours of the initial infusion for that original bleed. Results: Among the 546 M/M BEs treated with eptacog beta, 9 rebleeds occurred among 4 subjects within 24 hours, and 13 rebleeds occurred among 6 subjects within 48 hours. The rebleed incidence through 24 hours was 1.3% for the 75µg/kg IDR and 2.0% for the 225µg/kg IDR. Rebleed incidence through 48 hours for the 75 and 225µg/kg IDRs were 2.1% and 2.6%, respectively. Differences in rebleed incidence between the two IDRs were not statistically significant at either timepoint (Figure 1). The overall rebleed incidence in PERSEPT2 was 1.6% through 24 hours and 2.4% through 48 hours.

Conclusions:
BE treatment using either eptacog beta IDR led to low rebleeding incidence (<3%) through 24 and 48 hours in PwHABI <12 years during PERSEPT2.
Session: Posters/Exhibits/Break
Incidence of Gastrointestinal Bleeding in High-Risk Cardiovascular Patients Taking Antithrombotic Medications with Proton Pump Inhibitors
Mark Edwards1, Xiaowen Kong1, Jacob Kurlander1, Scott Kaatz2, James B Froehlich1, Twylla Tassava3, Christopher Giuliano4, Geoffrey D Barnes1
1University of Michigan-Michigan Medicine, Ann Arbor, MI, USA, 2Henry Ford Health- Division of Hospital Medicine, Detroit, MI, USA, 3Trinity Health-Ann Arbor, Ann Arbor, MI, USA, 4Ascension- St. John Hospital, Detroit, MI, USA

Background: Individuals who use concurrent anticoagulant and antiplatelet (APT) medications are at increased risk for gastrointestinal (GI) bleeding. It is unclear if the addition of a proton pump inhibitor (PPI) can reduce the risk of a first GI bleed among patients treated with direct oral anticoagulants (DOAC) also taking APT. Objectives: The primary objective was to assess whether the incorporation of PPIs contributed to a reduced risk of experiencing a first gastrointestinal bleeding event among patients taking DOAC and APT.

Methods: Medical record data from four centers participating in the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry was reviewed for patients prescribed a DOAC plus APT at baseline. Patients were excluded if they used non-treatment doses of a DOAC, had less than 6 months of follow up, or had prior GI bleeding. Two groups were identified for comparative analysis, (1) the DOAC and APT group (N=1172) and (2) the DOAC and APT + PPI group (N=601). Inverse probability of treatment weighting was used to adjust for baseline differences, and time-to-first-event analysis was conducted on the weighted populations.

Results: During follow up, there were 216 GI bleeding events, 75 major GI bleeding events, 113 emergency department visits for GI bleeding, and 108 hospitalizations for GI bleeding. Patient demographics were analyzed for two groups: one receiving DOAC and APT (N=1172) and the other receiving DOAC, APT, and PPI (N=601). The groups were comparable in terms of age, gender, BMI, and comorbidities. After adjustment, there was no statistically significant difference in the time to first GI bleeding or other GI bleeding related outcome. Conclusion: The use of a PPI was not associated with a reduced risk of GI bleeding in this retrospective analysis. Randomized trials are needed to determine if PPI therapy can reduce GI bleeding risk in this population.
Session: Posters/Exhibits/Break
Hemostatic outcome of surgical procedures in patients with hemophilia receiving concizumab prophylaxis: data from the phase 3 explorer7 and explorer8 trials
Matthew Evans1, Anthony K.C. Chan2, Chris Barnes3, Mary Mathias4, Silvia Linari5, Francisco-José López-Jaime6, Lone Hvitfeldt Poulsen7, Julien Bovet8, Jan Odgaard-Jensen8, Tadashi Matsushita9, Emily K. Waters10
1Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA, 2McMaster Children’s Hospital, McMaster Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada, 3Royal Children’s Hospital Melbourne, Victoria, Australia, 4Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, 5Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy, 6Hospital Regional Universitario de Málaga, Málaga, Spain, 7The Haemophilia Centre, Department of Haematology, Aarhus University Hospital, Aarhus, Denmark, 8Novo Nordisk A/S, Søborg, Denmark, 9Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan, 10Novo Nordisk Inc., Plainsboro, NJ, USA

Background: Concizumab, a monoclonal antibody targeting the tissue factor pathway inhibitor, has been developed for once-daily subcutaneous prophylactic treatment of hemophilia A (HA) and hemophilia B (HB) with and without inhibitors. The safety and efficacy of concizumab prophylaxis was investigated in the phase 3 explorer7 (NCT04083781; patients with hemophilia A or B with inhibitors [HAwI/HBwI]) and explorer8 (NCT04082429; patients with HA or HB without inhibitors) trials. Objectives: To detail the hemostatic outcomes related to minor surgical procedures performed on patients with HA and HB with and without inhibitors who received concizumab prophylaxis in the explorer7 and explorer8 trials.

Methods: Based on their prior treatment regimen, patients enrolled in explorer7 and explorer8 were exposed to no prophylaxis (arm 1) or concizumab prophylaxis (arms 2-4). After completing the main part of the trials, patients from any arm could continue in the trial extension, during which they received concizumab prophylaxis. Ethics committee approvals and informed consent were obtained where appropriate. Minor surgical procedures were permitted during both trials; these were defined as any invasive operative procedure in which only the skin, mucus membranes, or superficial connective tissue were manipulated. Planned major surgery was not permitted, and a concizumab pause was recommended for acute major surgery cases. Local or topical use of antifibrinolytics was permitted during surgical procedures, and patients undergoing minor surgical procedures continued to receive concizumab prophylaxis perioperatively with no change in dosage.

Results: In total, 278 patients in the explorer7 and explorer8 trials received concizumab prophylaxis. Of these, 30 patients underwent a minor surgical procedure, including 6 adolescents (20.0%), aged 12 to 17 years, and 24 adults (80.0%), aged 18 to 64 years. Within this group, 9 (30.0%) had HA, 10 (33.3%) had HB, 7 (23.3%) had HAwI, and 4 (13.3%) had HBwI. The most common minor surgeries were dental procedures (n=24); other minor surgeries included port removal, colonoscopy, arthrodesis, and urethral augmentation. Fifteen bleeding episodes were reported in 14 of 38 minor surgical procedures; 8 episodes required hemostatic intervention. Fourteen of the 15 bleeding episodes were classified as mild or moderate. The median duration of minor surgery-related bleeding was 2 days, and the mean (SD) number of factor product injections required to treat these bleeds was 1.5 (0.8). Of the 14 reported bleeds, 12 were related to dental surgical procedures, 1 was related to port removal, and 1 was related to venesection.

Conclusions: Approximately 11% of patients who received concizumab treatment during the explorer7 and explorer8 trials underwent minor surgical procedures. Most minor surgeries were dental procedures, and most surgery-related bleeding episodes were characterized as mild or moderate. These data indicate that minor surgeries can be conducted safely during treatment with concizumab.
Session: Posters/Exhibits/Break
Accuracy of a Warfarin Clinical Dosing Algorithm Enriched with Genetic Information Compared to the Use of Clinical Algorithm
Amr Fahmi1, Ahmed El Bardissy1, Mohamed Saad1, Mohamed Nabil1, Loulia Bader2, Mohamed Kassem1, Ahmed Mahfouz1, Hazem Elewa2
1Hamad Medical Corporation, Doha, Qatar, 2College of Pharmacy, QU Health, Qatar University, Doha, Qatar

Background: Genetic and clinical factors play an important role in warfarin dosing. This is especially important during the initiation phase. Previous research concluded that VKORC1 −1639 G>A (rs9923231), CYP2C9*2 (rs1799853) and *3 (rs1057910) and CYP4F2*3 (rs2108622) could explain more than 40 % of the warfarin dose. On the other hand, clinical factors alone explains 10% of the warfarin dose. A parameter that is widely accepted to evaluate warfarin dosing algorithms is the mean absolute error (MAE) which is the difference between the predicted warfarin dose and the actual dose. Objectives: To identify the impact of CYP2C9*2, *3, VKORC1−1639 G>A and CYP4F2*3 on warfarin dose in an Arab population of mixed nationalities; and to compare the mean absolute error of Gage et al. algorithm when using clinical+genetic factors versus using clinical factors alone.

Methods: A cohort of Arab patients newly started on warfarin had their dose calculated using Gage et al. clinical algorithm as published in www.warfarindosing.org . Each patient provided a saliva sample using Oragene Kits. DNA was extracted and samples were genotyped for rs9923231, rs1799853, rs1057910 and rs2108622. Association between genetic variants in VKORC1, CYP2C9, and CYP4F2 and the achieved maintenance dose was tested. MAE was compared between the clinical+genetic and clinical algorithm alone.

Results: In our preliminary results, 118 subjects from 12 Arabic countries were recruited. VKORC−1639 G>A, CYP2C9*2, CYP2C9*3 and CYP4F2*3 had a minor allele frequency (MAF) of 0.4, 0.09, 0.07 and 0.35 respectively. Compared to wild type subjects (*1), those with reduced function alleles (*2 or *3) in CYP2C9 required significantly lower warfarin dose (5.6 ± 2.8 mg Vs. 3.7 ± 1.6 mg, p<0.001). With regards to VKORC gene, patients who had the AA allele required significantly lower dose of warfarin compared to those with the AG allele (3.3 ± 1.3 mg Vs. 7.1 ± 3.2 mg, p<0.001), or GG allele (3.3 ± 1.3 mg Vs. 4.7 ± 2.1 mg, p=0.027). CYP4F2 on the other hand had no significant impact on warfarin dose. Dose prediction using the genetic+clinical factors was more accurate compared to the clinical factors alone as shown by lower MAE [1.3 ± 1 mg Vs. 1.9 ± 1.3 mg, p<0.001]. Conclusion: CYP2C9 and VKORC1 variants are important determinants of warfarin dose in the Arab population. The use of the genetic and clinical factors led to better dose estimation when compared to the clinical factors alone.
Session: Posters/Exhibits/Break
Risk Factors Associated with Venous Thromboembolism in Chronic Lymphocytic Leukemia
Ambarina Faiz1, Shuang Guo1, Ashwin Sridharan1, Yong Lin2, 3, Claire Philipp1
1Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA, 2Rutgers School of Public Health, Piscataway, NJ, USA, 3Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients both with solid tumors and hematological malignancies. Chronic lymphocytic leukemia (CLL) accounts for 30% of the cases of leukemia annually in the United States and predominantly affects elderly patients. However, risk factors associated with VTE are not known in this population. Objective: To evaluate the risk factors and mortality associated with VTE among elderly patients diagnosed with CLL.

Methods: The SEER-Medicare merged database, 2000 to 2015, was used to evaluate the risk factors for VTE in Medicare patients 65 years or older diagnosed with CLL. Data were extracted for sociodemographic characteristics, comorbid medical conditions, chemotherapy, survival, and death. Race was defined as White, Black or Asian. Venous thromboembolism was defined as a diagnosis of deep vein thrombosis or pulmonary embolism during the study period. Chi-square (x2) test was used to compare the distribution of categorical variables in CLL patients with and without VTE. Logistic regression was used to examine the odds ratios for the risk factors associated with VTE. Cox proportional hazard model was used to evaluate risk of VTE associated mortality in this population.

Results: Among 34,705 patients with CLL, 11.7% patients had a diagnosis of VTE. VTE was diagnosed in 11.6% White patients, 14.6 Black and 6.3% Asian CLL patients. After adjusting for sociodemographic characteristics and comorbid medical conditions, odds of having VTE was higher for females (OR=1.1, 95% CI, 1.0-1.2) and for Black patients (OR=1.2, 95% CI, 1.0-1.4) and odds of having VTE was lower for Asian patients (OR=0.5, 95% CI, 0.4-0.7) compared to White patients. Risk factors associated with a diagnosis of VTE included anemia (OR= 2.1, 95% CI, 1.9-2.3) and chemotherapy (OR=1.4, 95% CI, 1.2-1.6). Comorbid medical conditions associated with VTE were hypertension (OR=1.8, 95% CI, 1.6-2.0), heart failure (OR=1.6, 95% CI, 1.4-1.7), obesity and chronic lung disease (OR=1.3, 95% CI, 1.2-1.4), kidney disease (OR=1.2, 95% CI, 1.1-1.3), diabetes (OR=1.2, 95% CI, 1.1-1.2), and myocardial infarction and hyperlipidemia (OR=1.1, 95% CI, 1.0-1.2). Adjusted risk of death was higher for CLL patients with a diagnosis of VTE (HR=1.06, 95% CI, 1.02-1.10). Mortality was also higher for CLL patients ≥ 75 years of age (HR=2.39, 95% CI, 2.32-2.46) and for Black patients (HR=1.30, 95% CI, 1.23-1.38). Conclusion: VTE was diagnosed in 11.7% patients with CLL, and the adjusted risk of VTE was higher for Black patients and VTE risk was lower for Asian patients compared to White patients. Anemia and chemotherapy and several comorbid conditions were associated with the risk for VTE in elderly CLL patients. These findings may help to assess the risk of VTE in elderly patients diagnosed with chronic lymphocytic leukemia.
Session: Posters/Exhibits/Break
Impact on clinical care Thrombosis and Hemostasis
Jeff Federspiel

The United States Supreme Court's decision in Dobbs v. Jackson Women's Health Organization has altered the landscape for access to abortion services in the United States. We will review the impact of this decision on abortion care in the United States, particularly how these changes alter care for patients with bleeding and clotting disorders. We will explore the practical limitations of medical emergency exemptions to abortion restrictions in some state laws. Finally, we will outline practical tools for supporting patients with bleeding and clotting disorders who may face legal challenges with accessing reproductive health services.

Session: Abortion/Reproductive Health - When the law and healthcare collide - How laws that restrict access to reproductive care are affecting hemostasis and thrombosis patients
iCoagLab Permits Comprehensive Coagulation Profiling in Patients on Percutaneous Cardiac Pump Support
Eli J Foster, Nathaniel Hai, Ziqian Zeng, Seemantini K Nadkarni
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Background Rapidly changing coagulation status is a major challenge in managing and preventing bleeding in patients on mechanical circulatory support. While having positive implications on patients' long-term outcomes, percutaneous left ventricular assist devices (p-LVADs) have notoriously been associated with severe bleeding in 15-30% of patients during in-hospital treatment [1][2]. Conventional plasma tests that measure activated partial thromboplastin time (aPTT) and anti-Xa often are imprecise in the context of rapidly changing coagulation conditions in these patients and fail to accurately predict major bleeding events. These factors highlight a critical barrier to the wide-spread clinical adoption of implantable cardiac pumps: the ability to predict hemorrhage is restricted by the absence of tools to evaluate the coagulation system rapidly and comprehensively at the point-of-care. Objective Here, we present iCoagLab, a hand-held coagulation profiling instrument, as a method for timely and comprehensive blood coagulation assessment in patients with p-LVADs. The iCoagLab system is shown in figure 1. We aim to assess the accuracy of iCoagLab for comprehensive coagulation profiling in whole blood samples by comparing against Thromboelastography (TEG 6s) and standard clinical coagulation tests. Methodology iCoagLab quantifies the viscoelastic properties of clotting blood by measuring displacements of endogenous light scattering centers within the sample, through time-varying laser speckle intensity fluctuations of back-scattered light [3]-[7]. We test the accuracy of performing comprehensive coagulation tests using iCoagLab in patients (N=15) with implanted cardiac pumps (Impella 5.5 and CP pumps, Abiomed, Danvers, MA). For this study, we collected discarded blood samples from the hematology core lab at Massachusetts General Hospital. We initiate coagulation intrinsically using kaolin assays and extrinsically using recombinant human tissue factor assays. We use iCoagLab to extract intrinsic coagulation parameters relating to the rate (reaction time, R; activated clotting time, ACT; and clot rate, angle) and mechanical strength (maximum amplitude, MA) of clot formation, as well as extrinsic coagulation parameters prothrombin time, PT, and fibrinogen, QFA. The iCoagLab characterizes intrinsic parameters within 15 minutes while it characterizes extrinsically initiated clots in under 1 minute using 25uL of whole blood. Sample coagulation curves with labeled parameters in shown in figure 2. The iCoagLab values are then compared with corresponding Thromboelastography TEG 6S parameters and with fibrinogen levels, aPTT, PT, and anti-Xa, as measured by a Werfen ACL Top 350, using linear regression analysis. Results Statistically significant correlations were observed between iCoagLab and TEG 6s for R time (r=0.56, p<0.001, N=35), angle (r=0.38, p<0.05), ACT (r=0.64, p<0.001, N=36) and MA (r=0.70, p<0.001, N=45). Strong correlations were further observed between iCoagLab ACT and Werfen anti-Xa (r=0.57, p<0.001, N=72), iCoaglab angle and Werfen aPTT( r=-0.74, p<0.001, N=72), iCoagLab PT and Werfen PT (r=0.61, p<0.001, N=66), and iCoagLab MA and Werfen QFA (r=0.66, p<0.001, N=66). Conclusions Our results confirm the high accuracy of iCoagLab in quantifying actionable clotting parameters within 15 minutes in patients with p-LVADs using a small volume of whole blood. These studies will help pave the way towards addressing life-threatening bleeding complications swiftly at the point of care.
Session: Short Talks - Taking Lab Monitoring to the Next Level
Investigating the Relationship between D Dimer levels and Viscoelastic Characteristics of Blood Clots
Eli J Foster, Nathaniel Hai, Seemantini K Nadkarni
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Background Thrombotic activity is often monitored through the measurement of D Dimer concentration in blood plasma, with elevated levels of D Dimer leading to an escalation in care and monitoring for venous thromboembolism (VTE). The D Dimer test has high sensitivity, but low specificity as an indicator for VTE, frequently leading to unnecessary escalations in care [1]. Here, we investigate the relationship between D Dimer concentration and the viscoelastic properties of blood clots derived from measurements of laser speckle fluctuations in whole blood. Objectives We aim to investigate the relationship between D Dimer levels and viscoelastic properties of whole blood clots in order to develop a more specific and actionable metric for VTE risk. Methods The viscoelastic properties of whole blood clots are measured using iCoagLab, a point-of-care instrument that analyzes time-varying speckle intensity fluctuations to quantify blood coagulation status. Laser speckle intensity fluctuations arise from endogenous thermal motion of scattering particles, such as blood cells in the illuminated blood sample. During coagulation, the formation of a fibrin clot restricts the motion of blood cells, which slows down the rate of temporal speckle intensity fluctuations monitored by iCoagLab. For this study, we collected excess blood samples from 45 patients from the hematology core lab at Massachusetts General Hospital. D Dimer levels were measured using a standard latex agglutination assay, where concentrations greater than 500 ng/mL fibrin equivalent units were considered test-positive. We initiated the intrinsic coagulation pathway using a 6.89 mg/mL concentration of activated kaolin and used iCoagLab to measure the viscoelastic modulus of the blood until it reached a plateau phase, as shown in figure 1. From this coagulation curve, we extract intrinsic coagulation parameters related to the rate (reaction time, R; activated clotting time, ACT; and clot rate, angle) and mechanical strength (maximum amplitude, MA) of clot formation. iCoagLab parameters were compared with core lab plasma fibrinogen and D dimer levels using linear regression analysis. We included an analysis of fibrinogen because it is significantly involved in the initiation of clot formation and, therefore, may be useful in the analysis of D Dimer as a product of fibrinolysis. Results We observe a statistically significant negative correlation between iCoagLab MA and both fibrinogen (r=0.60, p<0.001) and D Dimer concentration (r=-0.32, p<0.05) (figure 2). The D Dimer correlation is noticeably stronger when only considering samples with a D Dimer value greater than 2000 ng/mL (r=-0.49, p<0.001). There is much more deviation from the overall trend for samples with D Dimer values less than 2000 ng/mL, though these results still warrant escalations in care. No correlation was observed for other iCoagLab parameters. Conclusions and Next Steps We report statistically significant relationships between D Dimer concentration and the maximum viscoelastic amplitude of intrinsically activated blood clots, as measured by iCoagLab. The relationship weakens for samples with D Dimer values below 2000 ng/mL. Further studies will be necessary to evaluate whether iCoagLab may offer higher specificity compared to D Dimer levels to predict VTE outcomes in patients in the future.
Session: Posters/Exhibits/Break
Immunothrombosis and septicemia
Alison Fox-Robichaud

Sepsis is defined as life threatening organ dysfunction due to a dysregulated host response to infection. The normal response to infection includes activation of both inflammatory and coagulation pathways. In sepsis, there is a dysregulated activation of the coagulation pathways in order to control the invading pathogen. This process of immunothrombosis includes changes in ADAMTS13 levels and activity, release of plasma cell free DNA and histones, primarily from the formation of neutrophil extracellular traps and reduced expression and activity of Protein C. In this presentation I will review the elements that lead to immunothrombosis, the consequences for organ function and the potential use of immunothrombosis for sepsis diagnosis, prognosis and therapeutics

Session: Immunothrombotic Syndromes
Impact of Anticoagulation in Acquired Hemophilia A
Heather Frazier, Sean Dougherty, Kia Salafian, Hillary Maitland
University of Virginia, Charlottesville, VA, USA

Background: Acquired Hemophilia A (AHA) is a rare autoimmune disorder that occurs due to the development of autoantibodies against factor VIII which leads to inhibition of the coagulation cascade and results in a propensity for hemorrhage. The estimated incidence is approximately 1.5 per million per year. It carries an exceptionally high morbidity and mortality rate, with severe or life-threatening hemorrhagic events occurring in 70-90% of cases, with 5-10% of these cases resulting in mortality. Several underlying conditions are associated with AHA, including autoimmune disorders, obstetrical and oncologic disease, and various medications, such as direct oral anticoagulants and antiplatelet therapy, both of whose usage has increased significantly over the past decade. Objectives: We aimed to evaluate whether patients prescribed an antiplatelet (APT) or oral anticoagulant (OAC) at the time of diagnosis of AHA experienced more severe bleeding and worse clinical outcomes compared to those with AHA with no prior exposure. Methods: This is a single-center retrospective study examining 16 individuals with AHA from April 2013 to April 2023. Individuals were categorized by the presence or absence of a prescribed anticoagulant then divided into class of anticoagulant (APT, OAC, or exposure to both). Primary end points included the number of blood product transfusions received, hospital length of stay (LOS), need for intervention or procedure, and degree of hemoglobin drop from baseline. Continuous variables were compared using t-test or Wilcoxon rank-sum test. Categorical variables were compared using chi-square test or Fisher's exact test. Results: In our cohort of 16 individuals, 9 were without prior exposure to anticoagulation or antiplatelet agents before the diagnosis of AHA while 7 were prescribed either an anticoagulant, antiplatelet agent, or both. Of those taking one of these classes of medications, 2 were prescribed OACs, 3 were prescribed APTs, and 2 were prescribed both classes. Please see Table 1 for baseline data and primary end point data in detail. In each group there was only one individual who required procedural intervention. There was a statistically significant increase in intramuscular bleeding with a mean of 1.0 and 5.0 (p value 0.035) in the non-exposed and exposed groups respectively. Conclusions: The increased rates of intramuscular bleeding in patients exposed to prior anticoagulation was statistically significant. Intramuscular hemorrhage is associated with increased morbidity due to the risk for compartment syndrome requiring surgical intervention. Our data demonstrates a trend towards the need for a longer hospitalization and more pRBC transfusions in individuals with prior exposure though notably, there is not an apparent increased trend for an increased rate of platelet transfusions. There is also a trend towards significance for higher factor VIII titer inhibitor levels in patients on anticoagulation at the time of diagnosis. While this study is limited in power by sample size, there are no comparable studies to date examining the impact of anticoagulation on individuals with AHA. With the increasing rates of anticoagulation therapy, further investigation is needed on the impact of therapeutic anticoagulant or antiplatelet use prior to the diagnosis of AHA and subsequent clinical outcomes.
Session: Posters/Exhibits/Break
Evaluation of anticoagulation management in patients with suspected heparin-induced thrombocytopenia awaiting diagnosis confirmation
Alyssa R. George, Katelyn Sylvester, Dareen Kanaan, Delaney Corcoran, Kenneth Lupi, Brian Schuler, Jean M. Connors
Brigham and Women's Hospital, Boston, MA, USA

Background: Heparin-induced thrombocytopenia (HIT) is a severe, prothrombotic, immune-mediated complication associated with the use of heparin. The 2018 American Society of Hematology guidelines recommend discontinuation of heparin products upon suspicion of HIT and initiation of a non-heparin anticoagulant while awaiting a definitive diagnosis. Despite these recommendations, patients are not always switched to an alternative anticoagulant even with an intermediate to high probability of HIT. We switched laboratory tests at our institution from a platelet factor 4 (PF4) enzyme-linked immunosorbent assay (ELISA; Immucor), which is run once daily, to the HemosIL AcuStar HIT-IgG (Werfen) test in October 2022 to expedite turnaround time; it is run on demand with an estimated result time of less than 2 hours. Objective: Our aim is to evaluate anticoagulation prescribing practices before and after the switch in laboratory assay to determine the influence of this new test on initial management of HIT, including discontinuation of heparin products and initiation of non-heparin anticoagulants.

Methods: This was a single-center, retrospective, quality-improvement analysis performed at Brigham and Women's Hospital and approved by the Mass General Brigham Institutional Review Board. Eligible subjects included adult patients tested for suspected HIT. Those included in the ELISA (Immucor) group were tested between February 1-April 30, 2022, and those in the HemosIL AcuStar HIT-IgG (Werfen) group between February 1-April 30, 2023. Patients were excluded if they did not receive any heparin products prior to testing. The major outcome is the percentage of patients transitioned to a non-heparin anticoagulant at the time of PF4 test ordering. Minor outcomes include the development of new or worsening bleeding (major and clinically relevant non-major bleeding as defined by the International Society on Thrombosis and Haemostasis) or thrombosis (venous thromboembolism (VTE), stroke, or arterial thrombus) within 72 hours of PF4 test order.

Results: Of the 123 patients identified in the Werfen group, 104 were eligible for analysis. The most common indication for heparin use was VTE prophylaxis (60.9%), with the majority receiving subcutaneous heparin (44.3%). The median time from PF4 test order to result was 163 minutes. The median provider-calculated 4T score was 5; median pharmacist-calculated 4T score was 4. Two patients had a positive PF4 result (1.9%). Heparin was discontinued at the time of PF4 test ordering in 85 patients (73.9%), however a non-heparin anticoagulant was started in only 12 patients (14.1%) while awaiting results. New or worsening thrombosis occurred in 12 patients (10.4%) within 72 hours following PF4 test ordering. Ten of these patients were continued on heparin throughout the diagnostic period. New or worsening bleeding occurred in 53 patients (46.1%) with majority of cases (56.6%) defined as minor bleeding. Results for the Immucor group are currently pending. Conclusion: This study will describe current prescribing practices surrounding initial anticoagulation management and clinical outcomes in patients with suspected HIT before and after implementation of a PF4 assay with faster turnaround time. The results may aid in optimizing institutional guidelines to improve patient care and determining the need for further electronic decision support.
Session: Posters/Exhibits/Break
The Impact of Multidisciplinary Perinatal Care for Women with Bleeding Disorders
Vanessa Giuliano1, Natalya E. O’Neill1, Shamshah Aratia7, Shalene Wong7, Allison Rupnaraine,7, Rebecca Sampat7, Filomena Meffe2,3, Jeffrey Wassermann8, Jillian M. Baker4-6, Grace Tang7, Michelle Sholzberg1,7,9,10
1Department of Medicine, University of Toronto, Toronto, ON, Canada, 2Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada, 3Department of Obstetrics and Gynecology, St. Michael’s Hospital, Toronto, ON, Canada, 4Department of Pediatrics, St. Michael’s Hospital, Toronto, ON, Canada, 5Department of Paediatrics, Division of Haematology-Oncology, The Hospital for Sick Children, Toronto, ON, Canada, 6Department of Paediatrics, University of Toronto, Toronto, ON, Canada, 7St. Michael's Hospital, University of Toronto, Toronto, ON, Canada, 8Department Of Anaesthesia, University of Toronto, Toronto, ON, Canada, 9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, 10Li Ka Shing Knowledge Institute, Toronto, ON, Canada

Background: Women with bleeding disorders are at increased risk of heavy menstrual bleeding, non-anemic iron deficiency, iron-deficiency anemia, post-partum hemorrhage, and reduced health-related quality of life. Despite this, women with bleeding disorders often face barriers to receiving medical care, and thus are underdiagnosed and undertreated. The perinatal period poses unique hemostatic challenges, requiring personalized risk assessment based on diagnosis and bleeding history. Consideration of factors such as anesthetic planning, mode of delivery, and neonatal bleeding risk require meticulous management. To address these matters, the Multidisciplinary Clinic for Women with Bleeding Disorders (MCWBD) was established in 2014 at St. Michael's Hospital. The clinic is comprised of a collaborative team including an adult hematologist, an obstetrician-gynecologist, a pediatric hematologist, an anesthesiologist, a nurse practitioner, a pharmacist, and specialized nurses. Together, they develop tailored care plans to optimize patient care for anesthetic interventions, labour, delivery, neonatal care, and the postpartum period. Objectives: This study aimed to characterize and understand the experiences of women with bleeding disorders who have been provided care plans by the MCWBD. We further aimed to assess the perceived effectiveness of these care plans.

Methods:
The study involved semi-structured interviews with patients and healthcare providers identified from the MCWBD. Women aged 18 years and above with bleeding disorders who had received a care plan from the MCWBD and undergone labor and delivery were included. Interview transcripts were coded and analyzed using descriptive qualitative analysis. Interviews continued until thematic saturation was reached.

Results:
Eleven patient participants were interviewed. Four primary themes emerged: 1) impact of bleeding disorder on pregnancy, 2) challenges with the health care system, 3) MCWBD provided effective, patient-centered care, and 4) experiences with individualized care plans. Subthemes pertaining to the impact of the bleeding disorder on pregnancy included: a) heightened fear surrounding bleeding complications, and b) healthcare-related emotional trauma linked to the perinatal journey. Subthemes on challenges with the healthcare system included: a) perceived discomfort of non-specialized healthcare providers in recognizing bleeding symptoms, and b) observed inadequate training/awareness to manage their bleeding disorder, reinforcing the need for patient self-advocacy for emotional and medical safety. Subthemes pertaining to the theme of MCWBD providing effective, patient centered care included: a) perceived sense of support, b) recognized improved access to care, and c) experienced unburdening by providing them with external advocacy. Subthemes pertaining to experiences with their individualized care plan included perceptions that the care plans were comprehensive, reassuring, and empowering. 


Conclusions:
This qualitative work provides evidence of benefit for multidisciplinary care for women with bleeding disorders - an already accepted standard of care for men with bleeding disorders. These findings suggest the need for widespread adoption of proactive, patient-centered, and coordinated multidisciplinary perinatal care for women with bleeding disorders.
Session: Posters/Exhibits/Break
Necessityof anti-Xa level monitoring for prophylactic enoxaparin in children and adolescents: A single institution experience
Rene Gonzalez1, Abigail Davison1,2, Sarah E. Sartain1,2, Clay T. Cohen1,2
1Texas Children's Hospital, Houston, TX, USA, 2Baylor College of Medicine, Houston, TX, USA

Background: Prophylactic anticoagulation with enoxaparin is often used in hospitalized children with increased risk of developing venous thromboembolism (VTE). At Texas Children's Hospital, weight-based prophylactic enoxaparin is utilized with a goal anti-Xa monitoring range of 0.2-0.4 units/mL. It is unclear whether monitoring of prophylactic levels is required. Objectives: To assess the percentage of patients within goal anti-Xa level range on their initial evaluation following initiation of prophylactic enoxaparin.

Methods: A retrospective analysis of the electronic medical record was performed to identify all patients 0-18 years of age admitted to Texas Children's Hospital between May 2021 and March 2023 who received subcutaneous enoxaparin for VTE prophylaxis. Subjects included in this study were any patient who received a twice daily dosing strategy of prophylactic enoxaparin (0.5 mg/kg subcutaneous every 12 hours) and had at least one anti-Xa level for evaluation. Peak anti-Xa levels not obtained within the therapeutic window of 4-6 hours following dose administration were excluded. Exclusion criteria included any patient receiving: treatment dosing of enoxaparin, prophylactic dosing frequency other than twice a day, and prophylactic dosing as a therapeutic treatment strategy in the setting of thrombocytopenia. Additional data collected included patient demographics, rationale for VTE prophylaxis, the number of enoxaparin dosing adjustments required to achieve prophylactic levels of 0.2-0.4 units/mL, and any bleeding and thrombotic complications noted during hospitalization. This study was approved by the Baylor College of Medicine Institutional Review Board.

Results: Prophylactic enoxaparin was administered to 138 patients. The most common reason for enoxaparin prophylaxis was critical illness in the setting of COVID or MIS-C, noted in 58.7% (n=81) of patients. Additional patient characteristics are outlined in Table 1. A prophylactic anti-Xa level was achieved on initial enoxaparin dosing in only 41.3% (n=57) of patients and was less common in younger patients; breakdown by age group for patients achieving goal anti-Xa level on initial dosing was: 32.3% (n=10) of patients <1 year, 39.4% (n=28) of patients 1-13 years, and 52.8% (n=19) of patients >13 years. Initial levels were more commonly found to be sub-therapeutic in patients <1 year (58%, n=18) vs patients 13 years and older (30.6%, n=11). Additional enoxaparin dosing and level outcomes are outlined in Table 2. The mean number of dose changes required to achieve a prophylactic anti-Xa level for patients <1 year was 3.3, for 1-13 years was 1.3, and for >13 years was 0.89. There were 5 (3.6%) minor bleeding events and 3 (2.2%) thrombotic events noted.

Conclusions: Our study demonstrates that monitoring anti-Xa levels for children and adolescents on prophylactic enoxaparin is required to ensure that adequate anticoagulation is being achieved. This is especially true in infants and children under 13 years of age who often require multiple enoxaparin dose adjustments prior to reaching prophylactic range. Future prospective studies are needed to determine the optimal enoxaparin levels for prophylaxis of children based on age and underlying VTE risk factors.
Session: Posters/Exhibits/Break
Artificial Intelligence and Venous Thromboembolism: Talking to the Experts
Anuranita Gupta1, Barbara D Lam2,13, Sabrina Zerbey2, William Robertson3, Rachel P Rosovsky4, Leslie Lake5, Laura Dodge6, Alys Adamski7, Nimia Reyes7, Karon Abe7, Ioannis Vlachos8, Jeffrey I Zwicker9,10, Mara Schonberg11, Rushad Patell12
1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 2Division of Hematology, Department of Medicine, Beth Israel Deaconess Medical Center,, Boston, MA, 3Weber State University, Ogden, UT, 4Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 5National Blood Clot Alliance, Philadelphia, PA, 6Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, 7Division of Blood Disorders and Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA, 8Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 9Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NYC, NY, 10Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NYC, NY, 11Division of General Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 12Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 13Division of Clinical Informatics, Beth Israel Deaconess Medical Center, Boston, MA,

Background: Venous thromboembolism (VTE) is a significant cause of preventable death among hospitalized patients. Artificial intelligence (AI) and its sub-branch machine learning (ML) may be useful in standardizing and improving VTE management in hospitalized patients. We previously conducted a national survey of 100 informaticians to explore their attitudes towards using AI for VTE management. For the current study, we interviewed a subset of these informaticians to explore their perspectives in depth.

Methods: The survey invited all respondents to share their email address if they were interested in participating in a follow up interview. These participants were then asked to recommend other informaticians for recruitment. We conducted 30-60 minute semi-structured interviews via videoconference which were recorded and transcribed. A codebook was developed, and two coders separately reviewed the interviews using inductive analysis. Overarching themes were agreed upon by discussion of the common codes between coders (Figure 1).

Results: Of the informaticians surveyed, 22 agreed to be interviewed. The final participant group included 5 clinician informaticians, 9 data scientists, 3 biomedical/computational biologists and 5 other designations. The major themes that emerged were that 1) AI is a powerful tool to reduce clinician burden and 2) AI is well suited to preventing and managing VTE (Figure 2). Participants reported that ML models can increase accuracy and efficiency of clinical practice and can therefore serve as decision support and management tools. Participants also reported that VTE management specifically is an area of medicine which that can be managed with AI given it is a clearly defined problem that lends itself to an algorithmic solution. The challenges included factors relating to the model itself and around humans' interaction with AI. The model factors included ethical concerns regarding bias and privacy, subpar quality of training data, and the potential for model inaccuracy and false positives. The human factors included clinician unfamiliarity with AI and the need to invest financial resources in developing these tools. There were multiple suggestions for implementation of AI. Participants noted that AI should be integrated into the electronic medical record (EMR), that it should have human oversight when being used and should be able to explain how it came to its conclusion. Before use in a medical setting, ML tools need to be validated as safe and effective and both providers and patients need to be oriented to the role of AI in clinical care. Although multiple challenges to implementing AI were identified, almost all participants agreed that patients prefer interacting with a human over an AI tool in discussing vulnerable topics relating to their medical care. Conclusion: Informaticians see AI as a promising tool to support clinical decision making about VTE management. Challenges identified to implementing AI/ML will have to be addressed in order to create an ethical and accurate model which reduces the burden on healthcare providers in the clinical setting.
Session: Posters/Exhibits/Break
Biopsychosocial pain mechanisms
Kalpna Gupta

Approximately 70% of patients with severe hemophilia A suffer from daily pain, which can manifest as recurrent, acute, and/or chronic. While factor VIII (FVIII) replacement and other therapies have been successful in reducing bleeding severity and frequency, pain may persist, affecting the overall quality of life. Globally, there is growing recognition of the need for mechanism-based understanding of hemophilia-specific pain. Among inherited blood disorders, sickle cell disease (SCD) is another major inherited condition accompanied by severe pain, both chronic and acute. Cell free heme may exist in the extravascular tissues, due to bleeding in hemophilia and hemolysis in SCD. Heme can activate inflammatory cells including neutrophils, macrophages and mast cells in the periphery, and glial cells in the central nervous system leading to the release of noxious proteases, neuroinflammatory agents and inflammatory cytokines, which can activate the nociceptors leading to pain. Heme can also directly activate the nociceptors. Using the factor VIII knockout (KO) mice, we established a model of acute and chronic pain of hemophilia. We will discuss the neuroinflammatory mechanisms underlying hemophilia pain using FVIII KO mice and humanized sickle cell mice. We believe that these mechanistic insights have the potential to develop novel therapies to prevent and/treat pain in these blood disorders.

Session: Ouch! Pain and Bleeding Disorders
Single Center Retrospective Comparison of Bivalirudin and Heparin for Therapeutic Anticoagulation in Pediatric Patients
Clayton Habiger, Shannon Carpenter
Children's Mercy Hospital, Kansas City, MO, USA

Background: The pharmacological choice for continuous anticoagulation therapy in pediatric patients has classically been unfractionated heparin. However, with heparin there are risks of treatment resistance in pediatrics given differences in developmental hemostasis, and contemporary medications such as bivalirudin offer a valuable alternative. Bivalirudin binds to thrombin and has shown encouraging results compared to heparin in pediatric patients receiving ECMO, but no comparison has been made in patients receiving therapeutic anticoagulation. Three years ago, Children's Mercy Pediatric Hematology department encouraged bivalirudin use over heparin use for therapeutic anticoagulation requiring a continuous infusion. Objectives: Compare clinical and laboratory outcomes in patients receiving bivalirudin and continuous heparin for therapeutic anticoagulation secondary to a thrombotic event.

Methods: A retrospective chart review between 1/1/13 to 12/31/22 was performed and looked specifically at patients who had a pediatric hematology consult for therapeutic anticoagulation who were not on ECMO or CRRT. Patients who were on prophylactic dosing or were using the medication for prophylaxis at therapeutic ranges were excluded.

Results: 46 patients received bivalirudin during this time while 135 patients received heparin. The time to therapeutic range was significantly shorter in the bivalirudin group compared to the heparin group (3.7 hours vs 18.6, respectively). Additionally, the bivalirudin group had fewer monitoring labs (0.09 vs 0.15), RBC transfusions (0.0019 vs 0.0097), plasma transfusions (0.00074 vs 0.0048), and dose changes (0.025, 0.54) per medication hour (all p<0.05). Both groups had similar rates of bleeding events (6.5% vs 16.3%; p=0.52) despite bivalirudin having more patients who had concurrent bleeding at the time of anticoagulation induction (21.7% vs 5.2%; p<0.05). None of the bivalirudin patients failed to achieve a therapeutic level while 18.6% of heparin patients required a change in anticoagulation due to failure to achieve therapeutic goal. Finally, when monitoring labs (heparinased PTT and Anti-Xa) were standardized to a percentage of goal there was significantly less variation in the bivalirudin group (p<0.001). The average age was older in the bivalirudin group (9.9 vs 1.1) so to account for this, patients were subdivided into under and over 6 months of age. There were 13 bivalirudin and 64 heparin patients who were under the age of 6 months and 33 bivalirudin and 71 heparin subjects older than 6 months of age. The same differences were noted in both subgroups (shorter time to therapeutic range, fewer monitoring labs, RBC transfusions, and dose changes, and more lab monitoring variability). There was no difference in bleeding events in both subgroups when compared with their age cohort. The bivalirudin group had fewer patients with congenital heart conditions (11% vs 47%) and this difference was still noted after subdividing the age groups.

Conclusions: Pediatric patients who received bivalirudin had shorter time to a therapeutic range, less lab variability, fewer dose changes, fewer monitoring labs and fewer transfusions with similar bleeding rates compared to patients who received unfractionated heparin.
Session: Posters/Exhibits/Break
Deep mutational scanning to probe function of coagulation proteins
Laura Haynes

As whole genome sequencing becomes increasingly more common clinical practice, the number of identified missense mutations in coding regions of the genome has grown exponentially. Only a fraction of these protein variants can be definitively classified as pathogenic or benign, approximately 70% classified as variants of unknown significance (VUSs). One approach to address this unmet need is deep mutational scanning (DMS). DMS is a powerful approach that couples the capabilities of modern high-throughput DNA sequencing with classical biochemical and cell biology techniques. At its most fundamental level, DMS identifies the effects of all amino acid substitutions at every position within a protein simultaneously by linking the phenotype being investigated with the cDNA encoding the protein of interest. We have extensively applied DMS to study plasminogen activator inhibitor-1 (PAI-1) as a critical regulator of fibrinolysis. By applying DMS to PAI-1, we have cataloged the effects of amino acid substitutions on its spontaneous transition to a latent state, protease inhibition, and interactions with its cofactor vitronectin.

Session: Unbiased tech approaches for hematological discoveries
Platelet aggregation testing in thrombocytopenic patients
Cathy Hayward

Background: Light transmission aggregometry (LTA) is important for diagnosing platelet function disorders (PFD) and forms of von Willebrand disease (VWD) affecting ristocetin-induced platelet aggregation (RIPA). Nonetheless, data is lacking on the utility of LTA for investigating thrombocytopenic patients and platelet rich plasma samples with low platelet counts (L-PRP). Previously, we developed a strategy for diagnostic LTA assessment of L-PRP that included: 1) acceptance of referrals/samples, regardless of thrombocytopenia severity; 2) tailored agonist selection, based on which are informative for L-PRP with mildly or severely low platelet counts, and 3) interpretation of maximal aggregation (MA) using regression-derived 95% confidence intervals, determined for diluted control L-PRP (C-L-PRP).



Methods:
To further evaluate the L-PRP LTA strategy, we evaluated findings for a subsequent cohort of patients.



Results:
Between 2008-2021, the L-PRP strategy was applied to 211/1810 (11.7%) consecutive diagnostic L-PRP aggregation tests for 192 unique patients (platelet counts X 10e9 /L, as median [range] for blood and L-PRP: 105 [13-282], 164 [17-249], respectively). Patient-L-PRP had more abnormal MA findings than C-L-PRP (p-values < 0.001). Among patients with accessible electronic medical records (n=181), L-PRP LTA uncovered significant aggregation abnormalities in 45 (24.9%), including 19/31(61.3%) with <80 X 10e9 platelets/L L-PRP, and it ruled out PFD, and VWD affecting RIPA, in others. The L-PRP LTA strategy helped diagnose type 2B and suspected platelet-type VWD disease, Bernard Soulier syndrome, familial platelet disorder with myeloid malignancy, suspected ITGA2B/ITGB3-related thrombocytopenia, and acquired PFD.

Conclusion: Diagnostic LTA with L-PRP, using a strategy that considers thrombocytopenia severity, is feasible and informative.

Session: Quality Improvement Efforts in Laboratory Hemostasis/Thrombosis Testing
Elevated Protein C is Protective Against Post Thrombotic Syndrome
Zijun He1, Vivian Thompson1, Dianne Thornhill1, Rick Shearer1, Christine Baird2, Marilyn Manco-Johnson1
1University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2University of Colorado Anschutz Medical Campus Research Laboratory, Aurora, CO, USA

Background: Genetic deficiency of protein C and S are well known risk factors for thrombosis. The impact of elevated protein C and S on thrombosis recovery in adult and pediatric patients have not yet been explored. Aims: We hypothesized that elevated levels of protein C and/or protein S would be associated with improved thrombus outcomes.

Methods: This was an analysis of a consented, prospective cohort study (Thrombo-PICS) that included children, adolescents, and young adult patients who presented with arterial or venous thrombosis. We examined thrombosis outcomes among patients with elevated, normal, and decreased levels of protein C or S within three months of a thrombosis event. Outcomes included bleeding on anticoagulation, clot recurrence, clot persistence, and Post Thrombotic Syndrome (PTS) measured at least 6 months from the onset of thrombosis. Thrombophilia traits including elevated FVIII, elevated lipoprotein(a), lupus anticoagulant (LA), anticardiolipin antibodies (ACA), anti-beta-2-glycoprotein-1 antibodies (B2GP1), the factor V Leiden mutation (FVL), the prothrombin mutation (PT20210M), and antithrombin III deficiency (ATIII) were collected within three months of thrombosis event. The presence of inflammatory markers including white blood cell count (WBC), C-reactive protein (CRP), and Erythrocyte Sedimentation Rate were also measured within this time frame. Overall results were presented descriptively, and chi-squared tests were used to evaluate group differences across each adverse outcome.

Results: Table 1 displays demographics and Table 2 shows thrombus outcome results. Prevalence of PTS in patients with elevated protein C at time of thrombotic event was significantly lower than those with normal or decreased protein C values (p=0.01). PTS did not significantly differ across protein S groups. There was no significant difference in the prevalence of other adverse outcomes between patients with low, normal, or high protein C or S. Elevated levels of protein C and S were inversely correlated with infection-associated thrombosis. There was a significantly higher rate of infection in the low protein C (p=0.004) and low protein S (p=0.02) groups. There was also a higher prevalence of inflammatory markers present during the acute period among patients with decreased protein C (p=0.04) as compared to those with elevated or normal levels.

Conclusions: These results suggest elevated protein C levels during the acute phase of a clotting event is predictive of better PTS outcomes. Conversely, decreased levels of protein C and S were associated with higher rates of infection and inflammation and subsequently with poorer thrombus outcomes. More work is necessary to further explore thrombus outcomes relative to levels of protein C and protein S.
Session: Posters/Exhibits/Break
Evolution of hemostasis/thrombosis laboratory methods including laboratory automation (ELISA-->LIA, manual-->automated ADAMTS13, on-demand vs. batch testing, new von Willebrand assays)
Rusty Higgins

Laboratory Hemostasis has continued to evolve with new technologies. Labor-intensive or batched tests are becoming more automated and accessible. Platelet-dependent von Willebrand factor (vWF) activity methods and terminology have changed substantially, and newer methods are being recommended by international guidelines. Rapid ADAMTS13 activity may become available in the future, as the hemostasis laboratory industry incorporates chemiluminescence technology into automated instruments. The newer automated tests may alter our interpretation of the laboratory data, either due to improved performance or recognized biases/interferences. Additionally, the relatively recent incorporation of preanalytical modules for hemolysis, icterus, lipemia (HIL) into automated coagulation analyzers may help flag samples at risk for significant interference, and laboratories will need create workflows to address these risks. Data analysis is more important than ever, and the new instruments and middleware capabilities can improve workflow and throughput. Specific examples of middleware applications including autoverification of factor testing (i.e. with parallelism assessment) and lupus anticoagulant algorithms will be discussed briefly. Lastly, hemostasis analyzers are increasingly being attached to track-driven automation systems, either as modular hemostasis workcells or as a part of total laboratory automation. Each laboratory will need to address their risks and benefits of these systems. With total laboratory automation (i.e. including hemostasis analyzers with chemistry and immunochemistry), the centrifugation protocol to produce platelet poor plasma, is an important consideration. Other considerations for track systems, including test menu, space, and staff engagement, will be discussed.

Session: Evolution of the Clinical Hemostasis/Thrombosis Laboratory
Mass spectrometry glycomics and determination of GPIb glycosites
Marie Hollenhorst

Background: Platelet glycoprotein (GP) Ibα is the major ligand-binding subunit of the GPIb-IX-V complex that binds von Willebrand factor. GPIbα is heavily glycosylated, and its glycans have been proposed to play key roles in platelet clearance, von Willebrand factor binding, and as target antigens in immune thrombocytopenia syndromes. Despite its importance in platelet biology, the glycosylation profile of GPIbα is not well characterized.

Objectives: The aim of this study was to comprehensively analyze GPIbα amino acid sites of glycosylation (glycosites) and glycan structures.



Methods:
GPIbα ectodomain that was recombinantly expressed or that was purified from human platelets was analyzed by Western blot, mass spectrometry glycomics, and mass spectrometry glycopeptide analysis to define glycosites and the structures of the attached glycans.



Results:
We identified a diverse repertoire of N- and O-glycans, including sialoglycans, Tn antigen, T antigen, and ABO(H) blood group antigens. In the analysis of the recombinant protein, we identified 62 unique O-glycosites. In the analysis of the endogenous protein purified from platelets, we identified 48 unique O-glycosites and 1 N-glycosite. The GPIbα mucin domain is densely O-glycosylated. Glycosites are also located within the macroglycopeptide domain and mechanosensory domain.



Conclusions:
This comprehensive analysis of GPIbα glycosylation lays the foundation for further studies to determine the functional and structural roles of GPIbα glycans.

Session: Unbiased tech approaches for hematological discoveries
Longitudinal Changes in Health-related Quality of Life (HRQL) during Anticoagulation Therapy in Cancer-associated Venous Thromboembolism Treatment
Taylor A Hopper1, Eva Ordonez Mazariegos2, Andrea Jimena Morales Arteaga3, Cristhiam M Rojas Hernandez2
1The University of Texas Health Science Center at Houston, Houston, TX, USA, 2The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 3Tecnologico de Monterrey, School of Medicine and Health Sciences, Monterrey, Mexico

Introduction: There are multiple options for treatment of cancer associated-venous thromboembolism (CAT) in patients with active malignancy. This provides the opportunity for patients and providers to tailor treatment to improve patient's health-related quality of life (HRQL) as well as adherence. Previous studies have documented the impact on HRQL by CAT. It is unknown how HRQL in CAT impacts anticoagulation adherence. Therefore, our objective was to explore how changes in anticoagulant selection overtime influences HRQL and adherence. Method: A longitudinal study of adult cancer patients with confirmed acute VTE without other comorbidities requiring anticoagulation were included in the population. They were followed 30 days, 3 months, and 6 months after enrollment to identify current anticoagulant therapy, complete HRQL questionnaires using a seven-point Likert scale, and a self-reported adherence tool. Adherence rates were calculated at 3 and 6 months using 95% confidence intervals. We compared categorical variables with Pearson Chi Squared tests and continuous variables with non-parametric methods, according to the distribution and number of groups of anticoagulants. Additionally, we plotted time to change of anticoagulant with the Kaplan-Meier method. During this 6-month follow-up period, there were no observed deaths.

Results:
Of the patients followed, 28 were included in the analysis as they had completed all surveys for baseline, 3 months, and 6 months. It was found that 11 patients changed anticoagulants, all of whom started on low molecular weight heparin (LMWH) except for one individual; this is a statistically significant change (P = .016) as the patients that started on direct oral anticoagulation (DOAC) changed less frequently. Furthermore, patients that did change treatment endorsed greater emotional distress and more negative symptoms than their counterparts (P = .036, P = .047). Conclusion: This study suggests that tailoring treatment to patients' emotional distress can improve HRQL without any impact on adherence. Therefore, it is critical for providers to identify a patient's stressors and negative symptoms to appropriately tailor their treatment. Furthermore, according to our analysis, change of anticoagulant occurs more frequently in the beginning of CAT treatment; therefore, proper counseling should be given to patients to ensure clear understanding of clinical course and likely treatment adjustments.
Session: Posters/Exhibits/Break
Temporal Trends and Predictors of Venous Thromboembolism in Hospitalized Chronic Lymphocytic Leukemia Patients
Michael Imeh1, Ani Gvajaia1, Chukwunonye Amaeshi2, Fidelis Uwumiro3
1Lincoln Medical and Mental Health Centre, Bronx, NY, USA, 2Montefiore Medical Centre, Bronx, NY, USA, 3University of Benin Teaching Hospital , Benin, Nigeria

Background/Objectives: Venous thromboembolism (VTE) is associated with inferior survival in patients with chronic lymphocytic leukemia (CLL). This study assessed the prevalence, trends, and predictors of VTE in hospitalized patients with CLL.

Methods: We analyzed adult hospitalizations for CLL with or without VTE from the 2017-2020 nationwide inpatient sample database using the International Classification of Diseases, 10th revision codes. Baseline characteristics were compared using χ2 tests and Student's t-test for categorical and continuous variables. Trends in CLL hospitalization, VTE incidence, mortality, and hospital costs were assessed using the Jonckheere-Terpstra test. The predictors of VTE were assessed using stepwise multivariable logistic regression. Illness severity, risk of mortality, and comorbidity burden were adjusted using all patient refined-diagnosis-related groups (APR-DRG) metrics and the Charlson comorbidity index. Hospital costs were adjusted for inflation using the medical expenditure panel survey index.

Results: The study analyzed 17,945 hospitalizations for CLL. Overall, the incidence of VTE was 7.3%. Most patients were male (64.3%) and white (78.9%), with a mean age of 71.8 years (SD, 11.6 years). During the study period, hospitalizations for CLL decreased from 4,670 to 4,245, marking a 9.1% reduction (Ptrend <0.001). However, the incidence of VTE showed an upward trend, increasing from 230 cases (4.9%) to 344 cases (7.4%; Ptrend <0.001). Concurrently, inpatient mortality rates declined, dropping from 400 cases (8.6%) to 214 cases (5.1%; Ptrend <0.001). Additionally, the mean cost of hospitalization for patients with VTE significantly increased from $73,141 to $100,630 during the period (Ptrend <0.001). Predictors of VTE identified in the study included prolonged hospital stay (≥16 days) (aOR: 1.60; 95% CI: 1.06-2.40; P=0.025), sepsis (aOR: 1.76; 95% CI: 1.33-3.12; P=0.004), major loss of function (APR-DRG severity = 2; aOR: 2.30; 95% CI: 1.07-4.98; P=0.034) or extreme loss of function (APR-DRG severity = 3; aOR: 3.99; 95% CI: 1.63-9.74; P=0.002), Medicare insurance (aOR: 1.27; 95% CI: 1.18-1.48; P=0.033), age ≥60 years (aOR: 1.08; 95% CI: 1.01-1.27; P=0.041), obesity (aOR: 1.22; 95% CI: 1.06-2.21; P=0.016), and other primary neoplasia (aOR: 2.62; 95% CI: 1.39-4.21; P=0.006). Conclusion: CLL hospitalization and VTE-associated mortality decreased. However, the incidence rate of VTE and associated resource utilization continue to exhibit an increasing trend. Obese patients aged over 60 years, particularly those with major functional loss, concurrent septicemia, or other primary neoplasia, who were hospitalized for ≥16 days exhibited a higher risk of developing VTE.
Session: Posters/Exhibits/Break
Outcomes and Predictors of Immune Thrombocytopenia in Hospitalizations for Antiphospholipid Syndrome: A Nationwide Inpatient Sample Analysis
Michael Imeh1, Ani Gvajaia1, Chukwunonye Amaeshi2, Fidelis Uwumiro3
1Lincoln Medical and Mental Health Centre, Bronx, NY, USA, 2Montefiore Medical Centre, Bronx, NY, USA, 3University of Benin Teaching Hospital , Benin, Nigeria

Background/Objectives: Immune thrombocytopenia (ITP) is reported to complicate up to 50% of hospitalizations for antiphospholipid syndrome (APS). We evaluated the impact of ITP on outcomes of APS hospitalization using nationwide data. In addition, we identified factors associated with an increased likelihood of ITP.

Methods: We queried the 2016-2020 nationwide inpatient sample database for adult APS hospitalizations using the relevant International Classification of Diseases, 10th revision codes. Pearson's χ2 analysis or Fisher exact tests were used to evaluate categorical variables; alternatively, continuous variables were analyzed using the t-test and Wilcoxon rank sum test for normally and non-normally distributed data, respectively. Predictors of ITP and the impact of ITP on mortality and odds of thrombosis were assessed using stepwise multivariable regression analysis, whereas its impact on duration of hospitalization and cost of care was evaluated using linear regression analysis. Illness severity, baseline risk of mortality, and comorbidity burden were adjusted using all patient refined-diagnosis-related groups (APR-DRG) metrics and the Charlson comorbidity index (CCI).

Results: The study analyzed 1,710 hospitalizations for APS, of which 345 (25.3%) cases of ITP were recorded. Most patients who developed ITP were female (56.5%) and white (69.7%), with a mean age of 44.5 years (SD, 2 years). APS with ITP was associated with a greater comorbidity burden compared with APS alone (CCI ≥2: 68.1% vs. 53%; P=0.026). A total of 149 mortalities were recorded in the study. ITP was correlated with greater odds of mortality (aOR: 1.12; 95% CI: 1.02-2.41; P=0.005), higher cost of care (mean: $108 441 vs. $136 345; P=0.033), and greater odds of venous thrombosis (aOR: 1.27; 95% CI: 1.08-2.28; P=0.042). Co-existing SLE (aOR: 3.19; 95% CI: 2.00-4.51; P=0.002) and age between 18 and 40 years (aOR: 1.97; 95% CI: 1.11-3.01; P=0.001) were correlated with greater odds of ITP in the study. Conclusion: APS with ITP was correlated with poorer outcomes, including mortality, venous thrombosis, and higher mean hospital costs compared with APS hospitalizations without ITP.
Session: Posters/Exhibits/Break
Factor II and X (Fiix) Monitored Warfarin Is More Effective Than PT-INR Monitored Warfarin and Direct Oral Anticoagulants in Patients Anticoagulated Long-Term for Non-Valvular Atrial Fibrillation. The Greater Reykjavik Oral Anticoagulation (GROAC) Study.
Arnar B. Ingason1,2, Brynja R. Gudmundsdottir1, Ragnar Palsson1,3,4, Arnar S. Agustsson1, Edward Rumba1, Daniel A. Palsson1, Indridi Reynisson1, Sigrun H. Lund5, Johann P. Hreinsson6, Einar S. Bjornsson1,5, Pall T. Onundarson1,5
1Landspitali National University Hospital, Reykjavik, Iceland, 2University of Vermont, Burlington, VT, USA, 3Massachusetts General Hospital, Boston, MA, USA, 4Harvard University, Boston, MA, USA, 5University of Iceland, Reykjavik, Iceland, 6Sahlgrenska University, Gothenburg, Sweden

Background: The antithrombotic effect of warfarin depends on reducing factors (F) II and X but PT-INR is influenced not only by reductions in factors FII and FX but also in FVII. Due to short half-life, FVII drives short-term PT-INR variability and, therefore, confounds warfarin management. The FII and FX (Fiix) test is only affected by FII and FX and ignores FVII. Fiix-monitored warfarin (Fiix-warfarin) has been shown to reduce thromboembolism (TE) without increasing major bleeding (MB) compared to PT-INR monitored warfarin (PT-warfarin) in mixed patient populations. Aim: Comparison of effectiveness and safety of Fiix-warfarin, PT-warfarin, apixaban, rivaroxaban, and dabigatran in non-valvular atrial fibrillation (AF).

Methods: Real-world TE and MB incidence was compared in all 6,417 AF patients residing in the Greater Reykjavik Area from 2014-2019 treated long-term (>6 months) with Fiix-warfarin (n=1,257), PT-warfarin (n=1,904), apixaban (n=1,171), rivaroxaban (n=1,536) or dabigatran (n=549). Patients were identified through a national outpatient prescription registry. All patients diagnosed with major events were referred to a single hospital system for diagnosis and treatment. Patient data and adverse events were extracted by searching the single electronic health record system used in the area as well as radiology and endoscopy records. Main outcomes were total TE, total TE or death from any cause, and MB by ISTH definition. Inverse probability weighting was used to yield balanced study groups. Outcomes were compared using Cox regression models, adjusting for baseline differences in patient groups.

Results: The propensity score weighted total TE with Fiix-warfarin was 1.1% per patient year (ppy), lower than with PT-warfarin (1.9%, adjusted hazard ratio (AHR) 1.86 [95% confidence interval (CI) 1.19-2.91]), apixaban (1.9%, AHR 1.94 [1.13-3.32]), dabigatran (2.2%, AHR 2.19[1.18-4.06]) or rivaroxaban (1.6%, AHR 1.58 [0.96-2.61]), see figure (left panel). The composite outcome of any TE or death with Fiix-warfarin was 2.9% ppy, which was lower than with PT-warfarin (3.8%; AHR 1.31: 1.00-1.72), apixaban (4.4%; AHR 1.56:1.11-2.16), dabigatran (4.6%; AHR 1.57:1.07-2.30) or rivaroxaban (4.5%; AHR 1.54:1.13-2.08), see figure (right panel). Acute myocardial infarction (AMI) occurred at a 2.6-3.3 fold higher rate with PT-warfarin, apixaban, dabigatran and rivaroxaban than with Fiix-warfarin whereas stroke and systemic embolism occurred at similar rates. The MB incidence was 2.7% ppy with Fiix-warfarin and did not differ significantly between the different OACs (PT-warfarin 2.5%; AHR 0.89 [0.65-1.22], apixaban 2.4%; AHR 0.86 [0.57-1.30], Dabigatran 2.2%; AHR 0.77 [0.48-1.23] and rivaroxaban 3.0%; AHR 1.07 [0.76-1.50]). The total intracranial hemorrhage rate was similar with the different OACs: 0.6% ppy with Fiix-warfarin vs PT-warfarin 0.5%; AHR 0.70 [0.35-1.37], apixaban 0.3%; AHR 0.53 [0.18-1.55], Dabigatran 0.6%; AHR 0.82 [0.22-2.06] and rivaroxaban 0.4%; AHR 0.59 [0.24-1.48]. Hemorrhagic stroke occurred in 0.1-0.2% ppy except with dabigatran (0.5%, NS).

Conclusions: In all-inclusive real-world practice, anticoagulation with Fiix-monitored warfarin was associated with lower incidence of total TE and composite total TE or death but not increased MB compared to patients on traditional PT-INR monitored warfarin, apixaban, dabigatran or rivaroxaban. Fiix-monitoring might replace the old PT-INR for the purpose of warfarin monitoring and become a new reference in oral anticoagulation studies.
Session: Short Talks - Taking Lab Monitoring to the Next Level
Enhanced activation of FVIII positively impacts clot formation in vivo using hemophilia A mice
Lacramioara Ivanciu1, 2, Mettine H.A. Bos1, Rodney M. Camire1, 2
1The Children's Hospital of Philadelphia, Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Philadelphia, PA, USA, 2University of Pennsylvania, Department of Pediatrics, Philadelphia, PA, USA

Background: Coagulation factor VIII (FVIII) circulates in blood as an inactive procofactor bound to von Willebrand Factor (vWF). Proteolytic cleavage by FXa and/or thrombin (Arg372, Arg740, and Arg1689) converts FVIII to its active form FVIIIa and released it from vWF. Biochemical studies have examined the roles of the individual FVIII activation sites; however, the importance of these cleavage sites in the regulation of FVIIIa cofactor activity in vivo is not understood. Objective: To better understand the role of individual activation sites to the development of FVIIIa cofactor activity and thus, clot formation at the site of vascular injury.

Methods: We used a FVIII derivative, FVIII-2RKR that only comprises the Arg372 site to investigate the impact of eliminating Arg740 and Arg1689 on FVIII activity at the site of vascular injury using hemophilia A (HA) mouse models.

Results: FVIII-2RKR is a heterodimer, that lacks the B- and a3 domains and thus cannot detectably bind to vWF. In a one-stage aPTT clotting assay, FVIII-2RKR demonstrated ~7-fold greater specific activity compared to FVIII-SQ. Consistent with this, FVIII-2RKR had a shortened lag time in a thrombin generation assay compared to FVIII-SQ. We initiated in vivo experiments with FVIII-2RKR using HA mice to explore its hemostatic performance using three injury models. In a ferric chloride (FeCl3)-induced injury model of the carotid artery two different experiments were conducted in which FVIII-2RKR (n=5; 1, 5 or 10 ug/kg) or FVIII-SQ (n=5; 5,10 or 50 ug/kg) were infused into HA mice either 10 minutes after or prior to injury. In either experiment, faster vessel occlusion was observed with FVIII-2RKR compared to FVIII-SQ reaching statistical significance at 5 ug/kg (p<0.004; 2RKR vs. SQ). Notably, infusion of FVIII-2RKR normalizes the time to occlusion using ~10-fold lower dose compared to FVIII-SQ. This is remarkable, considering that in vivo clearance of FVIII-2RKR (n=3, 40 ug/kg) was faster than FVIII-SQ due to impaired vWF binding. A FVIII variant (FVIII-2RKR-R372Q) that does not bind vWF and lacks procoagulant activity failed to induce vessel occlusion (n=5; 50 ug/kg). FVIII-2RKR (n=3; 1ug/kg) was also more efficacious in reducing bleeding in HA mice than FVIII-SQ (n=3; 1ug/kg) in a tail vein transection model. Based on biochemical experiments, the increased hemostatic potency of FVIII-2RKR is likely due to accelerated cleavage at Arg372 resulting in rapid FXa generation at the injury site. To test this further, we employed the cremaster muscle laser-induced injury model and compared the kinetics of thrombus formation in HA mice injected with FVIII proteins. Significantly greater accumulation of platelet and fibrin was observed with FVIII-2RKR than with FVIII-SQ (1ug/kg; n=3 mice; 15 injuries; p<0.0001). Quantitative analysis revealed that FVIII-2RKR increased platelet accumulation 2-3-fold and fibrin deposition 3-6-fold over FVIII-SQ.

Conclusions: Overall, our data indicate that proteolysis of FVIII at Arg740 and Arg1689 does not contribute in a direct way to expression of cofactor activity. Rather these cleavages appear to somehow impair cleavage at Arg372. The work also shows that accelerated activation of FVIII leads to enhance hemostatic potential using multiple injury models in vivo.
Session: Short Talks - Bleeding Back to the Basics
ATHN Transcends - Hemophilia Gene Therapy Outcomes Arm: A Long-Term Follow-Up Study on Safety and Effectiveness of Gene Therapy in People with Hemophilia
Staber Janice1, Blanca Salazar2, Roberto Guillen-Gonzalez2, Michael Recht3,4, Tammuella Chrisentery-Singleton5, Ulrike Reiss6
1Iowa Hemophilia and Thrombosis Center University of Iowa Stead Family Children’s Hospital, Iowa City, IA, USA, 2CSL Behring, King of Prussia, PA, USA, 3National Bleeding Disorders Foundation, New York, NY, USA, 4Yale University School of Medicine, New Haven, CT, USA, 5American Thrombosis and Hemostasis Network, Rochester, NY, USA, 6Hemophilia Treatment Center St. Jude’s Children’s Research Hospital, Memphis, TN, USA

BACKGROUND: American Thrombosis and Hemostasis Network (ATHN) Transcends (NCT04398628) assesses the safety and effectiveness of therapies for people with inherited bleeding and clotting disorders. The study arm "Hemophilia Gene Therapy Outcomes" assesses these same end points in person after receiving gene therapy. A new module within the Hemophilia Gene Therapy Outcomes Arm, the HEMGENIX® (etranacogene dezaparvovec-drlb) Module, is an observational, post-authorization, long-term, follow-up, multicenter study to investigate the short- and long-term effectiveness and safety of HEMGENIX® treatment in adults with hemophilia B. Etranacogene dezaparvovec-drlb is a somatic gene therapy product that aims to deliver a factor IX (FIX) (Padua variant) gene expression cassette to the liver of patients with hemophilia B. OBJECTIVES: Hemophilia Gene Therapy Outcomes Arm: (1) to determine the safety of adeno-associated viral vector (AAV)- or lentiviral vector (LV)-mediated factor VIII (FVIII) and factor IX (FIX) therapies used for participants with hemophilia. (2) to describe hemophilia gene therapy medication dosing regimens, the effectiveness of gene therapy treatment as measured by factor levels and bleeds, and the impact of gene therapy on health care utilization and health-related quality of life. HEMGENIX® Module: (1) to investigate the short- and long-term effectiveness profile of HEMGENIX® by following adults with hemophilia B who are treated with HEMGENIX® or are on continuous FIX prophylaxis for 15 years. (2) to investigate the short- and long-term safety profile of (HEMGENIX®) by following adults with hemophilia B treated with etranacogene dezaparvovec-drlb or are on continuous FIX prophylaxis for 15 years. METHODS: Data will be collected at time of enrollment, then every 3 months up to a year, and then every 6 months, and annually thereafter until year 15 after vector infusion. Eligibility criteria: Includes participants from trials, people considering gene therapy, and people treated with approved product. The HEMGENIX® Module will collect data from 2 patient cohorts for analysis: (a) people with hemophilia B treated with HEMGENIX® in the US where HEMGENIX is approved for commercial use. (b) People with hemophilia B on FIX prophylaxis and enrolled in the ATHN Transcends study. Enrollment in the HEMGENIX Module will be 5 years after receiving HEMGENIX treatment and providing study consent. The total study duration is 20 years. Additional modules may be added in the future. Modules offer the mechanism to collect post-marketing required evaluations on FDA-approved gene therapy products. ATHN Transcends has received central IRB approval and is currently being rolled out across participating American Thrombosis and Hemostasis Network (ATHN) Affiliates in the US. Enrollment is now open. CONCLUSION: ATHN Transcends: Hemophilia Gene Therapy Outcomes Arm is the only comprehensive follow-up registry study in the US for people with hemophilia considering or after having received gene therapy. Long-term follow-up after gene therapy is critical to confirm short-term findings from trials and identify the unknowns.
Session: Posters/Exhibits/Break
Deep phenotyping reveals a high prevalence of distressing bleeding symptoms in patients with hypermobile Ehlers Danlos Syndrome (hEDS) spectrum disease .
Rohith Jesudas1, Sarah Mathena 2, Kenneth L. Zhang3, Christina Laukaitis3,4, Jennifer Andrews2
1St. Jude Children’s Research Hospital, Memphis, TN, USA, 2University of Arizona, Tucson, AZ, USA, 3Carle Illinois College of Medicine, Urbana, IL, USA, 4Carle Foundation Hospital, Urbana, IL, USA

Background: The ISTH BAT has been used as a bleeding severity score (BSS) to quantify bleeding symptoms in patients with hEDS spectrum disease. The relationship between a higher BSS with patient concern and health related quality of life is unknown. Capturing patient experience using qualitative long form interviews to develop a measure of patient reported symptom burden has been used to better understand the impact of a disease. Since this method has not been used to describe the impact of bleeding symptoms in patients with hEDS spectrum disease, we used this in a previously identified cohort of hEDS patients to better understand the impact of the bleeding symptoms associated with hEDS Objectives: 1. To describe the bleeding severity in hEDS patients with the ISTH BAT score 2. To describe the bleeding severity in patients with hEDS using long form interviews to capture the impact on their functioning 3.To develop and explore a score in patients with hEDS for the impact of their bleeding symptoms on activity.

Methods: Participants were recruited via the University of Arizona hEDS Gene study and completed surveys on symptoms and well-being including Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36). Participants then completed an in-depth interview that included ISTH BAT and phenotypic symptoms. Interviews were scored via the ISTH BAT and interviews were inductively coded and quantified on the impact of 14 bleeding domains on bleeding distress and overall quality of life (Significant (1), Restrictive (2), and triggering Clinical evaluation (3)). Participants distress scores were totaled (≥6) for severity of bleeding distress in all domains and compared to their ISTH-BAT, SF36 and COMPASS scores.

Results: 35 participants (94% Female, mean age 45.2) with symptomatic hypermobility (79.3% with hEDS), completed the interview and 33 completed the interview and ISTH-BAT (94%). 30% of participants had a bleeding score of ≥6.Participants reported a mean distress score of 5.67 across all domains and mean ISTH-BAT of 4.97. Participants reported significant concerns in domains that typically do not qualify for a bleeding disorder evaluations in their daily life such as bruising (42.8% significant), oral/gum bleeding (20% significant) and menstruation bleeding (22.8% restrictive). Statistical results (p<.01) show individuals with a score of ≥6 on bleeding distress on the ISTH-BAT report high bleeding distress and impact on quality of life, but do not show significance differences on the COMPASS/SF36 domains.

Conclusions: Past studies have shown a higher incidence of bleeding but these are from groups of multiple etiologies. We are exploring bleeding symptoms in the hEDS population where vascular and classical EDS are excluded. Distress appeared to arise because of concern about potential negative social repercussions of excessive bruising (e.g. being perceived as a sign of physical abuse). The high frequency of visible and anxiety-provoking bruising in patients with hEDS suggests the need for healthcare providers to provide appropriate anticipatory guidance and documentation. This also highlights an unmet need to better understand the mechanisms of cutaneous bleeding in patients with hEDS.
Session: Posters/Exhibits/Break
Evolution of hemostasis/thrombosis laboratory professional role at the bench
Jing Jin

The field of clinical laboratory science has undergone significant changes over the years, with the roles of laboratory professionals evolving to meet the changing needs of healthcare. Initially, laboratory professionals primarily focused on performing routine laboratory tests and providing results. However, with advancements in technology, automation, and the increasing complexity of diagnostic tests, there is an urgent call for laboratory professionals to assume a more expansive role in the diagnostic process, by becoming active members of the clinical care team, beyond providing results.

In this evolving landscape, laboratory professionals are expected to involve in active collaboration with healthcare providers to optimize diagnostic testing and its interpretation, dialogue between laboratory professionals and clinicians to discuss test selection, interpretation of results, and seamless integration of laboratory data into patient management plans. By fostering effective communication and knowledge exchange, the expanded role of laboratory professionals holds the potential to enhance diagnostic accuracy, reduce unnecessary testing, and improve the quality of patient care.

This case-based coagulation presentation not only provides evidence of the necessity for an expanded role of laboratory professionals but also serves as an "interesting coagulation case" workshop, presenting a real-world perspective from a bench technologist.

Session: Evolution of the Clinical Hemostasis/Thrombosis Laboratory
UNC9426, a selective TYRO3 inhibitor, decreases human platelet activation and increases survival in a murine pulmonary embolism model
Samantha Judd1, Stephanie Springborn1, Adam Kidwell1, Deborah DeRyckere2, Douglas K. Graham2, Xiaodong Wang3, Brian Branchford1
1Versiti Blood Research Institute, Wauwatosa, WI, USA, 2Aflac Cancer and Blood Disorders Center and Children's Healthcare of Atlanta, Atlanta, GA, USA, 3Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

Introduction: Platelet activation is necessary for physiologic hemostasis, but unchecked activation can lead to pathologic thrombosis. Recent clinical studies of pediatric thrombosis etiology have identified inflammation as an independent risk factor for hospital-acquired venous thromboembolism. GAS6, an acute phase reactant that increases during inflammation, signals through TYRO3, AXL, and MERTK (TAM) receptors to induce a signal transduction cascade resulting in an activating conformational change in the aIIb/b3 integrin, thus allowing fibrinogen binding and subsequent activation of the platelets.

Methods: Following informed consent, human whole blood was drawn into sodium citrate and platelet rich plasma (PRP) was generated via differential centrifugation. Animal studies were performed in wild type C57BL/6 mice under supervision of the Institutional Animal Care and Use Committee. The TYRO3-specific small molecule inhibitor UNC9426 was reconstituted in DMSO prior to incubation with human PRP, or with a permeability-enhancing buffer prior to injection into mice. Light transmission aggregation was performed using collagen and ADP as agonists for human PRP incubated with either UNC9426 or DMSO control. Thrombin and convulxin were used to stimulate platelets prior to flow cytometry, in which fluorescent antibodies were used to detect P-selectin and bound PAC-1 on the surface of activated platelets in human whole blood samples. PRP incubated with either UNC9426 or DMSO control. Male and female 8-14-week-old mice were anesthetized and underwent intravenous injection with UNC9426 or buffer control, followed by intravenous injection of a collagen/epinephrine solution to induce systemic venous thrombosis.

Results: Compared to DMSO controls, UNC9426-treated human PRP samples exhibited decreased maximum aggregation after addition of collagen or ADP. The UNC9426-treated human whole blood samples demonstrated a reduction in P-selectin expression and PAC-1 binding to activated aIIb/b3 integrin compared to DMSO controls. Mice treated with UNC9426 demonstrated dose-dependent protection from collagen/epinephrine-induced pulmonary embolism model, with three-quarters of them surviving, compared to one-half of controls. Conclusion: UNC9426 is a novel TYRO3-specific small molecule inhibitor that decreases human platelet activation and demonstrates a protective effect in a murine pulmonary embolism model. This compound, and others like it, may represent an alternative strategy to decrease platelet activation and thrombosis risk.
Session: Short Talks - Insights on Platelet Biology
INR Above Five Warfarin Events Inpatient Require Focus on Preventable Cases to Lower Incidence
Benjamin/J Jung1, Lisa Baumann-Kreuziger1,2, Garret Newkirk1
1Froedtert and Medical College of Wisconsin, MIlwaukee, WI, USA, 2Versiti Blood Center of Wisconsin, Milwaukee, WI, USA

Background: The risk of bleeding increases when the International Normalized Ratio (INR) value is over five. Medical illness, decreased oral intake, and new drug interactions add variability and an unexpected response to warfarin dosing during a hospitalization. If providers dose warfarin conservatively, hospital length of stay is increased or patients are discharged with subtherapeutic INR. If providers dose warfarin aggressively, INR can increase rapidly and be supratherapeutic. Providers often use clinical decision support, risk assessment tools, and nomograms to select the warfarin dose, but these tools do not capture all the risks in an acutely ill patient. Objectives: Prevention of bleeding and International Normalized Ratio (INR) values over five is important for hospitalized patients. With a Vizient quality metric surrounding warfarin and INR values over five, hospitals can focus efforts to review patients and implement interventions to improve warfarin dosing and safety.

Methods: We identified hospitalized patients receiving warfarin with an INR > 5 using a data from Vizient and validated internal report and created a project team of pharmacists to implement process improvement. Previously only an INR >3.5 was flagged in the electronic health record (EHR) as out of range. We identified an INR increase of 0.5 in 24 hours or 0.8 in 48 hours as a risk factor for INR >5 and created flags to alert pharmacists in the EHR. To eliminate patients receiving two doses of warfarin within 24 hours. If the warfarin consult order were placed after 2000, administration of warfarin would not occur until the next evening. The education interventions include an email directly with pharmacists involved in management of patients with INR greater than five. We also updated the inpatient warfarin dosing nomogram and guideline about the intervention and educated pharmacists using in person presentations and email notification. Outcomes and Impact: Preventable cases fell into the following themes: missed drug interaction (including recently discontinued medications), escalated doses (either based on home dosing or initial dosing selection), not drawing a baseline INR to help guide dosing, not reducing or holding doses with quick INR movement, and giving two warfarin doses in under 24 hours due to evening hospital admission. The rates of preventable cases was 19/67 (28%) cases from July 20-21 (5 cases high initial dosing, 5 cases with fast INR climb without dose reduction, 4 cases with higher than home dosing given, 4 cases with drug interactions and 1 cases with two doses given within 24 hours. Preventable cases from July 21-22 were 18/61 (30%) (5 cases with no baseline INR, 5 cases with higher than home dosing given, 4 cases with high initial dosing for initial dosing, and 4 cases with two doses given within 24 hours). The number of patients receiving warfarin declined from 1537 to 1276 a decrease of 17 percent from 2020 to 2022, which affects the case rate. However, given the declining number of patients receiving warfarin, the case rate needs improvement for the health system to be a top performer on the Vizient metric.
Session: Posters/Exhibits/Break
A Phase 3, Randomized, Active-Control Study of Four-Factor Prothrombin Complex Concentrate Versus Frozen Plasma in Bleeding Adult Cardiac Surgery Patients
Keyvan Karkouti1,2, Jeannie Callum3,4, Kenichi Tanaka5, Deep Grewal2, Cristina Solomon6, Sigurd Knaub6, Sylvia Werner7, Gita Pezeshki7, Jerrold H. Levy8
1University of Toronto, Toronto, ON, Canada, 2University Health Network, Toronto, ON, Canada, 3Queen’s University, Kingston, ON, Canada, 4Kingston Health Sciences Centre, Kingston, ON, Canada, 5University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, 6Octapharma AG, Lachen, Switzerland, 7Octapharma USA, Paramus, NJ, USA, 8Duke University School of Medicine, Durham, NC, USA

Background: After cardiac surgery, patients frequently develop coagulopathic bleeding. The etiology of coagulopathy is multifactorial, including anticoagulation, hemorrhage, hemodilution and consumptive losses following tissue injury and during cardiopulmonary bypass (CPB). Reduced thrombin generation caused by coagulation factor deficiency is an important contributor to post-CPB bleeding. Prothrombin complex concentrate (PCC; off-label) and frozen plasma (FP) are administered for coagulation factor replacement during or after surgery; however, the efficacy-safety balance of PCCs in cardiac surgery is unknown, with limited studies in this setting. Objective: The LEX-211 (FARES-II) study will determine if four-factor PCC (4F-PCC, Octaplex, Octapharma) is clinically non-inferior to FP regarding hemostatic efficacy in patients undergoing cardiac surgery with coagulation factor deficiency.

Methods: LEX-211 (FARES-II; NCT05523297) is a Phase 3, multicenter, randomized, active-control, prospective trial, conducted at 13 hospitals in Canada and the United States. Patients ≥18 years old undergoing cardiac surgery with CPB, requiring coagulation factor replacement due to bleeding and known or suspected coagulation factor deficiency, are eligible. Exclusion criteria include heart transplant, insertion/removal of ventricular assist devices, expected survival of <24 h, severe right heart failure, heparin contraindications, thromboembolic events in the past 3 months, and IgA deficiency. When the blood bank receives the first order for coagulation factor replacement, patients will be randomized to receive 4F-PCC or FP (Figure 1). For 4F-PCC dosing, patients ≤60 kg will receive 1,500 international units (IU), and those >60 kg will receive 2000 IU. For FP, patients ≤60 kg will receive 3 U, and patients >60 kg will receive 4 U. Patients will receive a maximum of 2 doses of 4F-PCC/FP, according to their assigned group, within the 24-h treatment period. If further treatment is necessary, both groups will receive FP. The primary endpoint is the hemostatic response to 4F-PCC vs. FP, rated 'effective' if no additional hemostatic intervention (systemic hemostatic agents, i.e., platelets, cryoprecipitate, other coagulation factor products, a second dose of study drug, or surgical re-opening for bleeding) is required within 60 min-24 h following administration of the first dose. Secondary and safety endpoints are detailed in Table 1. An unblinded interim analysis (100 evaluable patients/group) is planned for futility or sample size re-estimation, if necessary. Non-inferiority of the primary endpoint 'hemostatic response' between 4F-PCC and FP will be assessed using a Farrington-Manning score test with a 0.10 non-inferiority margin at a one-sided alpha level of 2.5%. If non-inferiority is determined, the superiority of 4F-PCC with respect to the primary endpoint will be considered.

Results: LEX-211 (FARES-II) was initiated in Q4 2022 and is currently in progress. At present, >250 evaluable patients have been included in the study. Interim decisions will be available at the time of presentation. The overall sample size will be ≥410 evaluable patients with completion expected in Q4 2024.

Conclusions: The study findings have the potential to improve clinical approaches to bleeding management in cardiac surgery patients. Optimizing the management of bleeding related to coagulation factor deficiency may reduce the need for allogeneic blood products and has the potential to improve outcomes in surgical patients.
Session: Posters/Exhibits/Break
Influence of pharmaceutical industry on published clinical trial results
Divyanka Kavdikar1, Siddharth Suresh1, Fakiha Siddiqui2, Atul Laddu1, Jawed Fareed2, Arav Raghunathan1, Ishvari Mokadam1
1Global Thrombosis Forum , Suwanee, GA, USA, 2Loyola University , Chicago, IL, USA

Background There have been instances where the drug development process faced challenges and issues related to the accuracy of the data. Objectives We reviewed 3 reported cases where there were concerns about the data. Methods RECORD 4 trial The FDA approved rivaroxaban in July 2011 Results of the four RECORD trials revealed data integrity problems in the RECORD4 trial. Investigation was initiated after concerns were reported by the BMJ, and JAMA viewpoint The Lancet published the study in 2009 without mentioning data integrity problems. The Lancet issued a formal correction and apology in December 2022, acknowledging inaccuracies in the original paper. Janssen, the drug's marketer, acknowledged the FDA's concerns but stated that the study's safety and efficacy conclusions remain unchanged. The BMJ Report Brook Jackson filed a complaint with the FDA regarding issues in Pfizer's COVID-19 mRNA vaccine clinical trials, and reported manipulated data, lack of blinding, and inadequate follow-up on adverse events at three trial sites. The Lancet challenge The Lancet Challenge was introduced in 2003 by the editors of The Lancet, Dr. Richard Horton and Dr. Sabine Kleinert. Called for pharmaceutical companies to provide the raw data of their clinical trials for independent review to promote openness in reporting clinical trials and to ensure that published projects were accurate and unbiased. GlaxoSmithKline and Pfizer responded, providing free access to the raw data of their clinical trials. A huge step towards promoting honesty in the reporting of clinical trials opened the way for other efforts aimed to improve the reporting of clinical trial results, such as the International Committee of Medical Journal Editors (ICMJE) conditions for clinical trial registration and reporting, and the AllTrials campaign. The Rezulin story Troglitazone was developed by Parke-Davis as the first anti-diabetic drug for patients with insulin resistance. The FDA's medical officer cited Rezulin's potential to harm the liver and the heart and recommended against the drug's approval. Parke-Davis maintained that the risk of liver toxicity was comparable to placebo. Parke-Davis complained to the FDA, and the medical officer was removed from his post. Approved on January 29, 1997. May 17, 1998: a 55-year-old patient died of acute liver failure after taking troglitazone. June 4, 1988: The NIH dropped troglitazone from the study. Dr. David J. Graham, an FDA epidemiologist, concluded that patient monitoring was not effective in protecting against liver failure. Dr. Janet B. McGill, an endocrinologist wrote in a March 1, 2000 letter to Sen. Edward M. Kennedy: "I believe that the company... deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies." March 21, 2000, the FDA withdrew the drug from the market. Conclusions Industry involvement in data analysis and financial interest may lead to biased reports. Being honest, revealing financial relations to the industry, and the process of professional peer review are recommended. Our message is that honesty is the best policy, asking "What if I am given this drug by my physician, will I take it?".
Session: Posters/Exhibits/Break
Cellular indices of DVT
Priyanka Kavdikar1, Ragini Mohan1, Neha Thomas1,3, Fakiha Siddiqui2, Atul Laddu1, Jawed Fareed2, Nysha Reddy1
1Global Thrombosis Forum , Suwanee, GA, USA, 2Loyola University , Chicago, IL, USA, 3University of Westminster, London, United Kingdom

Background DVT, one of the most common and serious forms of VTE, can cause serious complications if the clots travel to the lungs resulting in PE. DVT is a major challenge to the members of the medical profession. The CDC reported that DVT/PE affect as many as 900,000 Americans each year, resulting in several hundred thousand hospitalizations and about 300,000 deaths (Figure 1 and 2). CDC and the American Society of Hematology convened a national workshop of experts in VTE, public health experts in VTE, and patient representatives and concluded that improved utilization in clinical practice of existing, proven-effective preventive measures is critical to reducing the disease burden from VTE. Systematic surveillance of DVT and PE is needed to provide nationally representative data on the prevalence and annual incidence of DVT and PE in the U.S. Objectives Our goal was to research the role of some important cellular indices in the diagnosis of DVT and found the following: Routine Complete Blood Count is an inexpensive laboratory test, where blood samples are collected with EDTA to evaluate RBCs, WBCs, and platelets. Methods We researched the published literature. Results Hemoglobin (HGB) is a protein that is used to transport oxygen in human blood. Low levels of HGB are shown to relate to higher mortality rates for patients with Pulmonary Embolism​, with a roughly 74% accurate reading. Other indices included Mean Platelet Volume (MPV), Platelet Count, and Red Cell Indices. Increased Red Cell Distribution Width (RDW) is a sign of thrombosis, as having high RDW in one area of the body while low in another may signal that a clot is blocking blood flow from one part of the body to another. Lower values for Hematocrit (HCT) correlated directly to higher mortality rates in thrombosis patients​, thrombocythemia can cause different complications including​ Stroke​, Myocardial Infarction. A higher value for mean platelet volume (MPV) causes a higher risk for DVT and Myocardial Infarction, as well as for VTE. An elevated Neutrophil Lymphocyte Ratio (NLR) is a sign of inflammation and has been shown to be associated with the recurrence of DVT. An elevated Platelet Neutrophil Ratio (PNR) is associated with inflammation and can be used as a predictor of poor outcomes. An elevated Platelet Neutrophil Ratio (PNR) is associated with inflammation and can be used as a predictor of poor outcomes. In conclusion, these cellular indices could serve as better indicators or diagnostic tools and prognostic markers for DVT and can help in accurate diagnosis in a timely manner. Conclusions •Increased RDW and HCT are associated with patients suffering from DVT. •Increased NLR is associated with a higher risk of DVT recurrence. •These cellular indices could serve as better indicators or diagnostic tools and prognostic markers for DVT. •Complete blood count data is routinely obtained in emergency and in-patient settings. It is a widely used, low-cost, convenient laboratory test that offers an abundance of metrics •These readily available blood cellular indices along with other testing strategies can help accurate diagnosis in a timely manner.
Session: Posters/Exhibits/Break
Recurrent Pregnancy Loss in Type 3 von Willebrand Disease with a Unique Mutation Profile
Amanda D. Kaveney, Claire Philipp
Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Background: Type 3 von Willebrand Disease (VWD) is characterized by undetectable levels of von Willebrand factor (VWF) correlating with reduced VWF function, decreased factor VIII (FVIII) activity and severe bleeding phenotype. Type 3 VWD is often a clinical diagnosis, confirmed by laboratory assays. Genetic testing may be useful for future family planning. Women with Type 3 VWD have an increased risk of primary and secondary postpartum hemorrhage. The risk of pregnancy loss and other pregnancy complications is unknown. Additionally, there is an overall lack of standardized treatment for pregnant women with Type 3 VWD. We present a case of recurrent pregnancy loss in a patient with Type 3 VWD and a unique mutational profile. Case: Patient is a 36 year old female with a diagnosis of Type 3 VWD. Patient presented with a ruptured ovarian cyst and associated hemoperitoneum. Exploratory laparotomy was complicated by perioperative bleeding and massive transfusion protocol. VWF testing demonstrated FVIII 5%, VWF antigen (VWF:Ag) <10%, VWF ristocetin cofactor activity (VWF:RCo) <5%. Due to recurrent gastrointestinal bleeding, patient was started on Humate-P prophylaxis three times per week. Family history was pertinent for excessive bleeding in her mother, two out of three siblings, and maternal grandfather. Her father had no bleeding history. Patient underwent genetic testing as part of preconception counseling and was found to have two clinically significant variants, c.3379+1G>A, heterozygous and c.1117C>T, heterozygous. Parents underwent genetic testing with father testing positive for heterozygous c.3379+1G>A and c.1117C>T and mother heterozygous for c.3379+1G>. Patient had multiple unsuccessful embryo transfers. She experienced miscarriage at 20 weeks after spontaneous pregnancy despite Humate-P prophylaxis with dose increases based on weight changes. Pregnancy loss was attributed to placental abruption with hemorrhagic amniotic fluid, associated cervical insufficiency, and coagulopathy in fetus. VWF testing of fetus: fibrinogen <70 mg/dL, FVIII 25%, VWF: Ag 36%, VWF:RCo 38%. Patient experienced a second miscarriage with second pregnancy despite daily Humate-P prophylaxis to maintain VW:RCo >30%. Patient presented at 14 weeks with cervical insufficiency without evidence of placental abruption and cerclage was placed. Patient presented with premature rupture of membranes at 16 weeks requiring D+E. There was no evidence of placental abruption, hemorrhage in amniotic fluid, or fetal coagulopathy. Discussion: Our case exhibits recurrent pregnancy loss in Type 3 VWD. This case demonstrates the need to establish optimal management guidelines and need for close collaboration with high risk obstetrics to improve pregnancy outcomes in women with Type 3 VWD. Our patient appears to exhibit an autosomal dominant inheritance pattern despite Type 3 VWD typically demonstrating an autosomal recessive inheritance pattern. Additionally, given she had two pathogenic mutations, her father carried both mutations and her mother one mutation, we were unable to reliably conclude whether she inherited these variants in cis or trans configurations. This has further implications for future offspring, including the likelihood of inheriting both variants and predicting associated bleeding phenotype. This highlights the utility but also potential limitations of genetic testing for potential risk assessment with family planning and during pregnancy.
Session: Posters/Exhibits/Break
Assessment and management of bleeding in pediatric patients with hypermobility syndrome
Nicole Kendel

Severe connective tissue disorders are known to be associated with increased bleeding symptoms due to modifications in collagen. These modifications in collagen are also associated with generalized joint hypermobility, which may present with milder symptoms and may not be diagnosed prior to presentation to a hematologist. Due to minimal associated hemostatic laboratory abnormalities, this entity is likely under-recognized and can lead to significant impact on health and overall quality of life. Dr. Nicole Kendel will discuss the pathogenesis of bleeding symptoms in severe connective tissue disorders and review the diagnosis of generalized joint hypermobility. In addition, the most common bleeding symptoms and appropriate management strategies within this population will be discussed.

Session: Bleeding in Hypermobility/Ehlers Danlos
Indirect comparison of prophylaxis efficacy between simoctocog alfa and efanesoctocog alfa in severe hemophilia A and their cost in the United States
Craig M. Kessler1, Fernando F. Corrales-Medina2
1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, DC, USA, 2University of Miami-Miller School of Medicine, and University of Miami-Hemophilia Treatment Center, Miami, FL, USA

Background: In rare diseases such as hemophilia A, direct head-to-head comparisons of treatments are not feasible. Matching-adjusted indirect comparison (MAIC) is a statistical method allowing an alternative approach to evaluate treatment efficacy between clinical studies. In MAIC, study populations are re-weighted based on clinically relevant patient characteristics to better match each other. Treatment decisions in hemophilia A are not only impacted by efficacy, but also by the cost, particularly as there is a need for life-long prophylaxis, which comes with a high economic burden. Objectives: Here we use MAIC to compare the efficacy of pharmacokinetic-guided, personalized prophylaxis with simoctocog alfa (Nuwiq®, a recombinant factor VIII (rFVIII)) versus prophylaxis with efanesoctocog alfa (Altuviiio®; a novel extended half-life Fc-fusion rFVIII) and evaluate their cost in patients with severe hemophilia A.

Methods: For the MAIC, individual patient-level data (IPD) were extracted from NuPreviq (phase IIIb study on simoctocog alfa) and aggregate published data from XTEND-1 (phase III study on once-weekly efanesoctocog alfa). Baseline age and body weight were used to re-weight IPD from 65 patients from NuPreviq to match the aggregate data of 133 patients from XTEND-1 (Group A). The following efficacy outcomes for the matched populations were examined: total annualized bleeding rate (ABR) and percentage of patients with zero bleeds (including treated and untreated bleeds); weekly consumption of FVIII; and percentage of bleeds treated with a single infusion. Annual cost of the two regimens was based on the match-adjusted patient populations and included both direct and indirect costs: prophylaxis, on-demand treatment of breakthrough bleeds, non-drug related costs (e.g. hospitalization, emergency services, outpatient care) and societal costs (absence from work). Costs of prophylaxis and on-demand treatment were based on wholesaler acquisition costs (simoctocog alfa: $1.90/IU; efanesoctocog alfa: $5.11/IU). Non-drug related costs were based on Centers for Medicare & Medicaid Services.

Results: No patients were excluded from the index study based on the key inclusion criteria for the comparator study. After matching, the effective sample size for simoctocog alfa was 35.3. The percentage of patients with zero bleeds was similar between matched simoctocog alfa population and efanesoctocog alfa (64.1% vs 55.5%; p=0.291, Figure 1). Similarly, there was no statistical difference in mean total ABR between simoctocog alfa and efanesoctocog alfa (1.5 vs 1.1, respectively; p=0.342, Figure 1). The mean weekly dose was significantly higher in patients treated with simoctocog alfa versus efanesoctocog alfa (98.3 IU/kg vs 52.2 IU/kg; p<0.001). Despite the higher dose required, the annual estimated cost of treatment per patient with simoctocog alfa was lower than with efanesoctocog alfa ($792,046 vs $1,116,488). Over 5 years, this translates to a difference of $1,622,209 per patient between the two regimens (Figure 2). Cost was largely driven by cost of prophylaxis as breakthrough bleed related- and other costs were similar between the regimens.

Conclusions: Based on MAIC, prophylaxis with simoctocog alfa resulted in similar zero bleed rates and total ABR as with efanesoctocog alfa, albeit with a higher weekly dose. Despite higher dosing, simoctocog alfa endured an estimated 29% lower cost burden than efanesoctocog alfa.
Session: Posters/Exhibits/Break
Transitioning from oral factor Xa inhibitor to unfractionated heparin using heparin-calibrated anti-Xa levels
Mahnoor M Khan1, Magdalena E Jasinska2, Jeremy P Kosacz3, Erin N Robinson1, Lisa M Thompson3, Brandon Pierce3, Anne E Rose1
1UW Health - Madison, Madison, WI, USA, 2University of Wisconsin School of Pharmacy , Madison, WI, USA, 3UW Health - Northern Illinois , Rockford, IL, USA

Background: Factor Xa inhibitors (FXAi) have become the most common choice for oral anticoagulation. However, FXAi can interfere with heparin-calibrated anti-Xa assays, making it challenging to titrate unfractionated heparin (UFH) infusions when anti-Xa levels are used. To account for this interference, some institutions choose to revert to monitoring UFH infusions with aPTT. Our health system uses an UFH titration nomogram targeting a higher anti-Xa goal (0.7-1.0 IU/mL) for patients with FXAi use in the previous 48 hours. Objective: The purpose of this study was to illustrate FXAi interference on baseline anti-Xa levels and evaluate the safety and efficacy of a higher anti-Xa goal for UFH titration with recent FXAi use.

Methods: A retrospective chart review of UFH infusions started within 48 hours of FXAi use was conducted at two hospitals within the health system. Patients were excluded if they were <18 years old, had bleeding on admission, if UFH was not administered within 48 hours of last FXAi dose, if last FXAi dose was unknown, if UFH was administered at a fixed rate, if UFH targeted an alternative anti-Xa range, or if other concurrent anticoagulants were given. UFH infusions that met inclusion criteria were assessed to determine if the standard anti-Xa or the higher anti-Xa range were used. The standard range group (SRG) anti-Xa target is 0.3-0.7 IU/mL and the higher range group (HRG) anti-Xa target is 0.7-1.0 IU/mL. Baseline characteristics, anti-Xa levels, major bleeding events, thrombotic events, and non-clinically significant bleeding events were collected for both groups. The study was not powered to show statistical significance; data is reported as descriptive statistics.

Results: One hundred and forty-three UFH infusions were included. Within these, 107 utilized the standard range and 36 utilized the higher range. The average time between last FXAi dose and the start of UFH infusion was 20.8 hours in the SRG and 18.8 hours in the HRG. The average baseline heparin anti-Xa level was 0.5 in the SRG and 0.9 in the HRG. In the SRG, the average anti-Xa levels within the first 24 hours after the UFH was started were 0.87, 0.72, 0.57, and 0.55 IU/mL. In the HRG the average anti-Xa levels within the first 24 hours after the UFH was started were 1.0, 0.86, 0.74, and 0.69 IU/mL. Two major bleeds occurred in the SRG and 1 major bleed in the HRG. One new thrombotic event occurred in the SRG and no thromboses reported in the HRG. There were 13 non-major bleeds in the SRG and 3 in the HRG.

Conclusions: Utilizing an UFH titration nomogram targeting a higher anti-Xa goal for patients with FXAi use in the previous 48 hours may offer a potential solution for UFH titration when anti-Xa interference is present.
Session: Posters/Exhibits/Break
Complement activation by HIT immune complexes
Sanjay Khandelwal

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by immune complexes (ICs) containing immunoglobulin G (IgG) antibodies to a multivalent antigen composed of platelet factor 4 and heparin. HIT ICs activate cellular FcγRIIA receptors to initiate diverse cellular effector functions including neutrophil degranulation, monocyte expression of tissue factor and platelet activation. Earlier studies (Cines et al., 1980) have shown that HIT ICs potently activate complement through the classical pathway. In recent studies, our laboratory has expanded on these earlier observations to show that classical pathway activation by HIT ICs is essential for promoting HIT procoagulant activity. Specifically, our studies showed that complement degradation (iC3b/C3c/C3d) products are incorporated into circulating ICs and facilitate binding to monocytes, neutrophils and B cells in a complement-dependent manner and promote FcgRIIA-dependent cellular activation. Based on these observations, we next asked if the complement activating properties of HIT ICs are predictive of their platelet activating potential. In this session, we will describe the role of complement in mediating the pathogenic effects of HIT antibodies and provide new data to show that the complement activating properties of HIT ICs are predictive of platelet activation in the serotonin release assay.

Session: Immunothrombotic Syndromes
Anti-GPIbα antibodies in FNAIT are associated with recurrent miscarriages
Christopher J. Khoury1-3, Pingguo Chen1-4, Guangheng Zhu2,3, Zoya Tawhidi1-3, Alan H. Lazarus1-4,8, Yiming Wang5, Karen Chong6, David Chitayat1,6, Heyu Ni1-4,7,8
1Department of Laboratory Medicine and Pathobiology, University of Toronto., Toronto, ON, Canada, 2Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada, 3Toronto Platelet Immunology Group, Toronto, ON, Canada, 4Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, 5Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto., Toronto, ON, Canada, 6The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada, 7Department of Physiology, University of Toronto, Toronto, ON, Canada, 8Department of Medicine, University of Toronto, Toronto, ON, Canada

Background: Recurrent miscarriage is defined as the loss of 3 or more consecutive pregnancies before the 20th week of gestation, affecting 1-2% of couples. It is often difficult to determine a cause for recurrent miscarriages, as more than half of cases remain unexplained following clinical investigation. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a suspected cause of miscarriages in humans, but clinical evidence is limited. FNAIT is classically defined by maternal antibody generation against specific human platelet antigens (HPAs) on fetal platelets, leading to thrombocytopenia, severe bleeding diatheses, and other obstetric complications. Most reported FNAIT cases (~70-90%) result from maternal alloantibodies targeting β3 integrin (HPA-1a), while cases caused by GPIbα antibodies (HPA-2b) are exceedingly rare (less than 1%). We previously described a non-classical mechanism of FNAIT in a murine model where maternal anti-GPIbα antibodies led to fetal platelet activation and thrombosis in the placenta, causing miscarriage in >83% of pregnant mice (J Clin Invest, 2011). Whether anti-GPIbα antibodies cause recurrent miscarriage in humans has not been explored. Aims: Examine sera from women experiencing unexplained recurrent miscarriages for anti-platelet antibodies and evaluate their effect on platelet function.

Methods: The 3 patients recruited for this study were patients seen in the Prenatal Diagnosis and Medical Genetics Program in the Department of Obstetrics and Gynecology at Mount Sinai Hospital, Toronto. Standard workup was performed but a definitive cause for recurrent miscarriages could not be determined. We used a monoclonal antibody immobilization of platelet antigen (MAIPA) assay and flow cytometry to detect IgG against specific platelet antigens in each patient's serum. O-sialoglycoprotein endopeptidase was used to cleave GPIbα from platelets for antibody binding assays. Gel-filtered donor platelets were incubated with patient serum or serum-purified IgG and then measured for markers of platelet activation (P-selectin and PAC-1) and desialylation (RCA-I) by flow cytometry.

Results: MAIPA assays revealed high levels of anti-platelet antibodies in two of three patients. Serum from patient 1 contained anti-GPIbα IgG, patient 2 serum had IgG against both GPIbα and integrin β3, while patient 3 had no detectable anti-platelet IgG. We detected strong antibody binding to donor platelets incubated with serum from patients 1 and 2 and then found that antibody binding was attenuated to GPIbα-depleted platelets. Donor platelets incubated with serum from patients 1 and 2, but not patient 3, induced platelet activation (P-selectin expression and PAC-1 binding) and desialylation (RCA-1 binding), and purified IgG from these patients did the same, which confirmed the effect on platelets was IgG-specific. Conclusion/Discussion: We detected anti-GPIbα antibodies in 2/3 patients experiencing unexplained recurrent miscarriages, which may explain the paucity of such cases in neonates. Additionally, serum and purified IgG from both anti-platelet IgG positive patients induced activation and desialylation of donor platelets, providing a potential mechanism for how anti-platelet IgG can cause miscarriage. GPIbα antibodies could cause miscarriage by inducing fetal platelet activation, promoting pathological blood clotting, and impaired blood flow to the placenta. These initial findings provide the first evidence that anti-GPIbα antibodies in FNAIT are associated with recurrent miscarriages in humans.
Session: Posters/Exhibits/Break
Healthcare Burden of Venous Thromboembolism in Hospitalized Cancer Patients: Nationally Representative Estimates Using the Largest All-payer Inpatient Database in the United States
Krish Khurana1, Giuseppe Maiocco2, Nareg H. Roubinian3, Mohammad Hussain2, Waqas Azhar2, Sujitha Ketineni2, Hareena Sangha4, Michael B. Streiff5, Aaron A. R. Tobian5, Ruchika Goel2,5,6
1Southern Illinois School of Medicine P4P program, Springfield, IL, USA, 2Southern Illinois School of Medicine, Springfield, IL, USA, 3Vitalant Research Institute, San Francisco, CA, USA, 4University of Texas Southwestern School of Medicine, Dallas, TX, USA, 5Johns Hopkins University School of Medicine, Baltimore, MD, USA, 6Vitalant Corporate Medical Affairs, Scottsdale, AZ, USA

INTRODUCTION: Among cancer associated hospitalizations, venous thromboembolism (VTE) [deep vein thrombosis (DVT)/pulmonary embolism (PE)] is a leading non-cancer cause of death. Data on co-diagnosis and healthcare impact of cancer associated thromboses vary, yet higher risk is known to be associated with specific cancer types, treatments, and comorbidities. This study utilizes a nationally representative database to report the co-diagnosis, mortality, and healthcare burden of VTE in cancer hospitalizations in the United States (US). METHODS: The Nationwide Inpatient Sample Healthcare Cost and Utilization Project (HCUP-NIS) is the largest all-payer inpatient database in the US, approximating a 20% stratified sample of inpatient discharges from >5000 hospitals across 48 states. Data from the 2020 HCUP-NIS was used to generate nationally representative estimates of cancer associated thrombotic events; CCSR and ICD-10 codes were used to identify hospital discharges in which co-diagnoses of any cancer type and VTE were listed. Age and gender adjusted Odds Ratios (aOR) were calculated and statistical comparisons of proportions and medians as applicable were performed via STATA V18.0. RESULTS: Of 31,297,020 US hospitalizations in 2020; 2,920,670 (9.3%) had cancer a listed diagnosis (Table 1). Of these, 221,205 (7.6%) had co-diagnosis of VTE [89,650(41%) PE, 163,430(74%) DVT, and 31,875(14%) both PE and DVT]. Median age (interquartile range (IQR)) for admissions with cancer and VTE was 67(58-75) years with 86.5% admissions classified as having major/severe underlying illness. VTE in cancer occurred at significantly higher rates than general admissions (aOR(95%CI) (aOR)=2.37(2.34-2.40);p<.0001) [PE (aOR(95%CI)=2.05(2.01-2.09);p<.0001, Table 1); DVT (aOR(95%CI)=2.48(2.45-2.52);p<.0001)]. Incidence varied by cancer subtype, with VTE being most common in liver (17.5%), pancreatic (15.3%), bile duct (14.0%), adrenocortical (13.4%), cardiac (13.2%), gallbladder (12.6%), Uterine (12.2%), Testicular (11.8%) and Endometrial (10.5%)cancer admissions. MORTALITY: Overall rates of all-cause mortality were elevated in cancer hospitalizations compared to general admissions (5.7% vs. 2.8%, aOR=1.54(1.52-1.56);p<.0001), Figure 1). Further, among cancer hospitalizations, odds of all-cause mortality for cancer admissions with VTE was higher as compared to without VTE (aOR=1.91(1.84-1.99);p<.0001). All-cause mortality among cancer hospitalizations was higher independently for both DVT (aOR=1.68(1.61-1.76);p<.0001) and PE (aOR=2.19(2.07-2.31);p<.0001). HEALTHCARE BURDEN: Cancer hospitalizations with VTE were associated with significantly longer median(IQR) length of stay than cancer without VTE [6(3-11)days versus 4(2-8)days; (p<.0001)] and higher hospital charges [$64,983($32,907-$137,615) versus $52,501($28,117-$99,894);p<.0001)]. CO-DIAGNOSES/PROCEDURES: Most common co-diagnoses in admissions with cancer and VTE included hyperlipidemia (56.8%), secondary metastasis (46.2%), hypertension (35.9%), anemia (34.4%), and renal failure (28.4%) (Figure 2). Highest coded procedural interventions in cancer and VTE admissions were RBCs or platelet transfusion (14.1%), respiratory ventilation (10.9%), airway insertion (6.6%), antineoplastic therapy (5.8%), and endoscopy/colonoscopy (4.3%) (Figure 2). CONCLUSIONS: These nationally representative data show that VTE is a frequent complication among hospitalized patients with cancer and highest co-diagnoses being reported in admissions with gastro-intestinal and genito-urinary cancers and those with metastasis. VTE in cancer is associated with significantly higher all-cause mortality, length of hospitalization, and total hospital expenditures than cancer admissions without VTE. These findings highlight the healthcare burden of cancer associated venous thromboses.
Session: Short Talks - Complications of Disease and Therapy in H&T
The risk of recurrent venous thromboembolsim and hemorrhage in the postpartum patient requring anticoagulation
Thomas Kiebalo1,2, Ann Malinowski1,4, Jose Carvalho1,5, Nadine Shehata1,2,3
1Mount Sinai Hospital, Toronto, ON, Canada, 2Department of Medicine, University of Toronto, Toronto, ON, Canada, 3Department of Hematology , University of Toronto, Toronto, ON, Canada, 4Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada, 5Department of Anesthesiology, University of Toronto, Toronto, ON, Canada

Background: Current anesthesia guidelines advise for the discontinuation of prophylactic low molecular weight heparin (LMWH) 12 hours prior, and therapeutic LMWH 24 hours prior to the use of neuraxial anesthesia (NA) for obstetrical patients. The first prophylactic dose of LMWH can be administered 12 hours after epidural insertion/spinal anesthesia and at least 4 hours following epidural catheter removal. There remains a paucity of evidence regarding the rates of recurrence of venous thromboembolism (VTE) during this highly procoagulant time. Furthermore, data are scarce on rates of significant bleeding including both postpartum hemorrhage and spinal hematoma in the setting of prophylactic vs. therapeutic anticoagulation. A retrospective single-centre study was designed to assess the risk of VTE as well as rates of significant bleeding in pregnant patients using the current society guidelines.

Methods: Individuals from a university-affiliated quaternary referral hospital were assessed from 2013 to 2023. Those who received either prophylactic or therapeutic anticoagulation with LMWH both antenatally and postpartum together with neuraxial anesthesia were included. Medical records were reviewed to determine the indication for anticoagulation and the correspondent dosage of LMWH, the mode of neuraxial anesthesia, mode of delivery, the time of epidural catheter/spinal anesthesia insertion, the time of epidural catheter removal, time of first LMWH injection postpartum, concurrent aspirin use, presence of thrombophilia, relevant laboratory markers (platelet count) and comorbid illnesses. All patients included in our analysis were assessed in either the Hematology or Thrombosis clinic antenatally and were all appropriately counselled on indications for anticoagulation discontinuation at the time of labour according to the current recommendations. The primary outcomes were: frequency of VTE recurrence, spinal hematoma and volume of postpartum blood loss.

Results: Of 2634 pregnancies, 251 fulfilled criteria, and 213 had complete data. Median age was 34 years, and median weight was 84 kg. The indication for prophylactic or therapeutic anticoagulation included: estrogen provoked VTE (n=117), other provoked (n=25), unprovoked VTE (n=55), MPNs (n=2), Thrombotic APLA (n=6) and Obstetrical APLA (n=8). Median platelet count at delivery 212 x10(9)/L. 35% were using concomitant ASA antenatally. 57% percent had vaginal delivery (n=112). 154 (72%) had epidural anesthesia, 56 (26%) had spinal anesthesia and three had combined spinal/epidural anesthesia. Median time to restarting LMWH was 8 hours from epidural catheter removal, and 12 hours from spinal anesthesia insertion. There were no spinal hematomas. Median blood loss was 400 mL. One patient who received prophylactic dose LMWH antenatally for a previous estrogen-provoked VTE developed superficial vein thrombosis on postpartum day 1. She underwent spontaneous vaginal delivery, with epidural anesthesia and prophylactic dose LMWH was initiated 13 hours after epidural removal. One patient with a history of remote unprovoked PE who had vaginal delivery and received epidural anesthesia developed early post-partum hemorrhage two hours after prophylactic LMWH post-partum, estimated blood loss of 2000 mL.

Conclusions: This study demonstrates a low rate of recurrence of VTE after interruption of anticoagulation and of bleeding. Further prospective perioperative studies are needed to support the safety of the current standard of practice in this patient population.
Session: Posters/Exhibits/Break
Prophylactic Treatment of Acquired Von Willebrand Disease in Non-Human Primates with VGA039, An Anti-Protein S Monoclonal Antibody
Benjamin Kim, Ian Huck, Lilley Leong, Tony Byun, Aline He, Abel Silva, Joanne Chan, Young Cho, Stephen J. Moore, Graham Parry, Sandip Panicker
Vega Therapeutics, Inc., South San Francisco, CA, USA

Background: VGA039, a pro-hemostatic monoclonal antibody targeting Protein S (PS), is being evaluated to treat von Willebrand Disease (VWD). VWD is the most common inherited blood disorder and can be associated with significant disease burden. Current VWD treatments have limitations in effectiveness and are burdensome; thus, there is a need for new therapeutic options. VGA039 attenuates PS cofactor activity for Tissue Factor Pathway Inhibitor alpha (TFPIα) and activated Protein C (aPC) and augments and restores thrombin generation (TG) during the initiation and propagation of coagulation. VGA039 binds only human and non-human primate (NHP) PS, limiting its assessment in existing animal models of VWD. Objectives: The present study aimed to develop a NHP model of acquired VWD to evaluate the efficacy of VGA039. Methods: An acquired VWD model in healthy NHPs (cynomolgus macaques) was developed through coadministration of an anti‑von Willebrand Factor (VWF) nanobody that binds the A1 domain of VWF, inhibiting its interactions with platelet GpIb/IX/V while depleting it from the circulation (subcutaneous 5 mg/kg daily; Days -4 to 3), and a neutralizing anti-Factor VIII (FVIII) monoclonal antibody (mAb) (intravenous 0.1 mg/kg; Day 1). Bleed time was measured for up to 20 minutes following Surgicutt puncture of the labial mucosa. Blood and plasma samples were used to monitor FVIII activity, VWF activity, ex vivo TG, and hematology and coagulation parameters. VGA039 efficacy was evaluated starting 3.5 hours post coadministration of anti‑VWF and anti‑FVIII. Results: Administration of anti‑VWF or anti‑FVIII alone produced minimal and/or inconsistent decreases in hemoglobin and prolongation of bleed time. In contrast, coadministration produced a severe VWD‑like phenotype characterized by VWF and FVIII deficiency, decreased ex vivo TG, prolonged aPTT, D-dimer abrogation, markedly decreased hemoglobin (Figure 1A), and prolonged bleed times (Figure 1B), demonstrating establishment of the model. Prophylactic VGA039 administration reduced the hemoglobin decrease (Figure 2A) and prevented bleed time prolongation (Figure 2B). Conclusions: Efficacy of VGA039 was demonstrated in a novel NHP model of acquired VWD. This proof-of-concept study supports clinical evaluation of VGA039 for the treatment of VWD.
Session: Short Talks - Industry Bleeding - No CME
Time to stable therapeutic anticoagulation using weight-based IV heparin dosing clinical decisions support program
Keri S. Kim, Jean Lee, Miranda Hart, John Garofalo, Jeffrey J. Mucksavage
University of Illinois Chicago College of Pharmacy, Chicago, IL, USA

Heparin is a high alert medication due to its potential to cause significant harm in hospitalized patients. National Patient Safety Goals set by The Joint Commission recommend that institutions develop IV heparin guidelines to assist with dosing and management of bleeding. Currently there are no recommended target metrics designed to maximize efficacy and safety with IV heparin. Some target metric proposals include achieving therapeutic anticoagulation within 24 hours of heparin initiation and utilizing clinical decision support included in electronic health record software. The purpose of this study is to determine compliance with the IV heparin dosing protocol at the University of Illinois Hospital and Clinics (Ul Health) since implementing a weight-based clinical decisions support (CDS) program. Additionally, time to stable therapeutic IV heparin will be described. This is a retrospective observational study. Patients were randomly selected between 6/1/2021 to 12/31/2022 if they were managed per the IV heparin dosing protocol for more than 24 hours. A therapeutic heparin dose was defined as the dose associated with aPTT range of 60-100 seconds, and a stable therapeutic heparin dose was associated with two consecutive aPTTs in the aPTT range 60-100 seconds. The primary outcome of this study is to determine time to stable therapeutic anticoagulation using IV heparin. Other outcomes include percent of patients achieving stable therapeutic anticoagulation, percent of patients achieving stable therapeutic anticoagulation within 24 hours of initiation, and the percent of therapeutic vs sub- or supra- therapeutic anticoagulation with every IV heparin doses. A total of 68 patients were included. The average age was 63 years, and the majority indication for heparin therapy was for the management of venous thromboembolism (68%). Average weight and body mass index were 85 kg and 29.8 kg/m², respectively. The total number of hours on IV heparin therapy was 6295.6 hours, and a total of 699 doses were evaluated. Stable therapeutic heparin was achieved in 69% of patients. Only 15% of patients achieved stable therapeutic heparin within 24 hours of initiation. Mean time to stable therapeutic anticoagulation was 40 hours. Heparin dosing protocol deviation occurred in 11% of all heparin dosing. In a total of 699 doses evaluated, 41% were therapeutic, 31% were sub-therapeutic and 18% were supra-therapeutic. One thrombotic and one bleeding event occurred during IV heparin therapy. Most patients were not discharged with oral anticoagulation therapy (53%), and patients who were discharged with an oral anticoagulant, apixaban was most frequently prescribed (35%). In conclusion, the IV heparin dosing protocol at UI Health led to achieving stable therapeutic anticoagulation on average 40 hours after initiation. Since the compliance of IV heparin dosing protocol was high, the next step is to revise IV heparin dosing protocol to achieve stable therapeutic anticoagulation faster and to maintain it longer.
Session: Posters/Exhibits/Break
Preliminary findings of utilizing aPTT assay as a screening tool for lupus anticoagulant
Suhhyun Kim, Daniel Sabath
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

Background: Existing literature suggests utilizing phospholipid depleted activated partial thromboplastin time (aPTT) assay to screen for presence of lupus anticoagulant (LA). While this may be feasible where LA testing is conducted for diagnosis of anti-phospholipid syndrome (APS) and in work ups of thromboembolic events and recurrent miscarriages, oftentimes testing for LA is ordered following an elevated aPTT result along with a mixing study in clinical scenarios where LA is not suspected initially. Although this has the potential to result in unnecessary testing for LA, the screening utility of initial aPTT for LA has not been thoroughly investigated. Objectives: The purpose of this study was to investigate the sensitivity and specificity of the initial screening test utilizing phospholipid based aPTT test for the detection of LA.

Methods: The LA test results as well as associated mixing studies and the initial aPTT (STA-PTT, Diagnostica Stago) were reviewed from a population of in-house University of Washington medical system patient population for dates ranging from 1/1/2020 to 1/1/2023. LA results were compared with the initial screening aPTT results.

Results: A total of 124 LA tests were identified following mixing studies and an aPTT result. The patient population comprised 60 males and 54 females from ages 19-89. Our preliminary results show that the initial aPTT test has a sensitivity of 87.1% and specificity of 30.1% with a positive predictive value of 29.3% and a negative predictive value of 87.5% for the presence of a LA. The correlation between the initial PTT and LA was not significant (r = 0.146, p= 0.105). In addition, a subset of 54 tests with elevated aPTT with mixing studies were identified. Of these, 30 had associated incomplete correction on mixing studies with 16 positive LA and 14 negative LA results. Of note, a repeated aPTT was measured with mixing study and LA test. aPTT measured with LA testing was significantly higher that initial aPTT and straight aPTT from mixing study (p= 0.039 and 0.014, respectively).

Conclusions: Our preliminary results show that aPTT as a screening assay is sensitive but has low specificity, indicating that it has a high probability of false positives. A subset of tests with elevated PTT with incomplete correction showed equivocal LA end results. In addition, for this subset of test, the repeat aPTT measurement with the LA testing was elevated. Further studies with larger sample size with these test parameters are underway to tease out the potential elevation in aPTT and investigate the efficacies of the utilities of aPTT assay as a screening tool in various clinical settings where LA is not initially clinically indicated.
Session: Posters/Exhibits/Break
Gathering and Disseminating Standardized Gene Therapy Data - The World Federation of Hemophilia Gene Therapy Registry
Barbara A. Konkle1, Flora Peyvandi2, Mayss Naccache3, Wolfgang Miesbach4, Brian O'Mahony5, Steven W. Pipe6, Mark W. Skinner7, Donna Coffin3, Glenn F. Pierce3
1University of Washington, Seattle, WA, USA, 2Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy, 3World Federation of Hemophilia, Montreal, QC, Canada, 4University Hospital Frankfurt, Frankfurt, Germany, 5Irish Haemophilia Society, Dublin, Ireland, 6University of Michigan, Ann Arbor, MI, USA, 7Institute for Policy Advancement Ltd, Washington, DC, USA

Introduction In this era of transformative biotechnology, the World Federation of Hemophilia (WFH) launched the Gene Therapy Registry (GTR) aimed at gathering comprehensive data on all people with hemophilia (PWH) who receive gene therapy worldwide. Methods The GTR is a prospective, observational, and longitudinal registry designed to standardize and centralize global data collection by establishing a single, unified data repository. Data entry occurs once, either directly into the GTR platform or through data transfer from National Registries. The GTR will disseminate specific de-identified data to various stakeholders. The GTR Scientific Advisory Board accesses global data for monitoring safety and efficacy. Hemophilia treatment centres (HTC) and National Registries will receive aggregated global safety data. Regulatory agencies and Health Technology Assessment organizations can request specific data to inform their decisions, while industry partners will receive product-specific data. Results The WFH is engaged with a broad network of HTCs and National Registries to establish mutually beneficial collaborations with the GTR. In North America specifically, the WFH GTR is collaborating with both the American Thrombosis and Hemostasis Network (ATHN) and the Canadian Bleeding Disorders Registry (CBDR) to ensure a common set of data is captured and easily linked to the GTR data set. De-identified data will be transferred from ATHN and the CBDR to the GTR on a regular basis. In the United States, hemophilia treatment centres can also enter data directly in the GTR, for patients not enrolled in ATHN. Similar collaborations have been established with other countries, including: Australia, Brazil, Ireland, Japan, France, Germany, Saudi Arabia, Spain, Sweden, the Netherlands, and the United Kingdom. Based on the GTR protocol, core data set and methodology, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has shown strong support for the GTR, endorsing it as the worldwide registry for consolidating all international data on PWH who receive gene therapy and encouraging collaboration of all HTCs and National Registries. The CHMP also emphasized the value of the GTR for post approval safety and efficacy studies of gene therapies, recommending its use as a planned data source for mandated Phase IV studies. Conclusion The GTR simplifies the data entry process, facilitates efficient data sharing, and provides valuable information to all stakeholders, advancing our understanding of gene therapy's safety, efficacy, and long-term effects, ultimately contributing to improved patient care and treatment outcomes.
Session: Online Poster Session
Monitoring bivalirudin anticoagulant effect by the addition of diluted thrombin time compared to activated partial thromboplastin time alone
Vadim Kostousov, Karen Bruzdoski, Jun Teruya
Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA

Background: Bivalirudin is gradually replacing unfractionated heparin for extracorporeal life support (ECLS) anticoagulation. Only activated partial thromboplastin time (aPTT, with heparinase HPTT) was utilized in our hospital as a main assay to monitor bivalirudin therapy until 2022. Since 2023 plasma diluted thrombin time (dTT) was implemented in routine coagulation analysis as the additional test for monitoring bivalirudin effect. Objectives: Our study aimed to compare bivalirudin infusion rate (BIR), HPTT, and bivalirudin levels measured by dTT before (2022) and after (2023) dTT implementation among infants on ECLS.

Methods:
HPTT, dTT and BIR values were extracted from the hospital database from patients younger than 3 years old on ECLS from January 2022 to November 2023; dTT was measured on STA-R-Max analyzer (Diagnostica Stago, USA) in stored specimens before implementation of dTT assay in 2022. Bivalirudin level at 0.8-2.5 µg/mL was considered as target range equivalent to goal HPTT interval of 60-80 sec based on in vitro spiking experiments. Statistical analysis was performed with Mann-Whitney U-test, two proportion Z-test using MS-Excel 2016; data is presented as mean±SD, with significance at p<0.05.

Results:
Total 169 specimens from 16 pediatric patients aged 0.4-35 months were analyzed: HPTT and bivalirudin concentration became significantly higher, once dTT was introduced into routine analysis (Table). This was accompanied with 1.5-time increase of drug infusion rate. Majority of specimens were within target range of bivalirudin level and fewer of them had extremely high values after dTT implementation.

Conclusions:
The implementation of new test for bivalirudin monitoring was accompanied with increased drug infusion rate and more precise goal attainment during ECLS. If this targeted therapy would lead to an improved clinical outcome deserves further study.
Session: Posters/Exhibits/Break
Timeliness of Hemostatic Therapy Administration for Patients with Bleeding Disorders in the Emergency Department
Emily Kraft, Vanessa Bourck, Yuxin Zhang, Lisa Duffett, Alan Tinmouth, Tzu-Fei Wang, Roy Khalife
Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada

Background: Patients with Bleeding Disorders (PWBD) presenting to the Emergency Department (ED) face critical health risks. Timely intervention is essential, as delays in emergency care can escalate the risk of pain, disability, anxiety, and hospital admissions, and in severe cases, may result in life-threatening outcomes. The urgency of administering hemostatic therapies is underscored by current standards and Canadian emergency room guidelines, which advocate for treatment of severe bleeding events within 30 minutes and mild-to-moderate events within 60 minutes. Despite these recommendations, adherence to these guidelines is not well documented. Objectives: This study examines adherence to these standards in emergency care for PWBD to benchmark performance measures for quality improvement initiatives.

Methods: We conducted a retrospective cohort study using administrative data and chart review between June 1, 2019 and December 31, 2022. We included patients with hemophilia or von Willebrand disease presenting to our institution's ED. We collected data on demographics, diagnosis, severity, clinical presentation, Canadian Triage and Acuity Scale (CTAS) score, hemostatic therapies, and time intervals from ED arrival to therapy administration. Data were analyzed descriptively to summarize time intervals. We used generalized linear regression models to compare time intervals with bleeding disorder diagnosis, disease severity, sex, prescriber specialty, and CTAS score.

Results: Among 241 ED visits in 122 PWBD, 35.7% (86/241) were for bleeding events. Of these events, 50% (43/86) were treated with hemostatic therapies, using clotting factor concentrates (CFCs) (36/43, 83.7%) or desmopressin (7/43, 16.3%). For patients presenting with non-bleeding events, 7.7% (12/155) received CFCs and 0.6% (1/155) received desmopressin. Median CTAS score was 2 (IQR 2 - 3). The recorded median time from triage to administration of hemostatic agents was 175 minutes (min) (IQR 93 - 364) for the 48 patients receiving CFCs and 206 min (IQR 152 - 269) for the 8 patients receiving desmopressin. Additional time intervals at multiple stages are presented in Table 2. Severe bleeding disorders were associated with statistically significant longer delays from time of ED triage to therapy administration, mean 300.19 min (95% CI 216.45, 397.59), compared to milder bleeding disorders, mean 165.49 (95% CI 102.81, 243.02), p <.05. Subgroup analysis by bleeding disorders did not demonstrate statistically significant differences between disease severity and time from ED triage to therapy administration. We did not observe statistically significant differences based on prescriber specialty or CTAS score. Sex was not associated with statistically significant differences in the time from ED triage to therapy administration. However, women experienced clinically significant delays, mean 304.70 min (95% CI 166.68, 484.04), compared to men, mean 215.06 min (95% CI 155.79, 283.87), p = 0.284. Conclusion: This study revealed concerning delays observed at multiple stages underscoring a critical gap in meeting accepted standards for timely hemostatic therapy administration to PWBD in the ED setting at our institution. Delays at various stages of care signify a pressing need for educational initiatives and quality improvement strategies aimed at expediting treatment. Improving the standard of care for PWBD is paramount to mitigate pain, disability, hospital admissions, and fatalities associated with bleeding events.
Session: Posters/Exhibits/Break
Comparative Protamine Sulfate and HEPA-Remove Neutralization Studies in Potency Adjusted Porcine and Bovine Heparin
Emily Krupa, Debra Hoppensteadt-Moorman, Walter Jeske, Jawed Fareed
Loyola University Medical Center, Maywood, IL, USA

Background: Protamine sulfate acts as a heparin antagonist to reverse the anticoagulant effects of heparin through an acid-base reaction. Protamine is commonly used in clinical settings to neutralize heparin-induced anticoagulation in patients following surgery and other bleeding complications. HEPA-Remove is a novel heparin neutralizer thought to exhibit effects similar to protamine. Aim: The purpose of this study was to compare the neutralization activities of protamine sulfate and HEPA-Remove inn various laboratory assays when supplemented in potency adjusted bovine and porcine heparin samples.

Methods: Bovine and porcine heparins samples were adjusted according to their USP potencies. The samples were supplemented in blook bank plasma (BBP) in a concentration range of 0-1 U/mL. Protamine sulfate and HEPA-Remove were freshly prepared and added to each heparin sample at a final concentration of 10 g/mL. Samples were then analyzed in an ACL Top 350 coagulation analyzer to determine their activated partial thromboplastin time (aPTT). Anti-Xa and anti-IIa assays were then conducted by amidolytic methods. Thrombin generation inhibition assays (TGA) studies were also done. Studies were repeated twice, and then statistical analysis was performed using SigmaPlot two-way ANOVA.

Results: Table 1. Compiled average results and standard deviation in each assay and sample. Conclusion: Bovine and porcine heparin samples were similarly neutralized by protamine sulfate and HEPA-Remove in aPTT, anti-Xa, and anti-IIa studies, with some exceptions at higher concentrations.
Session: Posters/Exhibits/Break
Management considerations in the surgical setting of suspected aquired factor deficiencies
Rebecca Kruse-Jarres

This presentation will be a case-based discussion on the surgical management for acquired hemophilia A, acquired von Willebrand syndrome and other rarer acquired factor deficiencies.

Session: Identification and management of acquired bleeding in the acute care setting
Surgical and procedural outcomes for patients with factor VIII deficiency taking Emicizumab prophylactically: A regional approach to data collection and analysis
Janice Kuhn1, Butler Regina2, Mailie-Howell Lisa2, Druzgal Colleen3, Sennett Margy3
1Virginia Commonwealth University, Richmond, VA, USA, 2Children's Hospital of Philadelphia, Philadelphila, PA, USA, 3University of Virginia, Charlottesville, VA, USA

Background Emicizumab (Emi) is a recombinant, humanized bi-specific antibody directed against activated factor IX and factor X. Emi is used to bypass the need for Factor VIII (FVIII) to prevent bleeding in persons with hemophilia A (PWHA) with and without inhibitors. While Emi improves hemostasis and is effective in preventing bleeding, it does not normalize hemostasis and interferes with standard coagulation tests. Experience to date with surgeries is limited. Objectives Primary objective: To evaluate bleeding and clotting outcomes of patients with Hemophilia A (PWHA), with and without inhibitors on Emi, who underwent major and minor surgery. Secondary objectives: 1) To examine the incidence of excessive bleeding or clotting in PWHA with and without inhibitors undergoing major and minor surgery with and without FVIII prophylaxis and/or bypassing agents. 2) To determine the amount of FVIII and/or bypassing agents' utilization in these patients and to compare the utilization to bleeding or clotting outcomes.

Methods: In 2021, the Mid-Atlantic Region III Hemophilia Treatment Centers (MAR) contracted through its core center with the American Thrombosis and Hemostasis Network (ATHN) to develop two data validation forms and data entry guides. The forms use the ATHN dataset (ADS), a de-identified data set derived from clinical data entered in ATHN Clinical Manager (CM) by hemophilia treatment centers, reducing the need for human subject research requirements and data re-entry. All data fields for this project were previously available in CM. The MAR Community of Practice Forum supported site recruitment and project implementation. The data elements from the ADS that were analyzed in the project objectives include: 1) Demographic Data: Year of birth, race, ethnicity, sex, education level, employment status, first 3 numbers of zip code. 2) Clinical Data: Diagnoses, inhibitor status, medication usage, and surgery/procedure details including month and year, type, anatomical location, and outcome. An Emi Surgery Project Committee from MAR received retrospective de-identified monthly data cuts for their review and analysis. Data analysis was descriptive in nature. The type of surgeries was classified into major and minor surgeries according to criteria established by Santagostino (Haemophilia 2015, 21, 24-40).

Results: Sixty-two surgeries/procedures have been analyzed as of December 1, 2023. All sixteen of the major surgeries/procedures used factor prophylactically with an average of 4.47 days of factor (0-15 range). Two cases also used an antifibrinolytic. Two surgeries (prostatectomy and tonsillectomy) had unexpected bleeding, but neither required the administration of blood products. No clotting was reported. Of the 32/46 minor surgeries/procedures, fourteen (10 ENT and 4 scopes) did not use any factor concentrate, and 22/46 used an antifibrinolytic. Of the 18 using factor concentrate, the average days of use was 2.9 days (range 1-7) with a mode of 1 day. No expected bleeding or clotting was reported. Nineteen dental surgeries were reported. Eight did not use factor concentrate. Seventy-five percent of those used an antifibrinolytic (Figure 1). Conclusion The MAR Emi Surgery and Procedure Project provides real world data on the hemostasis management of patients taking Emi. This abstract presents preliminary results in an ongoing project.
Session: Posters/Exhibits/Break
Contribution of platelet dysfunction to bleeding in Ehlers Danlos syndrome
Mariia Kumskova

Contribution of platelet dysfunction to bleeding in Ehlers Danlos syndrome

Mariia Kumskova, Gagan D. Flora, Manasa K. Nayak, Madankumar Ghatge, Ivan Budnik, Rakesh B. Patel, Aditi Jain, Janice Staber Steven R. Lentz, Anil K. Chauhan

Introduction: People with Ehlers-Danlos syndrome (EDS) exhibit an increased susceptibility to bleeding complications. Despite the long-recognized association between EDS and bleeding predisposition, we still lack a definitive understanding of the underlying mechanisms contributing to bleeding diathesis in people with EDS. This study aims to characterize the platelet function in a cohort of people with EDS and a murine EDS model.



Methods:
We recruited a cohort of people with different types of EDS, including classical, classical-like, hypermobile, and vascular. All people with EDS were matched with healthy controls by age and gender. All participants were included in accordance with the University of Iowa Institutional Review Board-approved protocol. The bleeding tendency in all study participants was assessed using the International Society of Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT). We employed COL5A1+/− mice as a murine model of the classical type of EDS. The function of human and mouse platelets was evaluated using standardized agonist-induced in vitro assays.



Results:
The mean ISTH-BAT score was 0.1 in healthy controls and 9.2 in people with EDS (P < 0.001). An abnormal ISTH-BAT score was observed in 33 out of 53 (62%) people with EDS and 0 of 53 healthy controls (P < 0.001). Evaluation of platelets from people with EDS demonstrated reduced aggregation and αIIbβ3 activation (with normal αIIbβ3 surface expression) in response to stimulation with collagen, collagen-related peptide (CRP), and thrombin receptor activator peptide-6 (TRAP), compared to healthy controls. Evaluation of collagen receptor expression on the surface of resting platelets showed a mild deficiency of GPVI in people with EDS compared to healthy controls (P < 0.001), while the integrin α2 levels were similar in both groups (P = 0.152). Analysis of GPVI downstream signaling revealed defects in LAT (Y220), Syk (Y525/526), PLCγ2 (Y1217), and talin (S425) phosphorylation in people with EDS (P < 0.05 vs. healthy controls), suggesting a defect in platelet inside-out signaling. Secretion of dense and α-granules as well as phosphatidylserine surface exposure upon dual activation with CRP and TRAP-6 were comparable between people with EDS and healthy subjects. In accordance with human EDS platelets, COL5A1+/− mice demonstrated a bleeding tendency characterized by prolonged tail-bleeding time in both sexes (P < 0.05 vs. wild-type control). Platelet function testing showed that COL5A1+/− mouse platelets recapitulated the abnormalities detected in people with EDS platelets.



Conclusions:
Our data affirm the observation that people with EDS exhibit an increased risk of hemorrhagic complications. EDS platelets exhibit reduced baseline GPVI expression associated with decreased agonist-induced platelet aggregation, αIIbβ3 activation, and impaired signaling.

Session: Bleeding in Hypermobility/Ehlers Danlos
Long-Term Efficacy and Safety With Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients With Immune Thrombocytopenia
David J Kuter1, Terry Gernsheimer2, Waleed Ghanima3, Umer Khan4, Brad Ward5, Ahmed Daak5, Nichola Cooper6
1Hematology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2University of Washington Medical Center, Seattle, WA, USA, 3Østfold Hospital Foundation, Gralum, Norway, 4Biostatistics, Sanofi, Bridgewater, NJ, USA, 5Sanofi, Cambridge, MA, USA, 6Department of Medicine, Hammersmith Hospital, London, United Kingdom

Background: Adult patients with immune thrombocytopenia (ITP) treated with rilzabrutinib showed rapid and durable platelet responses and acceptable safety profiles in a global phase I/II trial (NCT03395210). Objective: To report updated efficacy and safety of rilzabrutinib in patients receiving 400 mg BID for 2 years in a long-term extension (LTE) study.

Methods: ITP patients with 2 baseline platelet counts <30×109/L who responded to ≥1 prior ITP therapy but were unable to maintain adequate response to prior/concomitant therapies enrolled in the main study. Primary endpoints were safety and platelet responses (≥2 consecutive platelet counts ≥50×109/L and increased ≥20×109/L from baseline without rescue medication). Patients in the main 24-week study were eligible for LTE if platelet count was ≥50×109/L for ≥50% of last 8 weeks of treatment.

Results: As of 21 December 2022, 16 of 60 patients from the main study enrolled in LTE on rilzabrutinib 400 mg BID (n=11 with concomitant CS and/or TPO-RA). At enrollment, patients had median duration of ITP for 4.3 years, received a median of 3 (range, 1-9) unique prior therapies; 3 were splenectomized. The median treatment duration for main+LTE periods was 1032 days (range, 318-1506). Figure 1 shows median platelet counts over time. All LTE patients met the primary endpoint with median platelet count at LTE entry of 87×109/L. After LTE entry, median platelet counts for LTE patients were 92×109/L, 71×109/L, 61×109/L, and 64×109/L at 3, 6, 12, and 24 months, respectively. Table 1 shows platelet counts above various LTE thresholds; 14 (88%) patients achieved platelet counts ≥100×109/L during the LTE. Two patients received rescue medication during the LTE. All treatment-related adverse events were transient, grade 1/2 events with no related bleeding or thrombotic events, serious adverse events, or deaths.

Conclusions: With continued treatment through the LTE, rilzabrutinib 400 mg BID demonstrated durable clinical activity and remains well tolerated in patients with ITP.
Session: Posters/Exhibits/Break
Vitamin D Deficiency in Persons with Bleeding Disorders - a single center experience
Dan Leary, Mindy Simpson, Lisa Boggio
Rush Hemophilia and Thrombophilia Center, Chicago, IL, USA

Introduction: Vitamin D is a common, treatable vitamin deficiency in the United States. Overall, 15% of the pediatric population and 35% of the adult population has Vitamin D deficiency. No studies have described Vitamin D deficiency in Persons with Bleeding Disorders (PWBD: Hemophilia A (HA), Hemophilia B (HB), and Von Willebrand Disease (VWD)) in Chicago. Objective: To determine the status of Vitamin D Deficiency in PWBD at our center and to evaluate the association with type of bleeding disorder, age, race, and prescription for vitamin D supplementation. Patients and

Methods: After IRB approval, we performed a descriptive, cross-sectional study including 254 patients ages 1 to 76 years from Rush Hemophilia and Thrombophilia Center. Data were obtained on type of bleeding disorder, Age, Race, Vitamin D Supplementation prescription, and Vitamin D levels from 11/23/2010 - 3/2/2023. ANOVA analysis was performed. Vitamin D deficiency was defined as: Severe: <10 ng/mL, Moderate: 10-<20 ng/mL, Insufficient: 20-30 ng/mL, and Normal: >30 ng/mL.

Results: Patient mean age was 26.5 ± 16.4 years; 199 (78.3%) were male. Our population was 165 Caucasian (64.9%), 49 Black or African American (19.3%), 7 Asian (2.8%), 1 Hawaiian/Alaskan Native (0.4%) and 33 Other/Unknown (13.0%). 145 (57.1%) had HA, 27 (10.6%) had HB, 62 (24.4%) had VWD. A prescription for Vitamin D was given to 176 (69.7%) patients - all of those who were not Normal. Mean 25(OH)D level was 25.5±12.4 ng/mL among all bleeding disorders; 21 (8.30%) had severe deficiency, 78 (30.83%) moderate, 77 (30.43%) insufficient, and 78 (30.43%) were normal. In those with moderate and severe deficiency, 57 (65.5%) had HA, 6 (6.9%) HB, and 24 (27.6%) VWD. There was not an association between age or race and vitamin D status (p = 0.745). There was also no difference between type of bleeding disorder and vitamin D deficiency (p = 0.214).

Conclusions: The majority of our bleeding disorder patients (69.6%) have low vitamin D levels. An association with race, age, and prescription for Vitamin D was not demonstrated in deficient patients. As our bleeding disorder patients are at significantly increased risk of developing osteoporosis and osteopenia due to hemophilic arthropathy made worse by vitamin D deficiency, we suggest providers screen all bleeding disorder patients for Vitamin D Deficiency, treat with supplementation if needed, and monitor Vitamin D Serum titers throughout their care. Further evaluation of Vitamin D status is needed in this population.
Session: Posters/Exhibits/Break
Safety and efficacy of valoctocogene roxaparvovec gene transfer for severe hemophilia A: an update from 4 years after treatment
Andrew D Leavitt1, Johnny Mahlangu2, Emily Symington3, Doris V Quon4, Adam Giermasz5, Nigel S Key6, Steven W Pipe7, Bella Madan8, Sheng-Chieh Chou9, Robert Klamroth10,11, Jane Mason12, Flora Peyvandi13,14, Hua Yu15, Tara M Robinson15, Margareth C Ozelo16
1Adult Hemophilia Treatment Center, University of California San Francisco, San Francisco, CA, USA, 2Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg, South Africa, 3Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom, 4Orthopaedic Hemophilia Treatment Center, Los Angeles, CA, USA, 5Hemophilia Treatment Center, University of California Davis, Sacramento, CA, USA, 6UNC Blood Research Center, University of North Carolina, Chapel Hill, NC, USA, 7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA, 8Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom, 9Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 10Vascular Medicine and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany, 11Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany, 12Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women’s Hospital, Brisbane and University of Queensland, Brisbane, Australia, 13Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy, 14Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy, 15BioMarin Pharmaceutical Inc., Novato, CA, USA, 16Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is a gene transfer therapy for severe hemophilia A (HA) that prevents bleeding by enabling endogenous factor VIII (FVIII) production. Objectives: To evaluate the efficacy and safety of valoctocogene roxaparvovec during year (Y)4 post-treatment.

Methods: GENEr8-1 is an open-label, multicenter, phase 3 trial (NCT03370913) that enrolled 134 adult men with severe HA (FVIII ≤1 IU/dL) without FVIII inhibitors. Participants received a single infusion of 6x1013 vg/kg valoctocogene roxaparvovec (intention-to-treat [ITT] population). Bleeding episodes and exogenous FVIII use were self-reported after cessation of regular FVIII prophylaxis, which was scheduled for week (W)4 post-infusion. The primary analysis population for FVIII use and bleeding rate was the rollover population, which included 112 human immunodeficiency virus (HIV)-negative participants who enrolled from a prospective, non-interventional study using FVIII prophylaxis (270-902). FVIII activity (per chromogenic substrate assay [CSA] and one-stage assay [OSA]) and the Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A) were assessed in the modified ITT (mITT) population, which included the 132 HIV-negative participants. Safety and corticosteroid use were assessed in the ITT population. Return to prophylaxis was defined as "usual FVIII prophylaxis" administered at least once per week for ≥4 consecutive weeks or ≥2 emicizumab injections within 31 days. Alanine aminotransferase (ALT) elevation was defined as ALT >upper limit of normal or ALT ≥1.5x baseline.

Results: Overall, 118/134 ITT participants completed 208 weeks or more of follow-up (1 participant discontinued during Y4 due to death unrelated to treatment). Mean and median mITT FVIII per CSA were 16.1 and 6.7 IU/dL, respectively (27.1 and 13.5 IU/dL per OSA, respectively; Figure 1), in line with W156. During Y4, the mean annualized rate of treated bleeds was 0.9 (standard deviation [SD], 2.3) bleeds/y in the rollover population, an 81.3% reduction from baseline and consistent with previous data cuts (Figure 2); 81/110 (73.6%) participants had no treated bleeds during Y4. Similar to previous years, mean annualized FVIII infusion rate decreased 92.2% from baseline to W208 (mean, 10.6 infusions/y; median, 0.0 infusions/y). Health-related quality of life, as measured by mean Haemo-QOL-A Total Score at W208, improved 6.2 points from baseline (95% confidence interval, 3.9-8.4; P <0.0001), the fourth consecutive year at which the change exceeded the anchor-based clinically important difference of 5.5. Of the 24/134 participants who resumed prophylaxis with either FVIII or emicizumab, 11 did so during Y4. During Y4, 106/131 (80.9%) participants experienced an adverse event (AE), 10/131 (7.6%) experienced a treatment-related AE, 13/131 (9.9%) experienced a serious AE, and none experienced a treatment-related serious AE; no AEs led to study discontinuation in Y4. The most common AE during Y4 was ALT elevation, which occurred in 56/131 (42.7%) ITT participants (mostly grade 1-2; 1/131 [0.8%] participant experienced an ALT elevation grade ≥3). No participants initiated immunosuppressants for ALT elevation during Y4.

Conclusions: After 4 years of follow-up, valoctocogene roxaparvovec continues to provide long-term FVIII expression, bleed control, and improvements in health-related quality of life for participants with severe HA, consistent with earlier time points. Importantly, no new safety signals emerged.
Session: Short Talks - Industry Thrombosis - No CME
Procoagulant Rescue of Hemophilia B Causing Factor IX Variants by Factor FVIII Mimetics
Kyumin Lee1,2, Yani Suber1,2, Julia Q. Chau1,2, Sebastian E. Leyes Porello1,2, Bhavya S. Doshi1,2, Ben J. Samelson-Jones1,2
1The Children’s Hospital of Philadelphia, Division of Hematology, Philadelphia, PA, USA, 2University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

Background: The intrinsic Xase enzyme complex, composed of activated coagulation factor (F) IX (FIXa) and its cofactor FVIIIa, activates coagulation FX through proteolytic cleavage. Within the intrinsic Xase, FVIIIa binding allosterically activates FIXa and enhances FX substrate binding, though the details of the FVIIIa/FIXa interaction remain poorly understood. Deficiencies in the assembly of the intrinsic Xase complex result in bleeding disorders hemophilia B (HB) and hemophilia A (HA). The FVIII-mimetic emicizumab, a bi-specific antibody for FIXa and FX, has been widely adopted for prophylaxis for HA patients. However, treatment for HB patients still requires frequent intravenous FIX administration. Because FVIIIa and FVIII-mimetics are biochemically distinct, we hypothesized that the hemostatic activity of some HB-causing FIX variants with dysfunctional Xase assembly may be rescuable by FVIII-mimetics such as emicizumab. Method: Initial screening of HB-causing FIX variants rescued by emicizumab was completed with conditioned media of transiently transfected HEK293 cells using one-stage FIX assays (OSA) and thrombin generation assay (TGA). To account for the OSA activity of emicizumab, the FIX activity of the HB-causing variants was compared against the activity of wild-type (WT) FIX in the presence of an equal concentration of emicizumab. Additional biochemical characterization of variants identified in the initial screen was done with FIX protein purified via affinity chromatography from stable FIX-expressing HEK293 cell lines. Enzyme kinetic parameters in the absence or presence of emicizumab were determined using a purified-protein intrinsic Xase assay. Result: To date, we have identified >40 HB-causing factor IX variants that exhibit at least a twofold increase in OSA activity with a therapeutic concentration of emicizumab (300 nM), including the highly prevalent FIX-R333Q variant. Most of these rescuable variants also display a similar enhancement with the addition of emicizumab in a TGA. Consistent with the screening results, purified FIX-R333Q TGA and OSA activity was 40- to 100- fold lower than purified FIX-WT, but increased 3- to 20-fold with the addition of 300 nM emicizumab. The specific activity of recombinant FIX-R333Q increase twentyfold in the presence of 300 nM emicizumab (Figure 1). Interestingly, the specific activity of FIX-R333Q with emicizumab doubled with the addition of monoclonal FVIII inhibitors, suggesting that FIXa-R333Q is likely able to bind FVIIIa, but this complex has minimal enzymatic activity. Indeed, in the purified-protein intrinsic Xase assay, FIXa-R333Q failed to generate detectable FXa even at high concentrations 90 nM of FVIIIa. However, FIXa-R333Q with emicizumab in the intrinsic Xase assay produced FXa. Combined, these results suggest that the loss-of-function of the HB-causing high prevalence FIX-R333Q variant is due to an impaired interaction between FIXa/FVIIIa and that this impairment can be bypassed with emicizumab. Conclusion: The procoagulant activity of select HB-causing FIX variants with dysfunctional Xase complex assembly can be rescued with therapeutic amounts of emicizumab. Specifically, activated FIX-R333Q is likely unable to functionally interact with FVIIIa, but can be rescued with emicizumab. FVIII-mimetics may be an alternative prophylactic hemostatic therapy for HB patients with FIX variants with similar loss-of-function mechanisms.
Session: Short Talks - Bleeding Back to the Basics
Utility of thromboelastography with platelet mapping (TEG-PM) for monitoring platelet transfusion in qualitative platelet disorders
Robert H. Lee1,2, Tanvi Rudran2, Wolfgang Bergmeier1,2
1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Background: Hemostatic management of platelet function disorders may necessitate platelet transfusion. Patients with pathogenic variants in RASGRP2 (inherited platelet disorder (IPD)-18), the gene encoding for calcium- and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG-GEFI), have normal platelet counts but impaired platelet aggregation due to diminished activation of αIIbβ3 integrin. Importantly, this defect results in moderate to severe bleeding episodes, especially following surgical procedures, which require patients to be transfused with platelets and/or pro-hemostatic agents. We recently demonstrated that the hemostatic efficacy of transfused platelets is limited by dysfunctional endogenous platelets in a mouse model of IPD-18 (Rasgrp2-/- mice). Dysfunctional platelets were recruited to the forming hemostatic plug but did not participate in clot contraction. Consequently, higher amounts of transfused platelets were required to outcompete these dysfunctional cells and to reverse bleeding. For determining post-transfusion platelet ratios clinically, methods such as corrected count increment (CCI) are inaccurate in patients with high endogenous platelet counts and do not discriminate between healthy and dysfunctional platelets. We therefore sought to identify a clinical assay which could monitor healthy transfused platelets. Objective: Investigate the usefulness of thromboelastography with platelet mapping (TEG-PM) for monitoring healthy transfused platelets in the presence of an excess of dysfunctional platelets.

Methods: Whole blood from wild-type (WT) and CalDAG-GEFI deficient Rasgrp2-/- mice was tested in the TEG-PM assay using a TEG 5000 analyzer. Platelet counts and activation status were separately determined by flow cytometry using a BD Accuri C6 Plus benchtop cytometer, and aggregation was measured using a Chronolog light transmission aggregometer. Platelets and fibrin labeled in TEG clots were imaged on a Leica DM4000 scanning confocal microscope.

Results: In the TEG-PM assay using arachidonic acid (AA) as the platelet activator, WT samples (n=8) had average parameter values of K = 1.4 ± 0.6 sec, α-angle = 71 ± 8 deg and MA 64 ± 10 mm, while Rasgrp2-/- samples (n=4) were effectively flatlined with no calculated values. When WT and Rasgrp2-/- blood was mixed, the addition of WT platelets improved TEG parameters in a ratio dependent manner. Consistent with our previous study, a non-hemostatic ratio of 5 Rasgrp2-/- platelets to 1 WT platelet only minimally impacted K and α (6.6 ± 1.4 and 41 ± 4, respectively) while moderately improving MA (45 ± 6). In comparison, a pro-hemostatic 2:1 ratio improved K, α and MA closer to WT values (2.5 ± 0.7, 61 ± 6 and 55 ± 7, respectively). When we analyzed individual samples using the exact percentage of WT platelets as determined by flow cytometry, K and α were more predictive of a hemostatic ratio than MA. Fluorescence confocal imaging of TEG-PM clots demonstrated that only WT platelets activate and participate in contraction of the fibrin network even in the presence of Rasgrp2-/- platelets. We also found a weak association of light transmission aggregometry results with in vivo hemostatic efficacy, suggesting that this common clinical assay is not suitable for monitoring platelet transfusion ratios.

Conclusions: In conclusion, this proof-of-concept study demonstrates the potential use of TEG-PM to monitor platelet transfusion ratios in certain qualitative platelet function disorders.
Session: Posters/Exhibits/Break
Normalization of thrombin generation results using within-run plasma normalizator simultaneously.
Loic J. Letertre1,2, Pall T. Onundarson1, Jon T. Bergthorsson1,2
1Landspitali - The National University Hospital, Reykjavik, Iceland, 2The University of Iceland, Reykjavik, Iceland

Background: Automated thrombin generation (ATG) assessment theoretically has an almost limitless potential for assessing anticoagulation as well as hypercoagulable and bleeding phenotypes. However, ATG assessment has been limited by high intra- and especialy inter-assay as well as reagent-dependent variation. This has complicated ATG comparison from one center or study to another and has deterred clinical usability of the assay. Objectives: We hypothesized that within-run normalization of thrombin generation results using a suitable pooled normal plasma (PNP) in addition to applying standardized manufactured reagents and calibrators would reduce such variations. If successful, normalization would provide an improved ATG method and also a clinically meaningful unit that might bring ATG closer to clinical use.

Methods:
A single user measured ATG and standard clinical laboratory coagulation tests in pooled normal plasmas (PNPs) of different origin using a single manufacturer´s instrument and different lots of standard reagents. The tested PNPs included an in-house prepared double-centrifuged PNP frozen plasma, different lots of commercial frozen PNPs and a single lot of lyophilized PNP. ATG was also assessed in double-centrifuged plasma samples from 30 healthy individuals. Particle debris present in the plasmas was assessed using flow cytometric methods.

Results:
The raw calibrated ATG intra-assay variation performed on the PNPs was very low, i.e. coefficient of variation (CV%) below 6% for Peak TG and below 3.7% for ETP. Raw data inter-assay variation was within 10.7% for the Peak TG and within 3.1% for the ETP. The manufactured frozen plasma PNP GK7370 fitted best the median ATG in our normal cohort and was therefore selected as normalizator plasma. The in-house and lyophilized PNPs were less suitable for normalization. Using the selected normalizator plasma and standardized reagents, inter-assay variation remained low (below 12% for peak TG and 4.1% for ETP). Furthermore, following normalization, reagent lot-to-lot variation (CV%) was markedly reduced, i.e. 74% for ETPs, 78% for Peak TG and 92% for time to peak TG. Flow cytometry did not identify tissue factor in the PNPs although some debris of platelet membrane origin was present.

Conclusions:
Normalization of ATG using a frozen PNP that had ATG results fitting the median ATG of a normal cohort led to a marked reduction in reagent lot-to-lot variation. Normalization of ATG results by reducing reagent-dependent variation may help open the door for ATG use in clinical practice and comparative studies.
Session: Posters/Exhibits/Break
Understanding Primary Antiphospholipid Syndrome: Correlating Antiphospholipid Antibodies Profile and Titers with Thrombotic and Hematological Activity
Amaya Llorente-Chávez, Rodrigo Figueroa-Méndez, Gabriela A. Hernández-Molina, Alfonso Orozco-Collazo
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Mexico City , Mexico

Background: Thrombotic and hematological manifestations are common in primary antiphospholipid syndrome (pAPS) and little is known regarding the differences of the antibodies profile. Aim: To evaluate the coventional and extended profile of antiphospholipid antibodies in pAPS with thrombotic or hematological phenotype.

Methods: A retrospective study included patients with pAPS, diagnosed according to the Sapporo criteria with follow-up at third level of care in Mexico City from 1990 to 2021. Descriptive statistics, chi-squared test, Mann-Whitney U test, and logistic regression were performed.

Results: A total of 97 patients with pAPS were included; 73.2% were women with a mean age of 33.9 +11.5 years and a mean follow-up of 132 months (24-360). We found that 77% of patients presented thrombotic and 68% hematological manifestations. Patients suffered a mean of 1 (1-3) thrombotic event, being the most common type venous trombosis (VT) in 37.1%, followed by a combination of arterial and venous thrombosis (AVT) in 27.8% and the minority arterial thrombosis (AT) in 12.4%. Those who had AVT had higher titers of anticardiolipin (aCL) IgG and IgM in 34.6 and 9.6, respectively (p = 0.031), anti-β2 glycoprotein-I (aβ2GPI) IgM in 6.6 (p = 0.01) and anti-phosphatidyl serine/prothrombin (aPS/PT) IgG in 113.8 (p = 0.044) from the three groups. Patients with VT compared to those with AT had higher titers of aCL IgG in 9.6 vs 6.6 (p = 0.031), IgM in 10.8 vs 7.25 (p = 0.005), and aβ2GPI IgM in 5.7 vs 4.4 (p = 0.01). Cases with AT had higher titers of aPS/PT IgG in 55.4 (p = 0.044). Regarding the hematological activity; 63.9% patients had thrombocytopenia, most commonly being severe. A total of 59.7% had a triple marker. In comparison with patients without thrombocytopenia, 69.4% presented positive lupus anticoagulant vs. 48.6% (p = 0.043) and OR 2.5 (CI 95% 1.06-6.1). An 83.9% had positive aCL IgG vs. 62.9% (p = 0.019) and OR 3.21 (CI 95% 1.19-8.63) with a higher titer of 19.4 vs. 6.1 (p = 0.017). Also higher titers of aβ2GPI IgM of 6.8 vs. 5.2 (p = 0.019) as of aPS/PT IgM of 52.8 vs. 16.8 (p = 0.004). A 13.4% of patients had autoimmune hemolytic anemia, with higher aβ2GPI IgM titers of 7.1 vs. 5.9 when compared with those who did not present it (p = 0.026) and 77% had thrombosis. Those without hematological activity had more thrombosis (p <0.001). When comparing the groups with and without thrombosis, we observed that those with thrombosis had lower titers of aβ2GPI IgM in 5.8 vs. 7.4, p = 0.036 and aCL IgM in 9.4 vs 12.8, p = 0.09. They had higher aPS/PT titers in 61.2 vs. 12.1, p = 0.021. Conclusion: Differences were found regarding the titer and positivity of antibodies between the thrombotic or hematological phenotype; and also between the three groups of thrombosis. Knowing the serology of pAPS is useful to promptly identify patients with hematological or thrombotic activity as well of complications. In our knowledge this is one of the few studies that has compared the antibodies profile of the different phenotypes.
Session: Short Talks - Thrombosis - Special Populations
Genomic Variations in Factor VII deficiency predisposing to thrombophilia: A case of sinus venous thrombosis in a patient with Factor VII deficiency
Aaron C. Lobo 1, Paridhi Ghai1, Fabricio M Webber1, David H. Witt2
1Bridgeport Hospital/Yale New Haven Health , Bridgeport, CT, USA, 2Yale Smilow Cancer Center/Yale school of Medicine, Trumbull, CT, USA

Background: Congenital Factor VII (FVII) deficiency is the most frequently occurring rare inherited bleeding disorder and has a wide spectrum of clinical manifestations ranging from asymptomatic to life-threatening hemorrhage. This heterogenous presentation is influenced by FVII gene polymorphisms and results in poor correlation between FVII activity levels, antigen levels and the bleeding phenotype. A subset of patients with FVII deficiency have been known to present with thrombotic manifestations even in patients with a prior history of severe bleeding. Several genetic variants have been implicated to have thrombogenic pathogenicity, with varying potential mutational mechanisms causing thrombosis. Objectives: This case describes a patient with multiple thrombotic episodes in the setting of FVII deficiency who was subsequently identified to have a two potential prothrombogenic FVII genetic mutations.

Results: A 72 year old male diagnosed with Factor VII(FVII) deficiency with prior history of deep vein thrombosis in the setting of perioperative FVII replacement, presented to the hospital with unprovoked altered sensorium and right sided facial droop. Magnetic Resonance Imaging of the brain and venous sinuses was notable for straight vein, internal cerebral veins, and vein of Galen thrombosis with multiple bilateral thalamic, white matter and left caudate ischemic strokes in the setting of a venous thrombosis. He was initiated on a heparin drip and admitted to the intensive care unit for close neurologic monitoring and subsequently transitioned to enoxaparin on discharge. A workup consisting of age appropriate malignancy screening, inherited thrombophilia and JAK2 mutation were negative except presence of a positive plasminogen activation inhibitor -1 deficiency. An extended genomic assessment showed two single nucleotide variations leading to missense mutations: A354V/A294V mutation (autosomal recessive, likely pathogenic ) and V312M mutation (autosomal recessive, of unknown significance). FVII A354V/A294V gene variant present in the serine protease domain, has been frequently described in FVII deficient patients in both homozygous and heterozygous inheritance .This gene and its variants likely exert their influence by altering FVII interaction with FVII activators, substrates and cofactor . This resultant dysfunctional FVII, impairs activated FVII- Tissue Factor interactions without affecting the serine protease features possibly contributing its coagulopathic effects, but also resulting in clinical bleeding. FVII V312M is associated with a milder bleeding phenotype and is usually present as a heterozygous allele with coinheritance of an additional FVII gene variants. Conclusion: Factor VII deficiency with genetic variations that are thrombogenic, predisposes patients to clot. This can occur in the setting of hospitalizations, surgery, and treatment with factor replacement. In this case, the patient's prothrombotic state was likely brought about by compound heterozygous FVII gene mutations with thrombogenic potential and presence of concomitant plasminogen activation inhibitor-1 (PAI-1) deficiency.
Session: Posters/Exhibits/Break
Predicting Pulmonary Embolism in Patients with Deep Venous Thrombosis in the Emergency Department: A Quantitative D-dimer Diagnostic Approach from a Hospital in Mexico City
Oscar A Lopez Ramos1, David G Gonzalez Sanchez 2, Oliver A Gomez-Gutierrex2, Hector Segura Marin2, Andrea Rojas Guevara 1, Arely Gayosso Godinez 1
1Hospital Español , Mexico City , Mexico, 2Tecnologico de Monterrey , Monterrey , Mexico

BACKGROUND: Definitive diagnostic markers for venous thromboembolic disease remain elusive. Pulmonary embolism (PE) is a major cause of mortality with an estimated incidence of 15% in a postmortem analysis in Mexico. Finding quick, low-cost diagnostic methods has gained significance, especially in limited resource settings. Recent research has explored the potential use of D-dimer values to predict PE finding an incremental likelihood of PE with elevated D-dimer concentrations. OBJECTIVE: This study aims to evaluate the relationship between elevated D-dimer values and PE in patients diagnosed with deep venous thrombosis (DVT) in the emergency room. MATERIAL AND METHODS: Patients diagnosed with DVT via Doppler ultrasound between 2018 and 2022 at the emergency department of the Hospital Español in Mexico City, were selected for the study. Demographic and clinicopathologic characteristics of these patients were recorded using Excel and statistical analysis was conducted using SPSS. RESULTS: A total of 276 patients were diagnosed with DVT in the emergency department during the study period. Data from 68 patients was excluded due to a lack of D-dimer value or computed tomography pulmonary angiography leaving a remaining population of 208 patients. A total of 123 (59%) patients had an imaging study confirming the diagnosis of PE. The average D-dimer level was 10,011 ng/mL (range: 231-42,435 ng/mL). Demographic and clinical characteristics are presented in Table 1. ROC curve analysis demonstrated an area under the curve of 0.77 (95% CI, 0.705-0.840, p=0.034) for a D-dimer value ≥ 4905 ng/mL. This cutoff point of D-dimer ≥ 4,905 ng/mL demonstrated a sensitivity of 77% and specificity of 66% for diagnosing PE. Patients with a D-dimer value ≥ 4,905 ng/mL had a 6.9 times greater risk of having PE (OR 6.98, 95% CI 3.7-12.9, p<0.001). People with a D-dimer value ≥ 4,905 ng/ml were significantly more likely to be sedentary (p=0.1), older (p= 0.0001), and have a higher BMI (p=0.04). No statistically significant difference was found between a D-dimer level ≥ 4,905 ng/ml and complications during hospitalizations (p=0.7). CONCLUSION: This study focused on an emergency department in Mexico City and supports the growing body of evidence suggesting the quantitative use of D-dimer levels for the timely identification of patients with PE. Elevated D-dimer levels, ≥ 4,905 ng/mL, were identified as a potential indicator of coexisting PE in patients with DVT. These patients were more sedentary, older, and had a higher body mass index. The influence of these factors underscores the multifactorial nature of this relationship, emphasizing the importance of considering these factors in the clinical assessment of thromboembolic diseases. Our findings suggest that D-dimer levels ≥ 4,905 ng/mL can aid in the decision to order further diagnostic imaging studies for PE, particularly in limited resource Settings.
Session: Online Poster Session
Two-center external validation of a machine learning natural language processing (NLP) algorithm for venous thromboembolism (VTE) ascertainment
Shengling Ma1, Omid Jafari1, Arash Maghsoudi1, Jennifer La2, 3, Emily Zhou4, Iuliia Kovalenko5, Steven Horng3, 6, Nathanael Fillmore2, 3, Ang Li1, Barbara Lam6
1Baylor College of Medicine, Houston, TX, USA, 2VA Boston Healthcare System, Boston, MA, USA, 3Harvard Medical School, Boston, MA, USA, 4University of Texas Health Science Center at Houston, Houston, TX, USA, 5UPMC Harrisburg, Harrisburg, PA, USA, 6Beth Israel Deaconess Medical Center, Boston, MA, USA

Background The ability to identify VTE accurately and quickly in large clinical datasets is paramount for hemostasis and thrombosis research. Previously developed NLP algorithms have often relied on specific keyword extraction that are difficult to generalize to different healthcare systems. Objectives We recently derived a transformer-based machine learning NLP algorithm from 800 cancer patients at the Harris Health System (HHS) (doi.org/10.1182/blood-2023-184756). We aimed to externally validate this algorithm at two large healthcare systems. Methods We previously derived a novel VTE NLP algorithm by combining keyword-based pre-processing and a finetuned BioClinicalBERT transformer model on 2,000+ notes from HHS to reach a positive predictive value (PPV) of 98% and sensitivity of 98%. For the current study, we utilized free-text data from two clinical datasets: 1) Beth Israel Deaconess Medical Center (MIMIC-IV) and the 2) Veterans Affairs Healthcare System (VA) (Figure 1). For note-level validation (MIMIC-IV), we tested the algorithm on computed tomography angiography (CTA) radiology reports to identify PE during hospitalization. For patient-level validation (VA), we tested the algorithm on sequential radiology reports, discharge summaries, and outpatient progress notes to identify the first-ever VTE date after cancer diagnosis. Similar data pre-processing and model application was performed without model retraining. Gold standard, defined as acute pulmonary embolism (PE) in MIMIC-IV and PE or deep vein thrombosis (DVT) in VA, was determined by physician researcher manual chart adjudication. For patient-level validation, we classified an event as false positive if VTE occurred >90 days from the first predicted date. Results Free-text clinical notes from MIMIC-IV and VA had different physician/patient characteristics, formatting styles, and line break/return structures. The pre-processing algorithm was able to successfully identify the keyword-containing sentences in each dataset. In MIMIC-IV, we identified 17,438 CTA reports with PE keywords. The transformer NLP model correctly labeled 1,437 out of 1,598 positive predictions (PPV 90%) and identified 1,437 out of 1,531 positive PE events (sensitivity 94%) (Figure 2). In VA, we sampled 800 cancer patients with VTE keywords. After excluding 24 patients with known historic events, the transformer NLP model correctly labeled first VTE events in 410 out of 462 patients (PPV 89%) and identified 410 out of 474 positive VTE events (sensitivity 87%). The majority of false positives were related to sentences describing chronic events such as "Multiple bilateral pulmonary emboli are again seen…" and "There is residual pulmonary embolism...". Conclusions In this external validation study, our recently derived transformer-based NLP algorithm for VTE performed well at two healthcare systems. On a note level, the algorithm correctly labeled 9 out of 10 PE among 17,438 CTA reports. On a patient level (more challenging), the algorithm correctly identified 9 out of 10 first-ever VTE dates among 38,533 notes in 776 patients after cancer diagnosis. The algorithm accomplished these tasks in <2 hours with minimal researcher guidance. It also appeared generalizable to different populations (non-cancer vs. cancer) and outcomes (PE vs. PE/DVT). We believe machine learning-based NLP algorithms have the potential to replace cumbersome billing codes and chart reviews for VTE outcome ascertainment in database studies.
Session: Posters/Exhibits/Break
Germinal center and non-germinal center B cell response to factor VIII in hemophilia A patients
Maya Maarouf1, Ian Smith1, Wallace H Baldwin1, John F Healey1, Ernest T Parker1, Courtney Cox1, Robert F Sidonio, Jr1, Karen L Zimowski1, Glaivy Batsuli2, Bhavya S Doshi3, Shannon L Meeks1, Seema R Patel1
1Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, USA, 2Stanford University, Palo Alto, CA, USA, 3Department of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA

Background: Though effective at preventing bleeds, factor VIII (FVIII) mimetics do not provide persons with hemophilia A (PwHA) sufficient hemostatic activity to treat bleeds or protect during surgeries, resulting in the need for FVIII therapy. FVIII can induce inhibitors (anti-FVIII neutralizing antibodies), making clinical management of PwHA challenging. A lack of understanding regarding mechanisms that drive immunity to FVIII limits the ability to predict or prevent inhibitor formation. It has long been hypothesized that inhibitors develop through a germinal center (GC)-dependent process. However, inhibitors can be transient, or can wane or persist when FVIII is withdrawn; suggesting that the mechanisms driving inhibitor development may differ. Corroborating this, preclinical data demonstrate that inhibitors can form via a GC or non-GC process. Whether these findings extrapolate to PwHA is unknown. Thus, a pilot study that screened PwHA for formation of a GC or non-GC B cell response to FVIII was performed.

Methods: Plasma and PBMCs from unique subjects enrolled in an IRB approved Inhibitor Characterization study and Biorepository from Children's Hospital of Philadelphia were used. PwHA subjects (pediatric) included: 24 with inhibitors (PwHAi; 4 no immune tolerance induction (ITI) attempt, 4 failed ITI, 1 ongoing ITI, 15 successful ITI), 8 without inhibitors (>50 exposure days (ED) to FVIII), and 5 with <50 EDs to FVIII. Five adult healthy subjects were also included as controls. The FVIII specific B cell response was phenotyped using a FVIII B cell tetramer. The antibody response was measured by ELISA and Bethesda.

Results: Within the bulk population of B cells, a greater percentage of FVIII reactive B cells was observed in all PwHA (15%) compared to healthy subjects (3%; p<0.0001). The FVIII reactive B cells in healthy subjects primarily consisted of mature B cells. Fifty-four percent of PwHA demonstrated a greater percentage (if not sole presence) of FVIII specific double negative (DN) 3 B cells (10%) that associate with non-GC responses compared to FVIII reactive class-switched memory B cells (CSW MBCs; 4%) that indicate formation of a GC response (p=0.0001). Interestingly, of the PwHA that generated a non-GC response, 16 were PwHAi (4 no ITI attempt, 1 failed ITI, 11 successful ITI), 2 were without inhibitors, and 2 had <50 ED to FVIII. The remaining PwHA demonstrated a greater percentage (if not sole presence) of FVIII specific CSW MBCs (9%) than FVIII reactive DN2/3 B cells (3%; p<0.001). Conclusion: These data suggest that immunity to FVIII can form through both a GC and non-GC process, and that non-GC responses may correlate with the ability to tolerize patients to FVIII. While these findings are from a small cohort, these results corroborate the preclinical data, support the hypothesis that differential inhibitor responses may result from engagement of distinct pathways of antibody production, and highlight the need for future studies evaluating the role of these pathways on differential inhibitor formation. Doing this may identify biomarkers for predicting which patients will develop a non-GC response (waning inhibitors), and thereby, are most likely to benefit from ITI or FVIII therapy.
Session: Short Talks - Bleeding Back to the Basics
Nationally Representative Data on Co-diagnosis, Mortality and Healthcare Burden of Venous Thromboembolism in Hospitalized COVID-19 patients: Results from the National Inpatient Sample
Giuseppe Maiocco1, Krish Khurana2, Nareg H. Roubinian3, Stephanie Bitner1, Waqas Azhar1, Hareena Sangha4, Nikhil Gupta5, Evan M. Bloch6, Michael B. Streiff6, Aaron A. R. Tobian6, Ruchika Goel1, 6, 7
1Southern Illinois University School of Medicine, Springfield, IL, USA, 2SIU School of Medicine P4P program, Springfield, IL, USA, 3Vitalant Research Institute, San Francisco, CA, USA, 4University of Texas Southwestern School of Medicine, Dallas, TX, USA, 5Case Western Reserve University School of Medicine, Cleveland, OH, USA, 6Johns Hopkins University School of Medicine, Baltimore, MD, USA, 7Vitalant Corporate Medical Affairs, Scottsdale, AZ, USA

INTRODUCTION: COVID-19 increases the risk of thrombosis via multiple mechanistic pathways. Given heterogeneity of studies pertaining to COVID-19 and thrombosis, the reported prevalence of venous thromboembolism (VTE) [deep vein thrombosis (DVT)/pulmonary embolism (PE)] in COVID-19 varies. We evaluated the co-diagnosis, mortality, and healthcare burden of VTE in COVID-19 hospitalizations during the first nine months of the pandemic (April-December 2020) in the United States (US) using a nationally representative database. METHODS: The Nationwide Inpatient Sample Healthcare Cost and Utilization Project (HCUP-NIS) is the largest all-payer inpatient database in the US, approximating a 20% stratified sample of inpatient discharges from >5000 hospitals across 48 states. Data from the 2020 HCUP-NIS was used to generate nationally representative estimates of COVID-19 associated thrombotic events; CCSR and ICD-10 codes were used to identify hospital discharges in which diagnoses of COVID-19 and VTE were listed. Given limited cases of COVID-19 in the US from January-March 2020, analysis was restricted to April-December 2020. Age and gender Adjusted Odds Ratios (aOR) were calculated and statistical comparisons of proportions and medians as applicable were performed via STATA V18.0. RESULT: Of 23,856,131 US hospitalizations from April to December 2020; 1,630,410 (6.8%) listed COVID-19 as a diagnosis(Table 1A). Of these, 81,450 (5.0%) had co-diagnosis of VTE [45,860(56%) PE, 44,765(55%) DVT, and 9,175(11%) PE and DVT]. Median age (interquartile range (IQR)) for admissions with COVID-19 and VTE was 66(55-77) years with 98.7% admissions classified as having major/severe underlying illness. VTE in COVID-19 occurred at significantly higher rates than non-COVID-19 admissions (aOR(95%CI) (aOR)=1.37(1.35-1.39);p<.0001). By clot location, the odds of PE was higher in COVID-19 hospitalizations (aOR=1.78(1.74-1.82);p<.0001), with subsegmental PE occurring more commonly (aOR=2.00(1.89-2.12);p<.0001). Odds of DVT were also elevated in COVID-19 hospitalizations (aOR=1.02(1.00-1.05);p=.03), with lower extremity (aOR=1.24(1.21-1.27);p<.0001) and upper extremity (aOR=1.20(1.14-1.26);p=<.0001) DVTs occurring more frequently. MORTALITY: Overall rates of all-cause mortality were significantly higher in COVID-19 hospitalizations than general admissions (12.9% vs. 2.9%, aOR=5.00(4.94-5.07);p<.0001),Table 1B). Further, all-cause mortality for COVID-19 admissions with VTE was nearly twice as compared to those without VTE (aOR=1.98(1.90-2.06);p<.0001). Likewise, all-cause mortality was higher independently for both DVT (aOR=2.19(2.08-2.31);p<.0001) and PE (aOR=1.61(1.52-1.70);p<.0001). HEALTHCARE BURDEN: COVID-19 hospitalizations with VTE were associated with significantly longer median(IQR) length of stay than COVID-19 without VTE [9(4-18)days versus 5(3-9)days; (p<.0001)] and nearly twice median hospital charges [$84,417($39,188-$204,888) versus $44,091($23,680-$87,622);p<.0001)](Table 2A). CO-DIAGNOSES/PROCEDURES: Most common co-diagnoses in admissions with COVID-19 and VTE included respiratory failure (57.7%), renal failure (39.4%), diabetes (37.6%), hypertension (37.3%), and obesity (36.7%)(Figure 2). Highest coded procedural interventions in COVID-19 and VTE admissions were mechanical ventilation (32.6%), central line placement (25.0%), Remdesivir administration (24.3%), airway insertion (22.8%), and transfusion of convalescent plasma (12.4%) (Table 2B). CONCLUSIONS: These nationally representative data show that VTE was a frequent complication among hospitalized patients with COVID-19 during the first year of the pandemic. VTE in COVID-19 is associated with significantly higher all-cause mortality, length of hospitalization, and total hospital expenditures than COVID-19 admissions without VTE. These findings highlight the healthcare burden of COVID associated venous thromboses.
Session: Short Talks - Thrombosis - Special Populations
Health Literacy in Pediatric Thrombosis Patients and Parents/Caregivers
Athena Mancini, Denise Bastas, Sindi Mukaj, Gina Wong, Leonardo R. Brandão, Jennifer Vincelli , Diandra Rollan, M. Laura Avila
The Hospital for Sick Children, Toronto, ON, Canada

Background: Management of children and adolescents with acute thrombotic events and potential chronic complications includes both disease-specific (e.g., use of anticoagulants or compression garments) and general lifestyle strategies (e.g., modified physical activity while on anticoagulants to prevent bleeding and avoidance of risk factors for thrombosis). Patient engagement in the self-management of their condition improves health outcomes. However, knowledge and skills (i.e., health literacy) are important to effectively incorporate the expected disease-specific and lifestyle strategies. Objectives: To assess the health literacy levels of adolescent patients and parents/caregivers of patients with pediatric thrombosis and their perception of and satisfaction with their disease-specific knowledge.

Methods: Patients aged 10-18 years with a history of venous thrombosis and parents/caregivers of patients aged 0-18 attending the Thrombosis Clinic at The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada, for routine follow up, were prospectively recruited in this cross-sectional study. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine Short Form (REALM-SF) for adults, the REALM-TeenS for adolescents, the Health Literacy Assessment Scale for Adolescents (HAS-A), and the eHealth literacy scale (eHEALS). Self-perceived thrombosis knowledge was assessed using researcher generated questions, informed by previous research. Results were compared between patients and parents/caregivers.

Results: Eighty-six participants, including 36 adolescents and 50 parents/caregivers of children who sustained a venous thrombotic event were recruited between June 2023 and December 2023. The median age of adolescents at the time of participation was 16 years (25th-75th percentile 13-17 years) and 47% of parents/caregivers were younger than 40 years old. Health literacy, as measured with REALM, indicated that 22% of parents/caregivers and 28% of adolescents scored a grade range equivalent indicating that they will struggle with patient education materials. In total, 25% of adolescents had a reading level below their grade level. HAS-A scores showed low health literacy across the three domains in one to two-thirds of adolescents and 14%-41% of parents (Table 1). Overall, 78% of the adolescents and 58% of the parents/caregivers had one or more measures indicating low health literacy. Despite having direct experience with venous thrombosis and a median of 2 clinic visits (25th-75th percentile 1-4), ~25% of participants disagreed with the statements "I can recognize the symptoms of a blood clot", "I know the treatment options for a blood clot", and "I am aware of the long-term complications of a blood clot" (Figure 1). A key finding is that only one-third to a half of the participants were satisfied with how much they knew about the disease. Conclusion: Effective strategies to develop health literacy in this population are necessary to support the burden on patients and parents/caregivers to self-manage their condition. Such strategies will provide tools to translate health knowledge into behaviour, empowering these young patients to engage in health decision making and self-management across their lifespan.
Session: Short Talks - Thrombosis - Special Populations
Tolerability and Pharmacodynamic Effect of REGN9933, a Monoclonal Antibody Directed Against the Factor XI Apple 2 Domain: Results from a First-in-Human Study
Ethan Marin1, Guixian Lin1, Hisham Abdallah1, David Gutstein1, Andrew Kordahi2, Karoline Meagher1, Frederic Cauwberghs3
1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA, 2Regeneron Pharmaceuticals, Inc. (at time of study), Tarrytown, NY, USA, 3SGS (at time of study), Antwerp, Belgium

Background: Venous and arterial thromboembolic diseases are a leading cause of death worldwide. Current standard-of-care anticoagulants, although effective for the prevention and treatment of these diseases, are associated with an increased bleeding risk. REGN9933 is a monoclonal antibody that binds to the factor XI (FXI) apple 2 domain, thereby selectively blocking activation of FXI by activated FXII - an initial step in the intrinsic coagulation pathway. However, this mechanism may not interfere with FXI autoactivation, or activation by thrombin downstream of the extrinsic coagulation pathway, so REGN9933 may prevent thrombosis without increasing bleeding risk. Here, we report results from a first-in-human study (NCT05102136) of REGN9933 in healthy volunteers. Objectives: To evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of REGN9933 in healthy volunteers.

Methods: This was a Phase 1, randomized, double-blind, placebo-controlled, single-center study. Healthy volunteers received a single dose of REGN9933 (or placebo), with intravenous (IV) doses ranging from 3 mg to 300 mg, and subcutaneous (SC) doses of 100 mg and 300 mg. The primary endpoint was the incidence and severity of treatment‑emergent adverse events (TEAEs). Secondary/exploratory endpoints included the effect of REGN9933 on the coagulation cascade using intrinsic pathway-triggered (activated partial thromboplastin time [aPTT]) and extrinsic pathway-triggered (prothrombin time [PT]) coagulation assays, and FXI activity.

Results: In this Phase 1 study, 56 participants received REGN9933 or placebo (IV REGN9933, n=30; SC REGN9933, n=12; placebo, n=14). In the REGN9933 and placebo cohorts, the median age was 49.5 years and 45.5 years, and 69% and 86% were male, respectively. In the REGN9933 cohorts, 42.9% of participants experienced ≥1 TEAE, compared with 21.4% in the placebo cohorts. The most common TEAEs (≥5% of patients) across the REGN9933 cohorts were headache (12%) and oropharyngeal pain (5%). One participant experienced a TEAE related to REGN9933 (Grade 1 fatigue). No serious or severe TEAEs, or TEAEs of special interest (including moderate/severe bleeding), were reported. REGN9933 resulted in a dose‑dependent prolongation of aPTT (Figure 1). The maximum aPTT mean fold-change from baseline was 2.7 (8 hours post administration of IV REGN9933 300 mg), and this approximate level of aPTT prolongation was maintained for ~22 days. No meaningful changes in aPTT were observed with placebo. There was no detectable effect of REGN9933 on PT, and no clinically meaningful effect on bleeding time. REGN9933 suppressed FXI activity in a dose‑dependent manner; maximal suppression to approximately the lower limit of quantitation of the assay (5% activity) was achieved at IV REGN9933 ≥30 mg, and robust suppression was maintained to approximately Day 43 with IV REGN9933 300 mg (Figure 2). Changes in FXI activity were minimal in the placebo cohorts. REGN9933 displayed nonlinear pharmacokinetics across the dose ranges studied for the IV and SC cohorts.

Conclusions: These first-in-human data suggest that REGN9933 has a dose-dependent inhibitory effect on the intrinsic coagulation pathway without affecting extrinsic pathway activity. These findings, allied with the tolerability profile of REGN9933, support its continued development as an anticoagulant that may carry less risk of bleeding than existing therapies.
Session: Short Talks - Industry Thrombosis - No CME
Impact of mRNA COVID-19 Vaccination on D-Dimer Levels and Anti-PF4 Seroconversion in Healthy Adults: A systematic review
Evan Y Maroun M.S., Megan Centrella, Grace Hansen, Trevor Forsberg, Tariq Rahaman M.L.I.S., Hoang Nguyen M.D. Ph.D.
Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, FL, USA

Introduction: Vaccination complications have recently increased due to the novel world-wide administration of COVID-19 vaccinations since 2020. Considering the United States has paused Johnson & Johnson vaccine's administration, this paper aimed to analyze the coagulative effects of mRNA vaccinations (Pfizer-BioNTech and Moderna). Numerous research studies have explored the association of AstraZeneca and Johnson & Johnson vaccines with thromboembolic and coagulative events post-administration, however, few have studied the complications, or lack thereof, after receiving mRNA vaccines. Objective: Two outcomes of interest explored were D-dimer levels as well as positive serology of anti-platelet factor 4 (anti-PF4) antibodies after healthy participants received COVID-19 mRNA vaccination as compared to prior the administration of vaccination.

Methods:
A search conducted across multiple databases, shown in the PRISMA diagram, included keywords relating COVID-19 vaccination with measured D-dimer levels or anti-PF4. After extraction, abstracts were de-duplicated and blindly screened according to pre-defined inclusion/exclusion criteria using Rayyan platform. D-dimer levels were compared with established normal value of less than 0.5 mg/L, while positive serology for anti-PF4 post-vaccination percentage increases were analyzed. Initial database searches yielded 2007 articles which were de-duplicated to 1240. Further abstract screening and full-text analysis narrowed the search to 6 papers which included healthy participants with no predisposing autoimmune diseases or underlying complications, no COVID-19 infection within the past 3 months, as well as collected blood samples prior to COVID-19 vaccination.

Results:
Among 471 subjects analyzed for positive anti-PF4 serology, 15 (3.2%) tested positive post-vaccination. These antibodies remained stable post-vaccination with no adverse complications reported in all studies analyzed. Out of 278 participants tested for D-dimer levels, there was a 9.16% total increase (95% CI) between mean D-dimer levels of pre-vaccination (0.25 mg/L) and post-vaccination (0.27 mg/L). There was no significance associated with either one or two doses administered to participants, as well as absence of thromboembolic events within the time periods followed (up to 57 days, median follow-up of 15 days).

Conclusions:
The results of this systematic review are two-fold. First, there is no large population analyzed for D-dimer levels or anti-PF4 seroconversion post-vaccination, excluding recently infected COVID-19 participants or any underlying condition that may exponentiate these levels. Second, based on the study data included in this review, mRNA vaccines were not found to be associated with significant increases in D-dimer levels relative to 0.5 mg/L. Moreover, there is a minor anti-PF4 seroconversion rate post-vaccination, which remaining stable even after another dose, which resulted in no further complications during the follow-up period. These results support the continued administration of both Pfizer-BioNTech and Moderna vaccines to the public for COVID-19 infection preventative measures.
Session: Posters/Exhibits/Break
Value of Functional Protein S Activity Assays for Detection of Type II Protein S Deficiency
Katharine A. Marsden, Shelbey Bauman, Peter F. Mannion, Morayma Reyes Gil
Cleveland Clinic Foundation, Cleveland, OH, USA

Background: Protein S deficiency is a hereditary thrombophilia which occurs in three forms: Type I (quantitative), type II (qualitative) and type III (qualitative due to a gain of function). Literature suggests that of these, type II is the rarest and most difficult to diagnose. Type II protein S deficiency is only detectable by assaying protein S activity with a functional, clot-based test. However, this test is susceptible to interference, and has a lower specificity when compared to antigen assays used to detect free and total protein S levels. Due to this, the Choosing Wisely Guidelines released by the ABIM Foundation recommends against using protein S activity assays entirely. Instead, they suggest using only free protein S antigen assays. Although the rationale is to avoid false positive results from the protein S activity assay, it ultimately may result in a failure to detect type II protein S deficiency. Objectives: This study, performed at a tertiary medical center in the Midwestern region of the United States, aims to determine the proportion of false positives in functional assays as well as the percent of true type II protein S deficiency cases within this testing population.

Methods: All cases with abnormal protein S function within the institution were evaluated from July 2018 through July 2023 and classified as acquired or hereditary deficiencies. Cases were classified as acquired if there was evidence of liver disease, vitamin K deficiency, ongoing thrombosis, consumption, disseminated intravascular coagulopathy, or pregnancy. Possible hereditary deficiency cases were classified as type I, type II and type III: Type I if all assays were low, type II if both active and free protein S assays were low with normal total protein S, and type II if only protein S activity was low. The cutoff defined for normal total and free protein S levels was greater than 70% activity, and the low protein S activity cutoff was defined as less than 50%. Patients with low protein S activity but normal immunologic protein S and an elevated factor VIII were considered falsely low values. Chart review will be performed for remaining cases with low protein S activity with normal factor VIII and normal INR to rule out confounders such as vitamin K deficiency, warfarin use, acute phase reaction, or pregnancy.

Results: From a total of 8811 panels performed to assess for possible thrombophilia, 1586 (18%) were found to have decreased protein S activity. Of these cases, 563 (36%) were considered falsely decreased due to elevated factor VIII levels. 382 cases (4.4%) were considered possible hereditary deficiencies, further classified as: 217 type III (2.5%), 85 type II (1%), and 80 type I (0.9%).

Conclusions: Previous literature has indicated type I protein S deficiency is the most common subtype, followed by type III, with type II being much less common than type I or type III. However, our data indicates type II protein S deficiency may be more common than previously believed, which may call for current guidelines to be reevaluated to effectively capture this patient population.
Session: Posters/Exhibits/Break
Overcoming Distance and Travel Barriers for Virginia Bleeding Disorders Treatment Centers: A Comprehensive Needs Assessment
Erika J Martin, Lauren C Dunn, Katherine L Bains, Janice G Kuhn
Virginia Commonwealth University, Richmond, VA, USA

Background: In 2020, the Virginia Department of Health (VDH) contracted with Virginia Commonwealth University (VCU) to conduct a comprehensive needs assessment of Virginia Bleeding Disorders Program (VBDP). VBDP provides services to patients with inherited bleeding disorders through four Hemophilia Treatment Centers (HTCs). Significant changes in health care delivery and financing and advancements in hemophilia therapy led to the need to assess the unmet patient and family (P/F) needs, access to care and needed service adaptations. A key theme of travel and distance barriers emerged from the study findings. Objectives: To identify the unmet P/F needs and to recommend modifications in services to address changes in health care and access to care.

Methods: VBDP core team and VCU's Survey and Evaluation Research Laboratory conducted four focus groups of key stakeholders identified by consumer chapter groups and three separate surveys of P/F, Virginia HTCs, and Non-VA HTCs. Questions assessed unmet P/F needs including services needed to better serve Virginia residents receiving care at HTCs, needs of residents that seek care at HTCs outside of Virginia, impact of changes in healthcare delivery systems, implications of new treatment modalities, distance, and transportation to care, access to telehealth, and outreach to unserved/underserved populations. A systematic analysis of results highlighted key findings.

Results: Distance to the HTC or travel barriers was identified as a major theme. Seventy-three percent of VA HTC survey respondents identified distance to treatment was a barrier for half of their patients. Half of the HTCs provided satellite clinics. About half offered telehealth visits with physicians/nurse practitioners, social workers, and mental health providers. Challenges in telehealth visits included inability to do a complete examination (69%), lack of lab coordination (69%), lack of internet connection (50%), increased barriers for patients for whom English is not their first language (44%) and lack of smart phones (38%). Non-VA HTC respondents identified distance or geographic barriers as the main reason patients received care outside of VA. Although the respondents to the P/F survey did not identify distance to HTC as a barrier, 66% of VBDP's patients lived more than fifty miles from their HTC (Table 1). According to the focus groups, the distance between a patient and an HTC negatively influenced access to care. Participants from all groups identified rural areas in Virginia as regions that had limited or no HTC services. A statewide committee was convened for a year to create strategies to reduce distance or travel barriers. They developed a framework guide for health care providers considering a satellite clinic and collected resources to address availability of mobile devices, WIFI and language services to help patients access telehealth services. The committee presented this information at the 2023 VBDP Annual Stakeholders' meeting attended by all Virginia HTCs, VDH and local chapters. Additionally, resources were shared through the Virginia Hemophilia Foundation's webpage. Conclusion: The VBDP needs assessment identified distance and travel issues as a barrier to care. This finding led to the creation of a committee to develop strategies to reduce distance as a barrier to care.
Session: Posters/Exhibits/Break
Antithrombosis Stewardship as a Key Driver within a VTE Center of Excellence - AMBITION Investigators 
Angela M. Martoccia Grabazs, Preeyaporn Sarangarm, Sundeep S. Guliani, Jonathan L. Marinaro, Allison E. Burnett
University of New Mexico Hospital, Albuquerque, NM, USA

Background Pulmonary embolism (PE) and deep vein thrombosis (DVT), collectively known as venous thromboembolism (VTE), account for >250,000 hospitalizations in the United States annually. Patients with VTE have an increased risk of recurrent thromboembolism or death within the first 4 weeks of the index event, and thus require comprehensive initial anticoagulation management in addition to a well-defined plan for care transitions. Additionally, risk stratification is important in directing acute VTE management, such as initial anticoagulation and treatment setting (inpatient versus outpatient). The 2019 ESC guidelines for the diagnosis and management of acute PE as well as the 2021 update to 2012 CHEST guidelines for antithrombotic therapy in VTE recommend prompt initiation of parenteral anticoagulation to improve patient outcomes, with preference for low molecular weight heparin (LMWH) or fondaparinux over unfractionated heparin (UFH). Initial use of these agents has been associated with significant reduction in recurrent VTE, major bleeding and a trend toward lower mortality. Pharmacists are uniquely equipped to aid in optimization of VTE management, including initial and longer-term anticoagulation practices, as well as safe and effective transitions of care. In March 2023, our anticoagulation stewardship team partnered with the hospital's pulmonary embolism response team (PERT), emergency medicine services, urgent care clinic and imaging departments (radiology and vascular lab) to pilot a VTE Center of Excellence. In this pilot, real-time alerts for acute DVT and/or PE are sent via internal messaging to the multidisciplinary team for rapid initial risk stratification and initiation of preferred, evidence-based anticoagulation. Objectives This pre-post research is designed to assess the impact of pharmacy-driven anticoagulation stewardship on acute and longer-term antithrombotic management and care transitions for high-risk VTE. Methods Retrospective analysis of pre-post intervention will include all adult patients who present to defined care areas between January 2021 and September 2023 with high-risk VTE within service hours (Monday-Friday 0700-1730). Patients will be excluded if anticoagulation is started at an outside hospital or during UNMH admission for alternate primary diagnosis, if they are discharged from care locations without admission, and if they are pregnant or incarcerated. The primary outcome is time to first dose of parenteral anticoagulant following acute VTE diagnosis. Secondary outcomes include choice of first anticoagulant, hospital length of stay, mortality rate in hospital and within 30 days of VTE diagnosis, and rate of completion of a transitions of care (TOC) "bundle". Transitions of care services include provision of outpatient medication supply and patent/caregiver education at discharge, as well as placement of an outpatient anticoagulation referral. Time to follow up call and confirmation of maintenance anticoagulant coverage will also be assessed within the TOC bundle. Results Data collection and analysis is currently ongoing. Conclusions This research is designed to inform the impact of real time pharmacy-driven antithrombosis stewardship involvement on patient outcomes when completed as a component of a multidisciplinary pilot VTE Centers of Excellence program.
Session: Posters/Exhibits/Break
CHIEF: A retrospective self-control study of Children <12 with severe Hemophilia a without Inhibitors comparing Emicizumab to FVIII
Daniel Mashiach1,2, Patrice Mead1, Kendall Carneiro1, Jemily Malvar1, Guy Young1,3
1Children’s Hospital Los Angeles , Los Angeles, CA, USA, 2WesternU College of Osteopathic Medicine of the Pacific, Pomona, CA, USA, 3Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in Factor VIII (FVIII). For severe HA (SHA), prophylaxis has become the standard of care, however it imparts a high treatment burden and typically still results in an annualized bleeding rate (ABR) of 2-6. Emicizumab, a subcutaneously administered FVIII substitute, has become the de facto standard of care prophylaxis for children with SHA. Previous clinical trials have done ABR analyses with emicizumab in patients greater than 12 years old and in children with inhibitors to FVIII who were previously on bypassing agents, but their is limited data on emicizumab in non-inhibitor SHA children. This study aims to examine the ABR in pediatric patients who switched from FVIII to emicizumab prophylaxis. Objectives: To compare ABR, safety, costs, joint health, and physical activity of individuals <12 years old with SHA without inhibitors on FVIII prophylaxis therapy after they switch to emicizumab prophylaxis.

Methods: Using a retrospective electronic medical record chart review, we conducted a self-control analysis of 15 patients less than 12 years of age during equivalent periods of factor versus emicizumab prophylaxis collecting the data stated in the objectives above.

Results: The mean ABR on FVIII and emicizumab was 1.79 and 1.13, respectively, however substantially lower joint (FVIII, 0.94; emicizumab, 0.33) and spontaneous bleeds (FVIII, 0.79; emicizumab, 0.23). On FVIII, there were 74 bleeds in total for all subjects, of which 53% were mild and 47% were moderate bleeds, while on emicizumab there were 51 total bleeds, of which 51% were mild, 45% moderate, and 4% were severe bleeds. Nine administration safety events occurred to five patients while on FVIII, of which eight were due to port complications. No administration safety events were recorded for patients while administering emicizumab. The mean annual cost (based on wholesale acquisition cost) of FVIII prophylaxis was $515,340 (S.D. $199,540), compared to $328,410 (S.D. $137,230) for emicizumab prophylaxis. No notable changes in Hemophilia Joint Health Scores or physical activity were seen in patients during the duration of the study.

Conclusions: Emicizumab resulted in an improved ABR, especially for joint and spontaneous bleeds, had fewer administration complications, and was substantially less expensive compared to FVIII prophylaxis.
Session: Online Poster Session
Factor XIII testing- what is available? what are best practices for testing? effect of concentrates on lab tests? antigen versus activity testing? any remaining role for clot solubility?
Natalie Mathews

Factor XIII (FXIII) deficiency is considered to be the most underdiagnosed bleeding disorder. In addition to a high index of suspicion, an understanding of the benefits and limitations of the various FXIII assays is important for making a diagnosis. A few key challenges include the varying lower limits of detection for these assays and the lack of consistent concordance between activity and antigen results. However, as demonstrated by FXIII assay data over the last 10 years from the Hamilton Regional Laboratory Program in Hamilton, Canada and the Centre Hospitalier Universitaire Sainte-Justine in Montreal, Canada, certain lessons can be learned with respect to diagnosing and monitoring patients.

Session: Quality Improvement Efforts in Laboratory Hemostasis/Thrombosis Testing
COVID-19 Venous Thromboembolism Prophylaxis Guidelines
Sara McElroy1,2, Emily Cramer1,2, Lauren Amos1,2
1Children's Mercy Kansas City, Kansas City, MO, USA, 2University of Missouri-Kansas City, Kansas City, MO, USA

Background SARS-CoV-2 (COVID-19) infection and multisystem inflammatory syndrome in children (MIS-C) are established risk factors for venous thromboembolism (VTE) in children. Guidelines for VTE prophylaxis that were established at our institution at the beginning of the pandemic were extrapolated from adult data and recommendations. Patients who had any VTE risk factors in addition to COVID-19 met criteria for initiation of anticoagulation prophylaxis. Patients who were diagnosed with MIS-C met criteria regardless of additional risk factors. Objectives Our primary aim was to determine compliance with the established guidelines for COVID-19 VTE prophylaxis at our institution. Our secondary aim was to determine the incidence of VTE in patients admitted for COVID-19 or MIS-C. We intended to update the guidelines based on our patient outcomes. Methods This was a retrospective review of patients admitted for at least 48 hours to Children's Mercy Kansas City from March 2020 through February 2022 with COVID-19 or MIS-C. We collected demographic information as well as data on VTE risk factors including prior medical history, ICU status, and presence of a central venous catheter (CVC). We determined if the patient met institutional criteria for VTE prophylaxis and if they were started on VTE prophylaxis. We also collected data on what anticoagulant was administered and whether a VTE occurred. Statistical analysis was performed on the data using chi-square tests and logistic regression models. Results There were 678 patients who met the inclusion criteria. Of these, 573 (84.5%) had COVID-19, and 120 (17.7%) had MIS-C. There were 15 patients diagnosed with both COVID-19 and MIS-C. Among the 519 patients who met criteria for VTE prophylaxis, 348 (65.6%) were started on prophylaxis. The odds of starting prophylaxis were significantly higher in patients with a personal (6.54; CI 2.03-21.05) or family history (6.79; CI 1.55-29.86) of thrombosis or thrombophilia, a diagnosis of MIS-C (19.79; CI 2.30-170.14), admission to the ICU (2.28; CI 1.24-4.18), and a CVC (2.12; CI 1.16-3.86). Eighteen patients developed a VTE. The incidence of VTE in patients who were not on prophylaxis was 1.21% and in patients who were on prophylaxis, was 4.02%. The incidence of VTE in COVID-19 infection alone was 2.5% and in MIS-C, was 3.3%. All patients who developed a VTE met criteria for starting prophylaxis, and 77.8% were on prophylaxis. Most patients were in the ICU (72.2%), had a CVC (77.8%), and were on oxygen supplementation (77.8%). Conclusions We found a moderate level of adherence to the VTE guidelines established at our institution and identified risk factors to provide education about in order to improve adherence in certain high-risk populations. The incidence of VTE in our patients with COVID-19 and MIS-C is similar to VTE rates at other institutions. The higher VTE incidence in patients who were on prophylaxis likely reflects a generally higher risk population. We found that universally recognized VTE risk factors are appropriate to include as risk factors for thrombosis in hospitalized patients with COVID-19 and MIS-C.
Session: Posters/Exhibits/Break
Dual Direct Oral Anticoagulant Therapy in Challenging Thrombosis: A Case Series
Heather McPhaden1, Chornenki Nicholas1, Peterson Erica1, Lai Chieh Min Benjamin1,2, Lee Agnes1
1The University of British Columbia, Department of Medicine, Division of Hematology, Vancouver, BC, Canada, 2The University of British Columbia Centre for Blood Research, Vancouver, BC, Canada

Background: Venous thromboembolism (VTE) is a substantial cause of morbidity and mortality. While most respond to standard anticoagulant regimens, some patients follow an extraordinarily accelerated course and develop thrombosis in multiple organs over the course of days to weeks. Management of this 'thrombotic storm' of refractory events often involves escalating doses or switching to another anticoagulant such as low-molecular weight heparins (LMWH) or argatroban. While traditional anticoagulants target multiple factors in the coagulation cascade, direct oral anticoagulants (DOACs) block the activity of a single clotting factor. Dual DOAC therapy, using a factor Xa inhibitor (such as rivaroxaban or apixaban) and a factor IIa inhibitor (dabigatran), has the potential to 'mimic' the mechanism of action of LMWHs but does not require parenteral administration and have approved rapid-acting reversal agents. Objectives: This study describes the experience of using dual DOAC therapy in refractory cases of thrombosis at a single institution.

Methods: A retrospective chart review was conducted on eight patients with refractory thrombosis treated at Vancouver General Hospital, Vancouver, Canada with simultaneous dabigatran and an oral factor Xa inhibitor. We included all patients over the age of 18 who met the criteria by surveying local hematologists for eligible patients. The study was approved by the University of British Columbia Research Ethics Board (REB #: H23-02575).

Results: Eight patients (median age 54 years, 75% male) with multiple breakthrough thrombotic events despite therapeutic anticoagulation were included. Thrombotic events comprised deep vein thrombosis (8/8), pulmonary embolism (7/8), arterial thrombosis (1/8), and cerebral venous thrombosis (1/8). All patients initiated standard therapeutic anticoagulation upon diagnosis of acute VTE with a median of 3 breakthrough thrombotic events prior to dual DOAC use. Five patients had a positive heparin induced thrombocytopenia HIT screen but only two had HIT confirmed on serotonin release assay testing. Predisposing risk factors included remote prior VTE (2/8), antiphospholipid antibody syndrome (1/8), anabolic steroid use (1/8), homozygous factor V Leiden (1/8), oral contraceptive use (1/8), smoking (2/8), obesity (4/8), and metastatic malignancy (1/8). Dual DOAC therapy, initiated after failure of a median of 3 treatment lines (either dose increase or change in agent, see Figure 1), involved dabigatran and either apixaban or rivaroxaban. After initiation of dual DOAC, D-dimer levels were noted to decline rapidly (Figure 2) in all cases. Follow-up (median 35 months; range 6-107 months) indicated no recurrent thrombosis or bleeding complications during dual DOAC use. 7/8 patients later transitioned to a single anti-Xa agent, while 1/8 continued dabigatran alone. Three patients experienced subsequent thrombotic events after dual DOAC cessation.

Conclusions: Dual DOAC therapy may be a useful strategy for managing challenging thrombosis cases resistant to conventional anticoagulation. The absence of bleeding complications and lack of recurrent VTE during dual DOAC therapy in our case series support the potential safety and efficacy of this approach. The drop in D-dimer levels also provides evidence that clot formation was attenuated. Further research is warranted to validate these findings and explore the broader applicability of dual DOAC therapy in challenging thrombotic scenarios.
Session: Posters/Exhibits/Break
Risk of Thrombosis in SGLT2 Inhibitor-Associated Erythrocytosis: A Multi-Center Propensity-Matched Analysis
Meric Mericliler1,2
1Division of Hematology and Medical Oncology, Virginia Commonwealth University Health, Richmond, VA, USA, 2Massey Cancer Center, Richmond, VA, USA

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly utilized due to their cardiovascular and renoprotective benefits. These medications have been associated with erythrocytosis. The relationship between thrombotic risk and SGLT2i-associated erythrocytosis remains unknown. To date, no large-scale comparative studies have investigated the thrombotic outcomes in patients with SGLT2i-associated erythrocytosis. Objectives: The primary objective of this study was to investigate the risk of thrombotic outcomes in patients with SGLT2 inhibitor-associated erythrocytosis.

Methods:
Retrospective data of patients who developed erythrocytosis and those who did not within one month to one year following initiation of FDA-approved SGLT2is were retrieved from the TriNetX database. Erythrocytosis was defined by hemoglobin/hematocrit levels exceeding 16.5 g/dL/49% in males and 16 g/dL/48% in females. Patients with JAK2 mutations, including V617F and exon 12, were excluded. Patients were stratified based on gender. Propensity score matching (PSM) at a 1:1 ratio was performed to balance baseline characteristics. Patients were matched for age, race, and relevant comorbidities. The 1-year incidence of the following outcomes was assessed both before and after propensity score matching: venous thromboembolism, acute coronary syndrome (ACS), ischemic cerebrovascular disease (ICD) including transient ischemic attack and ischemic stroke, composite arterial events (ACS, ICD, and arterial embolism), composite thrombotic events (arterial and venous thrombosis), and mortality.

Results:
Patients with SGLT2i-associated erythrocytosis had significantly higher hemoglobin (16.2 ± 1.5 g/dL vs. 12.2 ± 2.1 in females; 16.9 ± 1.1 vs. 13.3 ± 2.4 in males) and hematocrit (49.3% ± 4.6 vs. 37.4% ± 6.9 in females; 50.9% ± 3.4 vs. 39.8% ± 7.9 in males) levels compared to controls. The majority of baseline comorbidities were more prevalent in patients with SGLT2i-associated erythrocytosis than in those who did not develop erythrocytosis after SGLT2-inhibitor treatment. Significant differences in race and age were also observed. After PSM, the differences in demographic characteristics and comorbidities were more balanced (Table 1). Before PSM, patients with SGLT2i-associated erythrocytosis, regardless of gender, had a significantly higher incidence of venous thromboembolism, acute coronary syndrome, ischemic cerebrovascular disease, composite arterial events, composite thrombotic events, and mortality (Table 2). Post-PSM analysis showed that patients with SGLT2i-associated erythrocytosis had a higher incidence of venous thromboembolism, composite arterial events, and composite thrombotic events. The incidence of acute coronary syndrome was similar between the groups in both the male and female cohorts. While males with SGLT2i-associated erythrocytosis had a higher incidence of ischemic cerebrovascular disease, this difference was not statistically significant in females. The post-PSM analysis showed no statistically significant differences in mortality rates (Table 3).

Conclusions:
The findings of this comparative study indicate an increased incidence of thrombotic events in patients with SGLT2i-associated erythrocytosis compared to those who do not develop erythrocytosis following treatment with SGLT2is. Similar results were observed even after propensity matching and controlling for relevant comorbidities. The limitations of this study include the use of retrospective aggregated patient data and reliance on diagnostic codes.
Session: Posters/Exhibits/Break
Prophylactic or post-traumatic treatment of hypofibrinogenemia and dysfibrinogenemia with FIBRGYA in eight clinical cases
Jessica N. Mistretta, Kristin T. Ansteatt, Michael D. Tarantino
Bleeding and Clotting Disorder Institute, Peoria, IL, USA

Background: Congenital fibrinogen disorders (CFDs) are rare and make up approximately 0.6% of all inherited bleeding disorders. Two subtypes include a quantitative deficiency of fibrinogen, congenital hypofibrinogenemia (CH), and qualitative defect of the fibrinogen molecule, congenital dysfibrinogenemia (CD). Patients with CD may have a thrombotic as well as a hemorrhagic disease phenotype. In the past, fresh frozen plasma or cryoprecipitate were the only options available for treatment and prevention of bleeding in patients with CFD. Today in the US, human plasma-derived concentrates (FIBRYGA, Octapharma, Lachlen, Switzerland, and RiaSTAP, CSL, Melbourne, Australia) are available and considered safe and effective treatment options for CD and CH. Guidelines for the treatment and prevention of bleeding are not established for CFDs, and especially for CD. Methods/

Results:
We present eight clinical cases of patients with hypo- or dysfibrinogenemia that were effectively treated with a pooled, plasma-derived fibrinogen concentrate (FIBRYGA) either prophylactically for elective or urgent surgery, or post-traumatic injury. The mean age of patients treated was 34 years (min-max 8-70 years). Three patients were male and five, female. Four patients had CH and four, CD. FIBRYGA was used to prophylactically treat a total of ten surgical procedures and two post-traumatic events in these patients. Dosing of FIBRYGA was based on the goal peak plasma fibrinogen concentration and the manufacturer's prescribing information, but modified to align with local laboratory reference ranges for the functional fibrinogen test. No acute or delayed infusion reactions (nausea, fever, rigors, headache) and no hypersensitivity reactions were noted. One patient developed two adverse events, one thrombotic and one hemorrhagic. This patient underwent left, above the knee amputation (AKA) and had a complicated postoperative period due to her multiple comorbidities including type 2 diabetes, hypertension, and long standing, poorly-controlled, severe peripheral arterial disease. She presented nineteen days after receiving FIBRGYA with a PE and multiple DVTs. Fifty-nine days later she presented with wound dehiscence and underwent an extensive excisional debridement with postoperative bleeding deemed to be secondary to her strap sliding during surgery and acting as a tourniquet for venous blood flow. Conclusion: For the majority (86%) of our patients described here with CH and CD, FIBRYGA was well tolerated and effective in preventing post procedural or post traumatic bleeding complications. The post procedural bleeding noted in one patient may have been due to inadequate fibrinogen concentration or other comorbid conditions. Further clinical studies are needed to determine the role of FIBRGYA and other HFC in the treatment of patients with CFD.
Session: Posters/Exhibits/Break
Novel Thrombophilia- Prothrombin Belgrade Variant in a Mexican Family
Natalie/A Montanez1,3, Miguel/A Escobar1,2,3
1University of Texas Health Science Center of Houston, McGovern Medical School, Department of Pediatrics, Houston, TX, USA, 2University of Texas Health Science Center of Houston, McGovern Medical School, Department of Internal Medicine, Houston, TX, USA, 3Gulf States Hemophilia and Thrombophilia Center , Houston, TX, USA

Background: The F2 gene encodes the prothrombin protein, which plays an essential role in hemostasis. A rare prothrombin variant (c.1787G>A, p. Arg596Leu), also known as Belgrade prothrombin, results in predisposition to thrombosis via disruption of thrombin-antithrombin binding. This variant has only previously been reported in individuals from Serbia, Japan, China, and India with no case reports outside of these geographical areas. Inheritance pattern is autosomal dominant. Objectives: We present the first case of a Mexican family with recurrent venous thromboembolism (VTE) associated with the prothrombin Belgrade variant with previously negative routine hypercoagulable studies.

Methods: Retrospective electronic medical record review of two Mexican female siblings found to have prothrombin Belgrade variant (c.1787G>A, p. Arg596Leu).

Results: Patient 1. A 34-year-old female with initial thrombotic event at age 22 - seemingly unprovoked left common femoral, superficial femoral, deep femoral, popliteal, posterior tibial and peroneal deep vein thrombosis. Other thrombotic events include age 29- right upper extremity superficial thrombophlebitis (antepartum); right lower extremity deep vein thrombosis (postpartum) and age 31- recurrent left femoral and popliteal deep vein thrombosis (post stent placement). Initial hypercoagulable studies including- functional levels of fibrinogen, antithrombin, protein C and S, factor V Leiden mutation, prothrombin G20210A mutation, and antiphospholipid antibodies resulted in negative findings. Comprehensive hereditary thrombophilia gene panel, including full gene analysis of F2 resulted in heterozygosity for prothrombin Belgrade variant (c.1787G>A, p. Arg596Leu). Patient 2. A 26-year-old female with initial thrombotic event at age 13 - seemingly unprovoked occlusive venous thrombus extending from the left iliac vein to the popliteal. Other thrombotic events include ages 21, 22, 23, 25- recurrent deep vein thrombosis in the left common femoral, superficial femoral, popliteal vein and paired posterior tibial veins. Initial hypercoagulable studies resulted in negative findings. Targeted familial variant testing for prothrombin Belgrade variant (c.1787G>A, p. Arg596Leu) was positive. Additional targeted familial variant testing resulted in heterozygosity for prothrombin Belgrade variant (c.1787G>A, p. Arg596Leu) in father and brother, both with personal history of recurrent VTE. Conclusion: Although rare, prothrombin Belgrade may be present relatively frequently in patients with a personal and/or family history of VTE, and in individuals of ethnicities not previously reported. Therefore, it may be important to consider pursuing comprehensive genetic thrombophilia testing in the setting of negative standard hypercoagulable studies with history of recurrence and positive family history.
Session: Posters/Exhibits/Break
Recurrent Venous Thromboembolism in a Symptomatic Hemophilia A Carrier
Natalie/A Montanez1,3, Joanna/M Larson1,3, Miguel/A Escobar1,2,3
1University of Texas Health Science Center of Houston, McGovern Medical School, Department of Pediatrics, Houston, TX, USA, 2University of Texas Health Science Center of Houston, McGovern Medical School, Department of Internal Medicine, Houston, TX, USA, 3Gulf States Hemophilia and Thrombophilia Center , Houston, TX, USA

Background: We present a symptomatic female carrier for hemophilia A who developed recurrent venous thromboembolism in the setting of a central venous access device with recurrent administration of human plasma-derived C1 esterase inhibitor (C1-INH) intravenous infusions for management of presumed hereditary angioedema. Objectives: Discuss a single case report of a symptomatic female carrier for hemophilia A with evidence of recurrent venous thromboembolism requiring anticoagulation therapy.

Methods: Case report, retrospective EMR review with IRB exemption.

Results: A 37-year-old Hispanic symptomatic hemophilia A carrier (Baseline FVIII: OS 99%, FVIII:C 60%, Genotype- Heterozygous c.2167G>A (p. Ala723Thr), ISTH BAT Score 10) presented with shortness of breath, chest pain, and syncope shortly following intravenous infusion of human plasma-derived C1-esterase inhibitor for management of presumed hereditary angioedema. Patient was tachycardiac, tachypneic, and febrile upon ER arrival. CT angiogram (CTA) chest revealed a left lower lobe lateral basilar segmental pulmonary embolism. Patient was initially treated with IV unfractionated heparin for 5 days prior to being discharged on PO apixaban for a total of 6 months. During the course of anticoagulation therapy patient experienced heavy menstrual bleeding and recurrent episodes of hematuria requiring temporary interruption in anticoagulation, resulting in recurrent venous thromboembolism (VTE) two months following initial thrombotic event with evidence of an acute left subclavian and axillary deep vein thrombosis. Acquired and congenital thrombophilia studies were negative (APLAs, ADAMTS13, F2, F5, F9, FGB, FGG, MPL, PROC, PROS1, SERPINC1, THBD). Diagnosis of hereditary angioedema was ruled out and human plasma-derived C1-INH therapy was discontinued. Conclusion: This case depicts the challenges of balancing risk vs benefits of anticoagulation in symptomatic hemophilia carriers with bleeding symptoms on anticoagulation and recurrent thrombosis with interruption in anticoagulation therapy. Thromboembolic events associated with human plasma-derived C1-INH use have been reported in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database, although thrombogenicity of medication remains debated. Initiation of anticoagulation in a hemophilia carrier should be evaluated on an individual basis, considering the risk vs benefits of anticoagulation in the context of factor VIII activity levels and clinical phenotype. Recently published clinical practice guidance document from EHA-ISTH-EAHAD-ESO on antithrombotic treatment in patients with hemophilia may be referenced for recommended approach for balancing thrombosis and hemostasis when using anticoagulant treatments in a patient with hemophilia.
Session: Posters/Exhibits/Break
Novel Point-of-Care (POC) platform for direct oral anticoagulants (DOAC) and vitamin K antagonists (AVK) testing: microDOAC and microINR assays
Tamara Montes, Mikel Santiago, Irene Mijangos
R&D Department, iLine Microsystems S.L., San Sebastián/Donostia, Spain

Background: The Point-of-Care (POC) assessment of oral anticoagulation therapy brings great value in patient monitoring as well as within critical clinical scenarios such as life-threatening hemorrhage or urgent surgical interventions. A cutting-edge POC device utilizing microfluidic technology has been developed, enabling the evaluation of both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). This novel platform will be suitable to run two assays: microDOAC assay, sensitive to clinically relevant DOAC levels for guiding treatment in rapid decision-making environments and a PT/INR assay. Objectives: We aim to analyze the accuracy, sensitivity, and specificity of a POC platform that performs a microINR assay in warfarin patients, as well as a microDOAC assay designed for the semiquantitative evaluation of apixaban, rivaroxaban, dabigatran, or edoxaban.

Methods: microDOAC assay was performed with normal donor whole blood samples obtained by venipuncture in a plastic tube without anticoagulant that were spiked with increasing DOAC concentrations (0-500 ng/mL). The remaining volume was appropriately citrated for measuring DOAC levels by anti-FXa and anti-FIIa activity (Diagnostica Stago). Receiver operator characteristic (ROC) curves were used to identify the assay values (in seconds) that best discriminate clinically relevant DOAC thresholds; additionally, sensitivity, specificity and agreement values were calculated. microINR assay evaluation was performed with warfarin patients to assess the accuracy and precision against a reference laboratory method, using capillary blood samples, and a venous blood sample for the laboratory reference (ACL TOP 500 with HemosIL RecombiPlasTin 2G reagent). Passing-Bablok regression analysis was performed to analyze results.

Results: 160 apixaban, rivaroxaban, edoxaban and dabigatran spiked samples were tested (80 samples ranging 0-100 ng/mL; 80 samples from 100-500 ng/mL) for microDOAC assay evaluation. ROC curves were generated to determine sensitivity and specificity at the clinically relevant DOAC concentrations where the area under the curve (AUC) was above 99% for apixaban and 95% for dabigatran (Fig. 1 and 2) for all clinically relevant thresholds. Both sensitivity and specificity values of microDOAC test for apixaban samples were high (>96%) at clinically relevant thresholds. Similar results were obtained with rivaroxaban, edoxaban and dabigatran samples. microINR analysis was performed in 68 normal non-anticoagulated donors and 245 patients anticoagulated with warfarin. Regression analysis between the results of the microINR assay and the reference system showed a strong correlation, showing a total equivalence with a slope coefficient of 1.00, an intercept of 0.08, and a correlation coefficient r of 0.973.

Conclusions: A novel Point-of-Care platform has been developed to enhance the quality management of patients on oral anticoagulation therapy (DOACs and VKAs) in various clinical environments. This new analyzer provides lab-quality results based on microfluidic technology, enabling real-time patient monitoring across diverse clinical setting with rapid results (<2 minutes), portable design, user-friendly interface, and connectivity for patient traceability.
Session: Posters/Exhibits/Break
Intrinsic Xase Ligand Interactions Impact FVIIIa Regulation
John J Morris1,2, Nicole A Parsons2, Robert J Davidson1, Lindsey A George1,2
1Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

Background: Disease pathology resulting from states of deficient and excess (f)actor VIII, hemophilia A (HA) or prothrombotic risk, respectively, highlight the significance of maintaining activated FVIII (FVIIIa) function within a defined physiologic window. FVIIIa function is downregulated by spontaneous A2-domain dissociation and proteolytic cleavage by activated protein C (APC). Prior biochemical studies have demonstrated that A2 dissociation occurs rapidly with markedly slower kinetics of APC cleavage, supporting a lesser/marginal role of APC cleavage in FVIII/FVIIIa regulation. However, the contributions of these two mechanisms have historically been studied in purified systems, where the inherent instability of the A2 domain introduces experimental limitations. Further, these studies frequently lack FIXa and FX, which decrease A2 dissociation and APC cleavage, respectively. As a result, we hypothesize the physiologically relevant mechanisms that regulate FVIIIa are unclear, and the role of APC cleavage is underrepresented in prior work. Objectives: Evaluate how FIXa and FX ligand interactions with FVIIIa impact FVIIIa inactivation. Define how the fractional saturation of FVIIIa by FIXa impacts A2-domain stability. Demonstrate that APC cleavage meaningfully contributes to FVIIIa regulation in vivo.

Methods: We generated a panel of recombinant FVIII variants resistant to APC cleavage (FVIIIR336Q,R562Q; FVIII-QQ), A2- domain dissociation (FVIIID519V,E665V; FVIII-VV [Wakabayashi et al., JTH 2009]), or both (FVIII-QQVV). First, we studied FVIIIa inactivation with purified components varying the state of FVIIIa-FIXa saturation, ±APC, and ±FX to assess these ligand interactions on FVIIIa regulation. We then evaluated the impact of FIXa and FX on FVIIIa inactivation in plasma-based assays. Finally, we confirmed these findings in an in vivo tail clip injury model using HA/CD4KO mice.

Results: In purified component assays, we found that the fractional saturation of FVIIIa by FIXa positively correlated with improved A2-domain stability, and the presence of FX reduced FVIII/FVIIIa APC cleavage, supporting that FVIIIa assembled in the intrinsic Xase is markedly stable. These results were replicated in thrombin generation assays where increasing FVIIIa saturation with FIXa improved A2-domain stability of FVIII-WT to that of an A2-stable FVIII variant, FVIII-VV, and the presence of FX blunted inactivation of FVIII-WT by APC, such that, in the presence of FX and APC, FVIII-WT activity was comparable to an APC-resistant FVIII variant, FVIII-QQ. The in vivo relevance of these findings was observed in a murine tail clip model. All FVIII variants with improved stability demonstrated improved hemostatic function compared to FVIII-WT (Figure 1A), suggesting that FVIIIa is not fully saturated with FIXa or FX in vivo. Notably, stabilizing the A2 domain had lesser hemostatic improvement (FVIII-VV, 2.4X) than inhibiting APC cleavage (FVIII-QQ, 5X) over FVIII-WT supporting that APC contributes to FVIIIa regulation in vivo. Administration of excess FX with FVIII demonstrated the same hemostatic effect as the corresponding protein with APC resistance, i.e., FVIII-WT and FVIII-VV hemostatic effect was analogous to FVIII-QQ and FVIII-QQVV, respectively (Figure 1B).

Conclusions: These data suggest that both A2-domain dissociation and APC cleavage meaningfully contribute to FVIIIa regulation under physiologic conditions and highlight the potential benefit of FVIII transgenes resistant to inactivation for HA gene therapy.
Session: Short Talks - Bleeding Back to the Basics
Natural History of Bleeding, Transfusion, and Antibody Prevalence in a Subset of Hermansky-Pudlak Syndrome Patients: Effects of Freeze-Dried Lyophilized Platelet Derived Hemostat Ex Vivo
Keith Moskowitz, Michael Fitzpatrick, Lisa Booth, Maria Abreau-Blanco, Matthew Dickerson, Anna Yu, Anya Derbij, W. Allan Alexander
Cellphire Therapeutics, Inc., Rockville, MD, USA

Background: HPS affects ~1 in 500,000 of the population, ~1500 patients are reported in continental US and Puerto Rico (PR). HPS is an autosomal recessive, multi-genotype, protein storage disorder that clinically presents as oculocutaneous albinism, expressing platelet delta granule deficiency with bleeding from birth, as well as colitis, and premature mortality from pulmonary fibrosis. Providing recommended HLA-matched platelets to treat uncontrolled bleeding is difficult. In practice platelet transfusions are avoided because alloantibody formation reduces eligibility for lung transplant. HLA-Matched, Freeze-Dried, Platelet Derived, Hemostat (FPH-M) is being developed as a potential cellular therapeutic to treat uncontrolled bleeding and potentially reduce alloimmunization risk. Unmatched FPH is in clinical trials (NCT05771831). Objectives: 1) Assess the natural history of bleeding in two cohorts of HPS subjects from the continental US and PR. 2) Determine the prevalence of antibodies to Class I HLA and platelet antigens in the continental US cohort. 3) Assess the compatibility of blood samples with FPH by crossmatch and hemostatic function of FPH in the presence of allogeneic antibodies.

Methods:
Forty-five subjects consented and completed bleeding history surveys and 32 from the continental US provided blood samples. Antibody prevalence was assessed by Luminex and the % calculated Panel Reactive Antibody (% cPRA) determined. Crossmatching with FPH was done by flow cytometry. The thrombin generation assay (TGA) and adhesion under shear over collagen and tissue factor using the Total Thrombus formation Analysis System (T-TAS®) were used to evaluate hemostatic function.

Results:
Of 45 subjects, 24% were male, 67% Hispanic or Latino, mean age 42. Of 34 females 58% were post-menopausal. Reported disorders included vascular 91%, ocular 93%, epistaxis 67%, gum bleeding 69%, dental bleeding 80%, bruising 96%, pulmonary bleeding 9% (one requiring transfusion/surgery). Important hemorrhage is common: hematochezia 62%, hematemesis 9%, joint bleeding 6%, intracranial hemorrhage 2%, retinal hemorrhage 7%, and bleeding with spinal tap/epidural 7%, during surgery 44% and 33% with major trauma 27% of whom received transfusions, mean transfusions 11 (range 0-134). 53% of menstruating females had anemia, 12% requiring transfusion while 32% had post-partum hemorrhage, 18% requiring transfusion. Class 1 HLA antibodies were identified in 10 of 32 samples. 60% of those would be incompatible with >50% of Apheresis Platelet Units by % cPRA. Of the ten samples with antibodies, only two (20%) with antibodies to platelet antigens cross-reacted with FPH. Based on the cPRA at least 50% of the samples were expected to be cross-reactive. TGA activity and thrombus formation as measured by TGA and T-TAS of FPH was present in samples from all subjects regardless of antibody presence.

Conclusions:
HPS presents with life altering co-morbidities and severe bleeding events that often require platelet transfusions. FPH hemostatic function in an ex vivo human HPS model and in vitro coagulation assays were not affected by single or multiple antibodies. FPH-M may be a future shelf-stable hemostatic alternative for bleeding in HPS patients that reduces the risk of alloimmunization by providing a patient-specific, phenotypically matched platelet hemostatic for transfusion. Further trials are needed to assess FPH in the HPS population.
Session: Posters/Exhibits/Break
Analysis of pharmacist interventions within a direct oral anticoagulation management protocol
Clara J Nickel2, Anne E Rose1
1University of Wisconsin Health , Madison, WI, USA, 2University of Wisconsin School of Pharmacy , Madison, WI, USA

Background: Direct oral anticoagulants (DOACs) are first line treatment options for nonvalvular atrial fibrillation and venous thromboembolism. In comparison to warfarin, DOAC therapy does not require regular therapeutic monitoring, which allows individual institutions the freedom to define their own structure for DOAC management. Common approaches for DOAC management include a population-based model where patients are flagged when potential issues are identified or a predetermined check-in model where patients are contacted at pre-set time points. Within UW Health's Anticoagulation Clinic, pharmacists contact DOAC patients at pre-set time points of initial visit, 3 weeks, 6 months, and 12 months post DOAC start date. During each visit, the pharmacist assesses for medication efficacy, medication changes, compliance, adverse effects, and need for periprocedural planning. Currently, there is a paucity of evidence defining an optimal protocol for the management of DOACs. This study aims to evaluate the timing and types of interventions made within the first year of DOAC therapy at pre-set contact times and outside of scheduled contact times to determine if a change is needed to our DOAC management protocol.

Methods: A single-center retrospective review was performed of all patients currently managed by the Anticoagulation Clinic at UW Health as of June 8, 2023. Patients were included if aged 18 years and older and within the first year of DOAC therapy. Patients were excluded from analysis if they had been on the anticoagulant prior to enrollment in the service or were hemodynamically unstable. The primary objective was to assess current monitoring practices by tracking the number and types of interventions made during and outside of predefined contact points. Baseline characteristics were also collected to evaluate appropriateness of dosing.

Results: A total of 427 interventions were performed by pharmacists for the 113 eligible patients. Approximately two thirds of the interventions (289/427, 67.7%) were completed within the predefined contact points and one third of interventions (138/427, 32.3%) were completed outside of the predefined contact points. Within the predefined contact points, the most common interventions were eligibility review and the initial DOAC visit (237/289, 82%). Few interventions were made at the 3-week and 6-month contact point (each 20/427, 4.7%); most were related to lab monitoring or periprocedural planning. One dose change was made at 6 months. The most common interventions during the predefined contact points included initial education (33%), ordering labs (27%), ensuring ability for patients to afford medications (24%), and optimizing DOAC regimen (5%) which included changing to an alternative DOAC, changing DOAC dose, and discontinuing interacting medications. The most common interventions made outside of predefined contact points included coordinating and reviewing labs (38%), periprocedural planning (27%), and optimizing DOAC regimen (8%) including adverse effect management. Conclusion: Most pharmacist interventions are made during the initial visit and outside of predefined contact points. This would support the preference for a population-based model that identifies patients who need pharmacist intervention versus those with a pre-set contact time.
Session: Posters/Exhibits/Break
How the lab can support clinical decision-making in acute critical bleeding
Nathan Nielsen

Timely laboratory data remains the foundation of resuscitation and stabilization protocols for the critically ill hemorrhaging patient. For atypical bleeding situations not covered by standard protocols, however, critical care clinicians receive very little training, and input from laboratory and peri-laboratory experts such as transfusion medicine and coagulation specialists becomes essential for optimal patient care. This talk will present 3 not uncommon scenarios where such input was invaluable (even life-saving), and conclude by providing suggestions for how to better bridge the lab-clinican divide.

Session: Lab support of clinical decision-making in the critically ill bleeding patient
Validating the JAKPOT prediction rule for identifying which patients with erythrocytosis are unlikely to have a JAK2 mutation
Kevin O'Sullivan1, Roosevelt Lu1, Jason A Freed1, George Goshua2, Justine Ryu2, Rushad Patell1, Barbara D Lam1
1Beth Israel Deaconess Medical Center, Boston, MA, USA, 2Yale Medical Center, New Haven, CT, USA

Background: Erythrocytosis has many causes, including Polycythemia Vera (PV). PV, a type of myeloproliferative neoplasm (MPN), is often driven by a JAK2 mutation and associated with an increased risk of thrombosis. The prediction rule JAKPOT was developed in 2022 to determine which patients with erythrocytosis benefit from JAK2 testing. Patients who met zero criteria (red blood cell count >6.45x1012/L, platelets >350x109/L, and neutrophils >6.2x109/L) were JAKPOT "low-risk" for harboring a JAK2 mutation. JAKPOT has not yet been externally validated. Aims: Externally validate the JAKPOT rule on a cohort of 2000 patients at a tertiary care center in Boston, Massachusetts, USA.

Methods: Demographics and laboratory data for 2000 random patients with JAK2 testing were extracted from the hospital data warehouse. Manual chart review identified patients who met inclusion criteria (those evaluated for erythrocytosis who had same-day JAKPOT variables available) and those who met exclusion criteria (a known diagnosis of MPN). Negative predictive value (NPV) was calculated using Python version 3.9.

Results: Of 2000 patients, 1502 were excluded (1113 referred for reasons other than erythrocytosis, 247 missing same-day JAKPOT variables, 87 known MPN diagnoses, 55 cancelled tests). Validation of JAKPOT on the remaining 498 patients demonstrated a 98.5% NPV (95% CI: 0.97-0.99). Of the 53 patients found to have a JAK2 mutation, 48 met at least one JAKPOT criteria and all were diagnosed with PV or a PV/Essential Thrombocythemia overlap syndrome. Of the 5 patients with JAK2 mutation who met zero JAKPOT criteria and were incorrectly deemed "low-risk", all were ultimately diagnosed with PV. Conclusion: The JAKPOT rule is effective at identifying patients with erythrocytosis who are at low risk of harboring a JAK2 mutation. Next steps include expanding the validation cohort to other institutions and conducting a cost-effectiveness analysis.
Session: Posters/Exhibits/Break
Hospitalization outcomes from venous thromboembolism in cancer patients: An analysis of the national inpatient sample data from 2016 to 2019
Youjin oh, Alejandro Vallejo, Alexandra Sueldo, Lina james, Angelo Caputi Zuniga, Ayobami Olafimihan, Ekrem Turk
John H. Stroger Jr Hospital , Chicago, IL, USA

Background: Thromboembolic events significantly impact cancer patients, leading to increased mortality and extended hospital stays. Identifying the factors contributing to these outcomes is vital for enhancing patient care and prognosis. Objectives: This study explores risk factors linked to inpatient mortality and length of hospital stay (LOS) in cancer patients hospitalized for thromboembolic events.

Methods: We analyzed 675,407 admissions for venous thromboembolism (VTE) from the HCUP-NIS database (2016-2019), among which admissions with any type of cancer diagnosis were selected. Subgroup was selected for admissions with at least one of ten high VTE risk cancers: malignancy of prostate, bladder, uterine, pancreas, brain, stomach, lung and bronchus, breast, ovary, and colon. We examined how factors like age (categories: <40, 40-65, >65), gender, race (White, Black, Hispanic, Asian, and Pacific Islanders), household income estimated by patient's ZIP code (by quartiles), admission type (elective vs. non- elective), and hospital size classified by bed size, location and teaching status (small, medium, large) impacted mortality and LOS. Logistic regression was used to assess mortality, while linear regression analyzed LOS correlations.

Results: The admissions for VTE among all types of cancers were 52,650. The median age was 70 (Interquartile ranges (IQR) 61-78) with a female population of 50.9%. The ethnicity distribution of those patients was found to be 75% White, 16% Black, 7% Hispanic, and 2% Asian and Pacific Islanders. The inpatient mortality rate was 5.8%, with a median LOS of 4 days (IQR 2-6 days). Significant mortality risk factors included age 40-65 (Odds ratio (OR) 1.68), age >65 (OR 1.86), male gender (OR 1.08), Asian or Pacific Islander ethnicity (OR 1.46), large hospital size (OR 1.41), and elective admission (OR 1.29). Non-White ethnicities experienced longer LOS. Higher income was associated with shorter LOS, as were smaller hospital sizes and non-elective admissions. The subgroup (n=29,986) was not significantly different for age, gender, mortality, and LOS compared to all admissions. The proportion of ethnic groups was 74% for White, 17% for Black, 6% for Hispanic, and 2% for Asian and Pacific Islanders. Asian and Pacific Islanders had higher mortality, as did patients in medium and large hospitals, and those with elective admissions. The White population had a shorter LOS, whereas large hospital and elective admissions were associated with a longer LOS.

Conclusions: In summary, our study highlights some risk factors associated with increased inpatient mortality and LOS among cancer patients admitted for thromboembolic events. These findings suggest male patients, those over the age of 40, and those of Asian descent have a significant association with higher inpatient mortality. The non-White population and lower- income population were also associated with longer LOS. Recognition of these factors may help healthcare providers streamline resources and enhance the quality of care for potentially vulnerable patient populations.
Session: Posters/Exhibits/Break
Trends of Acute Ischemic Stroke in Hereditary Hemorrhagic Telangiectasia: A Decade Study
Ayobami Olafimihan1, Stanley ozogbo2, Praise fawehinmi3, Gbolahan Olatunji4, Emmanuel Kokori4, Aderinto Nicholas5, Ekrem Turk1, Lina George1, Shaka Hafeez1
1John H. Stroger Jr Hospital , Chicago, IL, USA, 2Mercy Health- St. Elizabeth Hospital , Youngstown, OH, USA, 3Southern Illinois University Edwardsville, Chicago, IL, USA, 4University of Ilorin, Ilorin, Nigeria, 5Ladoke Akintola University of Technology, Ogbomosho, Nigeria

Background: Acute ischemic stroke (AIS) is a recognized complication of hereditary hemorrhagic telangiectasia (HHT). This is mostly attributed to paradoxical embolism in the presence of pulmonary arteriovenous fistulas (PAVF), a cause of pathological right-to-left shunt. Our study aims to establish the incidence trend of AIS in hospitalized patients with HHF in the United States, and the associated sociodemographic.

Methods: This is a retrospective study using the Nationwide Inpatient Sample (NIS) database (2010-2019). Using ICD-9 and ICD-10 codes, we identified hospitalized patients with HHF and stratified them based on having a primary diagnosis of AIS. Trend in the incidence of AIS was assessed using the annual percentage change (APC) by joinpoint regression. The groups were compared for socio-demographic differences and comorbidities. Statistical analysis was performed using t-test, univariate and multivariate logistic regression.

Results: There was a total of 32,913 admissions in patients with HHT. The incidence rate of acute ischemic stroke in the population was 1.9% (618), and the prevalence of PAVF was 3.2% (1,044). Over the decade, the incidence of AIS was similar (P= 0.6). Majority of HHT patients admitted with AIS were older (65.3 vs 62.2 years; p= 0.024) and had higher (≥3) Charlson comorbidity indices (52.0 vs 28.6%; P<0.001) compared to those without stroke. Both cohorts were similar by being mostly females (59.2 vs 59.8%) and Caucasian (71.3 vs 72.1%) with Medicare coverage (59 vs 59.2%), admitted to urban (94.3 vs 91.07%) and teaching (62.6 vs 62.4%) hospitals. Patient with AIS had higher prevalence of PAVF (9.7 vs 3 %; P<0.001), HTN (44.6 vs 34.3%; p=0.0189) and intracranial hemorrhage (4.9 vs 0.3%; P<0.001). They had lower proportion of obesity (1.6 vs 11.5%; P<0.001) compared to their counterparts without stroke. On multivariate adjusted analysis, patients with PAVF had over triple odds of having AIS compared to those without PAVF (adjusted odds ratio (AOR): 3.6, 95% confidence interval (CI): 1.94-6.77) Conclusion: The incidence of acute ischemic stroke in patients with hereditary hemorrhagic telangiectasia has been unchanged over the decade in view. PAVF is a significant predictor of AIS in HHT patients. Further studies are needed on possible interventions to improve the incidence of AIS in this population.
Session: Posters/Exhibits/Break
Prevalence and Outcomes of Heparin-Induced Thrombocytopenia in Inflammatory Bowel Disease: A Decade Study
Ayobami Olafimihan1, Ekrem Turk1, Praise fawehinmi2, Gbolahan Olatunji3, Emmanuel Kokori3, Aderinto Nicholas 4, Alejandro Vallejo1, Nkechi Akata5, Shaka Hafeez1
1John H. Stroger Jr Hospital , Chicago, IL, USA, 2Southern Illinois University Edwardsville, Edwardsville, IL, USA, 3University of Ilorin, Ilorin, Nigeria, 4Ladoke Akintola University of Technology, Ogbomosho, Nigeria, 5Meharry Medical College, Nashville , TN, USA

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease linked with increased venous thromboembolism risk. Hence, guidelines recommend the use of pharmacologic thromboprophylaxis in admitted IBD patients from any etiology. Consequently, frequent hospitalizations in IBD patients are associated with heightened exposure to heparin and an increased susceptibility to heparin-induced thrombocytopenia (HIT). Objective: Our goal is to assess the prevalence and outcomes of heparin-induced thrombocytopenia in IBD hospitalizations in the United States. Methodology: This is a retrospective study using the Nationwide Inpatient Sample (NIS) database (2010-2019). Using ICD-9 and ICD-10 codes, we identified hospitalized patients with IBD and stratified them based on having a secondary diagnosis of HIT. The groups were compared for socio-demographic differences. Primary outcomes were inpatient mortality, length of stay > 5 days (LOS), and total hospital charges (THC). Secondary outcomes included odds of acute venous thromboembolism (VTE), acute pulmonary embolism (PE), ischemic stroke and myocardial infarctions (MI). Statistical analyses were performed using t-test, univariate and multivariate logistic regression.

Results: Out of 3,093,631 admitted IBD patients, the prevalence of HIT was 0.07% (2,218). Among IBD patients with HIT, 60.5% had crohn's disease and 39.5% had ulcerative colitis. Majority of IBD patients with HIT were older (58.8 vs 53.1 years), covered by Medicare (56.5 vs 42.4%), and admitted to teaching hospitals (73.1 vs 63.7%) compared to those without HIT (P<0.001). On multivariate adjusted analysis, HIT was associated with almost five-fold higher mortality odds among hospitalized IBD patients (adjusted odds ratio (AOR): 4.6, 95% confidence interval (CI): 3.19-6.53). Those with HIT were five times more likely to have longer hospital stays (AOR: 5.3; 95% CI: 4.19-6.60) and had higher THC (β: $108,007; 95% CI: $87,500-$128,515) compared to those without HIT. On subgroup analysis, UC patients with HIT had six-time higher odds of mortality (AOR:6.25; 95% CI: 3.84-10.18), while CD patients with HIT had three-time greater odds of mortality (AOR: 3.13; 95% CI: 1.80-5.47) compared to those without HIT respectively. Additionally, HIT was associated with a higher odds of acute VTE (AOR: 10.1; 95% CI: 7.83 - 13.03), acute PE (AOR: 8.8; 95% CI: 5.96-12.88), acute MI (AOR:3.8; 95% CI:2.32-6.30), ischemic stroke (AOR: 5.8; 95% CI: 2.96 - 11.29), intracranial hemorrhage (AOR: 8.6; 95% CI: 4.05-18.25), GI bleeding (AOR: 1.7; 95% CI: 1.20-2.38), RBC transfusion (AOR: 3.7; 95% CI: 2.96-4.56), and platelet transfusion (AOR: 8.2; 95% CI: 5.50-12.25) in admitted IBD patients. Conclusion: The occurrence of heparin-induced thrombocytopenia (HIT) in hospitalized individuals with inflammatory bowel disease (IBD) is infrequent. Nevertheless, the presence of HIT in this subgroup is linked to significantly increased odds of inpatient mortality, extended hospitalization, and higher healthcare expenses. It is crucial for physicians to maintain a heightened level of suspicion to facilitate timely diagnosis and intervention, thereby mitigating adverse outcomes.
Session: Posters/Exhibits/Break
Heparin-Induced Thrombocytopenia among Cancer Hospitalizations: A Ten Year Retrospective Study
Ayobami Olafimihan1, Praise Fawehinmi2, Ekrem Turk1, Gbolahan Olatunji3, Emmanuel Kokori3, Aderinto Nicholas 4, oh youjin1, Chiamaka Nwachukwu5, Shaka Hafeez1
1John H. Stroger Jr Hospital , Chicago, IL, USA, 2Southern Illinois University Edwardsville, Edwardsville, IL, USA, 3University of Ilorin, Ilorin, Nigeria, 4Ladoke Akintola University of Technology, Ogbomosho, Nigeria, 5Tulane University School of Medicine, new orleans, LA, USA

Background: Cancer patients have high risk of thromboembolism and high likelihood of frequent exposure to heparin products. Also, they have many potential causes of thrombocytopenia including heparin-induced thrombocytopenia (HIT). There is paucity of literature on HIT in cancer patients. We sought to evaluate the impact of HIT on inpatient outcomes of individuals admitted non-electively for cancer. Method: This is a decade retrospective study utilizing the Nationwide Inpatient Sample (NIS) database (2010-2019). Using ICD-9 and ICD-10 codes, we identified patients non-electively admitted for cancer and stratified them based on having a secondary diagnosis of HIT. The groups were compared for socio-demographic differences. Primary outcomes were inpatient mortality, length of stay > 5 days (LOS), and total hospital charges (THC). Secondary outcomes included odds of acute venous thrombosis, acute pulmonary embolism, ischemic stroke, myocardial infarctions, and blood transfusions. Statistical analyses were performed using t-test, univariate and multivariate logistic regression.

Results: There were 5,316,703 patients admitted non-electively for cancer. The prevalence of HIT was 0.08% (4,198). Among cancer patients with HIT, 87.3% had solid malignancy and 12.7% had hematologic malignancy. Cancer patients with HIT were younger (64.4 vs 65.6 years), had higher African-Americans (17.7 vs 14.5%) and Hispanics (10.4 vs 9.1%), higher admissions to teaching (97.5 vs 94.0%) and urban (78.6 vs 68.8%) hospitals, and lower Medicare coverage (50.7 vs 55.8%) compared to those without HIT (P<0.001). On multivariate adjusted analysis, HIT was associated with three-times higher mortality odds among patients with malignancy (adjusted odds ratio (AOR): 3.2, 95% confidence interval (CI): 2.67 - 3.72). In comparison to those without HIT, those with HIT were five-fold more likely to have prolonged hospital stay greater than 5 days (AOR: 5.4; 95% CI: 4.34-6.64%) and had higher THC (β: $117,425; 95% CI: $102,007 - $132,843). On subgroup analysis, hematologic cancer patients with HIT had over double odds of mortality (AOR: 2.6; 95% CI: 1.58-4.16), while solid neoplasm patients with HIT had three-fold higher likelihood of mortality (AOR: 3.2; 95% CI: 2.72- 3.88) compared to those without HIT respectively. However, head-to-head comparison of hematologic cancer and solid cancer patients with HIT showed similar inpatient outcomes. Furthermore, HIT was associated with a higher odds of acute VTE (AOR: 11.5; 95% CI: 9.9 - 13.29), acute PE (AOR: 10.1; 95% CI: 8.48-11.95), acute MI (AOR: 3.6; 95% CI: 2.49 - 5.24), ischemic stroke (AOR: 4.7; 95% CI: 3.24 - 6.81), RBC transfusion (AOR: 2.4; 95% CI: 2.07- 2.79), and platelet transfusion (AOR: 3.2; 95% CI: 2.57- 4.07) in patients admitted for cancer. Conclusion: Heparin-induced thrombocytopenia, albeit an infrequent diagnosis among cancer patient, is associated with significantly higher inpatient mortality odds, prolonged hospital stay and higher health care cost. Efforts need to be directed at improving hospitalization outcomes for this patient subset.
Session: Short Talks - Complications of Disease and Therapy in H&T
DOAC's in the elderly
Abhinav Paknikar1, Keerti Chakravarthy1, Fakiha Siddiqui2, Atul Laddu1, Jawed Fareed2, Aarushi Dua1, Anish Joshi1
1Global Thrombosis Forum , Suwanee , GA, USA, 2Loyola University , Chicago , IL, USA

Background DOACs are routinely prescribed in the elderly to manage non-valvular atrial fibrillation and stroke prophylaxis. DOACs reduce the risk of stroke and systemic thromboembolism, without increasing the risk of major bleeding, with a favorable risk profile. Fluctuations in renal function, comorbidities, and concomitant antiplatelet use may necessitate more individualized dosing strategies with these agents. Objectives/methods We researched the use of DOACs and the challenges in their use in the elderly by reviewing the available literature. Results Age and AF The incidence of AF in the elderly population shows an increase in all the races studied (Figure 1) The Framingham Heart Study group had shown age to be the greatest risk factor for AF, surpassing other risk factors, including male sex, obesity, diabetes, smoking, hypertension, heart failure, and coronary artery disease. The quality of life is poor, with a larger number of hospitalizations, and more cardiovascular events in elderly patients with AF, compared to patients younger than 75 years old. Older age can increase the risk of stroke/systemic embolism, one of the most common complications of AF. Types of DOACs Factor Xa Inhibitors : Rivaroxaban and Apixaban Direct Thrombin Inhibitor (DTI) : Dabigatran Mechanism of action of DOACs (Figure 2) Apixaban, Rivaroxaban and Edoxaban inhibit Factor Xa Dabigatran inhibits Factor IIA. Indications of DOACs Provide both clinicians and patients with safer, more effective, and convenient therapeutic alternatives in thromboembolic conditions. Prevention and treatment of thrombosis in cardiovascular conditions including DVT and PE, atrial fibrillation, and recurrent thrombotic stroke. When should DOACs be avoided? Patients with severe hepatic disease in which warfarin is the only recommended anticoagulant. Dabigatran, apixaban, and edoxaban are viable options in patients with moderate hepatic impairment and do not require dose adjustments. Rivaroxaban should be avoided in patients with advanced renal insufficiency, apixaban is the drug of choice in this population Challenges for the use of DOACs in the elderly Often forget to take medications resulting in altered drug levels and efficacy. Accidental overdose of anticoagulants resulting in excessive risk of bleeding. Polypharmacy & Drug Interaction Altered Pharmacokinetics: Renal function declines with age, affecting excretion and causing a longer half life and elevated bleeding risk High risk of falls due to multiple reasons including stroke, imbalance, visual difficulties, arthritis, and frailty, resulting in increased risk of bleeding. Advantages of DOACs over warfarin No need for regular INR checks No dietary restrictions Stable and predictable dosage Fewer drug interactions Disadvantages of DOACs over warfarin High cost Absence of tests to measure drug levels or effect. Lack of universal reversal agents/antidotes Conclusions DOACs significantly reduce the risk of stroke and systemic thromboembolism in elderly patients, without increasing the risk of major bleeding. DOACs are safe and effective for use in the elderly but should be used with great caution. DOACs offer various practical advantages over warfarin in the elderly.
Session: Posters/Exhibits/Break
The role of factor XII in ECMO-associated thromboinflammation
Joe Palumbo

The role of FXII in ECMO-induced thromboinflammation Mousa Kharnaf MD, Spencer Hogue1, Leah Rosenfeldt, Rachel L. Cantrell2, Bal Krishan Sharma PhD, Cassandra Sprague, Daniel Leino. MD, William A. Abplanalp, Wioleta M. Zelek PhD, Keith R. McCrae MD, Young Jun Shim PhD, David Morales MD, James Tweddell MD, and�Joseph S. Palumbo MD. 1.The Heart Institute, Cincinnati Children's Hospital Medical Center and The University of ����Cincinnati College of Medicine, Cincinnati Ohio����� 2. Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center and The� �����University of Cincinnati College of Medicine, Cincinnati Ohio 3. Department of Pathology, Cincinnati Children's Hospital Medical Center and The� ����University of Cincinnati College of Medicine, Cincinnati Ohio� 4. Systems Immunity Research Institute and Dementia Research Institute, Cardiff University,� ����Cardiff, United Kingdom. 5. Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH The contact pathway has been shown to promote thrombosis in animal models of extracorporeal membrane oxygenation (ECMO). However, the role of contact pathway proteases in ECMO-induced inflammatory complications has not been studied. We�used a rabbit and Sprague-Dawley rat models of ECMO to define the role of the contact pathway in ECMO associated thromboinflammation. We have shown that factor XII (FXII) and factor XI (FXI) drive circuit thrombosis in a rabbit model of ECMO. These data also suggested that targeting FXII limits interstitial pulmonary edema and hemorrhage in ECMO, whereas heparin and FXI depletion do not. More recently, we confirmed the importance of FXII in ECMO circuit associated thrombosis using gene-targeted FXII deficient (FXII-/-) Sprague-Dawley rats. Moreover, comparisons of FXII-/-�and WT rats placed on ECMO with argatroban anticoagulation demonstrated that FXII plays a key role in multiple ECMO-associated inflammatory events, including neutrophil infiltration into tissues, bradykinin release from high molecular weight kininogen, and complement activation. Via a series of�in vitro�analyses, we showed that membrane oxygenator fibers (MOFs) can drive significant thrombin generation in a FXII and FXI-dependent manner. MOFs also augment thrombin generation initiated by TF. However, only FXI elimination prevented the increase in thrombin generation driven by MOFs in the setting of high levels of TF, suggesting MOFs augment thrombin-mediated FXI activation. Together, these data suggest that FXII drives both thrombotic and inflammatory complications in ECMO and could represent an important therapeutic target to limit ECMO-associated complications. However, the data also suggest that in contexts where there are high circulating levels of TF, targeting FXII alone may not be sufficient to prevent ECMO-associated thrombosis.�
Session: FXI & FXII
Real-world use and correlation between platelet-dependant activity assays of von Willebrand factor (vWF):Ab and vWF:GP1bM in patients with von Willebrand disease in the age of the new guidelines: A single-center study
Prarthana Parthasarathy, Kerry M Hege
Riley Hospital for Children at IU Health, Indiana University School of Medicine, Indianapolis, IN, USA

Background: von Willebrand disease (vWD) is the most common inherited bleeding disorder. Laboratory values of von Willebrand factor (vWF) levels vary in the context of hormone use, inflammation, and the stress of the blood draw itself. Furthermore, the type of platelet-dependent vWF activity assay compounds the diagnostic dilemma. Traditional gold-standards of ristocetin cofactor assays are known to have poor precision and a polymorphism that reduces the apparent activity. As a conditional recommendation, the 2021 ASH/ISTH/NHF/WFH guidelines suggested use of newer activity assays such as the vWF:GP1bM and vWF:GP1bR. The vWF:Ab assay measures the binding of a monoclonal antibody to the vWF A1 domain epitope, providing a non-ristocetin-based alternative. Objectives: 1.To determine the correlation and agreement between the non-ristocetin-based vWF:Ab and the newer vWF:GP1bM assay. 2.To describe real-world use of the vWF:GP1bM assay at a sigle-center since the publication of the 2021 ASH/ISTH/NHF/WFH guidelines.

Methods: A retrospective chart review of 104 patients with inherited vWD was completed with descriptive demographic statistics. Pearson coefficient and Bland-Altman analysis were used to determine the correlation and agreement respectively, between the two activity assays, with R stats package.

Results: A total of 104 patients diagnosed with vWD from May 2015 to October 2023 were captured through a retrospective chart review, with a noted median age of 15 years (1-23years). There were 66 females, 37 males, and 1 transgender male. Our cohort was 85% Caucasian, 9% Hispanic, 4% African American, and 2% Asian. All patients had a positive bleeding phenotype and were characterized to have Type 1 disease in 95 patients, Type 2A in 5 patients, with 2 patients each having Type 2M and Type 3 disease. Since the publication of the 2021 guidelines, vWF:GP1bM assay was sent in 38.4% patients, of which 17.4% were evaluated retroactively in patients diagnosed pre-guidelines. With each passing year from the 2021 ASH/ISTH/NHF/WFH guidelines, the vWF:GP1bM was evaluated in the new diagnosis of vWD in 50% patients in the first year, 59% in the second year and 57% in the third year-to-date. The vWF:Ab and vWF:GP1bM assays were significantly positively correlated with a Pearson coefficient of 0.8 (Fig.1 Correlation Plot) and 95% of the differences between the two activity assay measurements were noted to fall within the agreement interval (Fig.2 Bland-Altman analysis). There were 9 patients with vWF:Ab <19%, who were excluded from these analyses, with concurrent vWF:GP1bM ranging from 4-24%.

Conclusions: vWF:Ab, a non-ristocetin-based alternative, is well-correlated and within the agreement interval with the vWF:GP1bM assay for platelet-dependent vWF activity assessment, as estimated using our cohort with a sample size of 31 comparable values. The lower limit of quantitation of the vWF:Ab assay being <19% is a known limitation, which can lead to overestimating Type 1 disease subtypes. The use of vWF:GP1bM assays in these situations, could improve the diagnostic accuracy in vWD subtype characterization and subsequent management. Further work is needed on how best to implement this conditional recommendation on the 2021 guidelines.
Session: Short Talks - Taking Lab Monitoring to the Next Level
Comparative Analysis of Bleeding and Thrombotic Risks Among Immune Checkpoint Inhibitors: Insights from the FDA Adverse Event Reporting System
Emily L Paton1, Emma P Deloughery1,2
1Oregon Health & Science University, Department of Medicine, Portland, OR, USA, 2Oregon Health & Science University, Department of Medicine, Division of Hematology & Medical Oncology, Portland, OR, USA

Background: Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment in various cancers. With the diverse risk profiles of ICIs, ongoing post-marketing surveillance is crucial to understand their safety profiles. Notably, concerns surrounding an elevated risk of both bleeding and thrombotic complications have emerged in the literature, though with some conflicting evidence. The FDA Adverse Event Reporting System (FAERS) aggregates reports from clinicians and patients detailing side effects presumed to be linked to specific pharmaceutical interventions. There is a lack of comparative analyses on bleeding and thrombotic risks across different ICIs among FAERS reports. Objectives: This analysis compares reported bleeding and thrombotic complications of approved ICIs by clinicians in FAERS.

Methods: Using the FAERS database, adverse event data were gathered for approved ICIs: avelumab, atezolizumab, cemiplimab, durvalumab, ipilimumab, nivolumab, and pembrolizumab. Data were filtered by events of interest, including anemia, bleeding, hemolysis, venous thromboembolism (VTE)/pulmonary embolism (PE), and thrombocytopenia. The proportional reporting ratio (PRR) with a 95% confidence interval was used to compare rates of bleeding and thrombotic complications among ICIs. A PRR value greater than 2 was considered statistically significant. If a drug had fewer than 3 adverse events within a specific category, that drug was excluded from the analysis.

Results: 76,036 total adverse events were reported for ICIs from 2006-2023. The PRR was used to compare rates of VTE/PE, anemia, bleeding, hemolysis, and thrombocytopenia. Of the ICIs, avelumab had the highest PRR for VTE/PE (1.17 atezolizumab vs 1.60 avelumab vs 1.01 cemiplimab vs 1.13 ipilimumab vs 0.89 nivolumab vs 1.02 pembrolizumab), thrombocytopenia (1.23 atezolizumab vs 1.80 avelumab vs 0.73 cemiplimab vs 0.93 ipilimumab vs 1.14 nivolumab vs 0.74 pembrolizumab), and bleeding (1.24 atezolizumab vs 1.38 avelumab vs 1.20 cemiplimab vs 1.13 ipilimumab vs 1.26 nivolumab vs 0.68 pembrolizumab), though this was not statistically significant. Atezolizumab had the highest PRR for anemia (1.79 atezolizumab vs 1.05 avelumab vs 1.43 cemiplimab vs 0.93 ipilimumab vs 1.14 nivolumab vs 0.73 pembrolizumab). Between ipilimumab, nivolumab, and pembrolizumab, nivolumab had the highest PRR for hemolysis (0.63 pembrolizumab vs 1.41 nivolumab vs 1.10 pembrolizumab; atezolizumab, avelumab, cemiplimab, and durvalumab were excluded due to fewer than 3 reported cases of hemolysis).

Conclusions: Our results highlight that avelumab may have an increased risk of VTE/PE, thrombocytopenia, and bleeding compared to other approved ICIs, though statistical significance is not reached. Atezolizumab emerges with the highest PRR for anemia, also without statistical significance. Among pembrolizumab, nivolumab, and ipilimumab, nivolumab has the highest PRR of hemolysis. Our results may help guide future prospective studies or suggest to clinicians ICIs to avoid in patients with elevated bleeding or thrombotic risk.
Session: Online Poster Session
Continuing "The Pill" or Not?: VTE Treatment and Exogenous Hormones
Marie-Claude Pelland Marcotte

Combined hormonal contraception (CHC) is very commonly used in adolescents and young adults but is associated with a 2 to 9-fold increase in the risk of venous thrombo-embolism (VTE). The risk of VTE is influenced by the estrogen dose (with increasing doses associated with higher risk of VTE) and type of progesterone (with 3rd and 4th generation progesterone associated with higher VTE risk).

Once a VTE has occurred in an adolescent on CHC, it is safe and acceptable to continue CHC while the patient is receiving anticoagulation, to prevent abnormal uterine bleeding (AUB). However, once anticoagulation is discontinued, the risk of thrombotic recurrence with concurrent estrogen therapy is unacceptably high, and CHC should be stopped and/or changed for methods which do not put the patient at increased VTE risk, such as levonorgestrel intra-uterine device, implant, or progestin-only pill.

AUB is common in young women receiving anticoagulation and may negatively impact their quality of life. Adolescents on anticoagulation should be screened for AUB. Treatment options for AUB include: tranexamic acid during menstrual flow, hormonal therapy, treatment of anemia and iron deficiency, and/or adjustment of anticoagulation, as some anticoagulants appear to be more commonly associated with AUB than others. Referral to gynecology and screening for coagulopathy can be considered.

While they do not constitute absolute contra-indications to CHC, several conditions may increase the risk of VTE in adolescents, such as obesity, thrombophilia, or history of superficial vein thrombosis. In these adolescents, individualized, shared decision-making should inform the choice of contraception.

Session: Young, Wild and VTE - Treatment Considerations for Adolescents and Young Adults
Drop-of-blood coagulation analysis by i-QATTTM
Huy Q Pham1, Collette Barnor1, Daishen Luo1, Elizabeth M Cummins1, Nithya Kasireddy1, Daniel Arango2, Shaun Yockelson3, Damir B Khismatullin1
1Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA, 2The University of Texas Medical Branch, Galveston, TX, USA, 3Department of Anesthesiology and Perioperative Medicine, Ochsner Medical Center, New Orleans, LA, USA

Background: Blood coagulation testing is important for assessing bleeding/thrombotic risks in critical care patients and patients with coagulation disorders. Integrated quasi-static acoustic tweezing thromboelastometry (i-QATTTM) provides both viscoelastic and turbidimetric measurements of blood coagulation using a small drop of blood (4-6 μ L). Objectives: We aim to (1) establish the clinical validity of i-QATTTM by correlation analysis with gold-standard tests (INR/aPTT and TEG) and reference range measurements of coagulation parameters, and (2) investigate its capability to diagnose hypo- and hyper-coagulable states caused by abnormal fibrinogen, heparin, and coagulopathy.

Methods: Citrated whole blood (WB) samples were collected from 16 healthy volunteers using IRB-approved protocols No. 520566 and 944474, and from 8 liver transplant recipients using IRB-approved protocol No. 2020.245. Platelet poor plasma (PPP) samples were isolated from WB samples. Commercial PPP samples, including normal control, low and high fibrinogen, and factor-deficient, were obtained from Fisher Scientific (Hampton, NH) and Affinity Biologicals (Ontario, Canada). For blood samples obtained from healthy volunteers, aPTT/INR and fibrinogen tests were performed by Tulane Coagulation Laboratory, in parallel with i-QATTTM measurements. The first ~500 microliters from each WB sample from liver transplant patients were used for standard-of-care TEG testing at each timepoint of the liver transplant procedure, and the remainder of the sample was used for i-QATTTM analysis. INR values were also obtained for these samples at each timepoint. The linear correlation between the parameters of i-QATTTM and those of gold-standard tests was assessed using either the Pearson correlation coefficient (rp) or the Spearman rank correlation coefficient (rs). Reference ranges for i-QATTTM coagulation parameters were calculated using the established protocol. The i-QATTTM diagnostic capability was assessed by abnormal blood sample analysis. Here, we report the data on the following i-QATTTM parameters: clot initiation time (CIT), reaction time (RT), maximum clot firmness (MCF), and maximum fibrin level (MFL).

Results: Statistically significant differences in clot firmness, measured by relative angle θ , between normal and abnormal blood samples were observed at 6 min (p<0.05) (Fig. 1). As shown in Figure 2(a), CIT and RT were strongly correlated with aPTT (rp ≥ 0.83) and INR (rs ≥ 0.67) for PPP samples. CIT and MCF were strongly correlated with TEG R-time and MA (rp ≥ 0.64) for WB samples. Reference ranges for PPP CIT (2.65-4.72 for intrinsic or 0.63-2.04 for extrinsic pathway) established based on normal blood analysis ruled out abnormal coagulation caused by single factor deficiency (FVII, FIX, FX) or anticoagulant therapy (heparin) (Fig. 2b). PPP MCF had abnormal values corresponding to high and low fibrinogen levels outside the established reference range (3.76-9.53). Abnormal CIT and reduced MCF values were seen for WB samples from liver transplant patients with elevated INR (INR = 2.4) and from normal WB samples with platelet function reduced by Cytochalasin-D, respectively.

Conclusions: i-QATTTM strongly correlates with gold-standard techniques, and reference ranges of its parameters accurately describe normal coagulation and rule out abnormal cases. Furthermore, i-QATTTM can rapidly detect hypo- and hyper-coagulable states.
Session: Short Talks - Taking Lab Monitoring to the Next Level
Acquired hemophilia secondary to the Transplantation of Hematopoietic Progenitors. A Systematic Review
Rafael Pichardo-Rodriguez1, Cristhian Gonzales- Rospigliosi1, Dalia Pimentel-Ramirez1, Aracely Carrasco-Espinoza1, Lara Vela-Rojas1, Diana-Cristina Ramírez-Meyhuay1, Jhony A. De La Cruz-Vargas1, Alfredo Wong Chang2, Cristobal Frutos3
1Instituto de Investigaciones en Ciencias Biomédicas (INICIB). Universidad Ricardo Palma, Lima, Peru, 2Unidad de Trasplante de Médula �"sea. Hospital Nacional Edgardo Rebagliati-Essalud, Lima, Peru, 3Instituto de Previsión Social, Asuncion, Paraguay

BACKGROUND: Acquired hemophilia (AH) is a severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII or IX. Hematopoietic stem cell transplantation (HSCT), has been associated with the development of AH though evidence is limited. OBJECTIVES: To describe the clinical characteristics, therapeutic approaches, and outcomes in patients with AH developed after HSCT. METHODS: A systematic review of case reports was conducted following the PRISMA statement (PROSPERO: CRD42024512037). Case reports of post-transplant patients with confirmed AH diagnosis were included. Risk of bias was assessed, and qualitative synthesis of data was performed. RESULTS: Twelve clinical cases were included. The 58% presented high quality. Patients developed AH within a variable post-transplant time range (4 days to >2 years), with clinical presentations including hematomas, systemic hemorrhages, and epistaxis. A variety of pre-transplant conditioning regimens were observed, with thiotepa/cyclophosphamide being the most common. Allogeneic transplantation was more frequent than autologous. The majority of patients developed inhibitors to factor VIII and exhibited reduced levels of FVIII activity. Treatment included prothrombin complex concentrates, corticosteroids, and immunosuppressants, with Rituximab showing significant improvements in some cases. Despite treatment initiation, 50% of patients recovered, 25% had disease relapse and 25% died of hemorrhagic complications. CONCLUSIONS: Post-transplant AH is a severe complication requiring multidisciplinary evaluation and management. Navigating treatment specially in allogeneic HSCT recipients for malignant diseases where graft preservation is crucial poses a unique challenge. Although improvements were observed with different treatments, complications are notable, highlighting the need for further research to guide optimal management of this population.
Session: Online Poster Session
Accurate Measurement of Factor VIII Activity and Inhibitors in the Presence of Mim8
William Pickering1, Karin Nana Weldingh2, Mary Robinson1, Caroline Cogswell1, Wan Hui Ong Clausen2, Mirella Ezban2, Vlady Ostrow3
1Labcorp Colorado Coagulation, Englewood, CO, USA, 2Novo Nordisk A/S, Søborg, Denmark, 3Novo Nordisk Inc., Plainsboro, NJ, USA

Background: Mim8 (denecimig) is an activated factor IX (FIXa)/factor X (FX) bispecific antibody for the prophylactic treatment of hemophilia A (HA) with or without inhibitors. Measuring factor VIII (FVIII) activity and FVIII inhibitors in patients with HA is clinically important but can be challenging in the presence of FVIII mimetics. FVIII mimetics such as Mim8 interfere with activated partial thromboplastin time-based assays, while chromogenic substrate assays (CSAs) containing human or human/bovine proteins exhibit varied sensitivity to FVIII mimetics. In the presence of bispecific antibodies, FVIII activity can only be assessed using CSAs containing bovine FIXa/FX. Objectives: To investigate Mim8 interference with the measurement of FVIII activity in plasma samples containing standard half-life (SHL) and extended half-life (EHL) FVIII products and on the measurement of FVIII inhibitor levels.

Methods: To assess FVIII activity of SHL and EHL products, severe HA plasma was spiked with ADVATE®, Novoeight®, Esperoct®, or ELOCTATE® (5, 10, 15, 20, and 100 IU/dL final concentrations) and Mim8 (0, 3, 6, and 12 µg/mL final concentrations). FVIII activity was measured with the fully bovine Chromogenix Coatest® SP4 FVIII (DiaPharma Group, Inc) and mixed human/bovine CRYOcheck™ (Precision BioLogic, Inc) CSAs. Interference was defined as a ≥1.2-fold increase in FVIII activity relative to the corresponding sample without Mim8. To assess FVIII inhibitor levels, a FVIII inhibitor kit (Precision BioLogic, Inc) and 2 FVIII CSA kits using bovine FIXa/FX reagents (Factor VIII Chromogenic Assay [Siemens Healthineers], Chromogenix Coatest® SP4 FVIII [DiaPharma Group, Inc]) were used to test pooled congenital FVIII-deficient plasma (George King Bio-Medical) spiked with Mim8 (5, 10, 20, and 40 µg/mL) and FVIII inhibitor (Affinity Biologicals; 0.2, 1.0, and 4.8 Bethesda units [BU]). Mim8 interference was defined as a negative result (<0.6 BU) becoming positive (0.2 BU FVIII inhibitor samples) or a result falling outside ±25% of the unspiked sample result (1.0 and 4.8 BU FVIII inhibitor samples).

Results: Using the bovine CSA, no notable interference with FVIII activity was observed in samples spiked with SHL or EHL product at any FVIII/Mim8 concentration. Using the bovine/human CSA, a Mim8 dose-dependent increase in interference was observed in samples with FVIII concentrations ≤0.20 IU/mL. With both SHL and EHL products, increased FVIII levels correlated with reduced interference in a Mim8 dose-dependent manner. No Mim8 interference was observed at any FVIII inhibitor level, and inhibitor titers measured in all Mim8 spiked samples fell within ±25% of target. Siemens CSA inhibitor samples at 0.2 BU remained negative (<0.6 BU), with no reported results >0.4 BU. Spiked samples at 1.0 and 4.8 BU recovered within −5.0% to −3.0% and −2.1% to 2.4%, respectively, of the corresponding unspiked samples. Unspiked 1.0 and 4.8 BU samples recovered within 1.0% and 19.6% of target, respectively.

Conclusions: FVIII activity of SHL and EHL products was accurately measured in the presence of Mim8 using bovine CSAs. Using FVIII CSAs with bovine reagents, FVIII inhibitor levels up to approximately 5.0 BU were accurately measured in HA plasma in the presence of up to 40 µg/mL Mim8.
Session: Posters/Exhibits/Break
Sustained Efficacy and Safety 3 Years Following Infusion with Etranacogene Dezaparvovec in Adults with Severe or Moderately Severe Hemophilia B in the Phase 3 HOPE-B Clinical Trial
Steven W. Pipe1, Paul van der Valk2, Peter Verhamme3, Peter Kampmann4, Frank Leebeek5, Michiel Coppens6, Nigel Key7, Nathan Visweshwar8, Guy Young9, Richard Lemons10, Robert Klamroth11, Niamh O'Connell12, Sandra le Quellec13, Paul Monahan13, Cedric Hermans14
1Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA, 2Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands, 3Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium, 4Rigshospitalet, Copenhagen, Denmark, 5Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands, 6Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands, 7University of North Carolina, Chapel Hill, NC, USA, 8University of South Florida, Tampa, FL, USA, 9University of Southern California Keck School of Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA, 10University of Utah, Salt Lake City, UT, USA, 11Vivantes Klinikum im Friedrichshain, Berlin, Germany, 12National Coagulation Centre, St. James’s Hospital, Dublin, Ireland, 13CSL Behring, King of Prussia, PA, USA, 14Division of Haematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium

Background: Etranacogene dezaparvovec (formerly AMT-061), a gene therapy for the treatment of hemophilia B, comprises a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a factor IX (FIX) Padua R338L transgene under the control of a liver-specific promoter (LP-1). Etranacogene dezaparvovec is the first approved gene therapy for adults with hemophilia B in the EU, US and Canada. In the HOPE-B pivotal Phase 3 clinical trial (NCT03569891), etranacogene dezaparvovec demonstrated superior bleed protection compared to FIX prophylaxis up to Month 24 post-infusion. Ongoing follow-up continued from Year 2. Objectives: To report the efficacy and safety of etranacogene dezaparvovec up to Month 36 post-treatment in the HOPE-B Phase 3 clinical trial.

Methods:
In this open-label, single-arm, Phase 3 trial, adult male patients with severe or moderately severe hemophilia B, with or without pre-existing AAV5 neutralizing antibodies (NAbs), received a single infusion of etranacogene dezaparvovec (2×1013 gc/kg) following a ≥6-month lead-in period of FIX prophylaxis.

Results:
Among 54 patients who received etranacogene dezaparvovec, 52 completed 36 months' follow-up. The two patients (3.7%) who did not complete this follow-up, one with the highest AAV5 NAb titer (1:3212) and one who received a partial dose (~10% of the planned dose), did not express FIX Padua and remained on FIX prophylaxis. Mean annualized bleeding rate (ABR) for all bleeds during Months 7-36 was reduced by 64% versus lead-in (1.52 and 4.17, respectively; P=0.0004). Mean ± SD endogenous FIX activity was sustained at 41.5±21.7 IU/dL (n=50), 36.7±19.0 IU/dL (n=50), and 38.6±17.8 IU/dL (n=48) at Years 1, 2, and 3 post‑treatment, respectively. By Year 3, 1 patient (1.9%) expressed endogenous FIX activity levels <5 IU/dL, 3 patients (5.6%) between 5-<12 IU/dL, 26 patients (48.1%) between 12-<40 IU/dL, and 18 patients (33.3%) expressed levels ≥40 IU/dL. FIX activity levels were missing/uninterpretable for 4 patients (7.4%) at Year 3; 1 patient died (unrelated to treatment), 1 patient returned to continuous FIX prophylaxis at Month 30 post-treatment following a decline of FIX levels to 2-5% and bleeding phenotype recurrence, 1 patient had a liver transplant, and 1 patient had a non-analyzable sample due to hemolysis. At Year 3 post‑treatment, 51 patients (94%) remained free of continuous FIX prophylaxis; mean annualized FIX consumption decreased by 96% versus lead-in (P<0.0001). All patients experienced at least 1 treatment-emergent adverse event (AE), with no serious AEs related to treatment (1 case of hepatocellular carcinoma [HCC] and 1 death were reported before Year 2). A total of 38/54 (70.4%) patients experienced 93 treatment-related AEs. The most common AE was increased alanine transaminase (ALT). Nine patients (16.7%) received reactive corticosteroids for a mean ± SD of 81.4±28.6 days. No new deaths, HCC, or late treatment-related ALT elevations were reported during Year 3.

Conclusions:
Etranacogene dezaparvovec provides long-term FIX Padua expression, with the majority of patients expressing FIX activity levels in the mild or normal range at Year 3 post‑treatment, as well as superior bleed protection compared to FIX prophylaxis and a favorable safety profile.
Session: Posters/Exhibits/Break
Emicizumab Prophylaxis for the Treatment of Infants with Severe Haemophilia A without Factor VIII Inhibitors: Primary Analysis of the HAVEN 7 Study
Steven W. Pipe1, Peter Collins2, Christophe Dhalluin3, Gili Kenet4, 5, Christophe Schmitt3, Muriel Buri3, Víctor Jiménez-Yuste6, Flora Peyvandi7, 8, Guy Young9, Johannes Oldenburg10, Maria Elisa Mancuso11, 12, Kaan Kavakli13, Anna Kiialainen3, Markus Niggli3, Tiffany Chang14, Michaela Lehle 3, Karin Fijnvandraat15
1University of Michigan, Ann Arbor, MI, USA, 2School of Medicine, Cardiff University, Cardiff, United Kingdom, 3F. Hoffmann-La Roche Ltd, Basel, Switzerland, 4Sheba Medical Center, Ramat Gan, Israel, 5Tel Aviv University, Tel Aviv, Israel, 6Hospital Universitario La Paz-IdiPaz, Universidad Autónoma, Madrid, Spain, 7Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy, 8Università degli Studi di Milano, Milan, Italy, 9Children’s Hospital Los Angeles, Los Angeles, CA, USA, 10Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany, 11IRCCS Humanitas Research Hospital, Rozzano, Italy, 12Humanitas University, Pieve Emanuele, Milan, Italy, 13Ege University Faculty of Medicine Children's Hospital, Izmir, Turkey, 14Spark Therapeutics, Inc., San Francisco, CA, USA, 15University of Amsterdam, Amsterdam, Netherlands

Introduction: Venous access presents a significant challenge in infants with hemophilia A (IwHA) requiring prophylaxis. Subcutaneous emicizumab enables prophylaxis from birth, reducing bleed risk. Objectives: The HAVEN 7 (NCT04431726) primary analysis evaluates emicizumab prophylaxis over ≥52 weeks in IwHA.

Methods: IwHA in the Phase 3b, open-label study were aged ≤12 months without factor (F)VIII inhibitors. They received emicizumab 3mg/kg maintenance dose every 2 weeks (Q2W) for 52 weeks, continuing emicizumab for 7 years' planned follow-up. Endpoints include efficacy (negative binomial regression model-based annualized bleed rates [ABR] for treated, all, treated spontaneous, and treated joint bleeds), safety, pharmacokinetics, anti-emicizumab antibodies (ADAs), FVIII inhibitors, and biomarkers.

Results: At data cut-off (May 22, 2023), 55 male IwHA had received emicizumab for ≥52 weeks (54.5% previously minimally treated [≤5 exposure days, EDs], and 45.5% previously untreated [PUP]). Median (range) age: 4 months (9 days-11 months 30 days) at enrollment; 29 (12-39) months at cut-off. Median (range) treatment duration: 100.3 (52-118) weeks. ABRs (95% confidence interval) for treated, all, and treated joint bleeds were 0.4 (0.30-0.63), 2.0 (1.49-2.66), and 0.0 (0.01-0.09), respectively. Overall, 207 bleeds occurred in 46 IwHA (83.6%), 87.9% of which were traumatic. Of the 207 total bleeds, 42 bleeds in 25 IwHA were treated, all traumatic. Thirty (54.5%) IwHA had zero treated bleeds, and no IwHA had >3 treated bleeds. No intracranial hemorrhage occurred. One IwHA was up-titrated (Day 374) to 3mg/kg weekly per investigator request based on locally assessed decreasing emicizumab levels. Nine IwHA (16.4%) had ≥1 treatment-related adverse event (AE), all Grade 1 injection-site reaction. No AE led to emicizumab change/withdrawal. No deaths/thrombotic events/thrombotic microangiopathies occurred. Mean steady-state emicizumab concentrations were 57-66µg/mL, above those with the same regimen in HAVEN 2 and 3 (46-48µg/mL). No IwHA developed ADAs. Two PUPs developed confirmed inhibitors after three and ten FVIII EDs, respectively. Mean FIX and FX concentrations were not impacted by emicizumab treatment. Activated partial thromboplastin time was shortened to within reference range by Day 15 (the first time point at which blood samples were obtained) in most participants. Mean thrombin generation peak height increased during loading and was maintained between 67 and 88nmol/L thereafter. Mean FVIII-like activity increased from baseline, and was then sustained between 21 and 26U/dL.

Conclusions: This analysis suggests that emicizumab is efficacious and well tolerated in IwHA without FVIII inhibitors.
Session: Posters/Exhibits/Break
Long-Term Safety and Efficacy of Fitusiran Prophylaxis in a Phase 1/2 Open-label Extension Study in People with Moderate or Severe Hemophilia A or B
Steven W. Pipe1, Toshko Lissitchkov2, Sarah Mangles3, Pencho Georgiev4, Erin Feng5, Laurel A. Menapace6, Salim Kichou7, Shauna Andersson6, Marek Demissie6, Margaret Ragni8
1University of Michigan, Ann Arbor, MI, USA, 2Clinic Specialized Hospital for Active Treatment of Haematological Diseases, Sofia, Bulgaria, 3Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, United Kingdom, 4University Multiprofile Hospital for Active Treatment , Plovdiv, Bulgaria, 5Sanofi, Shanghai, China, 6Sanofi, Cambridge, MA, USA, 7Sanofi, Paris, France, 8University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA

Background: Fitusiran is a subcutaneous investigational siRNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia A or B, regardless of inhibitor status. Objectives: To evaluate the long-term safety and efficacy of fitusiran prophylaxis in people with hemophilia A or B, with or without inhibitors, in a Phase 1/2 open-label extension study (NCT02554773).

Methods: This Phase 1/2, single-arm, open-label extension study included males aged ≥18 years with moderate or severe hemophilia A or B, with or without inhibitors, who had completed the Phase 1 study (NCT02035605). Participants initially received once-monthly subcutaneous fitusiran 50 or 80 mg (original dose regimen [ODR]). Following a voluntary dosing pause in 2020 after reports of non-fatal thrombotic events, a revised AT-based dosing regimen was implemented, with dose adjustments based on individual participant responses, targeting AT levels between 15-35% to mitigate thrombotic risk. Primary and secondary endpoints were safety and annualized bleeding rate, respectively.

Results: Overall, 34 participants initiated the ODR (hemophilia A inhibitor/non-inhibitor, n=13/14; hemophilia B inhibitor/non-inhibitor: n=2/5). Following the voluntary dosing pause, 18 participants restarted on the revised AT-based dosing regimen (hemophilia A inhibitor/non-inhibitor, n=6/6; hemophilia B inhibitor/non-inhibitor, n=2/4), and 12 completed the study (Figure 1). Of those that restarted on the revised AT-based dosing regimen, 2 participants received 80 mg once-monthly (QM), 5 received 50 mg QM and 11 received 50 mg every other month (Q2M). One participant escalated from 50 mg Q2M to 50 mg QM following the restart as per investigator decision. AT levels were maintained in target range of 15-35% with the revised AT-based dosing regimen. Median (min-max) exposure was 1135 (28-1700) days on the ODR and 568 (227-625) days on the revised AT-based dosing regimen. No thrombotic events occurred in participants with the revised AT-based dosing regimen; thrombotic events occurred in 2/34 (5.9%) participants with the ODR. Alanine transaminase/aspartate aminotransferase (ALT/AST) elevations >3× upper limit of normal occurred in 6/34 (17.6%) participants with the ODR and 1/18 (5.6%) participants with the revised AT-based dosing regimen. Cholecystitis and/or cholelithiasis occurred in 4/34 (11.8%) participants with the ODR and 0/18 participants with the revised AT-based dosing regimen. Fitusiran prophylaxis maintained effective bleed protection over a 6-year period; observed median annualized bleeding rate was 0.70 with ODR and 0.87 with the revised AT-based dosing regimen (Figure 2).

Conclusions: Following implementation of the fitusiran revised AT-based dosing regimen, no thrombotic events and no cholecystitis and/or cholelithiasis were reported. ALT/AST elevation occurred in one subject. AT-based dose individualization may improve the safety profile of fitusiran, while maintaining effective bleed protection. The revised AT-based dosing regimen is under evaluation in ongoing clinical studies.
Session: Posters/Exhibits/Break
Transfusion Trends in the Obstetric Population with Analysis of a Soft Stop Transfusion EMR Alert
Maren Plant1, Sophia Cordes1, Caroline Bereuter1, Jaclyn Phillips1, Xiomara Fernandez2, Homa Ahmadzia1
1Department of Obstetrics and Gynecology, George Washington University , Washington, DC, USA, 2Department of Pathology, George Washington University, Washington, DC, USA

Background: Blood product transfusion plays an important role in treating obstetric hemorrhage, which is the leading cause of maternal mortality worldwide. Obstetric transfusion practices are varied, and research in this area is limited. The recent advent of EMR soft stop transfusion alerts has the potential to limit unnecessary transfusion in patients. Analysis of overall transfusion trends in the obstetric population and with respect to EMR alerts may inform further research and guidelines. Objective(s): This study aimed to analyze transfusion trends in the obstetric patient population at a large university hospital before and after implementation of a soft stop EMR alert notifying providers before transfusing patients with a hemoglobin greater than 8 g/dL. Study Design: The study included 17,744 patients who delivered at the hospital between February 2015 and December 2022. The EMR soft stop alert was implemented in February 2022. Patients were split into two cohorts-those prior to and those following the date of alert implementation. Records of hematocrit values and transfusion were pulled from the electronic medical record. Transfusion data included packed red blood cells, thawed plasma, and platelets. Means and medians were calculated for hematocrit drawn closest to admission and closest to discharge, and by the number of units received. Using a two-tailed unpaired t-test for samples with unequal variance, a p-value was calculated for number of units transfused in cohorts 1 versus 2.

Results: Of the 17,744 patients included in the study, 208 received postpartum transfusions of pRBCs, FFP, and/or platelets. Average estimated blood loss (EBL) was 1996 ± 1505 mL (range 150-1505). 170 participants were included in cohort 1 from February 2015-January 2022. 38 participants were included in cohort 2 (following alert implementation) from February 2022-December 2022. The average number of units transfused in Cohort 1 vs. Cohort 2 was 2.9 vs. 2.0 units (p=0.039). Cohorts 1 and 2 had an equal average hematocrit closest to discharge. The average hematocrit closest to discharge for the total population was 27.2% ± 5.0. Broken down by blood product units received, the average hematocrit closest to discharge for the total population was 27.1% ± 4.7, 27.2% ± 5.2, and 27.4% ± 5.1 for 1 unit, 2 units, and 3+ units respectively (Table 1). Conclusion(s): Our findings demonstrate a statistically significant decrease in the total number of units transfused after the EMR soft stop was implemented. While many factors influence the decision to transfuse, this alert may correlate with a reduction in the number of transfusions in obstetric patients. Overall, more research is needed to guide transfusion practices, including analysis of intrapartum transfusion with respect to postpartum transfusion.
Session: Posters/Exhibits/Break
Challenges in practical application of LA testing guidelines in North America: Mixing studies and beyond!
Jacqueline Poston, Andrew Goodwin

The diagnosis of Anti-Phospholipid Antibody Syndrome (APS) remains a clinical diagnosis supported by laboratory testing, which continues to challenge both clinicians and laboratorians. This presentation will describe the lack of standardization and limitations of current laboratory testing impacting the sensitivity and specificity of the APS diagnosis, as well as the clinical implications.

Session: Dissolving the Clot of Thrombilia Testing: Current Diagnostic Updates and Challenges
Novel Mechanism of Thrombosis and Hemostasis Involving Platelet Alpha-Dystroglycan
Viktor Prifti1,2, Aron A. Shoara2,3, Reid C. Gallant4, Sladjana Slavkovic2,3, Kanwal Singh3, Margaret Rand1, Walter Kahr5, Yiming Wang2, Heyu Ni1,2,3
1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, 2Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada, 3Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, 4Department of Medicine, University of Toronto, Toronto, ON, Canada, 5Department of Biochemistry, University of Toronto, Toronto, ON, Canada

Background: Alpha-dystroglycan (αDG) is a cell-surface adhesion glycoprotein. Patients with Duchenne muscular dystrophy (DMD) who have reduced αDG experience increased bleeding during major surgeries. DMD patients have also shown reduced platelet aggregation and adhesion responses. Furthermore, αDG is known to possess matrix metalloprotease cleavage sites and is shed during platelet activation. However, the precise mechanism of platelet expressed αDG in the processes of hemostasis and pathological thrombosis remain unclear. Objectives: We investigated the functional role of platelet αDG in hemostasis and thrombosis, by blocking αDG with inhibitory antibodies and observing the effect on platelet aggregation and thrombus size and stability. We then studied candidate binding proteins of αDG which were hypothesized to be major platelet activation/adhesion receptors.

Methods: ADP-, thrombin-, and collagen-induced aggregation assays were done with human platelet rich plasma (PRP) and gel-filtered platelets utilizing polyclonal (H-300) and monoclonal (VIA4-1) anti-αDG antibodies. Ristocetin- and VWF A1-induced agglutination assays were performed with VIA4-1 in human PRP and gel-filtered platelets. Cremaster arteriole thrombosis in vivo mouse model was utilized to investigate the inhibitory effect of anti-αDG antibody on thrombus formation. Bio-layer interferometry (BLI) was used to detect αDG binding to human αIIbβ3, fibronectin (Fn), αIIbβ3-Fn complex and also to GPIbα. Isothermal titration calorimetry (ITC) was utilized to quantify αDG-GPIbα binding thermodynamic parameters.

Results: ADP-, thrombin-, and collagen-induced human platelet aggregation was inhibited with H-300 and VIA4-1. Ristocetin- and VWF A1-induced human platelet agglutination was inhibited with VIA4-1. In vivo mouse thrombus formation was inhibited by H-300. BLI detected a weak interaction between αDG and conformationally active αIIbβ3 enhanced by the presence of fibronectin. Importantly, a high affinity interaction was detected between αDG and GPIbα, which was subsequently confirmed with ITC. Conclusion: Platelet αDG has a critical role in thrombosis and hemostasis. αDG was found to be a potential cognate receptor for GPIbα. αDG was found to have a mild binding affinity to αIIbβ3 and Fn in isolation. However, αDG demonstrated enhanced affinity to the Fn-αIIbβ3 complex. GPIbα may propagate outside-in signaling following interaction with αDG to support platelet activation. Our results suggest that anti-thrombotic pharmaceutical agents could be developed which may also enhance the care of muscular dystrophy patients.
Session: Short Talks - Insights on Platelet Biology
Unraveling the Anticoagulant Functions of FV Using Monoclonal Antibodies
Sean Quinn1, Francis Ayombil1, Matthew Bunce1, Rodney M. Camire1,2
1Department of Pediatrics, The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

BACKGROUND: Coagulation factor V (FV) has both pro- and anti-coagulant functions. As a key component of prothrombinase, activated FV (FVa) enhances the relative rate of thrombin generation by 300,000-fold compared to FXa alone. While the procoagulant functions of FV have been extensively studied, its anticoagulant functions are less understood. Together with protein S (PS), FV is thought to function as a cofactor for activated protein C (APC) and TFPIα in the inactivation of FVIIIa and FXa, respectively. Interestingly, FVa does not show these anticoagulant properties. OBJECTIVE: Here, we generated FV-specific monoclonal antibodies (mAbs) as tools to better understand FV function in these anticoagulant pathways and their procoagulant response. METHODS: Procoagulant FV-specific mAbs (GB5, IC1, 3H8, and 6C2) were identified from mice immunized with human FV. Kinetic binding studies using biolayer interferometry (BLI) were used to determine the affinities for antibody binding to physiologic forms of FV including FV, FV-short, and FVa. Immunoblotting, BLI binning, and peptide arrays were used to define the binding epitopes for our FV-specific mAbs. The hemostatic function of each mAb was assessed in tissue factor-initiated thrombin generation assays (TGAs) using pooled normal, or hemophilia A plasmas. The mechanism and effect of mAbs on APC and TFPI anticoagulant functions were evaluated via both plasma-based TGAs using PS-depleted plasma (PS-DP) and TFPI-depleted plasma (TFPI-DP) and in purified component assays (i.e. prothrombinase). RESULTS: All four mAbs bound physiologic forms of FV with sub-nanomolar affinities. Immunoblotting data confirmed that GB5 binds the light chain of FV. Further, GB5 blocked plasmin-mediated cleavage of FV light chain, suggesting its epitope is proximal to the known plasmin cleavage site at R1765. Additional experiments revealed that while IC1, 3H8, and 6C2 have distinct peptide sequences, they compete for binding to FVa which indicates that they have overlapping binding epitopes. In TGAs using pooled normal or hemophilia A plasmas, each mAb modestly enhanced thrombin generation. In the presence of added APC, 6C2 and GB5 completely restored thrombin generation, whereas IC1 and 3H8 partially restored thrombin generation. Purified component assays showed that the mAbs did not enhance thrombin activation of FV or FVa cofactor activity in prothrombinase. These results demonstrated that all four mAbs may alter APC anticoagulant functions in plasma with a procoagulant outcome. In TGAs using TFPI-DP, none of the mAbs altered thrombin generation suggesting that they may impact the TFPIa pathway. In addition, the effect of GB5 on thrombin generation was abolished in PS-DP. Together, these results show that the mAbs disrupt the APC and TFPIα anticoagulant functions of FV. In addition, GB5 disrupts FV anticoagulant function with PS. CONCLUSION: In summary, we have identified four distinct FV-specific mAbs which alter the APC and TFPIα pathways and are useful tools to better investigate the anticoagulant properties of FV. These antibodies may be useful for rebalancing coagulation via FV's anticoagulant functions.
Session: Short Talks - Thrombosis - Innovations in AC
Anticoagulation Stewardship: Appropriate use of Apixaban and Rivaroxaban Factor Xa levels in the Emergency Department
Firas Quran, Sara Zochert, Michael Gulseth, Alicia Martin
Sanford USD Medical Center and Hospital, Sioux Falls, SD, USA

Background: The use of Factor Xa (FXa) inhibitors has increased substantially since their implementation in recent guidelines. A couple benefits of FXa inhibitors include the ease of dosing and, most notably, lack of routine monitoring. Some facilities have the capability to obtain apixaban and rivaroxaban anti-Xa drug levels, however due to the lack of FDA approval and lack of evidence surrounding the support of monitoring their plasma drug concentration, utilization of FXa drug levels in direct patient care remains questionable. A previous study investigated plasma concentrations of rivaroxaban in relation to patients presenting with hemorrhages or thrombosis. Patients presenting with out-of-range concentrations had more bleeding or thrombus when compared to patients with expected concentrations. Patients with bleeding were found to have concentrations beyond the ninety-five percentiles, however patients with thrombosis were more likely to have concentrations below the fifth percentile. Additional trials have shown potential benefits for monitoring FXa drug concentrations in emergent situations. Potential indications for lab monitoring include: trauma, urgent surgery/invasive procedures, major bleeding, overdose, acute thrombosis, renal failure, liver failure, and potential drug-drug interactions. At our facility, we have a guideline that utilizes FXa drug levels to aid in transitioning from a FXa inhibitor to heparin intravenous infusion. Since there is no official therapeutic range for any FXa inhibitor, assessing anti-Xa level can be challenging. In our facility, we noticed potential overutilization of rivaroxaban and apixaban calibrated anti-Xa drug levels. This study will act as an anticoagulation stewardship review to validate appropriate use of these levels. Objectives: The main objective of this study is to standardize a list of appropriate indications of when to order non-FDA approved apixaban and rivaroxaban calibrated anti-Xa levels in the emergency department.

Methods: This is a retrospective cohort study of adults who had an apixaban or rivaroxaban anti-Xa level obtained in the emergency department between July 1, 2022, to June 30, 2023. Patients were excluded from this research if they were under the age of 18 or pregnant. Secondary outcomes including baseline characteristics, indication for the apixaban or rivaroxaban anti-Xa level (adherence/compliance, acute thrombosis, major bleeding, urgent invasive procedures/surgeries, trauma, overdose, renal failure, liver failure, and drug-drug interactions), financial impact of lab ordering, and patient outcomes (if lab result led to a change in therapy) will be analyzed. Results/Conclusion: Research is still in progress.
Session: Posters/Exhibits/Break
Coagulation biomarkers and laboratory support of critically ill patients
Sabrina Racine-Brzostek

Abnormalities in hemostasis are commonly observed in critically ill patients. Coagulopathies may complicate the patient's hospital course, leading to potentially adverse outcomes and an increase in mortality. This presentation will review the more commonly known and more readily available coagulation markers such as aPTT, PT/INR, platelets, fibrinogen, fibrin degradation products (e.g. D-dimer). However, these routine coagulation tests may fail to identify or detect clinically significant coagulation defects that contribute to bleeding. During a brief overview of coagulation and fibrinolytic pathophysiology, other less conventional biomarkers will be highlighted including antithrombin (AT), protein C, tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (tPA) and tissue plasminogen activator inhibitor (PAI). Also, the interplay between the coagulation and inflammatory pathways will be touched upon briefly. Finally, nonconventional assays will also be highlighted. As a technology becoming more mainstream in hospital settings, there will be an emphasis on viscoelastic testing which provides a comprehensive evaluation of the overall hemostatic process and may fill diagnostical gaps that standard coagulation testing may lack.

Session: Lab support of clinical decision-making in the critically ill bleeding patient
What is the role of family history in the management of VTE?
Ayan Ramanathan1, Ishan Dhaneshwar1, Joseph Caprini3, Fakiha Siddiqui2, Atul Laddu1, Jawed Fareed2, Krish Punyarthi1, Richa Mahajan1
1Global Thrombosis Forum , Suwanee , GA, USA, 2Loyola University , Chicago, IL, USA, 3Northshore University Health System , Evanston, IL, USA

Background VTE is a worldwide public health and medical care problem due to high morbidity, mortality, and rate of missed diagnosis, and considered as the most likely preventable fatality. The awareness of VTE in the general population is very low. Caprini Risk Score (CRS), widely used all over the World to determine the level of risk for thrombosis, includes many risk factors that occur in hospitalized patients with VTE. Objectives To increase awareness of VTE in the community regarding thrombosis-related risks, we assessed individual participants' baseline thrombosis risk scores before injury, illness or hospitalization occurred, employing a non-experimental design, involving cross-sectional survey methodology, and convenience sample. Methods Clinical protocol Participants (N=928) were recruited from the USA, UK, and India. Risk factors were assigned weights between 1 to 5 reflecting the power of each factor to cause a blood clot. The risk of VTE occurrence in patients was divided into low (0 ~ 1 points), risk (2 ~ 4 points), high (≥5 points), and very high (9 + points). The participants tested on their own electronic devices; the team was blinded to the identity of the participants. The participants logged in to the website, www.capriniriskscore.org. The study was approved by the IRB of DePaul University and was administered by high school students. Results A total of 247 (26.6%) participants reported a family history of blood clots (Figure 1). The age of those who have a family member with a history of blood clot is shown in Figure 2. The high average CRS in those over 75 years of age, any additional risk factor would indicate the need for anticoagulant prophylaxis following surgery in almost all these individuals, barring a significant bleeding risk was present. A large proportion of female respondents (34.9%) took contraceptives. If the members stop taking birth control one month before surgery, and eventually become pregnant, there is even more risk of thrombosis than being on birth control. In our study, 17.3% of respondents reported IBD, 26.1% had a history of diabetes, 30 % reported smoking (double the national average), and most of Asians had diabetes. It is time for the government and health providers to do something for community health. Conclusion Family history, smoking, diabetes, contraceptives, and IBD are important factors increasing the risk of VTE in people prior to illness or injury, which should improve public awareness of VTE as a first step to reducing the incidence of fatal PE events. A very important role of high school students in the collection of the data is by contacting their friends, relatives, and family friends. Knowing CRS and risk factors ahead of time is one of the best ways to lower the incidence of VTE. It is necessary to develop and apply strategies and interventions to increase public awareness of the dangers and prevalence of VTE.
Session: Posters/Exhibits/Break
Thromboelastometry (TEG): Utility in diagnosing of infection in Neurosurgery Intensive care unit (ICU) as compared to established biomarkers
Renu Rani, Deepak Agarwal
AIIMS, New Delhi, India

Introduction: Infection is a common cause of death in critically ill patients, and early diagnosis is mandatory to improve the prognosis. Established biomarkers for the diagnosis of sepsis are procalcitonin, interleukin 6, and C-reactive protein. However, the changes of coagulation and activation of hemostasis are marked of pathophysiologic relevance to the infection, and associated with increased mortality. These alterations can detect by thromboelastometry. AIMS: We investigated whether thromboelastometry variables can be used for the early detection of infection in Neurosurgery Intensive care unit (ICU) as compare to established biomarker.

Methods:
In the observational cohort study, blood samples were obtained from patients who admitted to the neurosurgery ICU on admission day 0 and subsequently samples were collected at day 3 and day 5. Later on patients were classified into two groups, who developed infection at day 3 (n=60) and who did not developed infection till day 5 (n = 40). TEG variables such as clotting time, clot formation time, maximum clot firmness, alpha angle, and lysis index were measured with thromboelastometry at the all three time points for both the groups. In addition, procalcitonin, interleukin 6, and C-reactive protein levels will also be determined simultaneously at all three points for comparison. Baseline characteristics, demographic data, biochemical parameters were obtained at the time of inclusion.

Results:
In comparison with noninfectious group, patients with infection showed significantly prolong (71.7% p=0.00) clot-formation time (R time) on the admission (Day0). Similar observations were obtained with the clotting time (k time), value was significantly prolong in the infectious group (41.7% p=0.05) on the admission. Alpha angle was not significantly different between groups , but the maximum clot firmness (MA) was slightly prolonged at day 5 (75%, p=0.03). Infection detection capability goes 9.3 (95% CI 1.5-57.6, p=0.01) time higher when three variables Clot-formation time (R time), clotting time (k time) and maximum clot firmness (MA) with abnormal value were combined on admission day and day5 respectively. Procalcitonin, interleukin 6, and C-reactive protein concentrations were tested for differences between patients with and without infection at different time of interval (Day0, day3, and day5).

Conclusions:
The thromboelastometry clot-formation time (R time) proved to be a more reliable biomarker of severe sepsis in critically ill adults than were procalcitonin, interleukin 6, and C-reactive protein. The results also demonstrate that early involvement of the hemostatic system is a common event in infection.
Session: Posters/Exhibits/Break
Title: Real-World Efficacy Data on adolescent Hemophilia A Patients Transitioning to BAY 81-8973 or BAY 94-9027 in the ATHNdataset
Michael Recht1, Jessica Charlet2, Thomas Moulton2, Michael Recht3,4
1American Thrombosis & Hemostasis, NetworkRochester, NY, USA, 2Bayer Pharmaceuticals, USA, Whippany, NJ, USA, 3National Bleeding Disorders Foundation, New York City, NY, USA, 4Yale University School of Medicine, New Haven, CT, USA

Background: Real-world data on recombinant factor VIII (rFVIII) product effectiveness are sparse; especially for pediatric patients transitioning between multiple products and changing treatment regimens. The ATHNdataset, sponsored by the American Thrombosis and Hemostasis Network, includes 17,109 people with hemophilia A (PwHA) as of 4/30/22, a potential source of data to evaluate therapeutic effectiveness. Objective: To evaluate the effectiveness and treatment regimens of adolescent PwHA transitioning from multiple previous products to a prophylaxis regimen with BAY 81-8973 (Kovaltry®) or BAY 94-9027 (Jivi®) in a real-world setting.

Methods: The ATHNdataset was queried for adolescents aged between 12 and less than 18 years with using BAY 81-8973 or BAY 94-9027. Data included demographics, treatment history, bleed rates and treatment regimens for individuals treating prophylactically. Query dates were between January 1, 2010 and April 30, 2022.

Results: A total of 13 adolescents were treating prophylactically with BAY 94-9027 and with some of their previous products, while 22 were treating prophylactically with BAY 81-8973 and with some of their previous products at data cut-off. Thirteen adolescents were treated prophylactically previously with another product and subsequently prophylactically treated with Jivi. All had severe disease. 80% of individuals were treating at least 3x/week with any of their previous products, while after transitioning to BAY 94-9027, 69% had a reduced treatment frequency of 2 or less infusions per week. In conjunction, their mean total annual bleed rate (ABR) was reduced from 1.96 to 0.19 after transitioning to BAY 94-9027. (Figure 1) Of the 22 patients treating with BAY 81-8973, 20 had severe, and 2 had mild disease. All were treating prophylactically previously with another product and subsequently prophylactically treated with BAY 81-8973. Twenty-eight per cent of patients were treated at least every other day with any of their previous products. After transitioning to BAY 81-8973, only 14% were still treated every other day. In conjunction, their mean total ABR was reduced from 1.44 to 0.83 after transitioning to BAY 81-8973. (Figure 2)

Conclusions: The data show that adolescents with hemophilia A who transitioned to BAY 94-9027 or BAY 81-8973 experienced overall a decrease in their prophylaxis regimen frequency and mean total annual bleed rates. The therapeutic burden of frequent infusions can be reduced and treatment efficacy can be improved when adolescent patients transition to either BAY94-9027 or BAY81‑8973. These data should be interpreted with caution owing to limitations of real-world studies. Further studies are needed to confirm the impact of switching to BAY94-9027 and BAY81‑8973 in real-world settings.
Session: Posters/Exhibits/Break
Fourth Interim Analysis of the HEM-POWR Study: Evaluating Real-World Effectiveness and Safety of Damoctocog Alfa Pegol in Previously Treated Patients With Hemophilia A in the United States
Mark T Reding1, Beng Fuh2, Vanessa Salinas3, Maissaa Janbain4
1University of Minnesota Medical Center, Minneapolis, MN, USA, 2East Carolina University, Greenville, NC, USA, 3Center for Inherited Blood Disorders, Orange, CA, USA, 4Tulane School of Medicine, New Orleans, LA, USA

Introduction or Background: Damoctocog alfa pegol (Jivi®, BAY 94-9027), an extended half-life, factor VIII product, has been approved since 2018 for previously treated patients (PTPs) aged ≥12 years with hemophilia A (HA) in the United States (US). Prior interim analyses of the ongoing, open-label multinational, prospective cohort HEM-POWR study (NCT03932201) have demonstrated effectiveness and safety of damoctocog alfa pegol. Aims and Objectives: An interim subgroup analysis of the effectiveness and safety of damoctocog alfa pegol in PTPs from US study sites enrolled in the HEM-POWR study.

Methods: HEM-POWR included PTPs with severe and non-severe HA receiving damoctocog alfa pegol by any treatment modality. The primary endpoint was annualized bleeding rate (ABR); safety was a secondary endpoint. The safety analysis set (SAF) included PTPs with ≥1 study dose in the observation period. PTPs fulfilling all inclusion criteria with a documented study dose and ≥1 documented infusion during the observation period were included in the full analysis set (FAS). Data were captured from patient diaries and physician records. Statistical analyses were explorative and descriptive. Patients provided informed consent and ethical approval was obtained.

Results: At data cut-off (1 August 2023), 31 American PTPs were included in the SAF and 26 in the FAS. The median observation period was over 2.5 years (Table). In the FAS, 92.3% of patients were aged ≥18 to <65 years (24/26). The majority of patients (61.5%, 16/26) had severe HA, 19.2% (5/26) had moderate, and 7.7% (2/26) had mild disease (data missing for 3 patients); 88.5% (23/26) were on a prophylactic regimen prior to enrolment (1 missing). The most common dosing regimens were twice weekly then every 5 days at baseline (11/24, 45.8%; 8/24, 33.3%), follow-up window 1 (11/23, 47.8%; 9/23, 39.1%), and follow-up window 2 (10/23, 43.5%; 9/23, 39.1%), respectively. The most common concomitant diseases were a positive test for Hepatitis C virus (6/26, 23.1%) or HIV (5/26, 19.2%), and hypertension (5/26, 19.2%). The median (Q1, Q3); mean (SD) total ABR prior to damoctocog alfa pegol was 3.0 (1.0, 4.0); 5.3 (9.5) and during observation period was 1.1 (0.4, 2.9); 3.7 (8.0) (Figure); the mean (SD) total difference was -1.9 (11.4). The mean (SD) difference from prior to damoctocog alfa pegol to during observation period for spontaneous bleeds was -2.7 (5.5), for joint bleeds was -1.7 (11.1), and for spontaneous joint bleeds was -2.4 (5.3). In the SAF, 15/31 patients (48.4%) reported treatment-emergent adverse events (TEAEs); none were study drug-related and 1 (3.2%) led to a change of treatment regimen. There were 7 (22.6%) patients who reported serious TEAEs, 1 (3.2%) led to a change of treatment regimen. No new inhibitor development or deaths were reported.

Conclusions: The results of this subgroup analysis of HEM-POWR continue to support the favorable effectiveness and safety profile of damoctocog alfa pegol in PTPs with severe and non-severe HA. The results provide insights into real-world clinical practice in the US and inform US stakeholders. Funded by Bayer.
Session: Posters/Exhibits/Break
TFPI as a modifier of fibrinolysis and bleeding in FXI deficiency
Stephanie Reitsma

Factor XI (FXI) deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical assays are good predictors of this bleeding risk, leading to clinical under- or over treatment. Compared to controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) has been implicated as a modifying factor in individuals with bleeding of unknown cause. We aimed to determine the potential of TFPI to modify bleeding risk in FXI-deficient individuals. We studied the effects of TFPI on thrombin generation, clotting and fibrinolysis in FXI-deficient plasma in vitro. Our data show that TFPI levels in plasma samples from FXI-deficient individuals correlate with parameters that distinguish FXI-deficient bleeders from non-bleeders. Plasma TFPI is increased in FXI-deficient bleeders. Coagulation and fibrinolysis parameters that differentiate FXI-deficient non-bleeders and bleeders are altered by plasma TFPI. Collectively, these data suggest plasma TFPI modifies bleeding risk in FXI-deficient individuals.

Session: Cutting to the chase- Fibrinolysis
Agnostic identification of plasma biomarkers for postpartum hemorrhage risk
Stephanie E. Reitsma1, Julia R. Barsoum2, Kirk C. Hansen3, Monika Dzieciatkowska3, Andra H. James4, Kjersti M. Aagaard5, Homa K. Ahmadzia2, Alisa S. Wolberg1
1Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA, 2Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The George Washington University School of Medicine and Health Science, Washington, DC, USA, 3Biochemistry and Molecular Genetics, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 4Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Department of Medicine under Hematology, Duke University School of Medicine, Durham, NC, USA, 5Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

Background. Postpartum hemorrhage (PPH) is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased PPH risk would enhance clinical care and may uncover mechanisms that lead to PPH. Objective. This study employed agnostic proteomic profiling of pre-delivery maternal plasma samples to identify differentially abundant proteins in controls and PPH cases. Study Design. Maternal pre-delivery plasma samples were procured from a cohort of >60,000 participants in a single institution perinatal repository. PPH was defined as a decrease in hematocrit of ≥10% or receipt of transfusion within 24 hours of delivery. PPH cases (N=30) were matched by maternal age- and delivery mode (vaginal or cesarean) with controls (N=57). Mass spectrometry was used to identify differentially abundant proteins using Intensity Based Absolute Quantitation (iBAQ). Statistically significant differences between groups were defined by a p-value of <0.05 after controlling for multiple comparisons. Results. By study design, cases and controls did not differ in race, ethnicity, gestational age at delivery, blood type, or pre-delivery platelet count. Cases had slightly, but significantly lower pre- and post-delivery hematocrit and hemoglobin. Mass spectrometry detected 1140 proteins, including 74 proteins for which relative abundance differed significantly between cases and controls (fold change >1.15, P<0.05). Of these differentially abundant plasma proteins, most had likely liver or placental origins. Gene ontology term analysis mapped to protein clusters involved in responses to wound healing, stress response, and host immune defense. Pregnancy is associated with significant changes in the levels of circulating coagulation and antifibrinolytic proteins. It is therefore interesting that despite the bleeding presentation, our agnostic approach taken in the present study showed that the relative abundance of most detected coagulation and fibrinolysis proteins did not differ between groups. Significantly differentially abundant proteins with the highest fold change (periostin, prostaglandin D2 synthase, and several serine protease inhibitors) did not correlate with pre-delivery hematocrit, hemoglobin, or platelet count but were predictive of PPH with logistic regression modeling revealing good-to-excellent area under the operator receiver characteristic curves (AUROC 0.802-0.874). Incorporating pre-delivery hemoglobin and hematocrit with our target proteins improved PPH predictability (AUROC 0.74 to 0.9) for periostin and prostaglandin D2 synthase, respectfully. Conclusion. Agnostic analysis of pre-delivery maternal plasma samples identified differentially abundant proteins in controls and PPH cases. Several of these proteins are known to participate in biologically plausible pathways for PPH risk. Our analyses suggest these proteins have potential value for predicting PPH. These findings identify candidate protein biomarkers for future validation and mechanistic studies.
Session: Short Talks - Bleeding: Outcomes and Predictors
Emicizumab for Severe von Willebrand Disease (VWD) and VWD/hemophilia A: the EmiVWD Study
Jonathan Roberts1,2, MIchael Tarantino1,2
1Bleeding & Clotting Disorders Institute, Peoria, IL, USA, 2Departments of Pediatrics and Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

Background: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, typically characterized by mucocutaneous bleeding, heavy menstrual bleeding, and bleeding with surgical or other hemostatic challenges. There has been increased focus on prophylaxis for VWD with significant bleeding, with currently limited treatment options. Emicizumab is an engineered, monoclonal, bispecific antibody that demonstrates factor VIII-like activity ultimately enhancing thrombin generation, transforming prophylactic therapy for many with in hemophilia A. Anecdotally, emicizumab has been utilized successfully for VWD prophylaxis in a small number of patients, and further investigation is warranted. Furthermore, some individuals have concomitant VWD/hemophilia A, and emicizumab requires investigation in these individuals. Objective: To evaluate if emicizumab is safe and efficacious for prophylaxis in severe VWD and concomitant VWD/hemophilia A.

Methods: We initiated a pilot multicenter, prospective open-label study of emicizumab prophylaxis in severe VWD and concomitant VWD/hemophilia A with a target of 40 patients to be enrolled. Participants must be ≥2 years old and will have a one-year retrospective chart review of annualized bleed rate and hemostatic therapies collected at the time of enrollment. Participants will then receive Emicizumab, 3mg/kg weekly for 4 weeks loading dose, followed by once weekly dosing of 1.5mg/kg for a total of 52 weeks total therapy. Per the emicizumab FDA-approved prescribing information for hemophilia A, dose up-titration to 3 mg/kg once weekly will be allowed after 24 weeks on prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). Treatment records will be maintained along with bleeding event logs. Breakthrough bleeding events may be treated with the patients usual on-demand factor VIII product, with antifibrinolytics or VWF/FVIII concentrates per the investigator's discretion. Central clinical laboratory testing will be completed, in addition to genetic testing to confirm accurate VWD diagnosis. Analysis will be performed through descriptive statistics to determine proof of principle.

Results: We aim to evaluate emicizumab safety and efficacy for prophylaxis in severe VWD and concomitant VWD/hemophilia A and establish bleed occurrence during emicizumab prophylaxis in VWD and concomitant VWD/hemophilia A. Safety of emicizumab in VWD will be evaluated by documenting all adverse events, including hypersensitivity reactions and thrombotic events. Secondary analyses will evaluate treatment burden, bleed occurrence vs that on previous therapy and bleed severity. Two study sites are currently open, in Peoria, IL and Tampa, Florida USA. Eight additional study sites are in process of opening. To date, three adult participants have enrolled on study. Two participants have reported type 3 VWD and one participant has severe type 1 VWD (Table 1) as diagnosed by the participant's primary clinical hematologist. Study qualifying laboratory values were obtained from historical laboratory values.

Conclusions: Prophylaxis in some patients with VWD or concomitant VWD/hemophilia A is important, and this study will shed light on utility of emicizumab prophylaxis in these disorders.
Session: Posters/Exhibits/Break
Evaluation of Real-world Treatment Patterns and Outcomes in Patients with Von Willebrand Disease Treated Prophylactically with Recombinant Von Willebrand Factor Across Treatment Centers in the United States
Jonathan C Roberts1, Maissaa Janbain2, Jessica R Marden3, Sanjana Sundaresan3, Natalia Nieto4, Bethany Jones4, Jorge Caicedo4
1Bleeding & Clotting Disorders Institute, Peoria, IL, USA, 2Tulane University School of Medicine, New Orleans, LA, USA, 3Analysis Group, Inc., Boston, MA, USA, 4Takeda Pharmaceuticals U.S.A., Inc, Lexington, MA, USA

Background: Von Willebrand disease (VWD) is a bleeding disorder caused by deficient or defective von Willebrand factor (VWF). People with VWD experience increased bleeding, which can lead to decreased quality of life, and may benefit from prophylactic treatment. Real-world effectiveness of prophylaxis with recombinant VWF (rVWF; vonicog alfa; Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA) was investigated in a retrospective center-based chart review. Objective: To evaluate the real-world clinical characteristics, treatment patterns, and outcomes of rVWF prophylaxis in people with VWD in the United States.

Methods: This observational study included participants aged ≥12 years with a confirmed VWD diagnosis from US healthcare centers who have received either routine or intermittent (for heavy menstrual bleeding [HMB]) prophylactic rVWF treatment. Eligibility criteria included availability of medical records during the baseline period (6 months pre-rVWF initiation) and rVWF period (≥6 months post-rVWF initiation). Annualized bleed rate (ABR), healthcare resource utilization (HCRU), and treatment patterns were the main outcomes of interest. Baseline characteristics were summarized descriptively. Outcomes were compared between the baseline and rVWF periods using Wilcoxon signed-rank tests and McNemar's tests.

Results: Data from 30 participants across 11 sites were analyzed; 23 (76.7%) participants received routine rVWF prophylaxis (mean ± SD age: 42.0 ± 21.4 years; 52.2% female), and 7 (23.3%) participants received intermittent rVWF prophylaxis (mean ± SD age: 27.6 ± 11.6 years; 100% female). All three VWD subtypes were represented (Type 1: 7 [23.3%]; Type 2: 13 [43.3%]; Type 3: 10 [33.3%]). Mean duration of prophylactic treatment was 2.9 years in the routine cohort and 2.2 years in the intermittent cohort; treatment is ongoing in most study participants (Table 1). Seventeen (73.9%) participants in the routine cohort received prior prophylaxis with plasma-derived VWF. Mean weekly initial dose in the routine cohort was 132.2 IU/kg and decreased by 14.2 IU/kg during the study period; participants received an average of 1.8 doses per week (Table 1). Mean initial dose in the intermittent cohort was 44.8 IU/kg and increased by 4.4 IU/kg during the study period; most participants received treatment during menses (Table 1). ABR decreased in the routine cohort, mainly driven by reductions in major bleeds (Table 2). Decreased ABR in the intermittent cohort was nonsignificant (Table 2). The number of participants without bleeds increased in both cohorts despite the longer timeframe of the rVWF period (Table 2). Total and bleed-related inpatient visits and number of surgeries decreased in the routine cohort (Table 2).

Conclusions: Study sample size is limited, owing to the rarity of people with VWD using prophylaxis. Participants receiving routine rVWF prophylaxis in this study experienced reduced ABR and HCRU relative to the baseline period, indicating that rVWF prophylaxis may result in fewer bleeds and less hospitalization. This study adds to the growing body of real-world evidence investigating the use of rVWF prophylaxis, including 2 clinical trials (Leebeek, 2022, Blood; Ragni, 2023, Lancet Haematol) and 1 observational study (ATHN 9: NCT03853486), and suggests potential effectiveness of routine and intermittent rVWF prophylaxis in people with VWD across all subtypes.
Session: Posters/Exhibits/Break
Design of a Prospective, Observational, Multicenter Study of the Effectiveness of Efanesoctocog Alfa on Long-term Joint Health in Patients With Hemophilia A in the United States and Japan
Jonathan C. Roberts1, Spencer Sullivan2, Eric F. Grabowski3, Doris Quon4, Jennifer Dumont5, Annemieke Willemze6, Nicole Tsao5
1Bleeding & Clotting Disorders Institute, Peoria, IL, USA, 2Mississippi Center for Advanced Medicine, Madison, MS, USA, 3Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 4Orthopedic Hemophilia Treatment Center, Los Angeles, CA, USA, 5Sanofi, Cambridge, MA, USA, 6Sanofi, Amsterdam, Netherlands

Background Efanesoctocog alfa (formerly BIVV001) is a first-in-class high-sustained factor VIII (FVIII) replacement therapy, designed to decouple FVIII from endogenous von Willebrand factor, thereby extending FVIII half-life. Clinical trials have established efficacy and safety of efanesoctocog alfa but use in real-world clinical practice has not been studied. Objectives To investigate effectiveness, usage, patient-reported outcomes (PROs), and safety with efanesoctocog alfa treatment in routine practice to understand real-world outcomes. Methods This prospective, observational study (NCT05911763) in the United States and Japan, will assess prophylactic (cohort A) and on-demand (cohort B) efanesoctocog alfa treatment (Figure 1). Efanesoctocog alfa is commercially available in both countries and participants are currently being enrolled. Approximately 200 participants will be enrolled over 2 years and observed up to 5 years. Inclusion criteria include diagnosis of hemophilia A (mild, moderate, severe), and initiation of efanesoctocog alfa ≤1 month before enrollment. Male and female patients of all ages can enroll. Participants with severe hemophilia (endogenous FVIII level <1 IU/dL [1%]) with joint imaging using Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) or Joint Tissue Activity and Damage Exam (JADE) ≤6 months before initiating treatment, or ≤3 months after initiating treatment, will enter sub-cohort A1. Participants with severe hemophilia ≤6 years old and no joint damage will enter sub-cohort A2. Participants will be excluded if diagnosed with another bleeding disorder, participating in an investigational product trial, or receiving an investigational product within ≤3 months of study inclusion, or diagnosed with an FVIII inhibitor (titer ≥0.60 BU/mL) at screening. Results Primary endpoints will be change from baseline in annualized joint bleed rate and target joint development and/or resolution, or recurrence (cohort A) (Figure 2). Selected secondary endpoints for all cohorts will include the number of injections and dose to treat a bleeding episode, all adverse and serious adverse events, inhibitor development, change from baseline in PRO measures, and changes in healthcare resource utilization. In cohort A, secondary endpoints will include change from baseline in Hemophilia Joint Health Scores, annualized bleed rates, percentage of participants with zero joint bleeds, and annualized factor consumption per kg body weight. Sub-cohort A1 endpoints will include change from baseline in HEAD-US total/domain scores or JADE musculoskeletal ultrasound and synovial hypertrophy, assessed at yearly intervals. Percentage of bleeding episodes treated with a single injection and changes in treatment regimen will be recorded for the on-demand cohort. Perioperative use-specific outcomes will be recorded across cohorts A and B. Conclusions The real-world experience of participants receiving efanesoctocog alfa in this study will provide insight into the long-term clinical impact of high-sustained factor levels including joint health. This study will also provide data on participants previously underrepresented in clinical trials. Study funded by Sanofi. Editorial assistance provided by Ella Ewins, PhD, of Fishawack Communications Ltd., part of Avalere Health; support funded by Sanofi.
Session: Posters/Exhibits/Break
Evaluation of nurse-managed heparin nomogram adherence after implementation of an electronic medical record-embedded heparin calculator
Taylor Robichaux1, John Lindsley1, Vi Gilmore1, Rosemary Duncan1, Catherine Kiruthi1, Erica Willits2, Michael Streiff3, Rakhi Naik3, Jennifer Yui3, Kathryn Dane1
1Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, MD, USA, 2Department of Nursing, The Johns Hopkins Hospital, Baltimore, MD, USA, 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Background Unfractionated heparin (UFH) is the most widely used anticoagulant. 1 Due to interindividual variability in dose response, therapeutic intensity UFH infusions require titration to target a therapeutic activated partial thromboplastin time (aPTT).2 After development of the first UFH nomogram in 1991, UFH nomograms have become a common method to guide therapeutic UFH infusion dose adjustments.3 Historically UFH nomograms were provider-driven, but in recent years nurse-driven protocols have become increasingly popular.4 Nurse-driven heparin nomograms have been shown to significantly reduce the time to therapeutic aPTT achievement compared to physician titration.4 At The Johns Hopkins Hospital (JHH) and Johns Hopkins Bayview Medical Center (JHBMC), a computerized nurse-managed heparin calculator was built into the EMR to reduce the risk of nurse-managed UFH medication errors and increase adherence to institutional nomograms. To our knowledge, there are no prior publications comparing the impact of EMR-embedded nurse-managed heparin calculators to traditional written UFH nomograms. Objective The purpose of this study is to evaluate the implementation of an EMR-embedded heparin calculator on nurse-managed heparin nomogram adherence. Methods A retrospective, observational cohort study was conducted at two institutions within a single health-system. Patients admitted to adult services who received nurse-managed UFH for 4 consecutive hours were included. Patients admitted between March 2019 and March 2021 constituted the pre-implementation cohort and patients admitted August 2021 through August 2023 were included in the post-implementation cohort. Nurse-managed nomogram adherence will be compared between the pre- and post-implementation cohorts. Assessment of therapeutic aPTT achievement at 6, 12, and 24 hours after initiation and adherence to recommended management of critical aPTT results will be compared between cohorts. Results A total of 3,065 patients were included in the pre-implementation cohort and 2,162 in the post-implementation cohort. The median (IQR) age was 63 (20) for both the pre- and post-implementation cohorts. A total of 3,323 patients received an infusion only, 115 received an initial bolus and infusion, 48 received an infusion and rebolus, and 1,741 received an initial bolus, infusion, and rebolus. The total number of patients with an aPTT critical action value was 601 and 644 in the pre- and post-implementation cohorts, respectively. A comparison of nomogram adherence, therapeutic aPTT achievement at 6, 12, and 24 hours, and adherence to recommended critical aPTT management will be conducted between the pre- and post-calculator implementation cohorts. Conclusion This project will provide valuable insight into the impact of an EMR-embedded nurse-managed heparin calculator on nomogram adherence and efficacy. These results will aid health systems in justifying the significant workload required to build and implement an EMR-based calculator. References 1. Qiu M, et al. Biomed Pharmacother. 2021 2. Jia Z, et al. J Transl Med. 2015 3. Cruickshank MK, et al. Arch Intern Med. 1991 4. Schurr JW, et al. Clin Appl Thromb Hemost. 2018
Session: Posters/Exhibits/Break
Utility of thromboelastography versus routine coagulation tests: cardiac bypass surgery.
ISABEL RODRIGUEZ MARTIN
Hospital Universitario Virgen del Rocio, SEVILLA, Spain

Background: Viscoelastic tests (rotational thromboelastometry, ROTEM®), together with the implementation of a specific algorithm for coagulation management in cardiac surgery, enable perioperative coagulopathy to be better controlled.

Methods: Retrospective cohort study including 675 patients who underwent cardiac surgery with cardiopulmonary bypass. The incidence of allogeneic blood transfusions and clinical postoperative complications were analyzed before and after ROTEM® implementation.

Results: Following viscoelastic testing and the implementation of a specific algorithm for coagulation management, the incidence of any allogeneic blood transfusion decreased (41.4% vs 31.9%, p=0.026) during the perioperative period. In the group monitored with ROTEM®, decreased incidence of transfusion was observed for packed red blood cells (31.3% vs 19.8%, p=0.002), fresh frozen plasma (9.8% vs 3.8%, p=0.008), prothrombin complex concentrate administration (0.9% vs 0.3%, p=0.599) and activated recombinant factor VII (0.3% vs 0.0%, p=0.603). Increased incidence was observed for platelet transfusion (4.8% vs 6.8%, p=0.530) and fibrinogen concentrate (0.9% vs 3.5%, p=0.066), tranexamic acid (0.0% vs 0.6%, p=0.370) and protamine administration (0.6% vs 0.9%, p=0.908). Similar results were observed in the postoperative period, but with a decreased incidence of platelet transfusion (4.8% vs 3.8%, p ¼ .813). In addition, statistically significant reductions were detected in the incidence of postoperative bleeding (9.5% vs 5.3%, p=0.037), surgical reexploration (6.0% vs 2.9%, p=0.035), and length of Intensive Care Unit (ICU) stay (6.0 days vs 5.3 days, p=0.026).

Conclusions: The monitoring of hemostasis by ROTEM® in cardiac surgery, was associated with decreased incidence of allogeneic blood transfusion, clinical hematologic postoperative complications and lengths of ICU stay.
Session: Posters/Exhibits/Break
Genetic engineering of megakaryocytes to uncover functions of platelet proteins
Jesse Rowley

As the precursor to platelets, megakaryocytes share many functions with platelets and are the natural choice for platelet function studies, but have been traditionally difficult to genetically modify. We have developed a CRISPR/CAS9 approach to generate and test gene deletions and precise genetic edits with high efficiency in human CD34+ cell derived megakaryocytes. We demonstrate both single and multiplex approaches to define proteins implicated in platelet function, and interrogate single nucleotide changes associated with inherited platelet disorders.

Session: Unbiased tech approaches for hematological discoveries
Keeping anticoagulation clinics relevant in the next decade
Kelly Rudd

Antithrombotic therapy is rapidly changing, making many wonder what "Anticoagulation Clinics" will look like in the next decade. This session will review the relevancy of current anticoagulation clinics, discuss the changing field of antithrombotic therapy, and explore the principles of Anticoagulation Stewardship. Tied to this exploration, the session will discuss ways traditional anticoagulation clinics may morph to ensure relevancy, while continuing to meet clinical and patient safety needs, well into the next decade.

Session: Clinical Challenges for Antithrombotic Management in the Ambulatory Care setting
Antithrombotic Stewardship and Health Equity in Peripheral Artery Disease
Kelly M. Rudd1,2, Kristie K. Roberts1, Cooper M. Hamilton2
1Oklahoma State University Center for Health Sciences Center College of Osteopathic Medicine, Tulsa, OK, USA, 2Oklahoma State University Center for Health Sciences Center College of Osteopathic Medicine, Tahlequah, OK, USA

Background: Peripheral Artery Disease (PAD) is an atherosclerotic disease which contributes to significant morbidity and mortality, including loss of limb, myocardial infarction, stroke, and death. Effective therapies to reduce PAD events are significantly underused, with the rates of amputations growing, particularly among African Americans, Hispanics, and Native Americans. A major limiting factor to providing early intervention is the ability to efficiently identify and screen at-risk patients. Objectives: 1) To initiate a PAD Antithrombotic Stewardship Practice, as an extension of the current Anticoagulation (warfarin) Clinic within an Indian Health Service hospital caring exclusively for Native American individuals, which 2) efficiently identifies and screens at-risk individuals, receives clinical consultations from facility providers, and provides PAD disease severity staging and evidence-based therapy initiation, when appropriate, while 3) delivering care and patient education in a culturally competent manner and with the utmost dignity and respect.

Methods: Evidence-based literature and clinical guidance documents were curated and utilized to develop a PAD patient screening and clinician decision support tool. The major PAD tool development goals were to improve access to high-quality, evidence-based care to drive improved clinical outcomes, while being adaptable for use across multiple care settings, by varied health professions, outside of this stewardship initiative. Clinical infrastructure was created to extend the services of the current pharmacist-led Anticoagulation Clinic to offer the PAD Antithrombotic Stewardship services. This included implementing an expanded pharmacist collaborative drug-therapy management agreement, establishing a registration system specific for PAD care, creation of a standardized patient care note within the electronic health record (EHR), and securing coding and billing of clinical services. At-risk individuals were identified via EHR query, which assessed the problem list of current patients for history of diabetes, tobacco use and/or inclusion of the EHR preset designations for vascular disease or claudication.

Results: Over 1,600 patients were identified by electronic health record query as meeting the predefined clinical criteria. Patient outreach began in January 2024 by the Anticoagulation Clinic pharmacist, offering PAD screening within the newly established clinic. The developed PAD Patient Screening and Clinical Decision Support Tool has been effectively utilized to drive PAD diagnosis, risk assessment, and pharmacologic treatment, while assisting in organizing information for EHR documentation. High-quality patient education materials, as developed by the American Heart Association, are utilized in patient education. Preliminary outcome data is not available at the time of abstract submission. The developed tool has subsequently been effectively utilized in several diverse settings, with high rates of patient and provider acceptance. Conclusion: The implementation of a PAD screening and treatment tool enhances anticoagulation and PAD stewardship and has demonstrated the ability to be effectively translated into use across various care settings to improve patient care in an at-risk population. The adaptation of a PAD Tool into a pharmacist-led anticoagulation clinic has allowed for effective and efficient identification of previously undiagnosed PAD, led to initiation of guideline driven antithrombotic therapy, while achieving high rates of patient and provider acceptance.
Session: Online Poster Session
First Real-World Experience Administering Etranacogene Dezaparvovec Gene Therapy for People with Hemophilia B
Matthew Ryan1, Andrea B. Miller1, Patrick O'Hearn1, Vidhi Desai2, Nathan Visweshwar3
1Hemophilia Outreach Center, Green Bay, WI, USA, 2CSL Behring, King of Prussia, PA, USA, 3University of South Florida, Tampa, FL, USA

Background: Etranacogene dezaparvovec-drlb (CSL Behring) is the first gene therapy for hemophilia B to be approved by the United States Food and Drug Administration (2022), the European Medicines Agency (2023), and Health Canada (2023). The gene therapy treatment journey is a multistep process and requires coordination between multiple stakeholders within a hemophilia treatment center (HTC). The first patients to receive etranacogene dezaparvovec-drlb were successfully infused at the Hemophilia Outreach Center in Green Bay, Wisconsin and the University of South Florida in Tampa, Florida. Objective: To describe the process by which HTCs prepared their centers and patients for administration of etranacogene dezaparvovec-drlb.

Results: Early education, both for HTC stakeholders and patients, was critical in addressing key steps in the treatment journey, including patient eligibility, preparation, administration, and post-administration monitoring, and long-term follow-up. The education was iterative, involved multiple stakeholders (physician, pharmacist, nurse, social worker, and patient) and required open communication among the HTC, patients, and manufacturer when appropriate. The manufacturer provided education in the format of ongoing trainings and a detailed handbook describing the gene therapy process as it relates to etranacogene dezaparvovec-drlb. From this education, HTCs developed their own center-specific protocols, checklists, and worksheets. These protocols provided clear guidance on how to manage every step of the process in addition to providing a contingency plan (e.g., for infusion reactions or transaminitis), ensuring the center's preparedness for administration. Practical elements to site preparation included establishing the care team (including the hematologist, pharmacist, and nursing staff, among others), assigning roles for administration day, and rehearsing administration day in advance. The HTCs also ensured infusion reaction supplies were available if needed and demonstrated the financial viability of gene therapy for people with hemophilia to the institution's finance department. Initial discussions between the hematologist and advanced practitioner to consult on patient eligibility occurred 4 to 8 weeks before infusion and covered liver health, prophylaxis compliance, likelihood of patient follow through, and insurance. After assessing eligibility and obtaining payer approval, details of the administration were discussed with the patient, including date, transportation, arrival time, duration of infusion and monitoring, and the possibility of admission. A handling and preparation policy was developed to ensure the gene therapy product was available for administration. During administration and for 3 hours post administration, patients were closely monitored for signs and symptoms of an infusion reaction. A post-treatment calendar was shared with the patient as a guide to follow-up visits for monitoring liver function and factor IX levels. Before patients left the infusion center, they were also given a corticosteroid prescription to use in the case of elevated liver function tests and a contact number at the HTC. Long-term follow-up care teams have maintained open communication with the patients. HTCs were encouraged to enroll their patients in the American Thrombosis & Hemostasis Network TRANSCENDS study for long-term data collection to characterize the safety and efficacy of etranacogene dezaparvovec-drlb. Conclusion: By implementing early and iterative education, developing center-specific protocols, and handling practical considerations, HTCs were able to successfully administer etranacogene dezaparvovec-drlb.
Session: Posters/Exhibits/Break
The evaluation of MRX PT DOAC assay for detection of clinically relevant factor Xa inhibitor drug levels
Brittany MA Salter1, Karen A Moffat1,2,3, Stephen A Carlino3, Liselotte Onelöv4, Sarah Ge1, Marina Atalla1, Raymond Melika1, Saumya Bansal1, Siraj Mithoowani1, Mark Crowther1,2
1Department of Medicine, McMaster University, Hamilton, ON, Canada, 2Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada, 3Hamilton Regional Laboratory Medicine Program, Hamilton, ON, Canada, 4Nordic Biomarker, Umeå, Sweden

Introduction: Direct oral anticoagulants (DOACs), including factor Xa (FXa) inhibitors, are increasingly prescribed and do not routinely require laboratory monitoring. Assessment of DOAC levels can be helpful in specific circumstances, especially when deciding on the need for anticoagulant reversal, which is costly and associated with increased thrombotic risk. Patients with DOAC drug levels below 50 ng/mL are unlikely to benefit from anticoagulant reversal strategies, however, drug specific anti-Xa levels are not widely available, limiting clinical utility. We previously showed that the research-use only MRX PT DOAC assay (Nordic Biomarker, Umeå, Sweden) can detect DOAC levels above 50 ng/mL, with a sensitivity and specificity ranging from 75-100%, and 44-86%, respectively. MRX PT DOAC measures the functional effect of DOACs using the clot-time ratio (CTR); the ratio between DOAC-sensitive prothrombin time (PT) and DOAC-insensitive PT. The purpose of this study was to assess the reproducibility of the PT DOAC assay across multiple coagulation analyzer instruments.

Methods: This was a retrospective study including 101 clinical samples with known apixaban, edoxaban, and rivaroxaban drug levels for further assessment using the MRX PT DOAC Assay (Table 1). Reagents, calibrators and quality control (QC) were provided by the manufacturer. The assay was run on three coagulation analyzers to determine reproducibility across instruments, including optical based (Werfen ACLTOP 750, Siemens SysmexCS2500) and Viscosity Based Detection (VBD) (Diagnostica Stago STACompact MAX) clot detection systems. The CTR was calculated using Microsoft Excel (Redmond, WA), with a manufacturer reference interval of 0.98-1.38. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for a CTR >1.38 to detect a DOAC drug level >50 ng/mL with corresponding 95% confidence intervals (CI).

Results: The median sensitivity of the MRX PT DOAC assay to detect DOAC drug levels >50 ng/mL was 66%, 100% and 100% for apixaban, edoxaban and rivaroxaban, respectively (Table 2). The median specificity of the MRX PRT DOAC assay to detect DOAC drug levels >50 ng/mL was 62%, 45%, and 75% for apixaban, edoxaban and rivaroxaban, respectively (Table 2). Conclusion: The PT DOAC assay demonstrates high sensitivity at ruling out clinically significant DOAC drug levels, especially for edoxaban and rivaroxaban. This was reproducible across multiple coagulation analyzers.
Session: Online Poster Session
Considering gene therapy in the context of new options for management of hemophilia
Ben Samelson-Jones

Considering gene therapy in the context of new options for management of hemophilia

B.J. Samelson-Jones

The Children's Hospital of Philadelphia, Division of Hematology, Perelman Center for Cellular and Molecular Therapeutics, Philadelphia, PA

University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA

The goal of hemophilia treatments is to normalize hemostasis and optimize health and well-being. The aspirational promise of gene therapy is to provide safe, durable factor expression at a level sufficient to prevent bleeding in all recipients. Adeno associated viral (AAV) vectors for both hemophilia A and hemophilia B have recently received regulatory approval. There are also several additional AAV products for hemophilia A and B in the late-stage clinical development as well as alternative gene therapy approaches that have recently entered clinical trials. Current gene therapy products are, to different extents, partially redeeming the promise of gene therapy with notable differences between hemophilia A and hemophilia B drugs. All current gene therapy drugs for hemophilia have limitations and additional improvements will be necessary for hemophilia gene therapy to wholly deliver on its promise.

In parallel to the exciting developments of gene therapies, other novel technologies for promoting hemostasis have also been translated into new treatments for hemophilia, including extended half-life factor products and non-factor therapies (NFTs). Thus, people with hemophilia (PwH) and their medical teams are confronted with an array of therapeutic options. This range of treatment choices allows PwH to prioritize and balance aspects of the drugs most important to them, such as hemostatic efficacy, safety considerations, and convenience of administration. Other considerations might include the robustness of the available clinical data as well as degrees of comfort with uncertainty.

However, the considerations around gene therapy are unique. As current AAV approaches only allow a single vector administration for the foreseeable future, the risks and benefits of current AAV drugs need to be weighed, not only against existing alternative treatments, but also against forthcoming AAV drugs. The nuances of AAV gene therapy clinical trial data need to be fully appreciated, including differences in observed and theoretical safety profiles, limitations of outcome data, and factor assay discrepancies. The long-term safety and efficacy of AAV gene therapy can also only currently be hypothesized about. PwH and their medical teams must balance a number of considerations when deciding about gene therapy in the context of current extended-half-life factors and NFTs.

Session: Not your mom's jeans: Updates on Gene therapy for Hemophilia patients
Improved Joint Health After Gene Therapy with Dirloctocogene Samoparvovec (SPK-8011) in People with Hemophilia A
Benjamin Samelson-Jones1, Peter Cygan2, Stacy Croteau3, Huyen Tran4, Margaret Ragni5, Jerome Teitel6, John Rasko 7, Spencer Sullivan 8, Jill Moormeier9, Kristina Haley10, Kristen Jaworski11, Amy MacDougall11, Alexander Long 11, Savina Jaeger 11, Tiffany Chang11, Gallia Levy11
1Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 2Department of Medicine, Division of Blood and Vascular Disorders, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA, 3Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children’s Hospital, Boston, MA, USA, 4Australian Centre for Blood Diseases, Monash University, Melbourne, Australia, 5Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 6St Michael's Hospital Haemophilia Treatment Centre, University of Toronto, Toronto, ON, Canada, 7Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown, Australia, 8Mississippi Center for Advanced Medicine, Madison, MS, USA, 9Department of Medicine, UMKC School of Medicine, Kansas City, MO, USA, 10Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA, 11Spark Therapeutics, Inc., Philadelphia, PA, USA

Background: Despite advances in new prophylactic regimens, joint health preservation in hemophilia A (HA) remains a concern. Dirloctocogene samoparvovec (SPK-8011), an investigational liver-directed adeno-associated viral-based vector gene therapy for HA, demonstrated reductions in annualized bleed rate of 82% (95% confidence interval [CI]: 55-93) and 99% (95% CI: 98-100) for participants who had previously received factor (F)VIII prophylaxis or on-demand treatment, respectively, in a Phase I/II trial. Objectives: To report outcomes of joint health measures in the same interim analysis of the Phase I/II trial.

Methods: In this open-label, multicenter, single-arm trial with a long-term extension (NCT03003533/NCT03432520; funded by Spark Therapeutics), males with HA (FVIII activity ≤2%) received dirloctocogene samoparvovec (George, et al. NEJM 2021). Joint health was assessed longitudinally after treatment using the Hemophilia Joint Health Score (HJHS) v2.1. Presence and resolution of target joints (TJs) were recorded using ISTH definitions. Impact on self-perceived function was assessed via the Hemophilia Activities List (HAL) questionnaire.

Results: Participants with baseline and Year (Y)1 data were included; two who lost transgene expression were excluded. Seven participants had 13 TJs at baseline prior to receiving dirloctocogene samoparvovec; in participants with sufficient follow-up time to assess for TJ resolution (n=5), all TJs (n=10) were resolved by Y1. By data cut-off (October 4, 2022), mean total HJHS improved from 20.0 (standard deviation [SD]: 11.7) at baseline (n=11) to 14.4 (SD: 6.5) at Y3 (n=7). Clinically meaningful improvements (a decrease of ≥4) from baseline were persistent at Y2 (−4.1) and Y3 (−6.4); improvements were observed regardless of prior treatment (on-demand or prophylactic FVIII) or the presence of TJs at baseline. Participants' self-perceived function (mean HAL score) improved from baseline to Y3, irrespective of TJ status or prior treatment.

Conclusions: In a Phase I/II trial of HA gene therapy, clinically meaningful improvements in joint health, ongoing at Y3, were persistent in participants who received dirloctocogene samoparvovec, suggesting that this treatment has the potential to improve the pain and musculoskeletal impact of HA. Improvement in participants' self-reported function and resolution of TJs supported these results. The small sample size limits interpretation. These observations will be further explored in a planned pivotal trial.
Session: Short Talks - Industry Bleeding - No CME
A Multi-Year Follow-up Study of Fidanacogene Elaparvovec Gene Therapy for Hemophilia B
Benjamin J. Samelson-Jones1,2, Lindsey A. George1,2, John E. J. Rasko3,4, Adam Giermasz5, Jerome M. Teitel6, Catherine E. McGuinn7, Jonathan M. Ducore5, Sharon Pennington8, Katherine A. High2, Jeremy Rupon9, Francesca Biondo10, Annie Fang11, Lynne M. Smith9, Matko Kalac11, Amit Chhabra11, Frank Plonski9
1Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 2Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, 3Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, Australia, 4Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia, 5Hemophilia Treatment Center, University of California Davis, Sacramento, CA, USA, 6St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada, 7Weill Cornell Medicine, New York, NY, USA, 8Mississippi Center for Advanced Medicine, Madison, MS, USA, 9Pfizer Inc, Collegeville, PA, USA, 10Pfizer Srl, Rome, Italy, 11Pfizer Inc, New York, NY, USA

Background: Fidanacogene elaparvovec is a recombinant adeno-associated virus gene therapy vector for hemophilia B that delivers a high-activity factor IX (FIX) variant (R338L). In a phase 1/2a study (NCT02484092), participants safely achieved therapeutic levels of FIX expression with low-dose vector administration. A long-term follow-up (LTFU) study (NCT03307980) was initiated to assess the multi-year safety and efficacy of fidanacogene elaparvovec in these participants. Objective: To report results from participants followed up to 6 years in the LTFU study. Methods: Fifteen participants with moderately severe to severe hemophilia B (FIX activity ≤2%) were treated with 5e11 vg/kg fidanacogene elaparvovec in a phase 1/2a study (1-year duration) and were then eligible to enroll in a LTFU for 5 additional years. Results: All 15 participants completed the phase 1/2a study, and 14 were enrolled in the LTFU. As of August 2023, all 14 participants completed ≥3 years of follow-up post infusion. Seven participants completed 6 years of follow-up, 2 discontinued from the study, 1 was lost to follow-up, and 4 remain ongoing in the trial. Nine serious adverse events (AEs) were reported in 4 participants; none were deemed treatment-related, and each occurred >1 year post infusion. No AE resulted in study discontinuation or death. After the first year post infusion, asymptomatic liver enzyme levels above the normal range were reported in 9 participants; none of these events were treated with corticosteroids. No liver masses or malignancies, thrombotic events, or FIX inhibitors were reported. Geometric mean FIX activity (measured with Actin-FSL one-stage assay) remained in the mild range post infusion (Table 1). Annualized bleeding rates (ABRs) were low throughout the duration of follow-up (Table 2). During the LTFU, 10 participants (71%) had no bleeding events. Four participants experienced a total of 24 bleeding events (17 spontaneous, 7 traumatic). Overall, bleeding events occurred when FIX activity levels were less than ~25%. Bleeds into joints tended to be in arthropathic and/or target joints. No participant resumed FIX prophylaxis. Conclusions: Fidanacogene elaparvovec demonstrated long-term efficacy and was well tolerated over 3-6 years, reflecting the longest follow-up of participants with hemophilia B in a gene therapy trial. A phase 3 study is ongoing to further investigate these findings.
Session: Posters/Exhibits/Break
Heavy Menstrual Bleeding May be Driven by Localized Endometrial Coagulopathy
Bethany T Samuelson Bannow1, Leslie Myatt2, Alison Edelman2
1Hemostasis & Thrombosis Center at Oregon Health & Science University, Portland, OR, USA, 2Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA

Background: Heavy menstrual bleeding (HMB) affects up to one third of menstruating individuals, as many as 20% of whom may have an underlying, inherited bleeding disorder (IBD). As HMB is often a presenting symptom of IBDs, distinguishing between those individuals who truly have systemic IBDs, which therefore require systemic treatment, vs those with uterine-specific abnormal bleeding is challenging. We hypothesize that individuals with HMB without an IBD or known anatomic cause will have a detectable difference in expression of specific coagulation factors by endometrial endothelial cells and that this will result in different concentrations of these coagulation factors in menstrual blood as well as different patterns in how these concentrations fluctuate over the course of menses. Objectives: to quantify the concentration of tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) in daily menstrual blood samples from those with and without HMB and observe trends in level variation over time.

Methods: Diagnosis of HMB was based upon pictorial blood loss assessment chart (PBAC scores), with scores >100 considered diagnostic of HMB. Menstrual blood was collected in study-provided menstrual cups kept in place for 2-8 hours, then decanted and centrifuged to create platelet-poor plasma. Peripheral blood was also drawn on day 1 of the same menstrual cycle and processed in the same manner. PAI-1 and TFPI concentrations were quantified using enzyme-linked immunosorbent assay kits.

Results: A total of 9 of 70 planned subjects have provided all menstrual and venous blood samples to date. Four of these subjects met criteria for HMB and 5 subjects did not meet criteria. Cycle means for menstrual blood PAI-1 and TFPI concentration for each participant are shown in Table 1. We have detected a marked trend toward higher TFPI levels among those with HMB (38.89 vs 8.23, p=0.09) while overall cycle mean PAI-1 was more similar between the groups (186.95 vs 179.19, p=0.90). However, as demonstrated in Figure 1, PAI-1 concentrations generally started at peak levels and then declined over time in the control cohort while levels remained stable or even increased in participants with HMB.

Conclusions: Our findings suggest the potential for uterine/endometrial level regulation of hemostasis which is unique from systemic hemostasis and which can be abnormal in individuals without systemic coagulopathies. They also suggest that the trajectory of changes on subsequent days of menses may play as much, if not more, of a role in HMB than cycle mean alone. This data has potential to lead to testing and diagnostic strategies which may help clinicians distinguish between those with true, systemic coagulopathies and localized disordered hemostasis, thus reducing overdiagnosis and overtreatment in those with purely uterine coagulopathy. It also has potential to help direct optimal treatment with current strategies and/or lead to investigations of new treatments for individuals with HMB due to uterine coagulopathy.
Session: Short Talks - Bleeding: Outcomes and Predictors
The relationship between different pain measures, depression, and social support and race and ethnicity in persons with hemophilia.
Maria E Santaella, Matthew Hartnett, Luke Luckey, Cynthia D Nichols
National Bleeding Disorders Foundation, New York, NY, USA

Background Community Voices in Research (CVR), a community-powered registry supported by the National Bleeding Disorders Foundation, collects information directly from persons with inheritable bleeding disorders (BDs) and their immediate family members with the goal of understanding their lived experience and identifying relevant research questions. Disparities in healthcare and health outcomes within minoritized and marginalized populations have been extensively documented in the literature. Addressing these potential differences necessitates that they first be defined and characterized. However, despite growing evidence that race/ethnicity may have a negative impact, few studies in BDs account for these variables when analyzing results. Objectives This analysis describes the relationship between age, birth sex, pain intensity, impact, and interference; depression, and social support and race/ethnicity in people with hemophilia A and B participating in CVR. Methods Data were collected 2019-2022. Self-reported measures used included PROMIS Pain Intensity 3a v2.0, Pain Interference 4a v1.1, and depression 8b v1.0; ASCQ-Me Pain Impact SF; and Duke-UNC Functional Support Questionnaire (FSSQ) (7 item version). Missing data were pairwise excluded to permit use of partial surveys. The 2-sample t-test with unequal variances and Pearson r (Bonferroni-adjusted) were used for analysis. Black/Indigenous/People of Color (BIPOC) included those with ≥1 race or ethnicity self-identified as Hispanic/Latino (105/30.8%), Black/African American (31/9.3%), Asian (15/4.5%), American Indian/Alaska Native (10/3.0%), South Asian (5/1.5%), Native Hawaiian/Pacific Islander (1/0.3%), or Middle Eastern (0). Relationship status was defined as whether or not the respondent was married or in a long-term relationship. P values <0.05 stand as statistically significant. Results Adult respondents with hemophilia A or B who disclosed race and/or ethnicity were included (n=341). Social support did not differ significantly by age, race/ethnicity, or relationship status, but was higher in males vs. females (28.5 vs. 26.7, p=0.036). All pain and depression measures were inversely correlated with social support (ranging from -0.30 to -0.57, p<0.001). Pain measures were positively correlated with depression score (correlations ranged from 0.50-0.62, p<0.001). Depression had a weak inverse correlation with age (r=-0.190, p=0.009); age was not significantly correlated with any of the pain measures. Age was lower in Black/African American (35.7 vs. 41.0, p=0.025) and Hispanic (37.5 vs. 42.1, p<0.001) respondents. When combined and compared to White/Caucasian non-Hispanic (WCnH), BIPOC respondents had higher scores for depression scores and all pain measures (Table 1). Ethnicity (Hispanic/Latino compared to non-Hispanic/Latino) demonstrated a similar pattern (Table 2). Those with Hispanic/Latino ethnicity who were born in the US had lower social support scores as well as higher pain interference, pain impact, and depression scores compared to those born outside of the US (Table 3). Conclusion When compared to WCnH, BIPOC/Hispanic participants reported significantly higher scores on depression and all pain measures, with no difference in social support. Among Hispanic participants, those born in the US had the highest pain and depression scores and less social support. To comprehensively understand the experience of minoritized and marginalized communities, future studies in BDs should not only collect and report race and ethnicity but they should also analyze results based on these variables.
Session: Posters/Exhibits/Break
Clinical Experience Using Regional Citrate Anticoagulation in Continuous Renal Replacement Therapy in a Neonate with Acute Kidney Failure: Case Report
Jessica Santoyo Cueva1, Luis Ruben Miranda Ramirez1, Michelle Cecilia Arechiga Andrade1, Erendira Reyes Ramirez1
1Instituto Pediacritica Hospital Puerta de Hierro Andares, Zapopan, Mexico, 2Instituto Pediacritica Hospital Puerta de Hierro Andares, Zapopan, Mexico, 3Instituto Pediacritica Hospital Puerta de Hierro Andares, Zapopan, Mexico, 4Instituto Pediacritica Hospital Puerta de Hierro Andares, Zapopan, Mexico

Objective: To describe our clinical experience using citrate as a regional anticoagulant during continuous renal replacement therapy in a critically ill neonate with acute kidney failure Case Report : 9-day-old neonate was admitted to the intensive care unit in the postoperative state for arterial switch operation for transposition of the great arteries with an inverted coronary pattern. The patient was connected to extracorporeal membrane oxygenation for eight days, then later presented acute renal failure and met the criteria to start continuous renal replacement therapy using citrate as the anticoagulant. Background: Continuous renal replacement therapy (CRRT) is the standard supportive therapy for kidney injury. During CRRT, regional citrate anticoagulation (RCA) is favored by many intensivists, nephrologists and hematologists because it avoids systemic anticoagulation as it inhibits the clotting cascade by chelating ionized calcium (iCa) and reduces bleeding as opposed to heparin anticoagulation. Discussion: Current pediatric and adult studies support regional citrate anticoagulation as an effective alternative to systemic heparin anticoagulation. Regional anticoagulation with citrate, only inhibiting the clotting cascade within the extracorporeal circuit, is an ideal option in the critically ill child with multiple organ failure at high risk for bleeding. Citrate should be infused into the access line of the extracorporeal circuit as proximally as possible because blood contacting the plastic tubing induces thrombogenesis. The citrate dose was set at 2.5-3.1 mmol/L to obtain a post filter ionized calcium concentration (iCa) of 0.25-0.35mmol/L. We suggest checking prefilter iCa levels within 1 hour of initiation to ensure a goal of less than 0.35 mmol/L, and once achieved, monitor proactively every 6-12 hours thereafter. There is a direct dose-effect relationship between citrate and calcium. Our patient was given supplemental IV calcium to avoid life-threatening arrhythmias from hypocalcemia. Beyond the filter, calcium was continuously infused on the return line of the hemofiltration catheter to restore the blood calcium levels. Calcium infusions were performed with calcium gluconate at 22mg.kg.hr. We suggest calcium replacement to occur through a separate central catheter and not within the extracorporeal circuit because calcium repletion reactivates the clotting cascade and calcium infused into the return line increases the risk of clotting within the catheter and the loss of the circuit due to catheter malfunction. We recommend monitoring serum calcium levels every 6-8 hours to ensure appropriate calcium replacement. Routine monitoring consists of: circuit/patient IoCa every 6 hours and international normalized ratio, complete blood cell count, urea, creatinine, magnesium, potassium, and phosphate every 24 hours; filter pressures and signs of bleeding or clotting were monitored continuously. Hemodynamic status and fluid balance, pH, bicarbonate were closely monitored. Conclusion:Citrate has emerged as the recommended first line anticoagulant for continuous renal replacement therapy in the intensive care unit based on its efficacy and safety profile. Several clinical studies support the superiority of RCA over standard heparin in terms of both prolonged circuit lifespan and reduced incidence of hemorrhagic complications and transfusional needs.
Session: Posters/Exhibits/Break
Emicizumab Prophylaxis in People with Hemophilia A: Summary of 10 Years of Safety Data on Thromboembolic Events and Thrombotic Microangiopathy
Katayon Sarouei1, Simona Barlera2, Letizia Polito3, Guillermo Tobaruela3, Juliana M.L Biondo1
1Genentech, Inc., South San Francisco, CA, USA, 2Parexel International, Milan, Italy, 3F. Hoffmann-La Roche Ltd, Basel, Switzerland

Background: The HAVEN 1 Phase 3 trial outlined thromboembolic events (TEs) and thrombotic microangiopathies (TMAs) as risks in people with congenital hemophilia A (PwcHA) when taking emicizumab with activated prothrombin complex concentrate (aPCC) at >100U/kg/24h for ≥24h. Objectives: We report updated safety data on emicizumab prophylaxis in PwcHA, as >24,000 people have now received post-market emicizumab (as of Jul 18, 2023; Roche, data on file).

Methods: Emicizumab safety reports from clinical trials, registries, expanded access, compassionate use and spontaneous post-marketing reports were analyzed for TEs/TMAs. TEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA v26.0) search strategy: 'Embolic and Thrombotic Events' Standardised Medical Query (Broad). TMAs were defined as MedDRA preferred terms: hemolytic uremic syndrome, microangiopathic hemolytic anemia, microangiopathy, TMA, thrombotic thrombocytopenic purpura and renal-limited TMA.

Results: As of Aug 01, 2023, 155 total events meeting TE/TMA criteria were found from 24 countries in the Roche Global Safety Database; 97 were in PwcHA, including 34 since the previous analysis (15-May-2022). Two TEs and the five TMAs were related to aPCC (>100U/kg/24h for ≥24h); 90 TEs were not. The new TMA since last analysis was due to aPCC exceeding dose guidelines to treat diverticular hemorrhage in a patient with severe HA who then recovered. In 81 non-aPCC- and non-device-related TEs, median (range) age at event was 48 (0.8-84) years; 55 (67.9%) TEs were related to ≥1 cardiovascular/thrombosis-related risk factor and 26 (32.1%) reported insufficient information. Eleven (13.6%) of the 81 TEs and two (40%) of the five TMAs led to emicizumab discontinuation. Five (6.2%) TEs were fatal: two myocardial infarctions and one cerebrovascular event in three people with multiple risk factors, and two disseminated intravascular coagulation events related to pneumonia in two people >70 years old.

Conclusions: No new safety concerns were observed since the last data cut-off and the benefit-risk profile remains positive. Health authorities no longer require special expedited safety reporting of TE/TMAs for emicizumab; however, monitoring and reporting of safety data are ongoing, with no new safety signals with increased patient emicizumab exposure found to date.
Session: Posters/Exhibits/Break
Unfractionated Heparin Use in the Setting of Acute Pulmonary Embolism
David Scott1, Zhongyuan Chen1, Aniko Szabo1, Lindsay Hammons1, Lisa Baumann Kreuziger1,2
1Medical College of Wisconsin, Milwaukee, WI, USA, 2Versiti Blood Center, Milwaukee, WI,

Background: Unfractionated Heparin (UFH) is a frequent treatment for acute Pulmonary Embolism (PE) in the United States due to the ability to stop therapy if adverse effects occur or procedural intervention is required. UFH is known for having pharmacokinetics with poor predictability, which can make it difficult to dose appropriately, and can result in variable time to therapeutic dosing. This suboptimal timeframe in addition to narrow therapeutic range can lead to unpredictable time to therapeutic anti-coagulation which could influence patient outcomes.

Methods: In a retrospective chart review of 346 patients who had activation of a Pulmonary Embolism Response Team for an acute PE from 2018 - 2021, we collected patient risk factors for PE, details regarding intervention for PE, and subsequent outcomes. Risk factors included time to therapeutic anticoagulation, supratherapeutic and subtherapeutic heparin levels, as well as PESI score. Outcomes were overall survival, and bleeding, and recurrent thrombosis. We used cox models to study potential predictors regarding clinical outcomes.

Results: Average time to therapeutic anti-coagulation using UFH in the setting of acute PE was 18.9 hours (as measured by anti- Xa assay >0.3).76 patients did not reach therapeutic UFH levels for >24 hours. Patients taking >24 hours to reach a therapeutic UFH level had a correlation with overall mortality (p=0.124). A weaker correlation was found at 30-day mortality ( p=0.332) and 90-day mortality (p=0.739). This was found to be independent on whether the patient was subtherapeutic or supratherapeutic before becoming therapeutic (Fig 1). Patients who were subtherapeutic or supratherapeutic before being therapeutic were found not to have a significant increased mortality, PESI score was found to be significantly associated with overall mortality with patients having a high PESI score had a significantly higher risk for overall mortality (p= 7.01e-10) than those with low PESI scores (Figure 1).PESI and supratherapeutic anticoagulation was not found to be associated with risk of intracranial hemorrhage. Using cox model analysis, we found that only PESI score was an accurate predictor of overall, cardiac-related, PE-related and pulmonary-related mortality, and that sub-therapeutic or supratherapeutic status before therapeutic status did not have a significant impact on this metric. Conclusion: UFH does not reach therapeutic anticoagulation for 18 hours on average. Not reaching therapeutic anticoagulation within 24 hours was associated with an increase in morality. High PESI scores were associated with mortality and represent a high-risk group to target interventions.
Session: Posters/Exhibits/Break
Seroprevalence and Seroconversion among People with Hemophilia A in the United States: Observations from the SAAVY (Seroprevalence of AAV antibodY) Study
Amy Shapiro1, Leonard A. Valentino2,3, David Hinds4, Manil Vaghela5, Erin Goodman4, Karim Iskander4, George Dela Cerda 4, Kim Schafer6, Steven Pipe7
1Indiana Hemophilia Thrombosis Center, Indianapolis, IN, USA, 2National Bleeding Disorders Foundation, New York, NY, USA, 3Rush University, Chicago, IL, USA, 4BioMarin Pharmaceutical, Novato, CA, USA, 5BioMarin Pharmaceutical, London, United Kingdom, 6Hemostasis and Thrombosis Center, UC Davis Health, Sacramento, CA, USA, 7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA

Background: Pre-existing immunity against adeno-associated virus (AAV) can restrict patient eligibility to AAV-mediated gene therapy, yet published data on AAV seroprevalence and seroconversion among people with hemophilia A (PwHA) are limited. Objective: To quantify the seroprevalence of antibodies to AAV5, AAV6, and AAV8 (including antibody titers) and seroconversion over time among PwHA. Methods: US adult PwHA in the observational SAAVY study were assessed for the presence of AAV antibodies at an initial blood draw (baseline) and randomized to have a follow-up assessment at either 3- or 6-months after the initial draw. Seroprevalence was described as the proportion and 95% confidence intervals (CI) of participants with antibodies to an AAV serotype at baseline. Seroconversion was described as the proportion of participants changing AAV serostatus between baseline and follow-up. Seroconversions from AAV- (no antibodies) to AAV+ (presence of antibodies) and AAV+ to AAV- were described separately. Antibody titers as measured by serial dilution were described among participants with antibodies (AAV+ participants). Results below the minimum required dilution (<20) were imputed as 20 for summary statistics.

Results: 106 participants had a baseline serostatus assessment. The mean age of participants was 45 years (standard deviation= 15 years) and the population was comprised of 47% with severe, 19% with moderate, and 34% with mild hemophilia A. 34.0% of participants (95% CI: 25.0%-43.8%) had AAV5 antibodies, 37.7% (28.5%-47.7%) had AAV6 antibodies, and 41.5% (32.0%-51.5%) had AAV8 antibodies at baseline. 45 and 41 of the 106 participants had a 3-month or 6-month re-assessment, respectively (n=20 were lost to follow-up). Zero of the 27 participants who were AAV5- at baseline and re-assessed at 3-months seroconverted to AAV5+, while 1 of the 27 (3.7%) AAV5- participants at baseline and re-assessed at 6-months seroconverted. Seroconversion was similar for AAV8 (1/29, 3.4% at 3-months; 1/19, 5.3% at 6-months), but higher for AAV6 at 6-months (1/28, 3.6% at 3-months; 4/23, 17.4% at 6-months). Seroconversion from AAV+ to AAV- was more frequently observed than AAV- to AAV+ for AAV5 and AAV8, though not for AAV6: AAV 5 (4/18, 22.2% at 3-months; 1/14, 7.1% at 6-months); AAV6 (1/17, 5.9% at 3-months; 1/18, 5.6% at 6-months); AAV8 (3/16, 18.8% at 3-months; 6/22, 27.3% at 6-months). Antibody titers were lowest for AAV5, followed by AAV6 and AAV8: median [interquartile range] AAV5 titer, 46.5 [20.0-129.5]; AAV6 titer, 899.5 [121.0-3072.5]; AAV8 titer, 176.5 [38.5-498.5]. Conclusions: Trends in seroprevalence between AAV serotypes and antibody titers were consistent with previous seroprevalence estimates for the US, with the AAV5 having a lower seroprevalence relative to AAV6 or AAV8. Seroconversion from AAV+ to AAV- was more frequently observed than AAV- to AAV+. Factors associated with seroconversion require further exploration, as well as exploration of seroconversion beyond 6-months. Though based on small numbers, data from the SAAVY study strengthen growing evidence that PwHA without AAV antibodies are likely to remain AAV- over a 6-month period.
Session: Posters/Exhibits/Break
Safety and Efficacy of Long-Term Treatment of Type 1 Plasminogen Deficiency Patients with Intravenous Plasminogen Replacement Therapy
Amy D Shapiro1, Heather McDaniel2, Robert W Decker3, Jeremy Lorber3, Karen Thibaudeau4, Joseph M Parker5
1Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA, 2Vanderbilt University, Nashville, TN, USA, 3Cedars Sinai Medical Center, Los Angeles, CA, USA, 4Kedrion, Laval, Canada, 5Kedrion, Fort Lee, NJ, USA

Background: Type 1 Plasminogen Deficiency (PLGD-1) is an ultrarare autosomal-recessive disorder of the fibrinolytic system, with an estimated prevalence of 1.6 individuals per million people. The primary manifestation of PLGD-1 is the development of abnormal extra-vascular fibrin-rich, ligneous lesions on mucosa throughout the body. The most commonly observed lesions are in the eye (ligneous conjunctivitis) with lesions also noted in other systems including the ears, mouth, central nervous system, skin, and respiratory, gastrointestinal, and genitourinary tracts. Lesions may have life-altering and life-threatening consequences including vision and/or hearing loss, airway obstruction, hydrocephalus, and infertility. Plasminogen, human-tvmh is a plasma derived human Glu-plasminogen concentrate indicated for the treatment of subjects with PLGD-1. It is a lyophilized formulation administered IV at a dose of 6.6mg/kg every 2 to 4 days at home or in the clinic. Plasminogen, human-tvmh was FDA-approved in 2021 in the US based on a phase 2/3 pivotal trial (Shapiro et al, 2023). IV plasminogen replacement therapy is the only approved therapy specific for this disorder. Here are reported the safety and continued efficacy of plasminogen, human-tvmh evaluated in a long-term extended treatment trial for PLGD-1 patients who previously participated in the phase 2/3 or expanded access clinical trials. Objectives: Determine the safety and the efficacy of plasminogen replacement therapy on the recurrence or development of new ligneous lesions during long-term maintenance treatment.

Methods: US patients with PLGD-1 who participated in the phase 2/3 pivotal trial (NCT02690714) or in individual expanded access trials were eligible for participation in this study. Patients continued receiving plasminogen, human-tvmh starting at the same dose and frequency as the qualifying trial. Frequency of dosing was adjusted by the investigator based upon clinical evaluation and drug availability. Safety and efficacy assessments were performed every 26 weeks until trial conclusion including physical examinations and laboratory testing as deemed necessary by the investigator. Blood samples for plasminogen activity trough levels and anti-plasminogen antibodies were collected at study site at the discretion of the investigator. Treatment continued until plasminogen, human-tvmh was commercially available.

Results: This long-term treatment protocol (NCT03642691) enrolled 12 patients, 7 pediatric and 5 adults. Eight (8) patients continued from the phase 2/3 pivotal trial and 4 patients were included from individual expanded access trials. Patients were treated for a mean duration of 159 (range 107 - 183) weeks. There were no new or recurrent ligneous lesions which developed during the observation time period under recommended treatment. However, there were recurrences in 4 subjects which ensued during reduced or missed dosing due to supply issues. The majority of adverse events were mild to moderate and did not require patients to interrupt or discontinue dosing. There were 5 reported severe adverse events however none were deemed drug related. Plasminogen activity levels when measured remained appropriate for the dosing interval and there was no development of anti-plasminogen antibodies.

Conclusions: Intravenous plasminogen replacement therapy was observed to be well tolerated and effective in this long-term extended treatment trial.
Session: Short Talks - Industry Thrombosis - No CME
The p.D1472H polymorphism in the VWF gene is common in Indian patients
Ritika Sharma, Manu Jamwal, Harikishen Senee, Narender Kumar, Arihant Jain, Pankaj Malhotra, Deepak Bansal, Reena Das, Jasmina Ahluwalia
Postgraduate Institute of Medical Education and Research, Chandigarh, India

Introduction: The p.D1472H polymorphism in the VWF gene may affect the measurement of activity levels by the VWF GPIbR assays and lead to abnormal activity to antigen ratios .This may impact the diagnosis of VWD. Population studies have shown this polymorphism to be commoner in some races. There is currently a paucity of information on the prevalence of this mutation in the Indian population and patients with bleeding.

Methods: Patients with a bleeding defect due to deficiencies in Factor II, V, VII, X, XIII, fibrinogen, VWF and platelet functions as suggested by preliminary coagulation screens, relevant factor assays, light transmission aggregometry or flow cytometry were subjected to targeted NGS resequencing. Patients of Hemophilia A who were negative for common inversion 22 and intron 1 and cases of Hemophilia B where Sanger sequencing initially failed to reveal a mutation were included. The VWF Ag and VWF GPIbR levels were assayed from plasma samples on the ACL TOP 500 Coagulation analyser using the LIA kits.Targeted next generation resequencing was done using a 66 gene panel on the Illumina Miseq platform. Cases of hemolytic anemia undergoing resequencing to diagnose the cause of anemia were included as non-disease controls.

Results: Three hundred and seven cases with a likely bleeding disorder and 72 with anemia and no bleeding (non disease controls) were screened. The positivity in cases was not significantly different from controls (66 i.e. 21% vs 21 i.e. 29%, p =1.5). The 6 homozygous cases comprised 4 cases with severe VWD and 2 with FVII deficiency. No controls were homozygous. In the heterozygous group (60), the mean VWF antigen and GPIbR values varied significantly among those with and without VWD; however, the GPIbR: VWF Ag ratios did not (p=0.27).The polymorphism was seen in 3 cases of severe and 1 each of Type 2, 2B and acquired Von Willebrand syndrome and 2 cases of low VWF (with no mutation in the VWF gene). Among the bleeding disorders, 21.3, 24, 17,40, 26,29 and 18.5% of cases with deficiency in VWF /FVII/FVIII / FIX/FXIII /rare coagulation factors or a platelet function defect, respectively, were positive for the polymorphism.

Conclusions: The p.D1472H polymorphism is frequent in the Indian population. Homozygosity is rare. The positivity across various coagulation factor deficiencies is comparable. The VWF GpIbR activity / VWF antigen ratio may not help to distinguish between individuals with or without the polymorphism.
Session: Posters/Exhibits/Break
How can clinicians help patients make decisions that align with their values?
Nadine Shehata

Shared decision making considers patient values and preferences in selecting treatment options and is particularly useful when the best available evidence cannot clearly recommend one treatment option as when risks are similar to benefits. Shared decision making is distinct from educational materials and incorporates decisions supports to assist personalized decision making by including evidence-based information on options balancing benefits and harms and eliciting individual values. The use of thromboprophylaxis and therapeutic dosing of low molecular weight heparin (LMWH) for anticoagulation for acute venous thromboembolism (VTE) during pregnancy as well as delivery options while using prophylactic or therapeutic LMWH are treatment decisions that have been identified as potentially benefitting from shared decision making. Values and preferences for health outcomes identified by pregnant individuals with VTE and decision supports being explored to assist the shared decision-making process will be discussed.

Session: Shared decision making between patients and clinicians
Are Medical Learners Adept at Recognizing Heavy Vaginal Bleeding?
Fartoon M Siad1, Andrea Lausman2, Filomena Meffe2, Carolyn Snider3, Martina Trinkaus1,4, Michelle Sholzberg1,4
1Department of Medicine, University of Toronto, Toronto, ON, Canada, 2Department of Obstetrics and Gynecology, Toronto, ON, Canada, 3Division of Emergency Medicine, Toronto, ON, Canada, 4Division of Hematology/Oncology, St. Michael’s Hospital, Toronto, ON, Canada

Background: More than half of reproductive-age females experience heavy vaginal blood loss (VBL), whether menstrual, lochial, or otherwise, and yet less than 10% seek medical attention for evaluation. Moreover, there is evidence that even when females present to medical attention that heavy VBL is serially under-recognized and untreated. Complications from heavy VBL adversely impact health-related quality of life. This makes characterizing and quantifying VBL critical. It is well documented that there are widespread knowledge and care gaps surrounding VBL due to structural multidimensional stigma. Importantly, it is unclear the extent to which medical learners confidently recognize symptoms and signs of heavy VBL. Objectives: To explore the understanding, attitudes, and perceptions of medical learners in characterizing VBL using an online survey.

Methods: An online survey was launched to assess trainees' ability to identify heavy VBL. Survey questions were informed by the literature and tested for validity. The survey was distributed online to trainees working at all local University affiliated hospitals. Results were analyzed using descriptive statistics. Institutional ethics approval was obtained.

Results: 73 learners (medical students, residents, and fellows) completed the survey. 88% of learners were between the ages of 25-34, and 56% self-identified as women. 27% were 3rd /4th level medical students, 30% were 2nd year residents, 43% 4th year residents or higher. 27% of residents were from Emergency Medicine, 14% Hematology, 12% Family Medicine, 10% Internal Medicine, and 10% Obstetrics and Gynecology. 94% of trainees reported asking about heavy VBL in the last 6 months. Most described feeling comfortable asking about and diagnosing VBL regardless of cultural, religious or ethnic background, sexual orientation, or gender. 56% were aware of bleeding assessment tools (BATs), 51% of menstrual cups, 21% of the pictorial bleeding assessment chart (PBAC) however, less than 60% had used BATs, less than 75% had used menstrual cups and less than 80% had used the PBAC in clinical practice (Figure 1). Overall, trainees acknowledged stigma surrounding iron deficiency without anemia, and that iron deficiency was associated with decreased health-related quality of life. They recognized the need to screen and not rely on patients being forthcoming about excessive VBL. Conclusion: Heavy VBL is exceedingly common, has important clinical and psychosocial ramifications, yet it continues to be stigmatized, underdiagnosed, and thus poorly treated. We found that while a broad range of medical learners described themselves as largely feeling comfortable with their skills in assessing VBL and being aware of tools to facilitate the diagnosis of heavy VBL, surprisingly few had used these tools in clinical practice. Our findings highlight important knowledge gaps surrounding VBL and interestingly, show excessive confidence in its diagnosis amongst medical learners. Targeted knowledge translation rooted in theory- and evidence-based implementation science is urgently required in this space. Next steps involve assessing trainee skills in practice and exploring patient lived experiences with VBL through qualitative interviews.
Session: Posters/Exhibits/Break
"There is so much power in just believing someone": Understanding the lived experiences of women with heavy vaginal blood loss
Fartoon M Siad1, Andrea Lausman2, Carolyn Snider3, Martina Trinkaus1, Filomena Meffe2, Michelle Sholzberg 1,4
1Department of Medicine, University of Toronto, Toronto, ON, Canada, 2Department of Obstetrics and Gynecology, Toronto, ON, Canada, 3Division of Emergency Medicine, Toronto, ON, Canada, 44Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada

Background: More than half of reproductive-age women experience heavy vaginal blood loss (VBL), whether menstrual, lochial, or otherwise, and yet only 5% seek medical attention for evaluation. In literature, those who experience heavy VBL often experience stigma, diagnostic uncertainties, interference with day-to-day activities, and confusion surrounding what constitutes 'normal' bleeding. Over the last century, women of reproductive age (WRA) experience menarche earlier, menopause later and are having fewer pregnancies. Thus, WRA are bleeding for longer periods of time which amplifies the impact of under/mis-recognition, mis-diagnosis and healthcare provider dismissal of heavy VBL. There is an urgent need to better evaluate and manage heavy VBL in a manner informed by patient voices. Objective: To document and understand the lived experiences of patients with heavy VBL using qualitative methods.

Methods: Recruitment of women from St. Michael's Hospital Hematology Clinic in Toronto, Ontario, Canada to elucidate narratives on the dimensions of vaginal bleeding-related experiences and healthcare interactions. Ethics approval was obtained through Unity Health Toronto Research Ethics Board (REB 21-126). Eligibility was determined by both clinical and self-reported heavy VBL and complications. We used semi-structured interview guide informed by literature to conduct the interviews lasting 30 - 45 minutes using virtual communication until qualitative thematic saturation was reached. Interviews were audio-recorded and transcribed verbatim. Coding and thematic analysis was performed with NVivo.

Results: Ten participants with heavy vaginal bleeding, self-identified as women, with equitable distribution across race and ethnicity with 50% White women, 40% Black women, and 10% Asian women were included in the study. 50% had a bachelor's degree and 20% had a graduate degree. Duration of excessive bleeding was over 10 years for 90% of women with prolonged time to referral to Hematology or Obstetrics/Gynecology. All participants experienced pain with heavy vaginal bleeding and were iron deficient. Emerging common themes include: shame around bleeding symptoms and concerns about over-disclosing, normalization of heavy vaginal bleeding leading to delayed diagnoses and treatment, lack of believing symptoms by healthcare providers once disclosed leading to mistrust of healthcare system, and fear of "feeling better". Discussion: Heavy VBL is exceedingly common, has important clinical and psychosocial ramifications, yet it continues to be stigmatized, underdiagnosed, and poorly treated. Preliminary findings of this study indicate themes of shame, normalization of pathology, mistrust of healthcare systems, fear of feeling better. Structural sexism and discrimination lead to normalization, desensitization, dismissal and blame placement. Targeted knowledge translation rooted in intersectionality-enhanced theory- and evidence-based implementation science is urgently required in this space to break cycles of harm and injustice.
Session: Posters/Exhibits/Break
Intersection of fibrin(olysis) and inflammation at the oral mucosa barrier
Lakmali Silva

Objectives: Herein, we focus on the role of fibrin, a proinflammatory molecule, excessive deposition of which can cause chronic inflammation and severe tissue damage via unknown mechanisms. Fibrin removal, fibrinolysis, is achieved by the proteolytic activity of plasmin. The critical role of defective fibrinolysis becomes evident in patients with the autosomal recessive disease: type I plasminogen (Plg) deficiency. Indeed, mucosal lesions in humans and mice with Plg deficiency are also characterized by excessive fibrin deposition. We hypothesized that insufficient plasmin-mediated fibrinolysis is a key contributor to mucosal immunopathology of periodontal disease.



Methods:
We sought to understand the mechanistic link between mucosal fibrin deposition and immunopathology by using an array of genetically engineered mouse models, including Plg-/-, and Plg-/-Fgg390-396A (mutation in the aMb2 integrin binding site on the fibrin gamma-chain).



Results:
We demonstrate that (i) Plg-deficient mice develop spontaneous and severe periodontal bone loss with persistent extravascular fibrin deposits compared with littermate controls, (ii) Plg-deficient mucosal lesions have a significantly increased neutrophil infiltration, (iii) abrogating the engagement of fibrin to neutrophils through the aMb2 leukocyte integrin receptor was sufficient to prevent Plg deficiency-associated periodontal bone loss, (iv) fibrin-aMb2-neutrophil engagement activated neutrophil effector functions, including the production of reactive oxygen species and neutrophil extracellular traps, and (v) removal of extracellular DNA by DNase I treatment and blocking NETosis via depletion of neutrophil elastase, controlled periodontitis in Plg-/- mice.

Conclusion: Our work uncovers fibrin as a critical regulator of neutrophil effector functions within the oral mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in oral mucosal disease, periodontitis.

Session: Cutting to the chase- Fibrinolysis
Electronic Medical Record Interventions In Reducing Inappropriate Testing For Heparin Induced Thrombocytopenia: Experience In A Large Teaching Hospital System
Mukul Singal1,2, Soon K. Low3,4, Peter A. Kouides5,6, Maura Wychowski6, Ronald L. Sham5,6
1Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA, 2Hematology and Oncology Fellowship, Rochester General Hospital, Rochester, NY, USA, 3Internal Medicine Residency Program, Rochester General Hospital, Rochester, NY, USA, 4Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA, 5Mary M. Gooley Hemophilia and Thrombosis Center, Rochester, NY, USA, 6Department of Hematology and Oncology, Rochester General Hospital, Rochester, NY, USA

Introduction Heparin induced thrombocytopenia (HIT) is a profoundly hypercoagulable state. Immunoassays detect anti-PF4/heparin antibodies have a high sensitivity but only modest specificity. Anti-PF4 ELISA testing is therefore only recommended in patients with sufficient pretesting probability of HIT to avoid erroneous over-diagnosis. The 4T score is validated to calculate the pretest probability of HIT in patients with thrombocytopenia. A high burden of HIT testing in patients with a low 4T score was noticed in our hospital system. Objectives The primary objectives of this study were to: (1) quantify the burden of anti- PF4 ELISA testing ordered in patients with a low pretest probability in our system, and (2) assess for reduction in such testing and assess for improvements in ordering patterns after introducing a 4T score calculation in the EMR. Methods We conducted a quality improvement project to assess the reduction in anti- PF4 ELISA testing in patients with pretest probability of HIT. As a first phase of our study, we incorporated changes into the electronic medical record (EMR) and compared HIT testing 3 months before and after the intervention. Results Our intervention resulted in a significant increase in the calculation of the 4T score by the primary teams (13/75 vs. 25/58, p =0.001) as well as the consultation a significant increase in the consultation with the hematology team (10/75 vs. 23/58, p <0.001) when suspecting HIT. We also noted a significant reduction in HIT testing in patients with a low 4T score (51/75 vs. 28/58, p = 0.022). Conclusions EMR based interventions were modestly successful in reducing inappropriate HIT testing in our hospital system and can be easily mirrored in other institutions. They likely need to be supplemented by additional interventions such as physician education, auditing of anti PF4 ELISA testing, and/ or oversight by anticoagulation stewardship teams. We will be creating targeted educational modules to consolidate the success of the current intervention.
Session: Posters/Exhibits/Break
HMB-001 for Prophylactic Treatment of Glanzmann Thrombasthenia: Phase 1/2 Trial Insights
Suthesh Sivapalaratnam1,2, Gillian Lowe3, Ashley Gosnell4, Ulrike Lorch5, Jigar Amin4, Catherine Rea4
1Queen Mary University of London, London, United Kingdom, 2Barts Health NHS Trust, London, United Kingdom, 3Comprehensive Care Haemophilia Centre, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom, 4Hemab Therapeutics, Cambridge, MA, USA, 5Richmond Pharmacology, London, United Kingdom

Background: Glanzmann Thrombasthenia (GT) is a rare and severe bleeding disorder caused by a deficiency of integrin αIIbβ3, a platelet receptor essential for platelet aggregation. People with GT experience debilitating and sometimes life-threatening bleeding episodes. Approximately 50% of people with GT report 1 bleed per day, and 13% report over 500 bleeds per year. The results of frequent bleeding are both psychosocial, with affected individuals frequently missing school and work, and physical because of iron deficiency and structural abnormalities as a consequence of bleeding. HMB-001 is a novel bispecific antibody being developed by Hemab Therapeutics to prevent and reduce the frequency of bleeding episodes in patients with GT. HMB-001 is designed to restore hemostasis through a mechanism mimicking that of recombinant FVIIa (rFVIIa); however, it relies exclusively on the proteolytic activity of endogenous FVIIa. One arm of HMB-001 binds to and accumulates endogenous activated coagulation factor VII (FVIIa) and its zymogen form (FVII) [collectively referred to as total FVII(a), while the second arm binds to the TREM-like transcript 1 receptor (TLT-1) on activated platelets. TLT-1 receptor is absent on the surface of resting platelets and is redistributed to the surface from alpha granules upon platelet aggregation. The combined effect of FVIIa accumulation and targeting to the surface of activated platelets via HMB-001 brings the activity of FVIIa to levels that are considered therapeutically effective based on clinical experience with rFVIIa. The Phase 1/2 clinical study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of HMB-001 in individuals with GT.  Study Design and

Methods: The ongoing Phase 1/2 study is composed of three parts: Part A (single ascending dose), Part B (multiple ascending dose), and Part C (extended dosing). The study includes male and female participants aged 18 to 65 years old who have a molecular diagnosis of GT.  

Results: Participants included in Part A of the study received HMB-001 subcutaneously at dose levels of 0.2 mg/kg, 0.5 mg/kg, or 1.25 mg/kg, respectively. An analysis of seven participants' screening hemoglobin (Hb) and ferritin levels revealed that all had ferritin levels that were consistently low (<30 mcg/L), indicating iron deficiency. There were no reported treatment-related adverse events at the time of the abstract submission. Pharmacodynamic data showed positive proof of mechanism with a dose-dependent accumulation of endogenous FVIIa and total FVII(a) as well as signs of coagulation activation based on a dose-dependent reduction in prothrombin time. The pharmacokinetic profile indicates a dose-dependent response and is supportive of infrequent, subcutaneous dosing. Further safety, tolerability, pharmacodynamics, and pharmacokinetics details will be summarized.  

Conclusions: Understanding the implications of iron deficiency anemia in GT and its potential influence on treatment outcomes is crucial for tailored patient care and the advancement of effective interventions. The initial safety, tolerability, pharmacodynamics, and pharmacokinetics results from Part A of the Phase 1/2 study are encouraging and support the further development of HMB-001 as a potential prophylactic treatment for GT.  
Session: Posters/Exhibits/Break
Laboratory tools to identify acquired coagulation factor abnormalities
Kristi Smock

Specialized coagulation laboratories play a critical role in the diagnosis and management of patients with acquired bleeding disorders. In this setting the testing is often complex and requires close clinical correlation for accurate interpretation. Detailed understanding of testing methodologies is invaluable in the interpretation of difficult cases. This session will use a case-based format to highlight test result patterns, including diagonsis of the acquired disorder and potential effects of treatment, for patients with acquired bleeding disorders.

Session: Identification and management of acquired bleeding in the acute care setting
A Phase 3, Double-Blind, Placebo-Controlled, Multicenter Study of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Cardiac Surgery Patients
Cristina Solomon1, Catrin Argyle1, Jerrold H. Levy2, Sylvia Werner1
1Octapharma AG, Lachen, Switzerland, 2Duke University School of Medicine, Durham, NC, USA

Background: Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) require adequate high-dose anticoagulation to prevent hemostatic activation and circuit thrombosis. Unfractionated heparin (UFH) is the mainstay anticoagulant therapy; however, up to 26% of patients undergoing CPB experience heparin resistance, often associated with decreased antithrombin levels. Antithrombin concentrate, a treatment option for managing heparin resistance, is only approved in the US for congenital but not acquired antithrombin deficiency. Objective: To evaluate the efficacy of two doses of antithrombin concentrate (Atenativ, Octapharma) versus placebo in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery necessitating CPB.

Methods: ATN-108 is an ongoing, prospective, ​double-blind, placebo-controlled, three-arm, multicenter Phase 3 study. The study adheres to the ethical principles outlined in the Declaration of Helsinki. Patients aged between 18 and 85 years with planned cardiac surgery with CPB are eligible for inclusion. All patients must be heparin-resistant (pre-CPB Hemochron activated clotting time [ACT] <480 s between 2 and 5 min following intravenous administration of 500 U/kg UFH) and provide voluntarily given written informed consent at the screening visit. All female patients of childbearing potential will require a pre-existing negative pregnancy test within 14 days before surgery. Exclusion criteria include patients who have received anticoagulant therapies directly prior to the study, including warfarin, direct oral anticoagulants, ticlopidine, prasugrel, clopidogrel, ticagrelor or a glycoprotein IIb/IIIa antagonist. Additionally, patients with pre-existing coagulopathy, renal insufficiency (serum creatinine level >1.5 mg/dL), history of anaphylactic reaction(s) to blood or blood components, refusal to receive transfusion of blood or blood-derived products, hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ will be excluded. Participation in another interventional clinical trial or previous participation in the current trial and treatment with any investigational product within 30 days is prohibited. Patients will be randomized 2:2:1:1 to receive 15 IU/kg Atenativ, 30 IU/kg Atenativ, 0.3 mL/kg saline, or 0.6 mL/kg saline. The need for additional pre-CPB therapy to restore heparin responsiveness (i.e., for those patients who do not achieve a Hemochron ACT measurement of ≥480 s within 2 to 10 min after administration of Atenativ or placebo) will be analyzed. The primary endpoint, the proportion of patients requiring no further therapy containing antithrombin for restoring pre-CPB heparin responsiveness, and for maintaining it during CPB, after administration of Atenativ or placebo, will be compared between groups using a one-sided Fisher's Exact Test. Secondary and safety endpoints are outlined in Table 1.

Results: ATN-108 is expected to start in Q2 2024 and will be performed across ~20 sites in Europe and the United States. Target enrollment is ~120 patients, assuming a 5% dropout rate. Study completion is anticipated in Q3 2026. Conclusion: The study findings could confirm the efficacy and safety of antithrombin concentrate in re-establishing and maintaining heparin responsiveness in patients undergoing CPB.
Session: Posters/Exhibits/Break
Role of antiplatelet and anticoagulant therapy in veno-occlusive crisis (VOC)
Erica Sparkenbaugh

Role of Antiplatelet and Anticoagulant Therapy in Veno-Occlusive Crisis

Erica M. Sparkenbaugh

Sickle Cell Disease (SCD) is caused by a mutation in the beta-globin gene, resulting in the presence of sickle hemoglobin (HbS). The aggregation of HbS in deoxygenated red blood cells (RBCs) triggers hemolysis, sterile inflammation, and endothelial activation, culminating in vaso-occlusive crisis (VOC). The complex pathophysiology of VOC involves the adhesion of sickled RBCs, activated platelets, and leukocytes to the endothelium, resulting in vascular obstruction and ischemia. Recurrent painful episodes characterize VOC, making it a primary cause of hospitalization and mortality in SCD patients. Despite affecting approximately 8 million people worldwide, treatment options for VOC and associated pain remain limited. Standard treatments include analgesics, hydration, and blood transfusion, which provide symptomatic relief but fail to address the underlying mechanisms triggering VOC. Emerging transformative stem cell and gene therapies are likely to be applicable to a very small number of people for the foreseeable future.

Chronic platelet activation and a hypercoagulable state are notable features of SCD, and significant research has been aimed at exploring these pathways in VOC and pain. Animal models of vaso-occlusion have revealed that targeting the ADP receptor P2Y12 to reduce platelet aggregation does not limit occlusion. Moreover, clinical trials that have employed P2Y12 antagonists such as ticagrelor and prasugrel have not been successful at reducing VOC. P-selectin, an adhesion molecule upregulated on both platelets and endothelial cells, is known to mediate VOC in mouse models. In 2019, Crizanlizumab (Adakveo), a monoclonal antibody targeting p-selectin, was approved to prevent VOC in SCD patients over the age of 16. Although initial clinical trial data were positive, real-world efficacy may not outweigh the risks associated with the treatment, which requires monthly infusions, possible infusion reactions, and modest efficacy.

The hypercoagulable state in SCD contributes to chronic thrombin generation, elevating the risk of venous thromboembolic events, and this cascade has also been implicated in VOC. Clinical trials exploring anticoagulants have demonstrated varying degrees of success. Tinzaparin, a low molecular weight heparin, shortened the duration of pain and hospitalization in one clinical trial. Conversely, trials with rivaroxaban and apixaban, which target factor X, have not yielded positive results, potentially attributed to sample size and length of treatment. We have employed a mouse model of SCD to investigate the coagulation cascade. When targeting the tissue factor (TF)-dependent pathway, including FX and thrombin, not only was inflammation and vascular congestion reduced, but also vascular stasis in a model of VOC. In more recent studies, we found that targeting the intrinsic coagulation factor, Factor XII (FXII) also reduced inflammation and venous thrombosis, as well as vaso-occlusion. Targeting FXII can reduce VOC without carrying a bleeding risk - a critical advantage over targeting FX and thrombin.

These data suggest that simultaneous intervention of multiple pathological processes in SCD with anticoagulants might offer superior outcomes in reducing VOC as compared to targeting platelets alone. Potential challenges such as bleeding risks and contraindications (eg stroke history), are important considerations when investigating anticoagulant therapies in SCD. Recognizing that vaso-occlusive episodes are likely to be a problem for many decades in the US and elsewhere in SCD, future research should prioritize larger and well-designed clinical trials and explore the long-term implications of these targeted interventions in shaping the landscape of SCD management.

Session: FXI & FXII
Individual Pharmacokinetic Evaluation of Fixed-Sequence Single-Dose Octocog Alfa, Rurioctocog Alfa Pegol, and Efanesoctocog Alfa in Adults With Severe Hemophilia A
Janice M. Staber1, Toshko Lissitchkov2, Anthony Chan3, Andrew Wilson4, Jennifer Dumont4, Annemieke Willemze 5
1Division of Hematology/Oncology, Department of Pediatrics, Carver College of Medicine, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA, 2Specialized Hospital for Active Treatment of Hematological Diseases, Department of Chemotherapy, Hemotherapy and Hereditary Blood Diseases at Clinical Hematology Clinic, Sofia, Bulgaria, 3McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada, 4Sanofi, Cambridge, MA, USA, 5Sanofi, Amsterdam, Netherlands

Background Efanesoctocog alfa (formerly BIVV001) is a first-in-class high-sustained factor VIII (FVIII) replacement therapy uniquely designed to increase recombinant FVIII (rFVIII) half-life in part by decoupling FVIII from endogenous von Willebrand factor. The Phase 1 sequential pharmacokinetic (PK) study (NCT05042440; EudraCT 2021-000228-37) assessed PK and safety outcomes for rFVIII in previously treated patients following sequential single doses of standard half-life FVIII (SHL, octocog alfa), extended half-life FVIII (EHL, rurioctocog alfa pegol), and efanesoctocog alfa. Efanesoctocog alfa had a 2.8-3.9-fold longer elimination half-life and 3.6-6.0-fold greater area under the curve (AUC) versus rurioctocog alfa pegol and octocog alfa, respectively. Objective To analyze individual patient-level PK profiles in the sequential PK study. Methods The study included previously treated male patients (≥150 exposure days of prior FVIII treatment with any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products), 18-65 years of age, with severe hemophilia A (<1 IU/dL endogenous FVIII). Patients received sequential single 50 IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout. Here, demographics/baseline characteristics, time points above 15% and 40% FVIII levels, and PK parameters (half-life [t1/2], AUC, clearance [CL], maximum FVIII activity [Cmax], incremental recovery [IR]) were assessed at the individual patient level for octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa. Results Thirteen male patients were enrolled, aged 26-47 years (mean [standard deviation, SD] 36.8 [6.5] years), with a mean (SD) weight of 87.8 (18.9) kg. In individual patient level comparisons, all patients experienced a longer t½ and greater AUC with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol (geometric mean [geometric SD] t1/2: octocog alfa, 11.0 [1.5] h; rurioctocog alfa pegol, 15.4 [1.4] h; efanesoctocog alfa, 43.3 [1.3] h; Figure 1). All patients experienced more days above 15%, and 40% FVIII activity levels with efanesoctocog alfa compared with octocog alfa or rurioctocog alfa pegol (average of ~4 days above 40% activity with efanesoctocog alfa vs <1 and 1 day for octocog alfa and rurioctocog alfa pegol, respectively; Figure 2). Clearance was lower with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol in all patients. The spread of clearance data indicates lower interpatient variability with efanesoctocog alfa (geometric mean [geometric SD] CL: octocog alfa 3.0 [1.5] mL/h/kg; rurioctocog alfa pegol 1.8 [1.4] mL/h/kg; efanesoctocog alfa: 0.5 [1.2] mL/h/kg). Cmax and IR were similar for all 3 FVIII therapies tested (Figure 1). There were 3 treatment-emergent adverse events (TEAEs) while receiving efanesoctocog alfa in 1 patient (2 mild and 1 moderate) and none reported for other treatments. No TEAEs were serious, led to treatment discontinuation, or were deemed related to efanesoctocog alfa treatment. Conclusion Consistent superiority regarding time over 40% FVIII activity, half-life, clearance, and FVIII exposure were observed with efanesoctocog alfa compared with SHL and EHL FVIII in all patients. No serious TEAEs or inhibitor development were reported for efanesoctocog alfa. Study funded by Sanofi and Sobi. Editorial assistance by Timothy Davies, PhD (Fishawack Communications Ltd., part of Avalere Health) funded by Sanofi.
Session: Short Talks - Bleeding: Outcomes and Predictors
Effect of DOAC Stop on Coagulation Factor Activity Levels
Dan A Stephens1, Ronda A Crist1, Karen A Moser1, Allison Carey1,2, Abdulrahman Saadalla1,2, Kristi J Smock1,2
1ARUP Laboratories Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA, 2University of Utah Department of Pathology, Salt Lake City, UT,

Introduction Direct oral anticoagulants (DOACs) have variable effects on common clot-based coagulation assays, including spuriously prolonging clotting times, false positive or false negative results in lupus anticoagulant (LA) testing, and falsely decreased one-stage clot-based factor activities. DOAC Stop (DS; Haematex) is an activated charcoal product designed to adsorb DOACs from plasma, reducing or eliminating the potential interference in basic clotting times and LA testing. We aimed to study the effects of DS on coagulation factor activities to determine whether treatment of plasma specimens with DS might impact factor activity levels. Significant off-target removal of coagulation factors would limit the utility of DS in the clinical laboratory. Methods Pooled normal plasma (Precision Biologic) was separated into 2 aliquots. One aliquot was treated with DS following manufacturer's instructions. Both aliquots were then assayed on a STA-R Evolution analyzer (Diagnostica Stago) for the following: Factors II, V, VII, VIII, IX, X, XI, XII, prekallikrein, fibrinogen (Clauss method), and von Willebrand factor (VWF:RCo) activities; von Willebrand factor antigen (VWF:Ag). The pre-treatment and post-treatment results were compared. Results Pre- and post- treatment factor activities did not demonstrate clinically significant differences. The small differences observed were not biased in one direction and were within the typical coefficients of variation of the assays for repeated testing. Conclusions Other studies have shown that DS can effectively neutralize DOAC effect in certain types of coagulation testing. We have further demonstrated that factor activities are largely unaffected by the treatment of plasma with DS, suggesting that DS could be used prior to performing factor assays and that DS does not show significant adsorption of coagulation factors. Future studies to further understand DS performance could include larger sample numbers and normal and abnormal patient specimens. Evaluation of DS on other von Willebrand factor activity assays may also be useful.
Session: Posters/Exhibits/Break
Characterization of the endothelial cell subpopulations marked by Tek and Cdh5 promoter driven Cre expression in different mouse strains
David Svilar1,2, Audrey Cleuren1,3, David Siemieniak1, David Ginsburg1,2,4,5
1Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA, 2Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA, 3Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK, USA, 4Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA, 5Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

Background: The endothelium plays an important role in maintaining hemostasis, and mice are often used to study this endothelial cell (EC) contribution. While mice from the same inbred strain are genetically identical, the considerable genetic variation between strains can lead to observed differences in phenotypes. Furthermore, in order to specifically target ECs using a Cre-recombinase system, studies often employ either Tek-Cre (also known as Tie2) or Cdh5-Cre (also known as VE-cadherin) mice. Although both genes are considered to be generic EC markers, it is unknown whether they target potential distinct EC subpopulations. Objectives: Characterize expression profiles of ECs targeted by either Tek- or Cdh5-Cre in C57BL/6J and CAST/EiJ mice in order to get a better understanding of strain-specific differences in EC gene expression profiles, as well as potential differences in EC subpopulations targeted by either Tek or Cdh5-Cre.

Methods: To evaluate the in vivo endothelial cell gene expression profiles, we utilized a Translating Ribosome Affinity Purification (TRAP) approach using the Ribotag mouse model, which selectively expresses the ribosomal protein RPL22 with a hemagglutinin (HA) tag in cells targeted by Cre-recombinase. This allows cell type-specific isolation of ribosomal complexes with their associated mRNA, that can then be isolated for downstream analyses to determine transcript abundance, as we have previously described. In addition to maintaining these mice on a C57BL/6J background, we also crossed them onto a genetically distinct strain within the Mus musculus species, CAST/EiJ.

Results: We have previously shown that Tek-Cre on a C57BL/6J background results in efficient targeting of ECs across organs. To determine if there are differences in EC expression profiles between mouse strains, we outcrossed our original C57BL/6J Ribotag, Tek-Cre mice into CAST/EiJ. The resulting Tek-Cre positive offspring were used to perform TRAP on liver and kidney. To our surprise, the majority of samples (33 out of 36) did not show enrichment of EC-specific markers after immunoprecipitation based on the HA-tag. This prompted us to use a constitutively expressing Cdh5-Cre model to determine whether the lack of EC enrichment was unique to the use of Tek-Cre. Combining the Ribotag with Cdh5-Cre on either a C57BL/6J or the CAST/EiJ background resulted in robust enrichment of known endothelial cell markers, indicating specific targeting. Additionally, the Cdh5-Cre model enriched for Tek expression, suggesting some overlap of Tek and Cdh5 cells and that transient Tek expression in non-ECs may contribute to Tek-Cre mosaicism in CAST/EiJ.

Conclusions: Our data suggests that either the presence of a constitutive Tek-Cre in the CAST/EiJ background leads to more frequent germline excision of our conditional Rpl22 allele as compared to this event occurring in C57BL/6J mice, or that the (transient) expression pattern of Tek is not limited to ECs in CAST/EiJ mice. Cdh5-Cre on the other hand, does provide specific targeting of the endothelial compartment in both C57Bl/6J and CAST/EiJ mice. Establishing this model allows us to compare EC gene expression profiles of C57BL/6J and CAST/EiJ mice, with future studies aimed at gaining insights into the phenotypic difference between ECs across mouse strains.
Session: Posters/Exhibits/Break
Acquired von Willebrand Syndrome in Monoclonal Gammopathy of Undetermined Significance: A Focus on Response to Treatment with IVIG
Tanna Tan1, Rajiv K. K. Pruthi2, Aneel A. Ashrani2, Meera Sridharan2
1Division of Internal Medicine, Mayo Clinic, Rochester, MN, USA, 2Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

Introduction: Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with an established association with monoclonal gammopathies. Intravenous immunoglobulin (IVIG) has been demonstrated to be efficacious in the treatment of AvWS associated with MGUS (AvWS-MGUS) and can lead to a sustained elevation in von Willebrand factor (vWF) levels after infusion. Objectives: Characterize the demographics and clinical presentation of AvWS-MGUS and assess response to IVIG treatment in AvWS-MGUS.

Methods:
The electronic medical record was queried for patients evaluated at Mayo Clinic from January 2003 to March 2023 with diagnosis of aVWS and MGUS. 68 patients were identified. Charts were reviewed to determine eligibility. Exclusion criteria included a diagnosis of multiple myeloma, smoldering myeloma, amyloidosis or Waldenström's macroglobulinemia; no confirmed MGUS; or VWF results not available at diagnosis. Data on patient demographics, laboratory and clinical presentation, initial treatments, and IVIG response were collected. Bleeding presentations were assessed using the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT). Baseline laboratory findings and bleeding presentation were compared between patients receiving and not receiving IVIG. Clinical response to IVIG was defined as cessation of active bleeding or prophylaxis of further bleeding events, including post-operative bleeding. Laboratory response to IVIG was characterized by sustained increase in VWF:Ag, VWF activity, and FVIII activity, or clinician-determined appropriate elevation in these levels.

Results:
37 patients met study criteria. Median age was 64.89 years. 36 patients had bleeding history at time of diagnosis. Most common bleeding symptoms were cutaneous (n=14), post-procedural (n=13), and gastrointestinal bleeding (n=11). Median M-spike was 0.5 (0.1-3.190) mg/dL (n=30). 7 patients did not have an evaluable M-spike. Median VWF:Ag, VWF activity, and FVIII levels at diagnosis were 19 (6-587)% (n=37), 24 (6-537)% (n=24), and 22 (6-330)% (n=36), respectively. VWF multimers were analyzed in 36 patients and were normal in 18.9%. Of 29 patients with VWF multimer abnormalities, the most common finding was reduced highest molecular-weight VWF multimers (n=18). 25 patients required hemostatic therapy including DDAVP (n=7), Humate-P (n=20), and anti-fibrinolytics (n=7). 21 patients (57%) received IVIG (table 1); indications included control of bleeding (n=6), and bleeding prophylaxis for surgery (n=6) and procedures not requiring general anesthesia (n=3). Median ISTH-BAT was 5 (range 0-11) in those receiving IVIG versus 4 (range 0-7) in those not receiving IVIG (p=0.065). Patients receiving IVIG had lower baseline VWF:Ag, VWF activity, and FVIII levels (table 1). Median change in VWF:Ag, VWF activity, and FVIII was 59% (13-528%) (n=20), 43% (6-251%) (n=14), 82% (21-218%) (n=19) at 16 hours (3-72hrs) after receiving IVIG. Both clinical and laboratory response rate to IVIG was 81%. Despite high response rates, 9 patients required additional treatments following IVIG (figure 1). 10 patients not receiving IVIG required desmopressin (n=1), Humate-P or Vonvendi (n=7), anti-fibrinolytics (n=1), or immunosuppression (n=1); these treatments were effective in 80% of the patients.

Conclusions:
In this large single-center cohort study assessing IVIG response in AvWS-MGUS, IVIG was typically used for bleeding refractory to VWF concentrate and was associated with a good initial clinical and laboratory response.
Session: Posters/Exhibits/Break
Clinical outcomes in mild-moderate and severe patients with hemophilia B: results from a real-world, multi-national survey
Sheena Thakkar1, Lisa Wilcox1, Valeria Merla1, Anna Kane1, Jose Alvir1, Surya Pemmaraju1, Jennifer Mellor2, Ella Morton2, Jade Garratt Wheeldon2, James Pike2, Nathan Ball2, Stevie Olsen2
1Pfizer Inc, New York, NY, USA, 2Adelphi Real World, Bollington, United Kingdom

Background: Hemophilia B is a heritable X-linked disorder characterized by recurrent and extended bleeding episodes resulting from a deficiency of factor IX. Hemophilia severity is determined by the extent of factor IX deficiency. This study aims to compare occurrence of bleeding episodes and resultant joint damage in those with mild-moderate and severe presentations of hemophilia B. Objectives: To compare bleeding outcomes, joint health and hospitalizations between mild-moderate and severe hemophilia B patients in a real-world setting.

Methods:
Data were drawn from the Adelphi Real World Hemophilia Disease Specific Programme™, a cross-sectional survey of hemophilia-treating physicians in France, Germany, Italy, Spain, the United Kingdom, and the United States of America between February 2020 - May 2021. Hematologists and hematologist-oncologists reported data on consulting male patients with hemophilia B (PwHB), including demographics, bleeds, joint health and hospitalizations. Patients were grouped by physician-reported baseline factor activity level: <1% factor were defined as severe, ≥1% were mild-moderate. Bleed severity was determined by physician perception and classed as mild, moderate, or severe. Differences between groups were analyzed using Fisher's Exact test or t-test, for categorical and continuous variables, respectively.

Results:
Overall, 142 physicians provided data for 312 PwHB. Mean (standard deviation; SD) age was 31.0 (17.8) years, 29% of patients had severe hemophilia, and 68% of patients were receiving treatment for hemophilia at data collection (mild-moderate: 57%; severe: 95%). Among those receiving treatment, 60% were treated prophylactically (mild-moderate: 39%; severe: 91%). Among severe PwHB, 57% had experienced ≥1 bleed in the 12 months prior to data collection compared to 45% of mild-moderate patients (p=0.08). Of those who experienced ≥1 bleed, mean (SD) number of total bleeds experienced was 2.1 (2.6) [mild-moderate: 1.9 (2.0); severe: 2.5 (4.0); p=0.03] and the mean (SD) number of joint bleeds was 0.8 (2.1) [mild-moderate: 0.7 (0.8); severe: 1.2 (3.5); p=0.15]. The most recent bleed for mild-moderate patients was determined by physician to be severe in 2% of cases, compared to 23% of cases for severe patients (p<0.01). Pain level associated with the bleed was determined to be severe in 1% of cases for mild-moderate patients compared to 14% for severe patients (p<0.01). Physicians reported 32% of PwHB had experienced joint problems due to hemophilia (mild-moderate: 26%; severe: 45%; p<0.01). Of PwHB, 18% had experienced synovitis in at least one joint (mild-moderate: 14%; severe: 28%; p<0.01) and 12% had been diagnosed with hemophilic arthropathy (mild-moderate: 6%; severe: 29%; p<0.01). In the 12 months prior to data collection, 15% of PwHB experienced at least one hospitalization due to hemophilia [mild-moderate: 11%; severe: 24%; p<0.01].

Conclusions:
Despite high rates of prophylaxis prescription, patients with severe hemophilia B had problems with their joints and experienced multiple bleeds. Those bleeds were more commonly reported as severe and associated with severe pain in this dataset. In addition, a greater number of severe patients had a recent hospitalization compared to mild-moderate patients. These data suggest patients with severe hemophilia require improved treatment to control clinical outcomes and the pain associated with these.
Session: Posters/Exhibits/Break
Red Blood Cell Haemolysis and platelet activation : the forgotten players of hypercoagulability
Neha Thomas, Stipo Jurcevic
University of Westminster, London, United Kingdom

Background Platelets play a major role in haemostasis, as they rapidly bind to damaged vessels, aggregate to form thrombi, prevents excessive bleeding and maintains the constant blood flow. Several studies have demonstrated the correlation between diseases that involve haemolysis and increased platelet activation causing hypercoagulability (Figure 1). Even though, the high risk of thrombosis in intravascular haemolytic conditions such as sickle cell disease and thalassaemia is widely accepted, the precise mechanisms responsible for the hypercoagulable state remains largely unknown. This study is aimed at understanding the molecular mechanisms of platelet activation in patients with haemolysis. This may help to determine an optimal therapeutic approach to prevent occurrence of thrombotic events in such conditions. Material and Methods The effects of haemolysis on platelet activation are studied by making use of an in vitro model. This model mimics haemolytic platelet activation using citrated whole blood samples, red blood cell (RBC) haemolysate and addition of the well-defined platelet agonist such as Protease-Activated Receptor-1 (PAR-1) agonist (a peptide that represents receptor binding sequence from thrombin molecule). PAR-1 is the main platelet receptor for thrombin. The levels of platelet activation are analysed using flow cytometry method. Results The presence of low concentration of PAR-1 agonist at 0.5mM resulted in a modest platelet activation (7%) as shown by expression of CD-62P (P-selectin) on platelet surface. Expectedly, the addition of higher concentrations of PAR-1 agonist resulted in moderate (22.0% at 1mM) or strong (92.5% at 5mM) platelet activation. The effects of RBC haemolysate on platelet activation were dose dependent with measurable activation (9.5%) determined at 0.04% RBC lysate (equivalent to 50 mg/L of free Haemoglobin) and strong effects at 0.2% RBC lysate (51% activation). Importantly, the combination of PAR-1 agonist (0.5mM) and RBC lysate (0.2% lysate - equivalent to 250 mg/L of free Haemoglobin) has shown a strong synergistic effect with a striking 68.9% activation. Conclusion Preliminary results using this in vitro model based on whole blood samples have established that RBC haemolysate at concentrations that are similar to those observed in patients causes striking platelet activation. Furthermore, a combination of agonist that binds to PAR-1 receptor (peptide from thrombin sequence) and RBC lysate have strong synergistic effects on platelet activation. This suggests that haemolytic crisis conditions in patients can cause hypercoagulable state. Notably, the platelet agonist such as thrombin acts synergistically with RBC lysate, which could be relevant in patients with comorbidities that trigger thrombin formation.
Session: Posters/Exhibits/Break
Real-World Use of Recombinant Factor IX Fusion Protein in Previously Untreated Patients with Congenital Hemophilia B from the ATHN 8 Study
Courtney D. Thornburg1, Martin Chandler2, Lynn Malec3, Matthew Manuel2, Carrie O'Neill2, Michael Recht4, 5, Elizabeth Taggart2, Hongseok Kim6, Vidhi Desai6, Hiren Shah6, Shannon L. Carpenter7
1Rady Children’s Hospital San Diego, San Diego, CA, USA, 2American Thrombosis and Hemostasis Network, Rochester, NY, USA, 3Versiti Blood Research Institute, Waukesha, WI, USA, 4Yale University School of Medicine, New Haven, CT, USA, 5National Bleeding Disorders Foundation, New York, NY, USA, 6CSL Behring, King of Prussia, PA, USA, 7Children’s Mercy Hospital, Kansas City, MO, USA

Background: People with hemophilia are at risk of developing neutralizing inhibitors to factor products. Previously untreated patients (PUPs) are particularly vulnerable, and development of inhibitors is most likely to occur within 20 exposure days (EDs). Recombinant factor IX fusion protein (rIX-FP) was shown to be safe and efficacious in preventing bleeding episodes among 12 PUPs with hemophilia B (NCT02053792); 1 of the 12 participants, an 11-year-old male with deletion of exons 7 and 8 of the FIX gene, developed factor IX (FIX) inhibitors. Large gene deletions are a known risk factor for inhibitor development. While some risk factors for inhibitor development are known, the ability to accurately predict who is at the highest risk for inhibitor development remains a challenge. To address this knowledge gap, a study was conceptualized to understand the variables contributing to inhibitor development. The American Thrombosis and Hemostasis Network (ATHN) ATHN 8 study is a US-based longitudinal cohort study of PUPs with moderate or severe hemophilia A or B (ATHN 8; NCT03818529). In the ATHN 8 study, 3 of 39 participants with hemophilia B developed inhibitors within the first 50 EDs. Here we present a subset of PUPs with hemophilia B from the ATHN8 study who received rIX-FP. Objectives: This report evaluates inhibitor development in PUPs with congenital hemophilia B who received rIX-FP in the real-world setting.

Methods: Data were collected for a subset of PUPs from ATHN 8 with hemophilia B who were born between January 2010 and September 2021 and received rIX-FP. Participants were enrolled at ATHN-affiliated sites until 50 clotting factor EDs, development of a confirmed neutralizing inhibitor, or study closure. Results were summarized descriptively.

Results: The study enrolled 10 males with moderate-to-severe hemophilia B who received rIX-FP. Among these 10 participants, none developed an inhibitor during the study. Of these, 60% (6/10) had at least 50 EDs. Mean FIX EDs was 45 days. Eight participants (80%) had severe hemophilia and were less than 1 month old (60%) at the time of their first bleed (Table 1 shows additional baseline demographics).

Conclusions: In the subanalysis of participants with hemophilia B who received rIX-FP, none developed inhibitors. This included 7 participants with more than 20 EDs, of whom 6 had more than 50 EDs. This is consistent with what was seen in the clinical trial.
Session: Posters/Exhibits/Break
The effect of Budd-Chiari Syndrome (BCS) in hospitalized hepatocellular carcinoma patients (HCC): A nationwide analysis.
Ekrem G Turk, Ayobami Olafimihan, Khaldun Obeidat, Youjin Oh, Lina James, Angelo Caputi Zuniga, Alejandro Vallejo
John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA

Backgrounds: HCC is a major global health challenge, being the most prevalent type of primary liver cancer and the sixth leading cause of cancer-related mortality worldwide, with a 5-year relative survival rate of 20.3%. BCS, characterized by obstruction of hepatic venous outflow, can significantly influence liver pathology and has been identified as a contributing factor to the onset of HCC. Though rare, a recognized connection exists between BCS and the subsequent development of HCC, the specific impact of BCS in patients primarily diagnosed with HCC, particularly regarding inpatient outcomes, remains underexplored. This nationwide study aims to elucidate the effects of BCS in hospitalized patients with a primary diagnosis of HCC, thereby providing valuable insights into the implications of this vascular complication in the HCC patient population.

Methods: Nationwide Inpatient Sample (NIS) was queried to determine adult hospitalizations with a primary diagnosis of HCC using ICD-10 codes. The primary outcome was defined as the effect of BCS on inpatient mortality. Secondary outcomes included length of stay (LOS), total hospital cost (THC), health care utilization, ICU admission. We evaluated the baseline characteristics using the t-test and chi-square test. Multivariable logistic regression analysis assessed the association of HCC with BCS and inpatient mortality adjusted by other variables.

Results: In a cohort of 62,300 HCC admissions, 1% had BCS. While HCC with BCS tended to be younger (mean age 63.2 vs. 64.8), more often female (26% vs. 25%), and more frequently African American (18.7% vs. 16.6%), with higher income and Medicaid coverage (25.8% vs. 24%) compared to without BCS, these differences were not statistically significant. However, a significant disparity was observed in the Charlson Comorbidity Index, with a higher proportion of HCC with BCS scoring greater than 3 (36% vs. 22%; p <0.001). Inpatient mortality for the entire HCC cohort was 8.2%, with a non-significant higher rate in the BCS subgroup (11.4%). Key factors associated with inpatient mortality included age, Charlson index, male gender, African-American race, and hospital teaching status and location. The mean LOS for HCC with BCS was longer (7.4 days) than those without BCS (5.7 days). The mean THC was higher in the BCS group ($105,937 vs. $91,518). Rates of ICU transfer were 5.7% for the BCS group and 3.9% for those without BCS, showing no significant difference, as was the case with other secondary outcomes. Conclusion: The apparent lack of statistical significance in many comparisons may be attributed to the relatively small proportion of HCC patients with concurrent BCS (1% of the cohort). This limited representation could potentially mask underlying associations and effects. Therefore, the observed trends, though not statistically significant, should not be disregarded in clinical context. Given the small sample size of HCC patients with BCS, further studies employing methods like propensity score analysis could provide a more nuanced understanding of the impact of BCS on HCC patients. While this study provides valuable preliminary data, its findings underscore the need for more in-depth research to fully understand the implications of BCS in HCC patients, particularly regarding clinical outcomes.
Session: Posters/Exhibits/Break
Emergency department utilization in a patient cohort with hemophilia:A Single Centre Experience
Kelsey Uminski1,2, Natalia Rydz1,2, Dawn Goodyear1,2
1Division of Hematology and Hematological Malignancies, Department of Medicine, University of Calgary, Calgary, AB, Canada, 2Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Calgary, AB, Canada

Background: With the development of effective hemostatic agents, and the establishment of hemophilia treatment centers (HTCs), there has been a shift in hemophilia care away from the hospital and into the patient home. Furthermore, individuals with hemophilia are now experiencing age-related health challenges previously uncommon to their care, potentially resulting in increased emergency department (ED) utilization for non-hemophilia related issues. The objective of this study is to describe ED utilization among a patient cohort with hemophilia and characterize reasons for ED care.

Methods: Adult patients with hemophilia A or B, of any severity, followed at the Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program were identified for study inclusion. ED health utilization data for each of the four hospital sites and two urgent care centers in Calgary, AB was obtained for the cohort, from 2014 through to 2022 from the electronic health record.

Results: A total of 191 patients with hemophilia A and B were identified for study inclusion: 153 patients with hemophilia A and 38 patients with hemophilia B. A total of 393 ED visits occurred over the study period. Most ED visits were triaged per the Canadian Triage and Acuity Scale (CTAS) as Level 2 (36.8%) or Level 3 (36.8%) in which patients were identified as needing emergent care, and rapid medical intervention or urgent intervention, respectively. An additional 5.3% of visits were identified as CTAS Level 1, severely ill requiring resuscitation. The median ED length of stay was 3.45 hrs (IQR 3.12-3.95). Figure 1 demonstrates the proportion of ED visits associated with a hemophilia related diagnosis. Table 1 demonstrates the categories of discharge diagnoses for ED visits. Gastrointestinal, skin and soft tissue, and musculoskeletal diagnoses represented 13%, 9.2% and 8.4% of ED visit diagnoses, respectively.

Conclusions: Our cohort of patients with hemophilia sought care in the ED for urgent and emergent indications. While hemophilia related presentations were observed, this represented a small proportion of total ED visits. This data provides a better understanding of the experience of patients with hemophilia in the ED and provides an opportunity to better understand evolving acute care needs in a contemporary hemophilia patient population.
Session: Posters/Exhibits/Break
Title: Recombinant ADAMTS13 replacement therapy in a pediatric patient with congenital thrombotic thrombocytopenic purpura.
Katrina` Unpingco1, Michael F. Guerrera2, Zahara Jones1, Alison Matsunaga1
1Hemophilia and Thrombosis Center UCSF Benioff Children's Hospitals, Oakland -San Francisco, CA, USA, 2Hemostasis and Thrombosis Center, Children's National Medical Center, Washington , DC, USA

Congenital Thrombotic Thrombocytopenic Purpura (cTTP) is a rare inherited blood disorder, characterized by a severe deficiency in ADAMTS13, leading to the presence of large von Willebrand multimers, which increases platelet aggregation and adhesion causing microthrombi. The incidence of TTP (both congenital and acquired) is 2-6 people per million per year, with cTTP causing less than 10% of these cases. The mortality and morbidity are potentially quite high if inadequately treated due to end organ damage from microthrombi. The treatment for cTTP has historically been replacement of ADAMTS13 through regular transfusions of Fresh Frozen Plasma (FFP), S/D treated pooled human plasma or immediate pure plasma derived Factor VIII replacement. We present the case of a 12-year-old female, diagnosed with cTTP [pathogenic c.2074C>T (p.Arg692Cys)] in the neonatal period due to anemia, thrombocytopenia and hyperbilirubinemia and previously treated prophylactically with FFP. This patient unfortunately suffered recurrent transfusion reactions to FFP, including anaphylaxis, despite trial of jumbo donation and solvent treated plasma products, causing significant anxiety and overall poor quality of life. A plea for compassionate use of novel recombinant ADAMTS13 replacement, still in trials at the time, was made to the Named Patient Program (NNP at Takeda Pharmaceuticals). Our patient was successfully transitioned to recombinant ADAMTS13 replacement every 2 weeks for the last 18 months without adverse effect or acute TTP events. The burden of treatment was also reduced.
Session: Posters/Exhibits/Break
Disparities in anticoagulation care across the spectrum
Sara Vasquez

A disparity is a "noticeable and usually significant difference or dissimilarity," and these can occur across the spectrum of anticoagulation care. There are known differences in the epidemiology of venous thromboembolism (VTE), such as higher risk of VTE with age, and with women earlier in life, men later in life, and higher risk of VTE in patients identifying as Black race. The goal of the 2014 National Action Plan for Adverse Drug Event (ADE) prevention, targeting anticoagulants, was to identify patients at higher risk of anticoagulant-induced ADEs so that targeted strategies can be developed to improve safety. The spectrum of anticoagulation care includes access to therapy, quality of therapy, and the humanistic outcome of therapy. Patients identifying with non-White racial groups may receive direct oral anticoagulants (DOACs) as first-line therapy less often than other groups. Education and patient satisfaction with service may improve anticoagulation treatment persistence. At-risk groups for receiving off-label DOAC dosing include patients of advanced age, Black race, and extremes of body weight. At-risk groups for poorer quality of INR control with warfarin include women and Black race. It is well-established that patients performing patient self-testing and/or self-management of the INR have better clinical outcomes compared to standard management. However, uptake of patient self-testing is generally poor. Groups of anticoagulated patients at-risk for lower quality of life and lower treatment satisfaction include women and older age. Limited health literacy correlates with a higher anticoagulation treatment burden. DOACs improve quality of life and treatment satisfaction for most patients, especially those in rural geographic regions. Strategies to eliminate disparities include assessing one's own practice for anticoagulation care disparities, using education as a foundation for improved adherence and persistence, which then can improve the quality of care, satisfaction, and quality of life. Additionally, creating processes and care pathways and systematically implementing them can ensure equitable treatment. Finally, a population health approach can be utilized to target at-risk groups for intervention to ensure optimal quality of care.

Session: Health Care Inequitity in the Treatment of VTE
Real-World Data on Emicizumab Prophylaxis in Older Persons with Hemophilia A: A Retrospective Single Center Cohort Study
Shalini Vemuru1, Stacey Fedewa2,3, Christine Kempton2,3
1Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA, 2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA, 3Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory, Emory University School of Medicine, Atlanta, GA, USA

BACKGROUND: Emicizumab is an effective treatment for hemophilia A. The thrombotic events observed in the phase 3 clinical trials have raised concern of using emicizumab in older populations, particularly those with underlying cardiovascular risk factors. However, real world data on the safety of emicizumab in older populations with hemophilia A, specifically whether these patients are at increased thrombotic risk, is limited. OBJECTIVES: This study aims to provide real-world evidence on the safety of emicizumab use in older patients with hemophilia A by investigating thrombotic events in patients ≥ 50 years old, who have begun emicizumab prophylaxis at a single Hemophilia Treatment Center (HTC). METHODS: This was a retrospective cohort study of patients ≥ 50 years old with severe and moderately severe hemophilia A, defined as baseline factor levels ≤2%, with or without inhibitors that began emicizumab since 2017 and were seen at Emory's HTC. Demographic, comorbidity, and treatment data were collected from electronic medical records and analyzed with Fisher's exact tests according to thrombotic events, defined as myocardial infarction, transient ischemic attack (TIA), cerebrovascular accident, deep venous thrombosis, or pulmonary embolism, occurring after emicizumab initiation. RESULTS: Twenty-six patients with hemophilia A, all male, were included in this study. One had a current inhibitor, three had a past inhibitor, and most (76.9 %) had previously received prophylactic factor replacement. The median observational time from initiation of emicizumab to the last date of follow up was 3.47 years [IQR 1.78 years]. Cardiovascular risk factors were common; 18 (69.2%) had hypertension, 11 (42.3 %) had hyperlipidemia, 3 (11.5%) had diabetes, and 14 (53.8%) had a smoking history. Two patients were on antiplatelet therapy during the study period. Prior to initiation of emicizumab, there was one thrombotic event, a TIA, which was followed by carotid endarterectomy. After initiation of emicizumab, three (11.5%) patients had a thrombotic event. One had experienced dysarthria secondary to a TIA. The second had a multifocal punctate bilateral middle cerebral artery infarct, although this was in the setting of simultaneous hemorrhagic stroke. The third had a left thalamic stroke. None of these three patients had prior thrombotic events or underwent surgery while receiving emicizumab. The time from initiation of emicizumab to thrombotic event was 836 days, 879 days, and 273 days, respectively. All these patients continued on emicizumab without a subsequent thrombotic event. Since emicizumab initiation, no significant differences in common cardiovascular risk factors (hypertension (p = 0.471), diabetes (p = 0.778), hyperlipidemia (p = 0.323), smoker (p = 0.111)) were found among patients with thrombotic events versus those without thrombotic events. CONCLUSIONS: In this cohort study of 26 patients seen at a single HTC, three thrombotic events occurred. Among those with a thrombotic event, all took emicizumab for over 200 days prior to their event and continued on emicizumab without a subsequent thrombotic event. In addition, most patients, even those with cardiovascular risk factors, did not have thrombotic events after initiation of emicizumab. This study adds to the small body of literature that supports emicizumab use in older adults with cardiovascular risk factors.
Session: Posters/Exhibits/Break
Clinical Utility and Performance of von Willebrand Factor Activity Assays in a National Reference Laboratory: The Vitalant Coagulation Laboratory's Experience with the Ristocetin Cofactor and VWF:GP1bM Assays
Angela Verdoni1, Mason Marshall2, Irina Chibisov1
1Vitalant Coagulation Laboratory, Pittsburgh, PA, USA, 2Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

Background: The Ristocetin Cofactor (RCoF) VWF activity assay has been utilized in the laboratory assessment of von Willebrand Disease for many decades. However, issues with high interlaboratory variability and assay interference have been well described. In the fall of 2022, a new VWF activity assay referred to as the VWF:GP1bM assay was FDA cleared for in vitro diagnostic use. The Vitalant Coagulation Laboratory began offering this assay as a clinical test in early 2023. Objective: To compare performance of the VWF:RCoF activity assay with the VWF:GP1bM activity assay by assessment of results in the context of available clinical and laboratory findings.

Methods: Data were extracted from the Vitalant Coagulation Laboratory LIS system for a seven-month period for the following assay results: VWF:RCoF activity, VWF:GP1bM activity, VWF Antigen level, FVIII clotting activity, Collagen/EPI and Collagen/ADP closure times, 1.2mg and 0.3mg ristocetin induced platelet aggregations, Collagen binding activity, and VWF Multimers. Cases were excluded from further analysis if data was not available for the VWF:RCoF activity, VWF:GP1bM activity and VWF Antigen level on the same sample. After exclusion, more than 400 cases were assessed. Each individual case was examined for whether the VWF:GP1bM and VWF:RCoF activity results were in qualitative agreement. Cases with qualitative disagreement were further examined by comparing other VWD test results and clinical histories to make a conclusion whether the VWF:RCoF or the VWF:GP1bM assay made a more accurate assessment of VWF activity.

Results: The VWF:GP1bM test yielded higher activity results overall than the VWF:RCoF activity assay. Thirty three percent of cases had a VWF:GP1bM/vW Antigen ratio >0.70 and a VWF:RCoF/vW Antigen ratio <0.70 whereas the reverse was true for only 1% of cases. Fifty percent of the cases analyzed had results that fell within the normal range for both the VWF:RCoF and VWF:GP1bM assays and thus there was no benefit of ordering the VWF:GP1bM activity test. Fourteen percent of cases were in agreement with a known/suspected case of Type 1 VWD based upon low results for the VWF:RCoF, VWF:GP1bM, and vW Antigen assays. Six percent of cases were in agreement with a known/suspected case of Type 2 VWD based upon low results for the VWF:RCoF and VWF:GP1bM assays and normal results for the vW Antigen assay. In 23% of cases, the VWF:GP1bM assay result was normal in the presence of a low RCoF result, making the presence of VWD less likely. However, in 5% of cases, VWF:GP1bM results were normal in the presence of low VWF:RCoF and other abnormal VWD testing and positive clinical history, pointing to a potential for misclassification in these cases.

Conclusions: The addition of the VWF:GP1bM activity result in the presence of the VWF:RCoF result was potentially beneficial in ~25% of cases analyzed, had no benefit in ~70% of cases, and may have resulted in a misclassification in ~5% of cases. These data show an overall benefit of ordering VWF:GP1bM activity test and also confirm the notion that no single VWD test is an ideal test for assessment of von Willebrand Disease.
Session: Posters/Exhibits/Break
Brain Volumes and Neurocognitive Outcomes in Children with Hemophilia A
Silvia Verhofste1, Ahmad Al-Huniti1, 2, Marci Novak1, Amy L. Conrad1, 5, 6, Ellen van der Plas3, 4, Lyndsay Harshman1, 5, 6, Janice M. Staber1, 5, 6
1Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA, 2*Current Location - Mayo Clinic , Rochester, MN, USA, 3Department of Psychiatry, University of Iowa, Iowa City, IA, USA, 4*Current Location -University of Arkansas for Medical Sciences, Pediatrics Arkansas Children's Hospital, Hematology/Oncology, Little Rock, AR, USA, 5The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA, 6Iowa Neuroscience Institute, Iowa City, IA, USA

Background: People with hemophilia are at an increased risk of intracranial hemorrhage. In addition, hemophilia-related sequelae, such as an increased risk of neuropsychiatric disorders and impairments in executive function, may exert a direct, negative impact on the developing brain. The effect of factor VIII deficiency, a protein essential for blood coagulation, on neuroimaging and neurocognitive outcomes in children with hemophilia A (HA) is not well characterized. Objectives: To compare neuroanatomical features between children with severe HA and healthy controls using quantitative structural magnetic resonance imaging (MRI). To examine differences in neurocognition between children with severe HA and healthy controls.

Methods: This single-center study included 32 males aged 6-16 years: nine with severe FVIII deficiency and 23 healthy controls. Volumetric/structural data from MRI and neurocognitive testing including Delis-Kaplan Executive Function System (DKEFS) and Behavioral Regulation Index of Executive Function (BRIEF) were compared using linear models including age to evaluate the association between brain volume and function.

Results: Children with HA had decreased mean cerebellar and hippocampal volumes (Figure 1A and 1B). Cerebellar gray matter volume was significantly smaller in the HA cohort compared to healthy controls, (Estimate=-0.375, 95% CI=-0.732:-0.019), t(26)=−2.07, p = 0.049) (Figure 1A). A reduction in cerebellar gray matter was associated with neurocognitive executive dysfunction as noted by abnormal scores on two executive function assessments: the DKEFS total switching accuracy (Estimate=0.549, 95% CI= -0.876:0.221), t(25) = -3.28, p=0.003) (Figure 2A) and total correct category switching (Estimate=0.538, 95% CI=-0.868:0.207), t(25)=−3.19, p=0.004) (Figure 2A), as well as the BRIEF behavioral regulation index score (Estimate=0.531, 95% CI=0.228:0.835), t(25)=3.44, p=0.002) (Figure 2B). Conclusion: Our study provides key insight into the lower brain volumes found in persons with HA and corresponding executive dysfunction. Structural brain volume assessment in persons with HA may provide an integrated measure and with further research could be a useful clinical tool when assessing risk for neurocognitive dysfunction.
Session: Posters/Exhibits/Break
Social Vulnerability and Hemophilia Care and Outcomes
Pooja Vijayvargiya1, Binh Le2, Christine L. Kempton1, 3, Vanessa R. Byams2, Brandi Dupervil2, Meredith Oakley2, Stacey A. Fedewa1, 3
1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA, 2Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA, 3Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory, Emory University School of Medicine, Atlanta, GA, USA

Background Despite advances in hemophilia management and outcomes over the past decade, disease complications and treatment challenges remain pronounced for socially vulnerable populations. Whether community factors influence hemophilia outcomes remains poorly defined. Objectives This study examines the association between social vulnerability as measured by the social vulnerability index (SVI) and treatment and health outcomes among people with hemophilia. Methods In this cross-sectional study, 14,112 people with hemophilia from 137 US hemophilia treatment centers (HTCs) who were enrolled in the Community Counts (CC) Registry between 2013 and 2022 were analyzed according to area-level SVI scores. The original SVI is based on census tracts; however, the CC includes participants' zip code when entering the Registry, therefore a census tract-zipcode crosswalk was used to assign participants' SVI. SVI is a composite measure of 15 factors that detail 1) socioeconomic status, 2) housing/transportation, 3) minority status, and 4) household composition with overall values ranging from 0 to 1, grouped as: low (0-0.33), middle (>0.33-0.66), or high (>0.66-1). Adjusted odds ratios (aOR) with 95% confidence intervals (CI) accounting for sex, age, race, ethnicity, and hemophilia severity were calculated to compare treatment and outcomes according to SVI. Results Overall, 31.9%, 42.5%, and 25.4% of participants were categorized as having low, middle, and high SVI, respectively. There was a disproportionate number of participants in the high SVI category among Non-Hispanic (NH) Black (48.9%), Hispanic (48.5%), American Indian/Alaska Native (51.4%), younger participants (<30 years, 27%), those with Medicaid (38.9%) or no insurance (32.2%), participants in the South (29.9%) and West (35.9%) regions, and those with closer (<15 miles, 36.5%) and further (>60mi, 28.2%) driving distances from an HTC. Compared to participants with low SVI, those with high SVI had a higher odds of inpatient admission (aOR: 1.40; 95% CI:1.28 - 1.52), emergency room visit (aOR: 1.26; 95% CI: 1.20- 1.34), number of treated bleeds (aOR: 1.09; 95% CI: 1.02 - 1.16), intracranial hemorrhage (aOR: 1.22; 95% CI: 1.04- 1.42), chronic pain (aOR: 1.20; 95% CI: 1.14 - 1.26), limited function (aOR: 1.24; 95% CI: 1.18 - 1.31), and missed days of work/school (aOR: 1.12; 95% CI: 1.05 - 1.21). Participants with a high SVI were also more likely to be on standard half-life products (aOR: 1.08; 95% CI: 1.05 - 1.11), and accordingly less likely to be on extended half-life products (aOR: 0.89; 95% CI: 0.83 - 0.96) or emicizumab (aOR: 0.64; 95% CI: 0.58 - 0.69) compared to participants with a low SVI. Conclusions In this study of US HTCs, higher measures of social vulnerability are not only associated with individual-level demographic factors but also with worse clinical outcomes (i.e. more emergency room and inpatient admissions), more functional burden (i.e. higher incidence of chronic pain, limited function, and missed days of work/school), and less optimized care (more treated bleeds and higher use of standard half-life products). Additional studies to better understand the multi-level social drivers of hemophilia care and outcomes can inform the development of potential interventions, which likely include those beyond the medical clinic.
Session: Short Talks - Bleeding: Outcomes and Predictors
Outcomes in North American Participants Who Received Efanesoctocog Alfa Prophylaxis in the XTEND-1 Study
Annette von Drygalski1, Tung Wynn2, Doris Quon3, Anthony KC Chan4, Angela C Weyand5, Davide Matino6, Jennifer Dumont7, Andrew Wilson7, Umer Khan8, Sriya Gunawardena9
1Division of Hematology/Oncology, Department of Medicine, University of California San Diego, San Diego, CA, USA, 2Department of Pediatrics, University of Florida, Gainesville, FL, USA, 3Luskin Orthopaedic Institute for Children, Los Angeles, CA, USA, 4Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada, 5Division of Hematology/Oncology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA, 6Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada, 7Sanofi, Cambridge, MA, USA, 8Sanofi, San Diego, CA, USA, 9Sanofi, Bridgewater, NJ, USA

Background: Efanesoctocog alfa (formerly BIVV001) is a first-in-class high-sustained factor VIII (FVIII) replacement therapy uniquely designed to overcome the von Willebrand factor-imposed FVIII half-life ceiling. Results from the Phase 3 XTEND-1 study (NCT04161495) in adolescents and adults with severe hemophilia A demonstrated that once-weekly efanesoctocog alfa is well tolerated and provides superior bleed protection versus prior standard-of-care prophylaxis. Efanesoctocog alfa prophylaxis provides high sustained mean FVIII activity levels within the normal to near-normal range (>40%) for most of the week and 15% at the end of the weekly dosing interval. Objective: To report outcomes on the subset of participants in XTEND-1 from North America.

Methods: Adult and adolescent participants on prior FVIII prophylaxis entered Arm A (52 weeks once-weekly efanesoctocog alfa prophylaxis [50 IU/kg]). A subset had enrolled in a 12-month observational pre-study (242HA201/OBS16221). Outcomes reported here include bleed rates, bleed treatment, joint health, pain, physical health, and safety. Model-based annualized bleed rate (ABR) was estimated using a negative binomial regression model. Mean difference and 95% confidence interval (CI) for intra-patient comparison of ABR pre-study and during XTEND-1 were calculated using paired t-test.

Results: Twenty-six participants from North America were enrolled in Arm A of XTEND-1. Mean (range) age was 31.1 (12, 72) years and 1 participant was female (4%). Mean (standard deviation [SD]) duration of the efficacy period was 43.6 (12.3) weeks. Median (interquartile range) overall ABR was 0.0 (0.0, 1.1) and model-based mean (95% CI) ABR was 0.64 (0.37, 1.12). Following switch from prior FVIII prophylaxis to efanesoctocog alfa prophylaxis, mean ABR reduced from 2.37 to 0.56 in the 9 participants with ≥6 months of follow-up in the observational pre-study and during XTEND-1 (mean difference [95% CI]: -1.80 [-3.72, 0.12], P=0.0621). Sixteen participants (62%) did not experience a bleeding episode during XTEND-1, and 23 (89%) did not experience a spontaneous bleeding episode (Figure). In total there were 14 bleeding episodes during XTEND-1, including 7 joint, 5 muscle, and 2 internal; all resolved with a single injection of efanesoctocog alfa (50 IU/kg). The least squares mean change (95% CI) from baseline to Week 52 in Patient-Reported Outcomes Measurement Information System Pain Intensity 3a T-score was -2.2 (-5.4, 1.0), n=20; Haemophilia Quality of Life Questionnaire for Adults Physical Health score was -11.3 (-22.2, -0.5), n=14; and Hemophilia Joint Health Score was -1.9 (-5.2, 1.4), n=18 (Table). Mean (SD) annualized factor consumption was 2806 (312) IU/kg. Twenty-one (81%) participants had ≥1 treatment-emergent adverse event (TEAE). Three patients (12%) reported treatment-emergent serious adverse events; no TEAEs led to discontinuation. Inhibitor development was not detected and there were no deaths.

Conclusions: Outcomes reported in this subset of participants from North America are similar to those observed in the overall population of XTEND-1. Once-weekly efanesoctocog alfa prophylaxis provided improved bleed protection compared with prior standard-of-care prophylaxis, with improvements in physical health, pain, and joint health. Funded by Sanofi and Sobi. Editorial assistance by Sarah Rupprechter, PhD, of Fishawack Communications Ltd., part of Avalere Health, funded by Sanofi and Sobi.
Session: Posters/Exhibits/Break
An Implementation Dilemma: Rejection of Thromboprophylaxis Recommendations in the Children's Likelihood of Thrombosis (CLOT) Trial
Shannon C. Walker, Benjamin French, Ryan P. Moore, Henry J. Domenico, C. Buddy Creech, Amanda S. Mixon, Daniel W. Byrne, Allison P. Wheeler
Vanderbilt University Medical Center, Nashville, TN, USA

Background: The Children's Likelihood of Thrombosis (CLOT) trial was performed at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV) from November 2, 2020 through January 31, 2022 and included 17,427 hospital admissions in the primary analysis (Trials 2022 and JAMA Network Open 2023). We identified 135 hospital-acquired venous thromboembolic (HA-VTE) events during the study period; 58 in the control group and 77 in the intervention group (risk difference: 2.2 per 1000 patients; 95%CI, -0.4 to 4.8 per 1000 patients, p=0.10). During the study, hematology recommendations for thromboprophylaxis in elevated risk patients were followed in only 25.8% of admissions. Objectives: We sought to identify the key drivers of provider rejection thromboprophylaxis recommendations so that targeted implementation efforts can be developed to improve acceptance rates in future studies.

Methods: In the CLOT trial, all eligible pediatric patients (<22 years old) admitted under inpatient status to MCJCHV during the study period underwent automated randomization into the intervention or control group. HA-VTE risk scores were calculated on admission and recalculated daily. HA-VTE risk scores in the intervention group were visible to the hematology study team in real time and patients at elevated risk (>2.5%) underwent clinical review; based on the clinical scenario, the study team determined whether to recommend thromboprophylaxis. Recommendations were discussed in person or via telephone with the providers on the patient's primary healthcare team and were documented in the patient's electronic medical record. All study related data, including reasons the study team did not recommend prophylaxis in patients with elevated risk and reasons why healthcare providers did not follow recommendations for thromboprophylaxis, were recorded in the study database.

Results: Within the intervention group, 41.4% of patients at elevated risk for HA-VTE were deemed clinically ineligible for thromboprophylaxis due to potential risks, including prematurity <34 weeks, active hemorrhage, upcoming surgical procedure, or thrombocytopenia. When recommendations to initiate thromboprophylaxis were made by the study team, the primary team followed these recommendations only 25.8% of the time. Clinical teams' acceptance of the recommendations varied from 41% (pediatric intensive care unit) to 0% (pediatric bone marrow transplant) [Table 1]. Reasons for rejecting study team recommendations most commonly included expectation of upcoming discharge, concern for bleeding, and lack of perceived HA-VTE risk.

Conclusions: While HA-VTE model performance remained strong (control group c-statistic = 0.799 (95% CI 0.725 to 0.856) in this prospective, randomized study, there was significant variability in the acceptance of the study team's recommendations for thromboprophylaxis. Clinical teams ranged from 41% overall acceptance to 0% acceptance. Future work will be needed to identify and overcome these implementation barriers.
Session: Posters/Exhibits/Break
A Comparison of Targeted High-Range versus Low-Range Anti-Xa Goal for Intravenous Unfractionated Heparin in Patients with Mechanical Circulatory Support Devices
Yue Wang, Long To, Mathew Jones, Kristin Griebe
Henry Ford Hospital, Detroit, MI, USA

Background: Patients presenting with cardiogenic shock are commonly supported by mechanical circulatory support (MCS) devices. Although MCS may restore organ perfusion, complications from the biomaterials and shear forces created by the devices can increase the risks of bleeding and thrombosis. Intravenous (IV) unfractionated heparin is currently the most commonly used anticoagulation therapy with MCS. Although current literature does not define optimal therapeutic targets when monitoring heparin in this setting, the most commonly accepted therapeutic range for anti-Xa is 0.3 to 0.7 units/mL. When patients are treated with IV heparin while on MCS devices, the bleeding risk increases. There have been bleeding events reported at different observed anti-Xa levels ranging from 0.1 to 0.7 units/mL in previous studies. At Henry Ford Hospital, the anti-Xa goal was decreased from a high range of 0.3 to 0.7 units/mL to a low range of 0.2 to 0.5 units/mL with the hypothesis that a lower range of targeted anti-Xa goal may decrease the incidence of bleeding while maintaining adequate antithrombotic effects. This study aims to evaluate if the targeted low-range anti-Xa goal decreases the incidence of bleeding compared to the high-range anti-Xa goal when patients receive IV heparin with MCS devices. Objectives: The primary endpoint is to compare the incidence of bleeding when using the targeted low-range versus high-range anti-Xa goal. The secondary endpoints are to compare the incidence of thrombosis using the low-range versus high-range goal and to describe clinical scenarios of protocol deviation. Independent confounding risk factors of developing bleeding and thrombotic complications will be assessed. ICU length of stay and mortality attributed to bleeding, thrombosis, and cohort overall will be reported.

Methods: This is a retrospective, single-center, quasi-experimental study to evaluate adult patients (older than 18 years old) on IV heparin for MCS devices with at least one anti-Xa collected during their hospital admission to the cardiovascular intensive care unit. The pre-cohort contains patients monitored in the high-range anti-Xa goal and the post-cohort contains patients monitored in the low-range anti-Xa goal. A planned subgroup analysis will be conducted on patients whose therapeutic ranges were changed during the course of therapy. Bivariate analysis will be used to compare the percentages of patients with each outcome according to exposure within the cohort. Multivariate logistic regression will be used to evaluate confounding factors. Kaplan-Meier curves will be used to describe time to event (bleeding, thrombosis, mortality attributed to bleeding or thrombosis). 304 patients are required for 80% power to detect a 15% reduction in major bleeding with an alpha of 0.05.

Results: in progress Conclusion: in progress
Session: Posters/Exhibits/Break
State of the art on FXI and FXII inhibitor data
Jeff Weitz

The goal of anticoagulation therapy is to attenuate thrombosis without perturbing hemostasis. Although the direct oral anticoagulants (DOACs) come closer to this goal than vitamn K antagonists (VKAs), bleeding is not eliminated with the DOACs. Thus, even with the DOACs, the annual rate of major bleeding in patients with atrial fibrillation is 2% to 3%, while the annual rate of intracranial bleeding is 0.3% to 0.5%. The fear of bleeding contributes to the failure of over one-third of patients with atrial fibrillation to receive any anticoagulant prophylaxis and among those given anticoagulation therapy, for up to 50% to be inappropriately treated with lower doses of the DOACs. Therefore, there remains a need for safer anticoagulants.

The DOACs inhibit factor (F) Xa or thrombin, downstream enzymes in the coagulation cascade. Interest in FXII and FXI, which are upstream of FXa and thrombin, as targets for new anticoagulants that are safer than those currently available stems from studies suggesting that those factors are important in thrombosis but have little or no role in hemostasis. Most of the focus is on FXI inhibitors because the epidemiological data linking clotting factor levels with thrombosis are stronger for factor XI than for factor XII. Thus, epidemiological studies and Mendelian randomization data reveal a reduced risk of thrombosis in subjects with low factor XI levels and an increased risk in those with elevated factor XI levels. In contrast, there is no such link with factor XII levels. Also, there is concern that feedback activation of factor XI by thrombin could overcome the effect of factor XII inhibitors.

Both parenteral and oral factor XI are currently under investigation. Phase 3 trials comparing once-monthly subcutaneous injections of abelacimab , an antibody that binds FXI and prevents its activation, with apixaban or dalteparin in patients with cancer-associated venous thromboembolism are underway (ASTER and MAGNOLIA trials, respectively). Abelacimab also is being compared with a placebo for stroke prevention in patients with atrial fibrillation (AF) who are deemed unsuitable for treatment with an oral anticoagulant in the LILAC TIMI-76 trial. Likewise, phase 3 trials with asundexian and milvexian, oral FXIa inhibitors, have also been initiated. Asundexian and milvexian will be compared with apixaban for stroke prevention in patients with AF who are at high risk for bleeding in the OCEANIC-AF and LIBREXIA-AF trials, respectively, and with placebo on top of antiplatelet therapy for secondary stroke prevention in the OCEANIC-Stroke and LIBREXIA-Stroke trials, respectively. Milvexian will also be compared with a placebo on top of antiplatelet therapy in patients with acute coronary syndrome (ACS) in the LIBREXIA-ACS trial. These trials, which will enroll about 78,000 subjects, will determine the future of FXI inhibitors as replacements for the DOACs and as safe platforms for antiplatelet therapy.

Session: FXI & FXII
Resumption of anticoagulation post bleeding event
Dan Witt

Resuming anticoagulation therapy after a potentially life-threatening bleeding complication evokes high anxiety levels among clinicians and patients trying to decide whether resuming oral anticoagulation to prevent devastating and potentially fatal thromboembolic events or discontinuing anticoagulation in hopes of reducing the risk of recurrent bleeding is best. The available evidence is mainly from observational studies that are likely limited by significant confounding. In many cases evidence supports resumption of anticoagulation therapy for gastrointestinal tract bleeding and intracranial hemorrhage survivors with some increase in risk of recurrent bleeding. It is reasonable to begin post-bleeding decision making with resuming anticoagulation therapy as the default plan. After considering factors related to the index bleeding event, the underlying thromboembolic risk, and comorbid conditions a decision to accept or modify the default plan can be made in collaboration with other care team members, the patient, and their caregivers using shared decision making. Although additional information is needed regarding the optimal timing of anticoagulation resumption, available evidence indicates waiting about 14 days may best balance the risk of recurrent bleeding, thromboembolism, and mortality following gastrointestinal tract bleeding. When to resume anticoagulation following intracranial hemorrhage is less clear. What type of anticoagulant to resume therapy with also requires further study.

Session: Anticoagulation for patients with bleeding related conditions
Monitoring Bivalirudin Therapy Using a Bivalirudin-Specific Chromogenic Anti-IIa Assay
Sean G Yates1, Ravi Sarode1, Sarita Paulino1, Ibrahim F Ibrahim2, Lisa K Skariah3
1Department of Pathology, Division of Transfusion Medicine and Hemostasis, University of Texas Southwestern Medical Center, Dallas, TX, USA, 2Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 3UT Southwestern Department of Pharmacy, University of Texas Southwestern Medical Center, Dallas, TX, USA

Background: Bivalirudin infusions are traditionally monitored with activated partial thromboplastin time (aPTT) despite demonstrating poor correlations with bivalirudin dose-response curves. The discordance between bivalirudin dose and aPTT may lead to over or under-anticoagulation, predisposing patients to a higher incidence of bleeding or thrombosis and requiring repeated dose adjustments. A bivalirudin-specific chromogenic anti-IIa assay that reports plasma concentrations of bivalirudin is available. Objectives: To evaluate the correlation between the bivalirudin dose, aPTT, and a chromogenic anti-IIa bivalirudin assay (bivalirudin-specific assay) to establish an anti-IIa therapeutic range for clinical use. We conducted a before-after retrospective cohort study to compare the incidence of adverse events and time in therapeutic range (TTR) for patients anticoagulated with bivalirudin using aPTT versus the bivalirudin assay.

Methods: Fifty-three plasma samples from 6 adult patients anticoagulated with bivalirudin were evaluated using aPTT and a bivalirudin-specific assay. The correlation between the bivalirudin dose and results of aPTT and the bivalirudin-specific assay was determined with the strength of correlation defined as follows: 0.00 to 0.19, very weak; 0.20 to 0.39, weak; 0.40 to 0.59, moderate; 0.60 to 0.79, strong; and 0.80 to 1.0, very strong. For the before-after retrospective evaluation, the following clinical data was recorded for each cohort: age, sex, clinical indication for bivalirudin, creatinine clearance (CrCl), initial and median bivalirudin dose, TTR, major and minor bleeding events, and thromboembolic events.

Results: A moderate dose-dependent correlation was observed between bivalirudin dose and aPTT results (R2=0.4). Conversely, a very strong correlation was observed between bivalirudin dose and bivalirudin plasma concentrations, as measured by the bivalirudin-specific assay (R2=0.8). A review of dose-response data led to the establishment of a bivalirudin-specific assay therapeutic range of 0.5-1.5 ug/mL. Of the patients undergoing bivalirudin anticoagulation included in the before-after analysis, aPTT was used to monitor therapy in 11 patients (11 encounters), and the bivalirudin-specific assay was used in 15 patients (16 encounters). Confirmed or suspected heparin-induced thrombocytopenia (HIT) were the two main indications for bivalirudin anticoagulation in either cohort. The mean TTR was significantly higher in patients monitored using the bivalirudin-specific assay versus aPTT (p=0.003). The incidence of minor bleeding events was not significantly different between the cohorts, and no major bleeding or thromboembolic events were observed in either cohort.

Conclusions: This study suggests that a bivalirudin-specific assay demonstrated a stronger correlation with the bivalirudin dose relative to aPTT. Patients anticoagulated with bivalirudin whose therapy was monitored using a bivalirudin-specific assay showed a significantly higher percent TTR than those monitored using aPTT. No significant differences in thromboembolic, major, or minor bleeding events in patients anticoagulated with bivalirudin were observed when comparing aPTT-based monitoring or the bivalirudin-specific assay.
Session: Posters/Exhibits/Break
Health-related quality of life and treatment burden in patients with hemophilia A/B without inhibitors on concizumab prophylaxis: results from the phase 3 explorer8 study
Guy Young1, Gary Benson2, Hermann Eichler3, Johnny Mahlangu4, Jesper Skov Neergaard5, Jan Odgaard-Jensen5, Jay Jay Thaung Zaw5, Jameela Sathar6, Huyen Tran7, Tadashi Matsushita8, Emily K. Waters9
1Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 2Department of Hematology, Belfast Health and Social Care Trust, Belfast, Ireland, 3Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Hospital, Homburg, Saar, Germany, 4Department of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa, 5Novo Nordisk A/S, Søborg, Denmark, 6Department of Haematology, Ampang Hospital, Selangor, Malaysia, 7Ronald Sawers Haemophilia Treatment Centre, Monash University, Melbourne, Australia, 8Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan, 9Novo Nordisk Inc., Plainsboro, NJ, USA

Background: Concizumab is a monoclonal antibody directed against the K2 domain of the tissue factor pathway inhibitor. The explorer8 study (NCT04082429) evaluated the safety and efficacy of once-daily subcutaneous prophylactic concizumab in patients with hemophilia A (HA) or B (HB) without inhibitors. Additionally, explorer8 assessed patient-reported outcomes (PROs), including health-related quality of life (HRQoL) and treatment burden. Objectives: This study aimed to compare PROs in patients with HA and HB treated with concizumab prophylaxis with PROs in those receiving no prophylaxis.

Methods: The explorer8 study included male patients aged ≥12 years with HA or HB. Exploratory end points included change from baseline to week 24 in 36-Item Short Form Health Survey, version 2 (SF-36v2), Bodily Pain and Physical Functioning scores, Hemophilia Treatment Experience Measure (Hemo-TEM) total score, Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 Pain Intensity score and v2.0 Upper Extremity score, and patient global impression of change on physical functioning (PGI-C). Estimated treatment differences (ETDs) were analyzed using an analysis of covariance (Hemo-TEM end points) or a mixed model for repeated measurements (all other end points). ETDs compared changes from baseline in patients on concizumab prophylaxis with those in patients on no prophylaxis.

Results: At week 24, HRQoL was improved in patients receiving concizumab prophylaxis vs no prophylaxis in some, but not all, PROs. Specifically, ETDs were not statistically significant for the SF-36v2 Physical Functioning score (HA: ETD, -0.46 [95% CI, -7.59 to 6.67]; P=0.895; HB: ETD, 1.00 [95% CI, -8.30 to 10.30]; P=0.823) or the PROMIS Upper Extremity score (HA: ETD, 6.69 [95% CI, -4.00 to 17.38]; P=0.191; HB: ETD, 1.45 [95% CI, -9.64 to 12.53]; P=0.782). In the PGI-C questionnaire, patients receiving concizumab prophylaxis reported their change in physical functioning at week 24 as "very much better" (HA, 35.5%; HB, 35.0%), "moderately better" (HA, 24.2%; HB, 22.5%), "a little better" (HA, 16.1%, HB, 30.0%), "no change" (HA, 19.4%; HB, 12.5%), "a little worse" (HA, 3.2%), or "very much worse" (HA, 1.6%) since starting concizumab prophylaxis. Patients receiving no prophylaxis reported "no change" (HA, 100%; HB, 75%), "very much better" (HB, 12.5%), or "moderately better" (HB, 12.5%) physical functioning over the same period. For the SF-36v2 Bodily Pain score, the ETD reached statistical significance in patients with HB (ETD, 14.64 [95% CI, 3.37 to 25.91]; P=0.014) but not in patients with HA (ETD, 4.12 [95% CI, -7.12 to 15.37]; P=0.453). PROMIS Pain Intensity scores were decreased in patients on concizumab prophylaxis; however, the ETD was not significant (HA: ETD, -0.22 [95% CI, -2.73 to 2.28]; P=0.855; HB: ETD, -2.11 [95% CI, -6.05 to 1.82]; P=0.272). Treatment differences on the Hemo-TEM total score were statistically significant in patients with HA (ETD, -25.54 [95% CI, -47.49 to -3.59]; P=0.026) and HB (ETD, -14.52 [95% CI, -26.34 to -2.70]; P=0.021), indicating reduced treatment burden with concizumab prophylaxis.

Conclusions: Concizumab prophylaxis is associated with improvements in certain aspects of HRQoL. Concizumab is associated with lower treatment burden compared with no prophylaxis and may enhance treatment adherence.
Session: Posters/Exhibits/Break
Bleeding Duet: A case of simultaneous acquired factor VIII deficiency and acquired von Willebrand syndrome
Richard Yu1, Mathew Strelau1, Thunisa Shanmugalingham1 , Mackenzie Bowman2, Arnaud Bonnefoy3, Paula James2, Chai Phua1
1University of Western Ontario, Department of Hematology, London, ON, Canada, 2Queens University, Department of Hematology, Kingston, ON, Canada, 3University of Montreal, Department of Hematology, Montreal, QC, Canada

Background: Acquired factor VIII (aFVIII) deficiency and acquired von Willebrand syndrome (AVWS) are both rare bleeding disorders and have only been reported in isolation. aFVIII is typically associated with lymphoproliferative disorders or autoimmune conditions that predisposes to autoantibody formation. The etiology of AVWS is much more heterogenous. They may also be associated with autoantibodies. However, other mechanisms include mechanical stress mediated proteolysis and adsorption from circulation mediated by glycoprotein Ib have been described as well. Here we present a case of concurrent aFVIII deficiency and AVWS. Case presentation: 73-year-old lady with history of prior stroke, STEMI, collagenous colitis, and no recent anticoagulation history, presented with chest pain and gastrointestinal bleeding. Initial bloodwork revealed hemoglobin of 49g/L and found to have an isolated elevated PTT at 64s. The workup of her PTT identified undetectable factor VIII levels <0.01 U/mL and factor VIII inhibitor was elevated at 28.8 Bethesda Units. Furthermore, von Willebrand Antigen was low at 0.12U/mL and activity was low at <0.15U/mL. Subsequent ELISA was performed to confirm presence of a distinct von Willebrand inhibitor. The patient was started on immunosuppression with oral prednisone, IV cyclophosphamide and IVIG. She also received factor VIII replacement, Obizur. Her autoantibody levels decreased in response to this treatment and her clinical bleeding has stopped. Further workup was negative for rheumatologic conditions, myeloma and solid organ malignancy. Colonoscopy revealed multiple angiodysplasias that were treated with argon plasma coagulation and echocardiogram was negative for aortic stenosis. The patient was successfully discharged in remission with recovery of her factor VIII, von Willebrand antigen and activity levels and followed up as an outpatient in the bleeding disorders clinic. Conclusion: To the authors knowledge, this is the first documented instance of two acquired bleeding disorders that occurred simultaneously in a single individual. Here we present the diagnostic steps taken to identify and then prove the presence of two distinct acquired autoimmune mediated bleeding entities and documented positive longitudinal response to immunosuppression.
Session: Posters/Exhibits/Break
Laboratory considerations on DOAC levels (including precision and what we've learned from external QA; comment on andexanet)
Jim Zehnder

A robust correlation between aPTT and anti-Xa assays for unfractionated heparin therapeutic monitoring is generally expected in patients with normal hemostasis. However, in the presence of other comorbidities present in hospitalized patients, this relationship is poor. Of note, the discordant pattern of high aPTT to anti-Xa served is an independent predictor of 30-day all-cause mortality, with a higher degree of discordance associated with increased odds of 30-day mortality. The strengths and limitations of monitoring strategies will be discussed. In the absence of prospective data validating a particular monitoring strategy, obtaining baseline coagulation studies (aPTT, anti-Xa, and PT/INR) before initiating heparin therapy, followed by subsequent paired aPTT and anti-Xa measurements can identify this group of patients with high all-cause mortality and presents an opportunity to use these tests to individualize care of these patients based on their presentation and risks of bleeding and thrombosis.

Session: Taking the result to the patient - laboratory considerations in thrombosis