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
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
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.
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.
LAMIA AIT OUALI1, FARID SLIMANI2, SAMIA OULARBI1, SAMIR TINE1,3
1APHP René Muret , Sevran, France, 2APHP Jean Verdier , Bondy, France, 3APHP Avicenne, Bobigny, France
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
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.
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
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
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.
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
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.
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
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.
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
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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.
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
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.
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
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
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.
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
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.
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
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.
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
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.
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
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
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.
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.
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
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.
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
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.
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
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
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.
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
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.
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
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
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.
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
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.
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
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.
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
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.
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
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
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.
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.
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
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.
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
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.
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
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.
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.
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
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.
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
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.
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.
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.
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
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
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.
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
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.
Emma DeLoughery, Thomas DeLoughery
Oregon Health & Science University, Portland, OR, USA
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.
Emma P. DeLoughery, Byron Wilson, Aaron Grossberg
Oregon Health & Science University, Portland, OR, USA
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.
Laura M. Dionisio, Giovani M. Favero
State University of Ponta Grossa, Ponta Grossa, Brazil
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.
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
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.
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.
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
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.
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.
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
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.
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
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
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
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.
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
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.
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
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.
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
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.
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
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.
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.
Eli J Foster, Nathaniel Hai, Ziqian Zeng, Seemantini K Nadkarni
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Eli J Foster, Nathaniel Hai, Seemantini K Nadkarni
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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
Heather Frazier, Sean Dougherty, Kia Salafian, Hillary Maitland
University of Virginia, Charlottesville, VA, USA
Alyssa R. George, Katelyn Sylvester, Dareen Kanaan, Delaney Corcoran, Kenneth Lupi, Brian Schuler, Jean M. Connors
Brigham and Women's Hospital, Boston, MA, USA
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.
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
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.
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
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.
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,
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.
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.
Clayton Habiger, Shannon Carpenter
Children's Mercy Hospital, Kansas City, MO, USA
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.
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.
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.
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
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.
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.
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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
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.
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.
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
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.
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
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.
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
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.
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
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
Amanda D. Kaveney, Claire Philipp
Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
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.
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
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.
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
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.
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.
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
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.
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
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
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.
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
Keri S. Kim, Jean Lee, Miranda Hart, John Garofalo, Jeffrey J. Mucksavage
University of Illinois Chicago College of Pharmacy, Chicago, IL, USA
Suhhyun Kim, Daniel Sabath
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
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.
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
Vadim Kostousov, Karen Bruzdoski, Jun Teruya
Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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.
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
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.
Emily Krupa, Debra Hoppensteadt-Moorman, Walter Jeske, Jawed Fareed
Loyola University Medical Center, Maywood, IL, USA
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.
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.
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
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.
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.
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
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.
Dan Leary, Mindy Simpson, Lisa Boggio
Rush Hemophilia and Thrombophilia Center, Chicago, IL, USA
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.
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
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.
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
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
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.
Loic J. Letertre1,2, Pall T. Onundarson1, Jon T. Bergthorsson1,2
1Landspitali - The National University Hospital, Reykjavik, Iceland, 2The University of Iceland, Reykjavik, Iceland
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.
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
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.
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
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.
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
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
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
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.
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
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
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.
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
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.
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
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.
Katharine A. Marsden, Shelbey Bauman, Peter F. Mannion, Morayma Reyes Gil
Cleveland Clinic Foundation, Cleveland, OH, USA
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.
Erika J Martin, Lauren C Dunn, Katherine L Bains, Janice G Kuhn
Virginia Commonwealth University, Richmond, VA, USA
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.
Angela M. Martoccia Grabazs, Preeyaporn Sarangarm, Sundeep S. Guliani, Jonathan L. Marinaro, Allison E. Burnett
University of New Mexico Hospital, Albuquerque, NM, USA
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
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.
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.
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
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
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.
Meric Mericliler1,2
1Division of Hematology and Medical Oncology, Virginia Commonwealth University Health, Richmond, VA, USA, 2Massey Cancer Center, Richmond, VA, USA
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.
Jessica N. Mistretta, Kristin T. Ansteatt, Michael D. Tarantino
Bleeding and Clotting Disorder Institute, Peoria, IL, USA
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.
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
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.
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
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.
Tamara Montes, Mikel Santiago, Irene Mijangos
R&D Department, iLine Microsystems S.L., San Sebastián/Donostia, Spain
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.
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
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.
Keith Moskowitz, Michael Fitzpatrick, Lisa Booth, Maria Abreau-Blanco, Matthew Dickerson, Anna Yu, Anya Derbij, W. Allan Alexander
Cellphire Therapeutics, Inc., Rockville, MD, USA
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.
Clara J Nickel2, Anne E Rose1
1University of Wisconsin Health , Madison, WI, USA, 2University of Wisconsin School of Pharmacy , Madison, WI, USA
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.
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.
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
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.
Youjin oh, Alejandro Vallejo, Alexandra Sueldo, Lina james, Angelo Caputi Zuniga, Ayobami Olafimihan, Ekrem Turk
John H. Stroger Jr Hospital , Chicago, IL, USA
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.
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
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.
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
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.
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
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.
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
Joe Palumbo
Prarthana Parthasarathy, Kerry M Hege
Riley Hospital for Children at IU Health, Indiana University School of Medicine, Indianapolis, IN, USA
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.
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
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.
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.
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
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.
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
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
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.
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
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.
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
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.
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
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.
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
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.
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.
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
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.
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
Firas Quran, Sara Zochert, Michael Gulseth, Alicia Martin
Sanford USD Medical Center and Hospital, Sioux Falls, SD, USA
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.
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.
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
Renu Rani, Deepak Agarwal
AIIMS, New Delhi, India
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.
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
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.
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
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.
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.
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
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
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.
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
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.
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
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
ISABEL RODRIGUEZ MARTIN
Hospital Universitario Virgen del Rocio, SEVILLA, Spain
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.
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.
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.
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
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.
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
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.
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
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.
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.
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
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.
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
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
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.
Maria E Santaella, Matthew Hartnett, Luke Luckey, Cynthia D Nichols
National Bleeding Disorders Foundation, New York, NY, USA
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
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
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.
David Scott1, Zhongyuan Chen1, Aniko Szabo1, Lindsay Hammons1, Lisa Baumann Kreuziger1,2
1Medical College of Wisconsin, Milwaukee, WI, USA, 2Versiti Blood Center, Milwaukee, WI,
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.
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
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.
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
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.
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
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.
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.
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
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.
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
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.
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.
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
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
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.
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.
Cristina Solomon1, Catrin Argyle1, Jerrold H. Levy2, Sylvia Werner1
1Octapharma AG, Lachen, Switzerland, 2Duke University School of Medicine, Durham, NC, USA
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.
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.
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
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,
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
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.
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
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.
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
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.
Neha Thomas, Stipo Jurcevic
University of Westminster, London, United Kingdom
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
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.
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
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.
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
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.
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
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.
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
Angela Verdoni1, Mason Marshall2, Irina Chibisov1
1Vitalant Coagulation Laboratory, Pittsburgh, PA, USA, 2Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
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.
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
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.
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
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
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.
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
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.
Yue Wang, Long To, Mathew Jones, Kristin Griebe
Henry Ford Hospital, Detroit, MI, USA
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
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.
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.
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
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.
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
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.
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
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.