Presentation Details
| Value of Functional Protein S Activity Assays for Detection of Type II Protein S Deficiency Katharine A.Marsden, Shelbey Bauman, Peter F.Mannion, Morayma Reyes Gil. Cleveland Clinic Foundation, Cleveland, OH, USA |
Abstract
Background: Protein S deficiency is a hereditary thrombophilia which occurs in three forms: Type I (quantitative), type II (qualitative) and type III (qualitative due to a gain of function). Literature suggests that of these, type II is the rarest and most difficult to diagnose. Type II protein S deficiency is only detectable by assaying protein S activity with a functional, clot-based test. However, this test is susceptible to interference, and has a lower specificity when compared to antigen assays used to detect free and total protein S levels. Due to this, the Choosing Wisely Guidelines released by the ABIM Foundation recommends against using protein S activity assays entirely. Instead, they suggest using only free protein S antigen assays. Although the rationale is to avoid false positive results from the protein S activity assay, it ultimately may result in a failure to detect type II protein S deficiency. Objectives: This study, performed at a tertiary medical center in the Midwestern region of the United States, aims to determine the proportion of false positives in functional assays as well as the percent of true type II protein S deficiency cases within this testing population. Methods: All cases with abnormal protein S function within the institution were evaluated from July 2018 through July 2023 and classified as acquired or hereditary deficiencies. Cases were classified as acquired if there was evidence of liver disease, vitamin K deficiency, ongoing thrombosis, consumption, disseminated intravascular coagulopathy, or pregnancy. Possible hereditary deficiency cases were classified as type I, type II and type III: Type I if all assays were low, type II if both active and free protein S assays were low with normal total protein S, and type II if only protein S activity was low. The cutoff defined for normal total and free protein S levels was greater than 70% activity, and the low protein S activity cutoff was defined as less than 50%. Patients with low protein S activity but normal immunologic protein S and an elevated factor VIII were considered falsely low values. Chart review will be performed for remaining cases with low protein S activity with normal factor VIII and normal INR to rule out confounders such as vitamin K deficiency, warfarin use, acute phase reaction, or pregnancy. Results: From a total of 8811 panels performed to assess for possible thrombophilia, 1586 (18%) were found to have decreased protein S activity. Of these cases, 563 (36%) were considered falsely decreased due to elevated factor VIII levels. 382 cases (4.4%) were considered possible hereditary deficiencies, further classified as: 217 type III (2.5%), 85 type II (1%), and 80 type I (0.9%). Conclusions: Previous literature has indicated type I protein S deficiency is the most common subtype, followed by type III, with type II being much less common than type I or type III. However, our data indicates type II protein S deficiency may be more common than previously believed, which may call for current guidelines to be reevaluated to effectively capture this patient population.
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