Factor VIII Coagulant Activity (FVIII:C) As an Independent Predictor of Bleeding across Different Subtypes of Von Willebrand Disease (VWD)

Title: Factor VIII coagulant activity (FVIII:C) as an independent predictor of bleeding across different subtypes of von Willebrand Disease (VWD)

Authors: Shruti Kharat M.Sc¹, Nayaab S. Khan PhD², Alina He², Chris Foo PharmD², Kranti Patil B.Sc¹, Gurpreet Saini M.Sc¹, Shreyas Tawde M.Sc¹, Benjamin Kim MD MPhil², Savita Rangarajan MD¹, Shrimati Shetty PhD¹

1. K.J Somaiya Hospital & Research Center, Mumbai, India
2. Star Therapeutics, Inc., South San Francisco, CA, USA

Background: VWD patients present with a wide spectrum of bleeding manifestations that oftentimes do not correlate with FVIII:C, von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), or mutation type; the bleeding phenotype can be quite different within the same family. The basis for this wide heterogeneity is poorly understood. Prediction of bleeding risk is important for an accurate prognosis and counselling. The extent to which thrombin generation (TG) correlates to laboratory results, bleeding, or health outcomes in VWD is unknown.

Aim: The study is planned to comprehensively characterize and evaluate the predictors of bleeding, including TG, across different subtypes of VWD.

Study design and methods: This is an ongoing, prospective study of VWD patients from a single center in Mumbai, India, who have an historical FVIII:C ≤50 IU/dL. Individuals with a new or historical diagnosis of VWD were enrolled in the study. Patients with acquired and platelet type VWD were excluded. The Institute Ethics Committee (academic) approval and informed consent were obtained. Following enrollment, pertinent medical history was collected. The ISTH Bleeding Assessment Tool (BAT), FACIT-Fatigue, SF-36, and EQ-5D-5L questionnaires were administered to assess bleeding phenotype, fatigue, health-related quality of life, and health status, respectively. Blood samples were collected for the following: VWF:Ag, VWF:RCo, FVIII:C, and VWF gene sequencing. The subtyping was done as per the most recent WFH/ISTH/ASH guidelines for the diagnosis of VWD (James, 2021). TG was assessed using platelet-rich plasma.

Interim results: As of July 2024, 46 (type 1=6, type 2=16, and type 3=24) VWD patients have been enrolled and fully assessed. Mutations were distributed throughout the gene, but 43% of the pathogenic mutations were located in exon 28 of VWF. The mean (SD) age of patients (males=19; females=27) was 32.09 (16.8) years. The mean (SD) ISTH BAT score was 3.60 (1.67), 7.82 (3.63), and 12.63 (6.6) in type 1, type 2, and type 3 VWD patients, respectively. Pearson correlation and regression analysis applied to assess predictive significance of different laboratory parameters with ISTH BAT score showed FVIII:C as an independent predictor (r=-0.34; P<0.05). Peak TG correlated with FVIII:C, VWF:Ag, and VWF:RCo (r=0.58, 0.52, and 0.35, respectively) and was increased among type 3 VWD patients using estrogen-containing hormonal contraception compared to those who did not; however, peak TG did not correlate with ISTH BAT or other health outcomes. Finally, while mean (SD) SF-36 scores of VWD patients trended lower for some domains when compared to those from a healthy Indian population (Sinha, 2013)—i.e., energy/fatigue: 66.30 (19.18) vs. 80.82 (19.22); emotional well-being: 68.76 (17.63) vs. 86.16 (14.92); pain: 75.87 (21.39) vs. 83.80 (26.98); and general health: 67.96 (19.44) vs. 79.41 (20.42)—they were not statistically significant.

Conclusions: Among the different variables, FVIII:C was found to independently predict the bleeding across different VWD subtypes. Estrogen-containing hormonal contraception, which is known to modulate Protein S levels, was associated with increased peak TG, even in type 3 VWD patients. Additional analyses to investigate predictors of patient-centered outcomes in VWD will be conducted.