PB0798 - Evaluation of thrombin generation capacity of plasma-derived Factor VIII/von Willebrand Factor in the Treatment of von Willebrand Disease

Background: The efficacy and safety of plasma-derived Factor VIII/von Willebrand Factor (pdFVIII/VWF) concentrates for the treatment of von Willebrand Disease (VWD) are supported by several clinical and real-world evidence studies. However, some concerns still remain related to a possible higher thrombotic risk due to secondary FVIII elevation.

Aims: To evaluate the in vitro procoagulant effect of two pdFVIII/VWF concentrates with different FVIII content (Fanhdi® and Humate-P®) in plasma from VWD patients by thrombin generation (TG) assay.

Methods: Plasma samples from patients with VWD type 1 (VWD1), 2A (VWD2A), 2B (VWD2B) and 3 (VWD3) (George King Bio-Medical, Inc.) were spiked with increasing concentrations of pdFVIII/VWF concentrates (25 to 200 FVIII IU/dL). Samples were analyzed by TG assay (Technothrombin® TGA, Technoclone), using RC High reagent and measuring the thrombin peak (TP); TP normal range: mean (SD) 597.0 (225.7) nM.

Results: TP levels increased dose-dependently with increasing FVIII concentrations and were similar between Fanhdi® and Humate-P® (Figure 1). VWD plasmas with endogenous FVIII (VWD1, VWD2A and VWD2B) needed lower doses of pdFVIII/VWF concentrate to reach normal TP range, while in FVIII-deficient samples (VWD3), TP was restored within the normal range at a higher dose (200 IU/dL). The highest TP was observed with endogenous FVIII (VWD1) samples spiked with Fanhdi® (584.6 [55] nM) and Humate® (586 [79.7] nM) at the highest FVIII dose, although TP levels were within normal range. FVIII estimated activity for each condition before and after Fanhdi® and Humate-P® is shown in Table 1.

Conclusion(s): Thrombin generation was dependent on FVIII activity in plasma samples of VWD patients. At supra-therapeutic VWF:RCo doses (>150 IU/dL), the procoagulant effect of pdFVIII/VWF concentrates did not exceed TG normal range in VWD plasma. These results validated the safety recommendation of not exceeding hemostatic FVIII activity (150 IU/dL) and suggested a low thrombogenicity risk of pdFVIII/VWF concentrates in VWD.