Background: Von Willebrand factor (vWF) supports hemostasis by promoting platelet adhesion and activation, acting as a carrier for FVIII, and modulating fibrinolysis. Quantitative (type 1 or 3) or qualitative (type 2) defects in vWF lead to the bleeding disorder von Willebrand Disease (vWD). Emicizumab (Hemlibra®, Roche) has proven effective for prophylaxis in FVIII-deficient Hemophilia A (HA) patients, providing a scientific rationale for its use in the management of type 3 vWD.

Aims: Investigate the efficacy and mechanisms by which emicizumab promotes hemostatic activity in HA and vWD plasma and whole blood.

Methods: Efficacy and Mode of Action (MoA) data was generated in multiple lots of HA and vWD patient plasmas and reconstituted blood using platelet aggregation/activation assays, thrombin generation (TG) assays and fibrinolysis assays.

Results: Emicizumab had no effect on platelet activation or aggregation, but promoted TG in HA and vWD type 3 plasmas (Table 1). Higher baseline TG was measured in reconstituted vWD type 2N plasmas (5-40% residual FVIII) compared to type 3 plasma, which increased a further 2.4 to 3.3-fold by the addition of 50 ug/ml emicizumab. In tissue plasminogen activator (tPA)-induced fibrinolysis assays, emicizumab promoted surprisingly high anti-fibrinolytic activity in vWD type 3 and HA samples (2.2 and 1.6-fold extension to clot lysis times, respectively, Table 2) compared to the anti-fibrinolytic activity of FVIII.

Conclusion(s): Emicizumab promotes hemostasis in HA and vWD plasma by supporting TG and delaying fibrinolysis, and is unlikely to directly affect platelet activation or aggregation. Our preliminary data suggest that emicizumab promotes higher TG in vWD type 2N plasma when compared to HA and type 3 plasmas. The anti-fibrinolytic mechanisms of emicizumab are under investigation. Overall, these data support the notion of emicizumab efficacy in vWD type 2N and 3 patients and provide early insight into its MoA.

Table

Table 1. Peak thrombin generation -nM- in Hemophilia A -HA- and vWD type 3/2N plasma spiked with emicizumab. Fold change in peak thrombin is calculated relative to the condition without emicizumab.

Table

Table 2. tPA-induced fibrinolysis times in Hemophilia A -HA- and vWD type 3 plasma spiked with emicizumab. Clot lysis times -in seconds- are expressed as the time from 50% clotting to 50% lysis in a TF-induced clotting reaction. Fold change in clot lysis times are calculated relative to the condition without emicizumab.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/in-vitro-investigation-of-emicizumab-efficacy-and-mode-of-action-in-vwd-type-2-and-3-samples/