Non-additive effect on thrombin generation when a plasma-derived factor VIII/ von Willebrand factor (FVIII/VWF) is combined with emicizumab in vitro

Maria-Isabel Bravo, Aida Raventós, Alba Pérez, Montserrat Costa, Todd Willis
Journal of Thrombosis and Haemostasis: JTH 2020 May 7

BACKGROUND: Emicizumab is an alternative non-factor approach for treating patients with hemophilia A. However, there is a potential risk of thrombotic events when emicizumab is concomitantly administered with pro-hemostatic therapies.

OBJECTIVES: To assess the hemostatic effect in vitro when a plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF) was added to hemophilia A plasma (HAp) in combination with emicizumab.

METHODS: HAp and HAp with FVIII inhibitors (HAp-i) samples with different concentrations of emicizumab (50 and 100 μg/mL) were combined with activated prothrombin complex concentrate (aPCC) at 0.5 to 2 U/mL, recombinant activated factor VII (rFVIIa) at 0.5 to 7 μg/mL, and pdFVIII/VWF at 0.1 to 4.5 IU/mL. Thrombin generation (TG: thrombin peak and endogenous thrombin potential) was determined using a Calibrated Automated Thrombogram assay.

RESULTS: When aPCC was added to HAp and HAp-i with emicizumab, TG dramatically increased (multiplier effect >4.5x). Addition of rFVIIa to HAp or HAp-i with emicizumab moderately increased TG in a concentration-related manner compared to rFVIIa alone. Addition of pdFVIII/VWF to HAp or HAp-i with emicizumab induced a TG response equivalent to those samples without emicizumab. In an in vitro model of immune tolerance induction with bleeds (HAp-i 15 Bethesda Units [BU]), combination of pdFVIII/VWF, emicizumab and rFVIIa did not trigger a multiplying effect on TG.

CONCLUSIONS: pdFVIII/VWF showed a non-additive effect on TG when combined in vitro with emicizumab. This finding suggests that emicizumab has limited ability to promote factor X activation in the presence of pdFVIII/VWF, thus reducing the risk of thrombotic events.

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