Abstract Number: OC 24.1
Meeting: ISTH 2021 Congress
Background: To restore hemostasis in hemophilia A/B patients with inhibitors, supraphysiological doses of activated factor seven (FVIIa) are commonly used. FVIIa mobilizes three complementary actions to achieve efficient clotting: a tissue-factor (TF)-dependent pathway on TF-expressing cells; a TF-independent pathway on platelets; and an endothelial protein C receptor (EPCR)-dependent pathway on endothelial cells. Eptacog beta (EB) is a recombinant FVIIa (possessing specific glycosylation) produced utilizing the rPRO Technology™ where Eptacog alfa (EA) is FVIIa produced from BHK cells. EB achieved relevant clinical hemostasis (PERSEPT clinical program) at doses 17% lower than EA (75 and 225µg/kg vs. 90 and 270µg/kg, respectively).
Aims: The study objective was to evaluate whether EB potency might be influenced by modulating the TF-independent pathway, focusing on EB-platelet interactions.
Methods: EB and EA were compared by: common hemostasis assays (PT, aPTT, FXa and FIXa generation, 0.5 nM TF/2 µM phospholipids activated TGT); binding to antithrombin and TF; and interaction with platelets pre-activated with convulxin and thrombin (±calcium).
Results: The first experimental step was to determine if the anti-FVIIa antibodies used throughout the studies equally recognize both EB and EA molecules. As assessed by common in vitro biological assays, both molecules exhibited similar hemostatic potency. Binding affinity (Kd) to antithrombin, TF, and activated platelet surfaces was also found to be similar. In contrast, the total amount of EB bound at the platelet surface (Bmax) was 40% higher than that for EA. Further experiments are now ongoing: to assess if elevated amount of EB bound at the platelet surface indeed leads to enhanced generation of FXa, as well as to elucidate the role of the EB glycosylation profile in the TF-independent pathway.
Conclusions: Increased capture of EB at the platelet surface (relative to EA) suggests that the TF-independent pathway could be important for the observed EB efficacy in clinical settings.
To cite this abstract in AMA style:Plantier J-, Evans S, Martres P. Evaluation of the Tissue Factor-Independent Mechanism of Action for Eptacog Beta [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/evaluation-of-the-tissue-factor-independent-mechanism-of-action-for-eptacog-beta/. Accessed June 25, 2022.
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