In healthy individuals, coagulation factor VIII, in its activated form (FVIIIa), functions as a cofactor to the serine protease FIXa in converting the zymogen FX into its active enzyme form, FXa. Factors VIIIa and IXa assemble on cell surfaces to form the "tenase complex" (FVIIIa:FIXa), which efficiently catalyzes the activation of factor X. In vitro, negatively charged phospholipids provide a suitable surface, whereas, in the body, this role is fulfilled by the plasma membranes of activated platelets (Gilbert and Arena, 1996).
FVIII deficiency or dysfunction, known as hemophilia A (HA), is an X-linked inherited bleeding disorder caused by mutations in the F8 gene.
Emicizumab (also referred to as ACE910; trade name: Hemlibra) is a bispecific humanized monoclonal antibody designed to restore the cofactor function of activated FVIIIa under conditions of F8 deficiency. It achieves this by bridging activated FIXa and FX, thereby facilitating efficient FIXa-catalyzed FX activation in HA patients (Sampei Z et al., 2013; Kitazawa T et al., 2017). Emicizumab recognizes the epidermal growth factor (EGF)-like domain 1 of FIX/FIXa with one arm and the EGF-like domain 2 of FX/FXa with the other (Kitazawa T et al., 2017). The moderate binding affinity of emicizumab (KD values of 1.58, 1.52, 1.85, and 0.978 µM for FIX, FIXa, FX, and FXa, respectively) allows the release of resultant FXa from emicizumab, freeing it to participate in subsequent reactions within the coagulation cascade (Kitazawa T et al., 2017).
Importantly, emicizumab does not interfere with the activity of antithrombin (AT) or tissue factor pathway inhibitor (TFPI) in emicizumab-mediated coagulation reactions in vitro (Noguchi-Sasaki M et al., 2018). Moreover, activated protein C (APC) was shown to suppress thrombin generation in emicizumab-driven hemostasis through APC-mediated inactivation of factor Va (FVa) in plasma from HA patients (Yada K et al., 2018). These findings suggest that emicizumab does not disrupt the negative feedback regulation of coagulation mediated by AT, TFPI, or APC.
