Concizumab (Alhemo®) and marstacimab (Hympavzi®) are humanized monoclonal antibodies that directly bind to the Kunitz-type protease inhibitor domain 2 (K2) of tissue factor pathway inhibitor (TFPI). This interaction inhibits TFPI-mediated suppression of factor Xa (FXa), a process that requires the K2 domain of TFPI. By preventing this inhibition, concizumab and marstacimab enhance FXa activity, thereby facilitating thrombin generation and promoting coagulation in patients with hemophilia A and B (Hilden et al., 2012; Waters et al., 2017; Eichler et al., 2019; Patel-Hett S et al., 2019; Pittman DD et al., 2022; Mahlangu JN et al., 2023; Jewell et al., 2024; reviewed by Peterson, 2012; Pasca, 2022).
TFPI exists in two primary isoforms, TFPIα and TFPIβ, both of which inhibit FXa and FVIIa but differ in localization and cofactor dependence (reviewed by Broze & Girard, 2012). This Reactome event depicts the binding of anti-TFPI antibodies, concizumab or marstacimab, to TFPIα, the soluble plasma isoform of TFPI. TFPIα regulates coagulation on negatively charged surfaces and relies on cofactors such as protein S and factor V-short for efficient activity.
