The relevance of FVIIa and EPCR interaction to the hemostatic effect of rFVIIa in hemophilia therapy. When high concentrations of rFVIIa were administered to hemophilia patients with inhibitors, rFVIIa, along with plasma zymogen FVII, binds to tissue factor (TF) at the injury site (1). The formation of the TF-FVIIa complex initiates the activation of FX to FXa and also FIX to FIXa. Once traces of FXa are generated, tissue factor pathway inhibitor (TFPI) binds FXa and TFPI-FXa forms a quaternary complex with TF-FVIIa, inhibiting further activation of FX by TF-FVIIa (not shown). The initial FXa generated by TF-FVIIa also associates with factor Va (FVa) on the endothelial cell surface to form the prothrombinase complex, which activates prothrombin (FII) to thrombin. The resultant thrombin promotes the activation of protein C bound to the EPCR on the endothelium and also activates platelets. EPCR-mediated APC generation inactivates FVa and blocks further thrombin generation by the prothrombinase complex on the endothelium. However, rFVIIa, when present at high concentrations, can activate FX to FXa on the surface of thrombin-activated platelets, independent of TF (2). FXa generated by FVIIa on activated platelets forms appreciable levels of the prothrombinase complex that could lead to thrombin burst capable of restoring hemostasis in hemophilia patients. rFVIIa, in addition to activating FX, also displaces protein C from EPCR by directly competing with protein C to bind to the EPCR (3). FVIIa displacement of protein C from the EPCR reduces APC generation. Reduced APC levels would diminish the extent of FVa inactivation by APC, which would lead to sustained thrombin generation on the endothelium. This, in addition to rFVIIa directly activating FX, contributes to rFVIIa hemostatic effect in hemophilia therapy.