Simplified scheme of pro- and anticoagulant reactions in health, in hemophilia A, and in combined FV and FVIII deficiency. Damage to the vessel wall results in activation of coagulation via FVIIaTF. FVIIaTF and FIXaFVIIIa activate FX; FXa then binds to FVa and activates prothrombin to thrombin. The anticoagulant functions of FV include being a carrier to TFPIα and a synergistic cofactor with protein S (ProS) to TFPIα as well as to APC. In health, the pro- and anticoagulant mechanisms are in balance. In contrast, in hemophilia A, the balance is shifted to anticoagulation with little thrombin generated. In F5F8D, because the anticoagulant functions of FV, TFPIα, and protein S are deficient, the low levels of FV and FVIII are sufficient to efficiently generate thrombin. Red arrows, procoagulant reactions; green arrows, anticoagulant reactions.