The role of EPCR in blood coagulation. In hemostasis, EPCR promotes the activation of protein C (PC) bound to it by thrombin (T):TM complex. The APC then down-regulates thrombin generation by interacting with phospholipids on the membrane and inactivating cofactors factor VIIIa and factor Va. However, in specific therapeutical conditions, such as administration of a high concentration of rFVIIa to treat hemophilic patients with inhibitors or trauma patients, the EPCR anticoagulant function may be diminished as the exogenously administered FVIIa effectively competes with plasma protein C for binding to EPCR and thus displaces protein C from the EPCR, resulting in down-regulation of APC generation. Down-regulation of APC generation could lead to increased thrombin generation as FVa and FVIIIa are relieved from their inactivation by APC. This mechanism may be responsible partly to the hemostatic effect conferred by therapeutic administration of rFVIIa.