NORMAL hemostasis in humans requires the interaction of a large number of plasma glycoproteins with blood platelets and vascular endothelial cells. This interaction results in the generation of a platelet plug and fibrin clot at the site of a vascular injury. Many of the plasma glycoproteins involved in blood coagulation are zymogens to enzymes that interact in a stepwise manner in a series of reactions that ultimately result in the generation of thrombin. Thrombin then catalyzes several important physiologic reactions, including generation of fibrin and activation of platelets. This mechanism of enzymatic signal amplification by sequential activation of zymogens of serine proteases has been referred to as the blood coagulation cascade. 4., 5., 6. Several of the enzymatic reactions in the coagulation cascade require additional plasma proteins which serve as cofactors. 7., 8., 9. These include factor Villa in activation of factor X by factor IXa and factor Va in activation of prothrombin by factor Xa (Fig 1). Both of these reactions involve a vitamin K-dependent enzyme (factor IXa or factor Xa) as well as a vitamin K-dependent substrate (factor X or prothrombin). Both reactions also require calcium and a phospholipid vesicle or cell surface. Another similarity between factor V and factor VIII is that the activity of these cofactors is regulated by limited proteolysis. Both cofactors circulate as inactive cofactors and are activated by serine proteases, such as thrombin or factor Xa (Fig 2). The activated cofactors are subsequently inactivated by another serine protease called activated protein C. 10., 11. These inactivation reactions also require a vitamin K-dependent cofactor called protein S, calcium ions, and a cell or phospholipid surface (Fig 3). Abnormal expression of cofactor activity in disease states can lead to either a bleeding diathesis or to pathologic thrombosis. Patients with an inherited deficiency of factor VIII (hemophilia A) 12 or factor V (parahemophilia) 13 have abnormal bleeding. Furthermore, an inherited bleeding disorder characterized by the combined deficiency of factor V and factor VIII has also been described. 14 In contrast, infants with homozygous deficiencies of protein C develop purpura fulminans neonatalis and die of thrombotic complications during the neonatal period if untreated. The thrombotic complications in these patients appear to result from their inability to inactivate factor Va and factor VIIIa. 11