Thrombophilia: The discovery of activated protein C resistance

This chapter focuses on a physiologically important natural anticoagulant system which is known as protein C system. This system regulates blood coagulation by cleaving and inhibiting the activated forms of coagulation cofactors V and VIII (Va and VIIIa). Protein C, which is the key component of the system, is vitamin K dependent and circulates in plasma as a zymogen to a serine protease. The protein C system is activated in response to intravascular thrombin generation. Thrombin, which functions as a procoagulant enzyme in the extravascular space, has the potential to attain anticoagulant properties intravascularly. Binding of thrombin to thrombomodulin (TM), a high-affinity receptor on the surface of intact endothelial cells, is associated with modulation of thrombin function. Procoagulant properties are lost and anticoagulant properties are gained because thrombin bound to TM efficiently activates protein C. Activated protein C (APC)-mediated cleavage and inactivation of factor Va and factor VIIIa is potentiated by another vitamin K-dependent plasma protein, protein S, which, unlike protein C, is not a zymogen to a serine protease. © 1995 Academic Press Inc.