Gene targeting in hemostasis: protein C.

Protein C (PC) is the zymogen form of a serine protease, activated protein C (APC), a naturally occurring anticoagulant. In control of the coagulation of blood, APC functions by attenuating thrombin formation. It serves this role through inactivation, by limited proteolysis, of two important cofactors for overall clot formation, one of which, Factor Va (FVa), stimulates prothrombin activation, and another, Factor VIIIa (FVIIIa), enhances activation of coagulation Factor X (FX). In maintaining the fluidity of blood, APC also indirectly functions in fibrinolysis, in one manner by directly inactivating an inhibitor of plasminogen activation, plasminogen activation inhibitor-1 (PAI-1), and in another manner via its role in attenuating thrombin production, with the resulting effect of limiting production of another thrombin-dependent fibrinolytic inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI). PC, and other components of the PC anticoagulant pathway, e.g., protein S (PS), thrombomodulin (Tm), and endothelial cell protein C receptor (EPCR), also can serve as anti-inflammatory mediators, through a number of different thrombin-dependent and thrombin-independent mechanisms. A large number of symptomatic and asymptomatic mutations occur in PC in humans, which express a variety of phenotypes. Generation and characterization of a murine model of a total PC gene inactivation has demonstrated that while an untreated total PC deficiency results in neonatal death through DIC-related abnormalities, a valuable resource is now available to study phenotypes of less severe deficiencies of this protein. Such studies will lead to advances in an understanding of the relative role of this protein system in the various pathways in which it has an influence.