The Role of Cofactors and the Endothelial Cell Surface in Protein-c Activation

ANTICOAGULANT PATHWAY P ROTEIN-C is a vitamin-K-dependent plasma zymogen.’ After activation, activated protein-C differs from the vitamin-K-dependent plasma clotting factors in that it potently inhibits coagulation5 by inactivating factors V6’7 and VIII,7’8 and it facilitates fibrinolysis in vivo9”#{176} by elevating circulating plasminogen activator levels.tO Clinical evidence of protein-C involvement in the regulation of coagulation comes from the observation that low levels of protein-C are associated with recurrent familial thrombosis.”2 To understand the role of protein-C in hemostasis, it is useful to discuss the protein-C anticoagulant pathway. This pathway can be conveniently divided into three parts: (1 ) protein-C activation; (2) the inhibition of coagulation through the inactivation of factors V/Va and Vill/Vitla by activated protein-C, and (3) the inhibition of activated protein-C by a plasma protease inhibitor specific for this enzyme. Each part of this pathway involves unique proteins and/or receptor surfaces. A schematic diagram of the role of protein-C in the regulation of blood coagulation is shown in Fig. 1.