Heparin-protein C interaction.

Activated protein C is a vitamin K-dependent plasma protein which inhibits blood coagulation at the levels of factors V and VIII in the clotting cascade and which enhances blood clot lysis by raising the levels of circulating plasminogen activator. Activation of protein C occurs when thrombin binds to an endothelial cell associated cofactor, thrombomodulin. The thrombin-thrombomodulin complex rapidly activates the protein C. The activated protein C has a relatively long half-life in plasma and thus can serve as a circulating anticoagulant as well as elevate the levels of plasminogen activator. Heparin interacts with the protein C system in at least two distinct ways. First, the activation of protein C in vivo can be blocked by administration of low levels of heparin. The heparin brings about the inhibition of thrombin either before thrombin is bound to the cell-associated thrombomodulin or after the thrombin is complexed to the thrombomodulin. Secondly, activated protein C has its own unique inhibitor, activated protein C inhibitor. Inhibition of activated protein C by this inhibitor is stimulated by relatively high levels of heparin (5-10 u/ml). The physiologic significance of heparin-activated protein C inhibitor remains to be demonstrated.