Role Of Antithrombin And Tissue Factor Pathway Inhibitor In The Control Of Thrombosis And Mediation Of Heparin Action

Deficiency of any of the two coagulation inhibitors antithrombin (AT) and tissue factor pathway inhibitor (TFPI) lowers the resistance to thrombosis. Hereditary deficiency of AT leads to a high risk of thrombosis, which occasionally responds poorly to heparin therapy. Experimental deficiency of TFPI lowers the resistance to infusion of both tissue factor and endotoxin, both regarding microvascular thrombosis and fatality. Administration of either AT or TFPI protects against micro- and macrovascular thrombosis. Injection of heparin and some other glycosaminoglycans releases intima-bound TFPI to the blood. Heparin accelerates the inhibitory effects of both inhibitors, in particular the effect of AT. The influence of the two inhibitors on the various anticoagulant reactions have been studied using blocking antibodies. It is suggested that the anticoagulant and antithrombotic effects of heparin are mainly mediated by the accelerated inactivation of thrombin, factor IXa and factor X by AT, and augmented inactivation of tissue factor-factor VIIa by TFPI released to the blood.