Anticoagulant Actions of Tissue Factor Pathway Inhibitor on Tissue-Factor-Dependent Plasma Coagulation

Abstract

The initiation and propagation of in vivo coagulation are thought to be catalyzed by factor VIIa-tissue factor (an activator of factor X and factor IX) and factor IXa-factor VIIIa (an activator of factor IX), respectively. The enzymatic activity of factor VIIa-tissue factor is abrogated by tissue factor pathway inhibitor (TFPI), which anchors a quaternary complex consisting of equimolar TFPI, factor Xa, factor VIIa, and tissue factor in which both factor Xa and factor VIIa are inactive. This study compared the anticoagulant effectiveness of TFPI (which also inactivates prothrombinase-bound factor Xa), hirudin (which inactivates thrombin), and heparin (which catalyzes the inactivation of factor Xa and thrombin by antithrombin III). Factor X and prothrombin activation were initiated by adding 5 pM r-tissue factor in a suspension of coagulant phospholipids and CaCl₂ to defibrinated plasma. Compared on the basis of their ability to delay the initiation of and inhibit factor X and prothrombin activation, the anticoagulant effectiveness of 0.5 nM TFPI was greater than those of 10 nM hirudin and ∼ 100 nM (0.1 unit/mL) heparin. However, a 100-fold molar excess of TFPI over tissue factor could not abrogate factor X and prothrombin activation in plasma. These results suggest that propagation of tissue-factor dependent coagulation is catalyzed by factor IXa-factor VIIIa, which unlike factor VIIa-tissue factor, is not inactivated by TFPI.

Key words:

Tissue factor pathway inhibitor - thrombin - factor Xa - tissue factor