INITIATION OF THE TISSUE FACTOR PATHWAY OF COAGULATION IN THE PRESENCE OF HEPARIN - CONTROL BY ANTITHROMBIN-III AND TISSUE FACTOR PATHWAY INHIBITOR

Activation of factor X by both the unactivated tissue factor:factor VI I complex (TF:VII) and the activated tissue factor:factor VIIa complex (TF:VIIa) has been studied in the presence of tissue factor pathway i nhibitor (TFPI), antithrombin III (ATIII), and heparin. At near-plasma concentrations of TFPI, ATIII, and factor X, factor X activation that occurs in response to TF:VII is essentially abolished in the presence of heparin (0.5 mu mol/L). This effect requires both inhibitors, acti ng on different targets: (1) ATIII, which in the presence of heparin b locks the activation of TF:VII, and (2) TFPI, which inhibits the TF:VI Ia that is generated. In the absence of ATIII. TFPI alone with or with out heparin reduces but does not abolish factor X activation. Converse ly, in the absence of TFPI, ATIII + heparin reduces but does not aboli sh TF:VIIa generation and allows continuing activation of factor X. Th ese results indicate that when the unactivated TF:VII complex is the i nitiating stimulus, heparin-dependent reduction in the rate and extent of factor X activation requires both ATIII and TFPI. In contrast, a I F:VIIa is used to initiate activation, only TFPI is involved in its re gulation. (C) 1996 by The American Society of Hematology.