THE ACTIVATION OF FACTOR-X AND PROTHROMBIN BY RECOMBINANT FACTOR VIIAIN-VIVO IS MEDIATED BY TISSUE FACTOR

The human coagulation system continuously generates very small quantit ies of Factor Xa and thrombin. Current evidence suggests that basal le vel activation of the hemostatic mechanism occurs via Factor VIIa-depe ndent activation of Factor X, but direct proof has not been available for the participation of tissue factor in this pathway. To examine thi s issue, we infused relatively high concentrations of recombinant Fact or VIIa (approximately 50 mug/kg body wt) into normal chimpanzees and observed significant increases in the plasma levels of Factor IX activ ation peptide, Factor X activation peptide, and prothrombin activation fragment F1+2. Metabolic turnover studies with radiolabeled Factor IX activation peptide, Factor X activation peptide, and F1+2 indicate th at elevated levels of the activation peptides are due to accelerated c onversion of the three coagulation system zymogens into serine proteas es. The administration of a potent monoclonal antibody to tissue facto r, which immediately neutralizes function of the Factor VIIa-tissue fa ctor complex in vitro, abolishes the activation of Factor X and prothr ombin mediated by the infused recombinant protein, and also suppresses basal level activation of Factor IX and Factor X. The above results s uggest that recombinant Factor VIIa functions as a prohemostatic agent by interacting with endogenous tissue factor sites, but definitive pr oof will require studies in hemophilic animals using relevant hemostat ic endpoints.