ACTIVE SITE-BLOCKED FACTOR-IXA PREVENTS INTRAVASCULAR THROMBUS FORMATION IN THE CORONARY VASCULATURE WITHOUT INHIBITING EXTRAVASCULAR COAGULATION IN A CANINE THROMBOSIS MODEL

To assess the contribution of Factor IX/IXa, to intravascular thrombosis, a canine coronary thrombosis model was studied. Thrombus formation was initiated by applying current to a needle in the circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycyl-arginyl-Factor IXa (IXai), a competitive inhibitor of Factor IXa assembly into the intrinsic Factor X activation complex, bovine Factor IX, or heparin. Animals receiving saline or Factor IX developed coronary occlusion due to a fibrin/platelet thrombus in 70 +/- 11 min. In contrast, infusion of IXai prevented thrombus formation completely (> 180 min) at doses of 460 and 300-mu-g/kg, and partially blocked thrombus formation at 150-mu-g/kg. IXai attenuated the accumulation of I-125-fibrinogen/fibrin at the site of the thrombus by approximately 67% (P < 0.001) and resulted in approximately 26% decrease in serotonin release from platelets in coronary sinus (P < 0.05). Hemostatic variables in animals receiving IXai, remained within normal limits. Animals given heparin in a concentration sufficient to prevent occlusive thrombosis had markedly increased bleeding, whereas heparin levels that maintained extravascular hemostasis did not prevent intracoronary thrombosis. This suggests that Factor IX/IXa can contribute to thrombus formation, and that inhibition of IXa participation in the clotting mechanism blocks intravascular thrombosis without impairing extravascular hemostasis.