ANTITHROMBOTIC EFFECTS OF ORALLY-ACTIVE SYNTHETIC ANTAGONIST OF ACTIVATED FACTOR-X IN NONHUMAN-PRIMATES

Background Since activated factor X (FXa) has a Central role in hemostasis and thrombosis, it is an attractive target for antithrombotic strategies. Accordingly, we evaluated the relative antihemostatic and antithrombotic effects of an orally active amidinoaryl propanoic acid inhibitor of FXa, APAP, in baboons. Methods and Results With a two-component thrombogenic device that induced the concurrent formation of both arterial-type platelet-rich and venous-type fibrin-rich thrombus when interposed in chronic exteriorized arteriovenous (AV) femoral shunts flowing at 40 mL/min, thrombus formation was compared for oral versus parenteral APAP by measurement of In-111-platelet deposition, I-125-fibrin accumulation, thrombotic obstruction of flow, and circulating levels of blood biochemical markers of thrombosis. The direct infusion of APAP (120 mu g/min) into AV shunts proximal to thrombogenic devices for 1 hour achieved local drug levels of 4.3+/-0.4 mg/L and substantially reduced the accumulation of platelets and fibrin in the formation of venous-type fibrin-rich thrombus (P<.01) but not in the formation of platelet-rich arterial-type thrombus (P>.1). APAP was subsequently removed from plasma with plasma clearance rates of T(50)alpha of 6.3 minutes and T(50)beta of 99 minutes. The oral administration of APAP (50 mg/kg) produced peak plasma levels of 3.7+/-1.4 mu g/mL at 30 minutes and gradually declining plasma levels over about 6 to 8 hours, with bioavailability estimated to be approximately 5% to 12%: Oral APAP decreased platelet deposition (P<.01) and fibrin accumulation (P<.05) in venous-type thrombus but failed to decrease platelet or fibrin accumulation in arterial-type thrombus (P>.1 in both cases). Oral and infused APAP prolonged the activated partial thromboplastin time and prevented thrombus-dependent elevations in plasma fibrinopeptide A, thrombin-antithrombin III complex, beta-thromboglobulin, and platelet factor 4 levels. Additionally, APAP produced dose-dependent inhibition of FXa bound to thrombus on segments of vascular graft interposed in exteriorized AV shunts for 15 minutes. Conclusions An oral synthetic antagonist of FXa, APAP, inhibits the formation of venous-type fibrin-rich thrombus by inactivating bound and soluble FXa without impairing platelet hemostatic function.