In vivo Evaluation of DX-9065a, a Synthetic Factor Xa Inhibitor, in Experimental Vein Graft

Abstract

An in vivo effect of a novel synthetic Xa inhibitor, DX-9065a, was evaluated in a highly thrombogenic venous graft model. A woven Tetron tube graft was interposed in the inferior vena cava of rabbits. All the grafts were completely occluded within 5 hours after a bolus injection of heparin (50 U/kg) given just prior to the grafting. The following agents were continuously given to the respective group of rabbits for 2 h after the bolus injection of heparin; heparin (50 U/kg/h, UFH-group), DX-9065a (0.05 mg/kg/h, DX-group) and argatroban (32 microG/kg/h, MD-group). During a 5-h observation period, the anti-Xa activity in circulating blood between the UFH- and DX-group and the anti-thrombin activity between the UFH- and MD-group were not significantly different. The graft patency in the DX-group (4/4) and MD-group (4/4) was significantly better than that in the UFH-group (3/10). Ultrastructural analysis of the luminal surface of the harvested graft by scanning electron microscopy revealed the reduced formation of fibrin networks entrapping erythrocytes in the DX- and MD-group in comparison with the patent UFH-group. In conclusion, a novel synthetic Xa inhibitor DX-9065a exerts a potent in vivo antithrombotic effect, which was comparable with argatroban, a synthetic thrombin inhibitor.