Lack of Plasminogen Activator Inhibitor-1 Enhances the Preventive Effect of DX-9065a, a Selective Factor Xa Inhibitor, on Venous Thrombus and Acute Pulmonary Embolism in Mice

Abstract

We have studied the physiological effects of DX-9065a, a selective factor Xa (FXa) inhibitor, and heparin in experimental venous thrombus and acute pulmonary embolism. Moreover, the effects of these compounds were also evaluated under the condition of plasminogen activator inhibitor-1 (PAI-1) deficiency. A thrombus was induced in the murine femoral vein. The compounds prolonged the time to occlusion in a dose-dependent manner. Pulmonary embolism was induced by continuous induction of venous thrombi in the left jugular vein. The mortality of mice increased time-dependently. Histological evidence of thromboembolism in the lung was obtained in all mice. Treatment with DX-9065a, but not heparin, reduced the mortality at 6 h after initiation of venous thrombi. In separate experiments, pulmonary thromboembolism was induced in PAI-1 knockout mice. The mortality in PAI-1 knockout mice was reduced compared with that of wild-type mice. Moreover, when DX- 9065a was administered to PAI-1 knockout mice with pulmonary thromboembolism, mice survived well without marked bleeding. These findings indicate that the dual inhibition of coagulation FXa and PAI-1 could be beneficial in the treatment of acute pulmonary embolism.