Abstract 16146: Rivaroxaban Prevents the Development of Chronic Thromboembolic Pulmonary Hypertension in Mice - Novel Beneficial Effects of the FXa Inhibitor -

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) remains a fatal disorder. We have recently demonstrated that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a crucial role in the development of CTEPH. However, the role of factor Xa (FXa) in the pathogenesis of CTEPH remains to be elucidated. Methods and Results: TAFI-overexpressing (TAFI-Tg) mice developed PH with phenotypes similar to CTEPH patients, including organized thrombus with multiple obstruction of pulmonary arteries and reduced survival under hypoxia. TAFI-Tg mice showed substantial pulmonary vascular remodeling, elevated right ventricular systolic pressure (RVSP), and RV hypertrophy (RVH) after 3 weeks of hypoxia. To evaluate the effect of FXa inhibition in CTEPH, we treated TAFI-Tg mice with rivaroxaban (1.2 g/kg PO) or vehicle during 3 weeks of hypoxia. After 3 weeks, 25% of the TAFI-Tg mice with vehicle died, whereas 13% of those treated with rivaroxaban did. Rivaroxaban significantly reduced RVSP and RVH in TAFI-Tg mice compared with vehicle ( n =12 each, both P n =5 each, all P + CD11b + Ly6G – cells in the lungs were significantly increased in TAFI-Tg mice compared with controls, suggesting a crucial role of monocytes/macrophages in TAFI-mediated pulmonary artery inflammation. Importantly, rivaroxaban treatment significantly reduced the number of perivascular Mac3 + cells compared with vehicle ( n =5 each, P n =6 each, all P n =4 each, P Conclusion: These results indicate that rivaroxaban inhibits the development of mouse model of CTEPH through suppression of inflammation and cell proliferation.