Abstract 14975: Effect of the Factor Xa Inhibitor Rivaroxaban on Arterial Thrombosis in Wildtype and Hypercholesterolemic Apolipoprotein E-Deficient Mice
The novel oral anticoagulant rivaroxaban is a highly potent and specific inhibitor of factor Xa. Recent experimental and clinical data highlight the effectiveness and safety of rivaroxaban in the prevention of venous thrombosis. In the present study, we employed the rose bengal (RB) photochemical injury model in the mouse carotid artery to evaluate the anti-thrombotic effects of rivaroxaban in the arterial tree and to test, whether they also extent to hypercholesterolemic mice. Injection of 50 μg/g RB via a jugular vein catheter was followed by illumination of the carotid vessel using a 561 nm laser beam. In wild-type (WT) mice (n=17), initial complete cessation of carotid artery blood flow was observed 11±1.9 min, and stable occlusion 16±2.4 min after exposure to the laser. Rivaroxaban, at the dosage of 1.0, 1.5, 2.0, or 3.0 μg/g, prolonged the time to first occlusion to 19±2.1, 20±2.4, 30±4.8 and 37±4.6 min, respectively (n=12 mice per group, P<0.01 for 3.0 μg/g vs. vehicle); the time to stable occlusion increased to 32±5.6, 34±4.0, 46±4.8 and 58±1.9 min, respectively (P<0.05 and P<0.001 for 2.0 and 3.0 μg/g). Importantly, rivaroxaban also exerted antithrombotic effects in hypercholesterolemic apolipoprotein E−/− mice fed high-fat diet for 4 weeks: in this mouse model, 1.5 and 3.0 μg/g rivaroxaban prolonged the time to first occlusion from 9.4±1.1 to 22±2.6 and 48±3.5 min (n=9, P<0.01 for 1.5 μg/g and P<0.001 for 3.0 μg/g), and the time to stable occlusion from 11±0.9 to 30±3.2 and 54±3.4 min (P<0.001 for 1.5 and 3.0 μg/g vs. vehicle). Rivaroxaban (1.5 and 3.0 μg/g) also prolonged the tail bleeding time from 1.7±0.4 to 6.4±1.1 and 8.8±0.8 min in WT mice, and from 1.2±0.1 to 3.9±0.3 and 7.7±0.3 min in apoE−/− mice (P<0.001 for both dosages vs. vehicle in WT and apoE−/− mice). In conclusion, rivaroxaban potently and dose-dependently inhibited carotid artery thrombus formation induced by photochemical vascular injury in both WT and hypercholesterolemic apoE−/− mice and prolonged the tail bleeding time at the antithrombotic effective dosages tested. Importantly, rivaroxaban showed comparable efficacy in both mouse models, suggesting that the beneficial effects of rivaroxaban might extent to preventing atherothrombosis in clinical practice.
- © 2010 by American Heart Association, Inc.