Abstract 360: Rivaroxaban Enhances the Antiplatelet Activity of Aspirin via Inhibition of Nox2-mediated Thromboxane A 2 and Isoprostane Biosynthesis

Abstract

Background: A recent study demonstrated that a combination of rivaroxaban, an inhibitor of factor Xa, plus aspirin (100mg/day) reduces cardiovascular events in patients with stable vascular disease, compared to aspirin alone but the underlying mechanism is still unknown. Methods: In vitro study was performed consisting in measuring agonist-induced platelet aggregation, thromboxane (Tx)B 2 and isoprostane biosynthesis, soluble Nox 2 -dp, a marker of Nox2 activation, and PLA 2 activation in platelets from healthy subjects (n=5) added with or without scalar doses of aspirin (25-100 uM) and/or rivaroxaban (15-120 ng/ml). Furthermore, we measured urinary excretion of isoprostanes, and soluble Nox2 before and after 3 months of 20 mg rivaroxaban (n=25) or warfarin (n=25) treatment in atrial fibrillation(AF) patients. Results: In vitro study showed that rivaroxaban significantly reduced platelet aggregation, TxB 2 and isoprostane biosynthesis and Nox2 and PLA 2 activation in a dose-dependent fashion. Also, rivaroxaban dose-dependently inhibited aggregation of platelets treated with low-(25uM) as well as high-(100uM) aspirin doses. In low-dose aspirin-treated samples an incremental inhibition of platelet TxB 2 biosynthesis was achieved; conversely, in platelets treated with high doses of aspirin a significant inhibition of isoprostanes and Nox2 was observed. Inhibition of platelet aggregation by rivaroxaban was detected also in platelets stimulated with convulxin suggesting that its antiplatelet effect was GPVI-dependent. In addition, convulxin elicited PLA 2 activation, that was inhibited by rivaroxaban as well as by a Nox2 inhibitor. Finally, in AF patients treated with rivaroxaban a significant reduction of urinary isoprostanes and soluble Nox2 and GPVI as compared to warfarin-treated ones was detected. Conclusion: Here we show that rivaroxaban inhibits platelet aggregation via GPVI interaction and eventually Nox2-mediated thromboxane and isoprostane biosynthesis in aspirin-treated platelets so providing a novel mechanistic insight into the beneficial effects of combining rivaroxaban with aspirin.