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Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet-Induced Thrombin Generation and Prothrombinase Activity

From pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main, Germany (Dr Graff, Dr von Hentig, Dr Harder); Bayer HealthCare, Wuppertal, Germany (Dr Misselwitz, Dr Kubitza, Dr Becka); and International Institute for Thrombosis and Vascular Diseases, Frankfurt am Main, Germany (Dr Breddin [deceased]).

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase-induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen-induced endogenous thrombin potential was reduced by 80% and 90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor-induced endogenous thrombin potential was reduced by 40% (5 mg) and 65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase-induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet-induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.

Key Words: Direct factor Xa inhibitor • oral anticoagulant • thrombin generation • platelets • PiCT

Address for correspondence: Jochen Graff, MD, pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, University Hospital, Frankfurt/Main, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany; e-mail: graff{at}em.uni-frankfurt.de.

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