Tobias Petzold1,2, Manuela Thienel1,2, Lisa Dannenberg3, Philipp Mourikis3, Carolin Helten3, Aysel Ayhan3, René M'Pembele3, Alina Achilles3, Kajetan Trojovky3, Daniel Konsek3, Zhe Zhang1, Ron Regenauer1, Joachim Pircher1,2, Andreas Ehrlich1,2, Enzo Lüsebrink1,2, Leo Nicolai1,2, Thomas J Stocker1,2, Richard Brandl4, Franz Röschenthaler5, Jan Strecker1, Inas Saleh1, Michael Spannagl6, Christoph H Mayr7, Herbert B Schiller7, Christian Jung3, Norbert Gerdes3, Till Hoffmann8, Bodo Levkau9, Thomas Hohlfeld10, Tobias Zeus3, Christian Schulz1,2, Malte Kelm3, Amin Polzin3. 1. From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München (T.P., M.T., Z.Z., R.R., J.P., A.E., E.L., L.N., T.J.S., J.S., I.S., C.S.), Ludwig-Maximilians-University Munich, Germany. 2. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., J.P., A.E., E.L., L.N., T.J.S., C.S.). 3. Cardiology, Pulmonology and Vascular Medicine, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf (L.D., P.M., C.H., A. Ayhan, R.M., A. Achilles, K.T., D.K., C.J., N.G., T.Z., M.K., A.P.). 4. St Mary's Square Institute for Vascular Surgery and Phlebology, Munich (R.B.). 5. German Heart Center, Institute for Laboratory Medicine, Technical University Munich (F.R.). 6. Anesthesiology and Transfusion Medicine, Cell Therapeutics and Hemostaseology (M.S.), Ludwig-Maximilians-University Munich, Germany. 7. Helmholtz Zentrum München, Institute of Lung Biology and Disease, Group Systems Medicine of Chronic Lung Disease, Munich, Germany, Member of the German Center for Lung Research (DZL) (C.H.M., H.B.S.). 8. Institute of Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Medical Center Düsseldorf (T. Hoffmann). 9. Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen (B.L.). 10. Cardiovascular Research Institute Düsseldorf (CARID), Institute of Pharmacology and Clinical Pharmacology, Medical Faculty of the Heinrich Heine University Düsseldorf (T. Hohlfeld).
Abstract
RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.
RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillationpatients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.
Authors: Annette von Drygalski; Vikas Bhat; Andrew J Gale; Patricia M Averell; Thomas J Cramer; Darlene J Elias; John H Griffin; Laurent O Mosnier Journal: Blood Adv Date: 2020-08-11
Authors: Ihsan Gadi; Sameen Fatima; Berend Isermann; Khurrum Shahzad; Ahmed Elwakiel; Sumra Nazir; Moh'd Mohanad Al-Dabet; Rajiv Rana; Fabian Bock; Jayakumar Manoharan; Dheerendra Gupta; Ronald Biemann; Bernhard Nieswandt; Ruediger Braun-Dullaeus; Christian Besler; Markus Scholz; Robert Geffers; John H Griffin; Charles T Esmon; Shrey Kohli Journal: Circ Res Date: 2020-12-23 Impact factor: 17.367