Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

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.

• Authors: Tobias Petzold, Manuela Thienel, Lisa Dannenberg, Philipp Mourikis, Carolin Helten, Aysel Ayhan, René M'Pembele, Alina Achilles, Kajetan Trojovky, Daniel Konsek, Zhe Zhang, Ron Regenauer, Joachim Pircher, Andreas Ehrlich, Enzo Lüsebrink, Leo Nicolai, Thomas J Stocker, Richard Brandl, Franz Röschenthaler, Jan Strecker, Inas Saleh, Michael Spannagl, Christoph H Mayr, Herbert B Schiller, Christian Jung, Norbert Gerdes, Till Hoffmann, Bodo Levkau, Thomas Hohlfeld, Tobias Zeus, Christian Schulz, Malte Kelm, Amin Polzin
• Journal: Circulation research (Circ Res) Vol. 126 Issue 4 Pg. 486-500 (02 14 2020) ISSN: 1524-4571 [Electronic] United States
• PMID: 31859592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Factor Xa Inhibitors
• Fibrinolytic Agents
• Platelet Aggregation Inhibitors
• Receptor, PAR-1
• Rivaroxaban
• Factor Xa

Topics

• Animals
• Arteries (metabolism, pathology)
• Blood Platelets (drug effects, metabolism)
• Factor Xa (pharmacology)
• Factor Xa Inhibitors (pharmacology)
• Fibrinolytic Agents (administration & dosage, pharmacology)
• Humans
• Mice, Inbred C57BL
• Platelet Activation (drug effects)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Receptor, PAR-1 (agonists, metabolism)
• Rivaroxaban (administration & dosage, pharmacology)
• Thrombosis (metabolism, prevention & control)