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Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.
Circulation Research ( IF 20.1 ) Pub Date : 2019-12-20 , DOI: 10.1161/circresaha.119.315099
Tobias Petzold 1, 2 , Manuela Thienel 1, 2 , Lisa Dannenberg 3 , Philipp Mourikis 3 , Carolin Helten 3 , Aysel Ayhan 3 , René M'Pembele 3 , Alina Achilles 3 , Kajetan Trojovky 3 , Daniel Konsek 3 , Zhe Zhang 1 , Ron Regenauer 1 , Joachim Pircher 1, 2 , Andreas Ehrlich 1, 2 , Enzo Lüsebrink 1, 2 , Leo Nicolai 1, 2 , Thomas J Stocker 1, 2 , Richard Brandl 4 , Franz Röschenthaler 5 , Jan Strecker 1 , Inas Saleh 1 , Michael Spannagl 6 , Christoph H Mayr 7 , Herbert B Schiller 7 , Christian Jung 3 , Norbert Gerdes 3 , Till Hoffmann 8 , Bodo Levkau 9 , Thomas Hohlfeld 10 , Tobias Zeus 3 , Christian Schulz 1, 2 , Malte Kelm 3 , Amin Polzin 3
Affiliation  

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.

中文翻译:

利伐沙班通过抑制FXa驱动的血小板活化(通过蛋白酶激活的受体1)来减少动脉血栓形成。

理由:与维生素K拮抗剂相比,用FXa(Xa因子)抑制剂包括利伐沙班治疗的房颤患者心肌梗死发生率有所降低。同时,低剂量利伐沙班已被证明可降低冠心病患者的死亡率和动脉粥样硬化血栓形成事件。然而,这种减少的基础机制仍是未知的。目的在这项研究中,我们假设利伐沙班的抗血栓形成潜力与迄今未知的利伐沙班效应有关,后者影响血小板反应性和动脉血栓形成。方法和结果在这项研究中,我们确定FXa是PAR-1(蛋白酶激活受体1)的有效直接激动剂,可导致血小板活化和血栓形成,而利伐沙班可以抑制它。我们发现利伐沙班降低了使用活体显微镜在动脉血栓形成的小鼠模型中的动脉血栓稳定性。在体外研究中,招募了接受永久性利伐沙班治疗以预防中风的房颤患者,相应的对照组以及首次服用利伐沙班之前和之后新发房颤的患者(时间序列分析)。利伐沙班可减弱血小板聚集反应以及在动脉血流条件下胶原和动脉粥样硬化斑块材料上的血栓形成。我们显示,利伐沙班的抗血小板作用是血浆依赖性的,但与凝血酶和利伐沙班的抗凝能力无关。结论在这里,我们确定FXa是通过PAR-1起作用的有效的血小板激动剂。所以,
更新日期:2020-02-14
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