长期抑制因子Xa通过改变血小板蛋白质组减轻急性心肌梗死和中风后的血栓炎症。
Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.
作者信息
Polzin Amin, Benkhoff Marcel, Thienel Manuela, Barcik Maike, Mourikis Philipp, Shchurovska Khrystyna, Helten Carolin, Ehreiser Vincent, Zhe Zhang, von Wulffen Franziska, Theiss Alexander, Peri Sameera, Cremer Sophie, Ahlbrecht Samantha, Zako Saif, Wildeis Laura, Al-Kassis Gabrielle, Metzen Daniel, Utz Amelie, Hu Hao, Vornholz Lilian, Pavic Goran, Lüsebrink Enzo, Strecker Jan, Tiedt Steffen, Cramer Mareike, Gliem Michael, Ruck Tobias, Meuth Sven G, Zeus Tobias, Mayr Christoph, Schiller Herbert B, Simon Lukas, Massberg Steffen, Kelm Malte, Petzold Tobias
机构信息
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital, Düsseldorf, Germany; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Analytical Chemistry, University of Vienna, Vienna, Austria.
出版信息
J Thromb Haemost. 2025 Feb;23(2):668-683. doi: 10.1016/j.jtha.2024.10.025. Epub 2024 Nov 16.
BACKGROUND
Immediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.
OBJECTIVES
Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke.
METHODS
We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI.
RESULTS
Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap formation in mice and patient samples. Proteome and RNA expression analysis of FXa inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.
CONCLUSION
Long-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.
背景
即时活化因子X（FXa）抑制在动脉血栓形成的情况下具有直接抗血小板作用，但关于长期治疗对缺血性心血管疾病中血小板功能的影响知之甚少。
目的
因此，我们分析了长期FXa抑制在急性心肌梗死（AMI）和中风背景下对血小板衍生效应的影响。
方法
我们在体内评估了急性与慢性FXa抑制对小鼠AMI和中风后血栓炎症的影响。从机制上，我们确定了在慢性FXa非维生素K拮抗剂口服抗凝治疗下血小板基因表达和蛋白质组的变化，并表征了其对血小板生理学的功能后果。在一个前瞻性招募的AMI患者队列中，我们确定了基于心血管磁共振的心脏终点，以及FXa非维生素K拮抗剂口服抗凝对AMI患者队列临床终点的影响。
结果
慢性而非急性FXa抑制可减小小鼠脑梗死和心肌梗死面积，并在AMI后24小时改善心脏功能。从机制上，我们在小鼠和患者样本中发现血栓炎症反应减弱，中性粒细胞胞外诱捕网形成减少。FXa抑制剂治疗患者的蛋白质组和RNA表达分析显示，膜运输和分泌机制中的关键调节因子减少，阻碍了血小板α颗粒和致密颗粒的释放。随后，从中风和心肌梗死患者分离的血栓中，血栓炎症中性粒细胞胞外诱捕网密度降低。与未接受抗凝治疗的患者相比，接受FXa抑制剂治疗的AMI患者心肌梗死后梗死面积减小。
结论
长期FXa抑制可诱导血小板中的抗血栓炎症蛋白质组特征，改善心肌梗死和中风后的梗死面积。
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