A 2-Step Mechanism of Arterial Thrombus Formation Induced by Human Atherosclerotic Plaques
A 2-Step Mechanism of Arterial Thrombus Formation Induced by Human Atherosclerotic Plaques
复制标题
DOI：
10.1016/j.jacc.2009.11.051
复制
发表时间：
2010-03-16
影响因子：
24
通讯作者：
Siess, Wolfgang
中科院分区：
文献类型：
--
作者：
Reininger, Armin J.;Bernlochner, Isabell;Siess, Wolfgang
目的探讨动脉粥样硬化斑块（AS）易损斑块诱导动脉血栓形成的机制，以重新评估和改进目前的抗血栓治疗策略。动脉粥样硬化血栓形成被认为是血小板活化和凝血过程不可分割的缠结，涉及斑块组分，如组织因子（TF）和胶原蛋白以及血液传播的TF和凝血因子XIIa（FXIIa）。抗凝血剂和抗血小板剂的组合是目前的treatment.Methods人类动脉粥样硬化斑块材料暴露于血液或血液成分在生理钙/镁浓度。在静态和动脉血流条件下，通过最先进的显微镜和生理学技术测量血小板聚集和凝血。血小板膜TF、血小板膜胶原、FXIIa和血小板糖蛋白VI（GPVI）均被特异性抑制。GPVI介导的血小板粘附和聚集到斑块胶原蛋白上的快速第一阶段在1分钟内发生。凝血的第二阶段在延迟>3分钟后开始，伴随凝血酶和纤维蛋白的形成，并且完全由斑块TF驱动。凝血仅发生在血小板聚集体提供的流动龛中，没有证据表明血液传播的TF和FXIIa的作用。抑制GPVI，但不是斑块TF抑制斑块诱导的血栓形成。结论血栓形成斑块的主要成分胶原和TF诱导血小板活化和凝血，分别在2个连续的步骤。特异性靶向第一步是至关重要的，可能足以抑制动脉粥样硬化血栓形成。（J Am科尔心脏病学杂志2010;55：1147-58）（C）美国心脏病学会基金会2010年
Objectives The aim of this study was to understand the initial mechanism of arterial thrombus formation induced by vulnerable human atherosclerotic plaques to re-assess and improve current antithrombotic strategies.Background Rupture of atherosclerotic plaques causes arterial thrombus formation that might lead to myocardial infarction and ischemic stroke. Atherothrombosis is considered as an inseparable tangle of platelet activation and coagulation processes, involving plaque components such as tissue factor (TF) and collagen as well as blood-borne TF and coagulation factor XIIa (FXIIa). A combination of anticoagulants and antiplatelet agents is the present treatment.Methods Human atheromatous plaque material was exposed to blood or blood components at physiological calcium/magnesium concentration. Platelet aggregation and coagulation were measured under static and arterial flow conditions by state-of-the-art microscopic and physiological techniques. Plaque TF, plaque collagen, FXIIa, and platelet glycoprotein VI (GPVI) were specifically inhibited.Results Plaques induced thrombus formation by 2 discrete steps. The rapid first phase of GPVI-mediated platelet adhesion and aggregation onto plaque collagen occurred within 1 min. The second phase of coagulation started after a delay of >3 min with the formation of thrombin and fibrin, and was driven entirely by plaque TF. Coagulation occurred only in flow niches provided by platelet aggregates, with no evidence for a role of blood-borne TF and FXIIa. Inhibition of GPVI but not plaque TF inhibited plaque-induced thrombus formation.Conclusions The major thrombogenic plaque components-collagen and TF-induce platelet activation and coagulation, respectively, in 2 consecutive steps. Targeting specifically the first step is crucial and might be sufficient to inhibit atherothrombus formation. (J Am Coll Cardiol 2010;55:1147-58) (C) 2010 by the American College of Cardiology Foundation