Department of Transfusion Medicine and Hemostaseology, Clinic of Anaesthesiology, University Clinic Munich, Munich, Germany.
J Am Coll Cardiol. 2010 Mar 16;55(11):1147-58. doi: 10.1016/j.jacc.2009.11.051.
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.
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.
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.
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.
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.
本研究旨在了解易损性人动脉粥样硬化斑块诱导动脉血栓形成的初始机制，以重新评估和改进当前的抗血栓策略。
动脉粥样硬化斑块破裂会导致动脉血栓形成，可能导致心肌梗死和缺血性中风。动脉血栓形成被认为是血小板激活和凝血过程不可分割的纠结，涉及斑块成分，如组织因子 (TF) 和胶原蛋白以及血液中的 TF 和凝血因子 XIIa (FXIIa)。抗凝剂和抗血小板药物的联合应用是目前的治疗方法。
在生理钙/镁浓度下，将人动脉粥样硬化斑块材料暴露于血液或血液成分中。通过最先进的显微镜和生理技术，在静态和动脉流动条件下测量血小板聚集和凝血。特异性抑制斑块 TF、斑块胶原蛋白、FXIIa 和血小板糖蛋白 VI (GPVI)。
斑块通过 2 个离散步骤诱导血栓形成。快速的第一阶段是 GPVI 介导的血小板在斑块胶原蛋白上的黏附和聚集，发生在 1 分钟内。第二阶段的凝血在 >3 分钟的延迟后开始，形成凝血酶和纤维蛋白，完全由斑块 TF 驱动。凝血仅发生在血小板聚集提供的流动龛中，没有证据表明血液中的 TF 和 FXIIa 起作用。抑制 GPVI 而不是斑块 TF 抑制了斑块诱导的血栓形成。
主要的血栓形成斑块成分——胶原蛋白和 TF——分别在 2 个连续步骤中诱导血小板激活和凝血。靶向特异性的第一步是至关重要的，可能足以抑制动脉血栓形成。
