A 2-Step Mechanism of Arterial Thrombus Formation Induced by Human Atherosclerotic Plaques

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:55

Article

Reininger, Armin J.²  Ravanat, Catherine³  Smethurst, Peter⁴  Farndale, Richard W.⁴  Gachet, Christian³  Brandl, Richard⁵  Siess, Wolfgang¹ 

[1] Univ Munich, Inst Prevent Cardiovasc Dis, Univ Clin Munich, D-80336 Munich, Germany

[2] Univ Clin Munich, Clin Anaesthesiol, Dept Transfus Med & Hemostaseol, Munich, Germany

[3] Univ Strasbourg, EFS Alsace, INSERM, UMR S949, Strasbourg, France

[4] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[5] Clin Schwabing, Dept Vasc Surg, Munich, Germany

关键词: aggregation;    atherothrombosis;    collagen;    fibrin;    glycoprotein VI;    plaque;    platelet;    tissue factor;    thrombin;   

DOI  :  10.1016/j.jacc.2009.11.051

来源: Elsevier

【 摘 要 】

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

【 授权许可】

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