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A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques.

Abstract：

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.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Reininger AJ,Bernlochner I,Penz SM,Ravanat C,Smethurst P,Farndale RW,Gachet C,Brandl R,Siess W

doi

10.1016/j.jacc.2009.11.051

subject

Has Abstract

pub_date

2010-03-16 00:00:00

pages

1147-58

issue

11

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(10)00090-2

journal_volume

55

pub_type

杂志文章

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