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CLINICAL RESEARCH: PLATELETS AND THROMBOSIS

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

Armin J. Reininger, MD, PhD^_*, Isabell Bernlochner, MD, Sandra M. Penz, PhD, Catherine Ravanat, PhD, Peter Smethurst, PhD, Richard W. Farndale, PhD, Christian Gachet, MD, PhD, Richard Brandl, MD^|| and Wolfgang Siess, MD^,_*

^_* Department of Transfusion Medicine and Hemostaseology, Clinic of Anaesthesiology, University Clinic Munich, Munich, Germany
Institute for Prevention of Cardiovascular Diseases, University Clinic Munich, Munich, Germany
INSERM UMR-S949, EFS-Alsace, Université de Strasbourg, Strasbourg, France
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
^|| Department of Vascular Surgery, Clinic Schwabing, Munich, Germany

Manuscript received August 5, 2009; revised manuscript received November 9, 2009, accepted November 18, 2009.

^_* Reprint requests and correspondence: Dr. Wolfgang Siess, Institute for Prevention of Cardiovascular Diseases, University of Munich, Pettenkoferstrasse 9, 80336 Munich, Germany (Email: wsiess{at}med.uni-muenchen.de).

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.

Key Words: aggregation • atherothrombosis • collagen • fibrin • glycoprotein VI • plaque • platelet • tissue factor • thrombin

Abbreviations and Acronyms   CTI = corn trypsin inhibitor   FXII = coagulation factor XII   GPVI = glycoprotein VI   PFP = platelet-free plasma   PPP = platelet-poor plasma   PRP = platelet-rich plasma   TF = tissue factor

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