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* Institute for Prevention of Cardiovascular Diseases,
Department of Transfusion Medicine and Hemostaseology, University of Munich, Munich;
Department of Vascular Surgery, Klinikum Munich-Schwabing, Munich;
Rudolf-Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg;
|| Vascular Biology and Hemostasis, Institute of Clinical Chemistry, University of Munich, Munich, Germany; and
Department of Biochemistry and
Department of Hematology, University of Cambridge, Cambridge, UK
1Correspondence: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum Innenstadt, Universität München, Pettenkoferstr. 9, D 80336 München, Germany. E-mail: wsiess{at}med.uni-muenchen.de
Lipid-rich atherosclerotic plaques are vulnerable, and their rupture can cause the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke. Although the role of plaque-based tissue factor as stimulator of blood coagulation has been recognized, it is not known whether plaques can cause thrombus formation through direct activation of platelets. We isolated lipid-rich atheromatous plaques from 60 patients with carotid stenosis and identified morphologically diverse collagen type I- and type III-positive structures in the plaques that directly stimulated adhesion, dense granule secretion, and aggregation of platelets in buffer, plasma, and blood. This material also elicited platelet-monocyte aggregation and platelet-dependent blood coagulation. Plaques exposed to flowing blood at arterial wall shear rate induced platelets to adhere to and spread on the collagenous structures, triggering subsequent thrombus formation. Plaque-induced platelet thrombus formation was observed in fully anticoagulated blood (i.e., in the absence of tissue factor-mediated coagulation). Mice platelets lacking glycoprotein VI (GPVI) were unable to adhere to atheromatous plaque or form thrombi. Human platelet thrombus formation onto plaques in flowing blood was completely blocked by GPVI inhibition with the antibody 10B12 but not affected by integrin 
2ß1 inhibition with 6F1 mAb. Moreover, the initial platelet response, shape change, induced by plaque was blocked by GPVI inhibition but not with 2ß1 antagonists (6F1 mAb or GFOGER-GPP peptide). Pretreatment of plaques with collagenase or anti-collagen type I and anti-collagen type III antibodies abolished plaque-induced platelet activation. Our results indicate that morphologically diverse collagen type I- and collagen type III-containing structures in lipid-rich atherosclerotic plaques stimulate thrombus formation by activating platelet GPVI. This platelet collagen receptor, essential for plaque-induced thrombus formation, presents a promising new anti-thrombotic target for the prevention of ischemic cardiovascular diseases.—Penz, S., Reininger, A. J., Brandl, R., Goyal, P., Rabie, T., Bernlochner, I., Rother, E., Goetz, C., Engelmann, B., Smethurst, P. A., Ouwehand, W. H., Farndale, R., Nieswandt, B., Siess, W. Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI.
Key Words: atherosclerotic plaques • ischemic stroke • thrombogenicity • arterial thrombus
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