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Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques

Nergiz-Unal, R., Cosemans, J.M.E.M., Feijge, M.A.H., van der Meijden, P.E.J., Storey, R.F., van Giezen, J.J.J., Egbrink, M.G.A.O., Heemskerk, J.W.M. and Kuijpers, M.J.E. (2010) Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques. Plos One, 5 (4). Art no.e10130 . ISSN 1932-6203

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Abstract

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y(12) in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis.

Methodology: Plaques in the carotid arteries from Apoe(-/-) mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y(12) blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated.

Principal Findings: Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y(12) blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y(12) reduced the thrombi and increased embolization events. These P2Y(12) effects were present at shear rates >500 s(-1), and they persisted in the presence of coagulation. P2Y(12)-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding.

Conclusions/Significance: Platelet P2Y(12) receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y(12) function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Nergiz-Unal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Acute Coronary Syndromes; Glycoprotein-VI; Procoagulant Activity; Whole-Blood; Atherosclerotic Plaques; Complementary Roles; Flowing Blood; Activation; Collagen; Adhesion
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 07 May 2010 10:32
Last Modified: 08 Feb 2013 17:00
Published Version: http://dx.doi.org/10.1371/journal.pone.0010130
Status: Published
Publisher: Public Library Science
Identification Number: 10.1371/journal.pone.0010130
URI: http://eprints.whiterose.ac.uk/id/eprint/10812

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