on July 1, 2004
Published online before print July 1, 2004, doi: 10.1161/01.ATV.0000137974.85068.93
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Submitted on May 6, 2004
Accepted on May 28, 2004
Principal Role of Glycoprotein VI in 
2
1 and IIb3 Activation During Collagen-Induced Thrombus Formation
Christelle Lecut ;
From the Departments of Biochemistry (C.L., M.J.E.K., J.W.M.H.), Molecular Cell Biology and Genetics (J.L.V.B.), and Biophysics (M.A.M.J.V.), CARIM, Maastricht University, The Netherlands; the Laboratory for Thrombosis Research (A.S., K.V., H.D.), KU Leuven, Campus Kortrijk, Belgium; and E348 Institut National de la Santé et de la Recherche Médicale (C.L., M.J.-P.), Faculté Xavier Bichat, Université Paris, France.
* To whom correspondence should be addressed. E-mail: jwm.heemskerk{at}bioch.unimaas.nl.
Objective--High-shear perfusion of blood over collagen results in rapid platelet adhesion, aggregation, and procoagulant activity. We studied regulation of 
2
1 and IIb3 integrin activation during thrombus formation on collagen.
Methods and Results--Blockade of glycoprotein (GP) VI by 9O12 antibody or of P2Y purinergic receptors permitted platelet adhesion but reduced aggregate formation, fibrinogen binding, and activation of 21 and IIb3, as detected with antibodies IAC-1 and PAC1 directed against activation-dependent epitopes of these integrins. Combined blockade of GPVI and P2Y receptors and thromboxane formation abolished integrin activation but still allowed adhesion of morphologically unstimulated, nonprocoagulant platelets. Exogenous ADP partly restored the suppressive effect of GPVI blockade on integrin 21 and IIb3 activation. Adhesion was fully inhibited only with simultaneous blocking of GPVI and 21, indicating that the integrin can support platelet-collagen binding in the absence of its activation. Blockade or absence of GPIb only moderately influenced integrin activation and adhesion unless GPVI was inhibited.
Conclusions--GPVI- and autocrine-released ADP induce affinity changes of 21 and IIb3 during thrombus formation on collagen under flow. Integrin changes are dispensable for adhesion but strengthen platelet-collagen interactions and thereby collagen-induced platelet activation.
Key words: ADP • collagen • glycoprotein VI • integrins • platelets • thrombus
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