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 Blood, 15 November 2004, Vol. 104, No. 10, pp. 3221-3227.
Prepublished online as a Blood First Edition Paper on July 29, 2004; DOI 10.1182/blood-2004-03-1145.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Distinct roles of ADP receptors in von Willebrand factor–mediated platelet signaling and activation under high flow

Mario Mazzucato, Maria Rita Cozzi, Paola Pradella, Zaverio M. Ruggeri, and Luigi De Marco

From the Blood Bank, Centro di Riferimento Oncologico-Istituto di Ricerca e Cura a Carattere Scientifico, National Cancer Institute, Aviano, Italy; and the Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Thrombosis and Hemostasis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.

We have investigated the role of adenosine diphosphate (ADP) receptors in the adhesion, activation, and aggregation of platelets perfused over immobilized von Willebrand factor (VWF) under high shear stress. Blocking P2Y1 prevented stable platelet adhesion and aggregation, indicative of a complete inhibition of {alpha}IIb{beta}3 activation, and decreased the duration of transient arrests from 5.9 seconds ± 2.8 seconds to 1.2 seconds ± 0.8 seconds; in contrast, blocking P2Y12 inhibited only the formation of larger aggregates. Moreover, blocking P2Y1 decreased the proportion of platelets showing early intracytoplasmic Ca++ elevations ({alpha}/{beta} peaks) from 20.6% ± 1.6% to 14.6% ± 1.5% (P < .01), and the corresponding peak ion concentration from 1543 nM ± 312 nM to 1037 nM ± 322 nM (P < .05); it also abolished the Ca++ elevations seen in firmly attached platelets ({gamma} peaks). Blocking P2Y12 had no effect on these parameters, and did not enhance the effect of inhibiting P2Y1. Inhibition of phospholipase C had similar consequences as the blocking of P2Y1, whereas inhibition of Src family kinases abolished both type {alpha}/{beta} and {gamma} Ca++ oscillations, although the former effect required a higher inhibitor concentration. Our results demonstrate that, under elevated shear stress conditions, ADP signaling through P2Y1 may contribute to the initial stages of platelet adhesion and activation mediated by immobilized VWF, and through P2Y12 to sustained thrombus formation.


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