Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice

Platelet activation is characterized by shape change, induction of fibrinogen receptor expression and release of granular contents, leading to aggregation and plug formation(1). While this response is essential for hemostasis(2), it is also important in the pathogenesis of a broad spectrum of diseases, including myocardial infarction, stroke and unstable angina. Adenosine 5'-diphosphate (ADP) induces platelet aggregation, but the mechanism for this has not been established, and the relative contribution of ADP in hemostasis and the development of arterial thrombosis' is poorly understood. We show here that the purinoceptor P2Y(1) is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation. Activation of P2Y(1) resulted in increased intracellular calcium but no alteration in cyclic adenosine monophosphate (cAMP) levels. P2Y(1)-deficient platelets partially aggregated at higher ADP concentrations, and the lack of P2Y(1) did not alter the ability of ADP to inhibit cAMP, indicating that platelets express at least one additional ADP receptor. In vivo, the lack of P2Y(1) expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism. These findings support the hypothesis that the ATP receptor P2Y(1) is a principal receptor mediating both physiologic: and pathological ADP-induced processes in platelets.