P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries.
The critical role for ADP in arterial thrombogenesis was established by the clinical success of P2Y12 antagonists, currently used at doses that block 40-50% of the P2Y12 on platelets. This study was designed to determine the role of P2Y12 in platelet thrombosis and how its complete absence affects the thrombotic process. P2Y12-null mice were generated by a gene-targeting strategy. Using an in vivo mesenteric artery injury model and real-time continuous analysis of the thrombotic process, we observed that the time for appearance of first thrombus was delayed and that only small, unstable thrombi formed in P2Y12-/- mice without reaching occlusive size, in the absence of aspirin. Platelet adhesion to vWF was impaired in P2Y12-/- platelets. While adhesion to fibrinogen and collagen appeared normal, the platelets in thrombi from P2Y12-/- mice on collagen were less dense and less activated than their WT counterparts. P2Y12-/- platelet activation was also reduced in response to ADP or a PAR-4-activating peptide. Thus, P2Y12 is involved in several key steps of thrombosis: platelet adhesion/activation, thrombus growth, and stability. The data suggest that more aggressive strategies of P2Y12 antagonism will be antithrombotic without the requirement of aspirin cotherapy and may provide benefits even to the aspirin-nonresponder population.
Andre
Patrick
P
Cardiovascular Biology, Millennium Pharmaceuticals Inc, South San Francisco, California 94080, USA.
Delaney
Suzanne M
SM
LaRocca
Thomas
T
Vincent
Diana
D
DeGuzman
Francis
F
Jurek
Marzena
M
Koller
Beverley
B
Phillips
David R
DR
Conley
Pamela B
PB
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins; D008638:Mesenteric Arteries / Q000293:injuries* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000209:etiology*
D005343:Fibrinolytic Agents; D008565:Membrane Proteins; C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D001241:Aspirin