Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity.
OBJECTIVE
In vivo, activated platelets contribute to the initiation of thrombin generation through the exposure of phosphatidylserine to form a procoagulant catalytic surface and through platelet-leukocyte interactions, which lead to the exposure of leukocyte tissue factor (TF). On the basis of observations that the platelet P2Y1 and P2Y12 receptors both contribute to thrombosis and thrombin formation in an in vivo model of TF-induced thromboembolism, we further characterized the role of these receptors in thrombin generation.


RESULTS
By using the selective P2 antagonists MRS2179 and AR-C69931MX, the P2Y12 receptor was found to be involved in thrombin-induced exposure of PS on isolated platelets and consequently in TF-induced thrombin formation in platelet-rich plasma. By contrast, the P2Y1 receptor was not involved in phosphatidylserine exposure nor in thrombin generation in platelet-rich plasma. In addition, both receptors were found to contribute to the interactions between platelets and leukocytes mediated by platelet P-selectin exposure, which result in TF exposure at the surface of leukocytes.


CONCLUSIONS
Overall, these results point to a differential involvement of the 2 platelet ADP receptors in the generation of thrombin and provide further evidence for the relevance of molecules targeting these receptors as antithrombotic agents.
Leon
Catherine
C
Institut National de la Santé et de la Recherche Médicale U.311, Etablissement Français du Sang-Alsace, 10 rue Spielmann, 67065 Strasbourg Cédex, France.
Ravanat
Catherine
C
Freund
Monique
M
Cazenave
Jean-Pierre
JP
Gachet
Christian
C
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007962:Leukocytes; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D010446:Peptide Fragments; D010718:Phosphatidylserines; D010949:Plasma; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013917:Thrombin / Q000096:biosynthesis*; D013927:Thrombosis / Q000378:metabolism*
D008565:Membrane Proteins; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D019007:P-Selectin; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; C546383:P2ry1 protein, mouse; C548577:P2ry12 protein, mouse; D010446:Peptide Fragments; D010718:Phosphatidylserines; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; C086309:thrombin receptor peptide SFLLRNP; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D013917:Thrombin