Key result
Combined partial attenuation of thrombin and ADP signaling in mice provided substantial protection against arterial thrombosis with relatively little increase in bleeding compared to single pathway inhibition.
P2ry12 signaling is more important than PAR signaling in hemostasis models, whereas PAR signaling is more important in arterial thrombosis models, providing mechanistic insights for new antithrombotic strategies.
Toward understanding their redundancies and interactions in hemostasis and thrombosis, we examined the roles of thrombin receptors (protease-activated receptors, PARs) and the ADP receptor P2RY12 (purinergic receptor P2Y G protein-coupled 12) in human and mouse platelets ex vivo and in mouse models. Par3(-/-) and Par4(+/-) mouse platelets showed partially decreased responses to thrombin, resembling those in PAR1 antagonist-treated human platelets. P2ry12(+/-) mouse platelets showed partially decreased responses to ADP, resembling those in clopidogrel-treated human platelets. Par3(-/-) mice showed nearly complete protection against carotid artery thrombosis caused by low FeCl(3) injury. Par4(+/-) and P2ry12(+/-) mice showed partial protection. Increasing FeCl(3) injury abolished such protection; combining partial attenuation of thrombin and ADP signaling, as in Par3(-/-):P2ry12(+/-) mice, restored it. Par4(-/-) mice, which lack platelet thrombin responses, showed still better protection. Our data suggest that (i) the level of thrombin driving platelet activation and carotid thrombosis was low at low levels of arterial injury and increased along with the contribution of thrombin-independent pathways of platelet activation with increasing levels of injury; (ii) although P2ry12 acts downstream of PARs to amplify platelet responses to thrombin ex vivo, P2ry12 functioned in thrombin/PAR-independent pathways in our in vivo models; and (iii) P2ry12 signaling was more important than PAR signaling in hemostasis models; the converse was noted for arterial thrombosis models. These results make predictions being tested by ongoing human trials and suggest hypotheses for new antithrombotic strategies.
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Cornelissen et al. (2010) studied Hemostasis and thrombosis. PAR and P2ry12 genetic ablation or pharmacological inhibition vs. Wild-type mice or untreated platelets was evaluated on Carotid artery thrombosis occlusion and hemostasis (tail bleeding time and blood loss). Combined partial attenuation of thrombin and ADP signaling in mice provided substantial protection against arterial thrombosis with relatively little increase in bleeding compared to single pathway inhibition.
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