The platelet P2 receptors in thrombosis.
Adenosine diphosphate (ADP) and adenosine triphosphate (ATP) play a crucial role in hemostasis and thrombosis, and their receptors are potential targets for antithrombotic drugs. The ATP-gated channel P2X (1) and the two G protein-coupled P2Y (1) and P2Y (12) ADP receptors selectively contribute to platelet aggregation. Because of its central role in the formation and stabilization of a thrombus, the P2Y (12) receptor is a well-established target of antithrombotic drugs such as clopidogrel, which has proven efficacy in many clinical trials and experimental models of thrombosis. Competitive P2Y (12) antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials. Studies in P2Y (1) and P2X (1) knockout mice and experimental thrombosis models using selective P2Y (1) and P2X (1) antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs. Because both P2X (1) and P2Y (1) receptor inhibition result in milder prolongation of the bleeding time as compared with P2Y (12) inhibition, the idea is put forward that combinations of P2 receptor antagonists could improve efficacy with diminished hemorrhagic risk. However, further studies with stronger and more selective P2 receptor antagonists are required to validate such a point of view.
Gachet
Christian
C
INSERM U.311, Etablissement Français du Sang-Alsace, 10 Rue Spielmann, BP 36-67065 Strasbourg Cedex, France. christian.gachet@efs-alsace.fr
Hechler
Béatrice
B
D000244:Adenosine Diphosphate / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D001808:Blood Vessels / Q000293:injuries; D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006474:Hemorrhagic Disorders / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; C546383:P2ry1 protein, mouse; C548577:P2ry12 protein, mouse; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; C446540:thienopyridine; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine