Purinergic Signalling

, 7:325 | Cite as

The P2Y12 receptor as a target of antithrombotic drugs

  • Stephen O’Connor
  • Gilles Montalescot
  • Jean-Philippe Collet
Original Article


ACS Platelets P2Y12 inhibitors ADP Clopidogrel Prasugrel Thrombosis Platelets 


  1. 1.
    CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348(9038):1329–1339CrossRefGoogle Scholar
  2. 2.
    Bhatt DL, Bertrand ME, Berger PB, L'Allier PL, Moussa I, Moses JW et al (2002) Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 39(1):9–14PubMedCrossRefGoogle Scholar
  3. 3.
    Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R et al (2005) Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366(9497):1607–1621PubMedCrossRefGoogle Scholar
  4. 4.
    Collet JP, Cayla G, Cuisset T, Elhadad S, Rangé G, Vicaut E et al (2011) Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J 161(1):5–12.e5PubMedCrossRefGoogle Scholar
  5. 5.
    Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D et al (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305(11):1097–1105PubMedCrossRefGoogle Scholar
  6. 6.
    Born GV (1985) Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation 72(4):741–746PubMedCrossRefGoogle Scholar
  7. 7.
    Gachet C (2006) Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 46:277–300PubMedCrossRefGoogle Scholar
  8. 8.
    Abbrachio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA (2006) International Union of Pharmacology LVIII: update on the P2Y G Protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341CrossRefGoogle Scholar
  9. 9.
    Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C et al (2005) The recently deorphanized GPR80 (GPR99) proposed to be the P2Y15 receptor is not a genuine P2Y receptor. Trends Pharmacol Sci 26(1):8–9PubMedCrossRefGoogle Scholar
  10. 10.
    Jin J, Kunapuli SP (1998) Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA 95(14):8070–8704PubMedCrossRefGoogle Scholar
  11. 11.
    Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409(6817):202–207PubMedCrossRefGoogle Scholar
  12. 12.
    Savi P, Zachayus JL, Delesque-Touchard N, Labouret C, Herve C, Uzabiaga MF et al (2006) The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci USA 103(29):11069–11074PubMedCrossRefGoogle Scholar
  13. 13.
    Haslam RJ (1973) Interactions of the pharmacological receptors of blood platelets with adenylate cyclase. Ser Haematol 6(3):333–350PubMedGoogle Scholar
  14. 14.
    Savi P, Pflieger AM, Herbert JM (1996) cAMP is not an important messenger for ADP-induced platelet aggregation. Blood Coagul Fibrinol 7(2):249–252CrossRefGoogle Scholar
  15. 15.
    Schwarz UR, Geiger J, Walter U, Eigenthaler M (1999) Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets—definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 82(3):1145–1152PubMedGoogle Scholar
  16. 16.
    Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C (2005) Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 3(1):85–92PubMedCrossRefGoogle Scholar
  17. 17.
    Trumel C, Payrastre B, Plantavid M, Hechler B, Viala C, Presek P et al (1999) A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood 94(12):4156–4165PubMedGoogle Scholar
  18. 18.
    Kauffenstein G, Bergmeier W, Eckly A, Ohlmann P, Leon C, Cazenave JP et al (2001) The P2Y(12) receptor induces platelet aggregation through weak activation of the alpha(IIb)beta(3) integrin—a phosphoinositide 3-kinase-dependent mechanism. FEBS Lett 505(2):281–290PubMedCrossRefGoogle Scholar
  19. 19.
    Lova P, Paganini S, Hirsch E, Barberis L, Wymann M, Sinigaglia F et al (2003) A selective role for phosphatidylinositol 3,4,5-trisphosphate in the Gi-dependent activation of platelet Rap1B. J Biol Chem 278(1):131–138PubMedCrossRefGoogle Scholar
  20. 20.
    Lova P, Paganini S, Sinigaglia F, Balduini C, Torti M (2002) A Gi-dependent pathway is required for activation of the small GTPase Rap1B in human platelets. J Biol Chem 277(14):12009–12015PubMedCrossRefGoogle Scholar
  21. 21.
    Gurbel PA, Bliden KP, Hayes KM, Tantry U (2004) Platelet activation in myocardial ischemic syndromes. Expert Rev Cardiovasc Ther 2(4):535–545PubMedCrossRefGoogle Scholar
  22. 22.
    Cattaneo M (2011) The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 117(7):2102–2112PubMedCrossRefGoogle Scholar
  23. 23.
    Picard-Fraire C (1983) Ticlopidine hydrochloride: relationship between dose, kinetics, plasma concentration and effect on platelet function. Thromb Res Suppl 4:119–128PubMedCrossRefGoogle Scholar
  24. 24.
    Picard-Fraire C (1984) Pharmacokinetic and metabolic characteristics of ticlopidine in relation to its inhibitory properties on platelet function. Agents Actions Suppl 15:68–75PubMedGoogle Scholar
  25. 25.
    Yoneda K, Iwamura R, Kishi H, Mizukami Y, Mogami K, Kobayashi S (2004) Identification of the active metabolite of ticlopidine from rat in vitro metabolites. Br J Pharmacol 142(3):551–557PubMedCrossRefGoogle Scholar
  26. 26.
    Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O et al (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38(1):92–99PubMedCrossRefGoogle Scholar
  27. 27.
    Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP et al (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84(5):891–896PubMedGoogle Scholar
  28. 28.
    Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP (2003) Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101(10):3908–3914PubMedCrossRefGoogle Scholar
  29. 29.
    Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr et al (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 116(7):e148–e304PubMedCrossRefGoogle Scholar
  30. 30.
    Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM et al (2009) Focused updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120(22):2271–2306PubMedCrossRefGoogle Scholar
  31. 31.
    Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF (2010) Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 103(4):841–848PubMedCrossRefGoogle Scholar
  32. 32.
    Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schomig A et al (2009) Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 53(10):849–856PubMedCrossRefGoogle Scholar
  33. 33.
    Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O et al (2008) Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 51(14):1404–1411PubMedCrossRefGoogle Scholar
  34. 34.
    Kereiakes DJ, Gurbel PA (2008) Peri-procedural platelet function and platelet inhibition in percutaneous coronary intervention. JACC Cardiovasc Interv 1(2):111–121PubMedCrossRefGoogle Scholar
  35. 35.
    Kim KA, Park PW, Hong SJ, Park JY (2008) The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 84(2):236–242PubMedCrossRefGoogle Scholar
  36. 36.
    Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108(7):2244–2247PubMedCrossRefGoogle Scholar
  37. 37.
    Fontana P, Hulot JS, De Moerloose P, Gaussem P (2007) Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 5(10):2153–2155PubMedCrossRefGoogle Scholar
  38. 38.
    Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O et al (2010) Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 56(2):134–143PubMedCrossRefGoogle Scholar
  39. 39.
    Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L et al (2011) Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 89(1):65–74PubMedCrossRefGoogle Scholar
  40. 40.
    Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ et al (2010) Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 363(20):1909–1917PubMedCrossRefGoogle Scholar
  41. 41.
    Silvain J, Bellemain-Appaix A, Barthélémy O, Beygui F, Collet JP, Montalescot G (2011) Optimal use of thienopyridines in non-ST-elevation acute coronary syndrome following CURRENT-OASIS 7. Circ Cardiovasc Interv 4(1):95–103PubMedCrossRefGoogle Scholar
  42. 42.
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015PubMedCrossRefGoogle Scholar
  43. 43.
    van Giezen JJ, Berntsson P, Zachrisson H, Bjorkman JA (2009) Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res 124(5):565–571PubMedCrossRefGoogle Scholar
  44. 44.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C et al (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361(11):1045–1057PubMedCrossRefGoogle Scholar
  45. 45.
    Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G et al (2007) Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 50(19):1852–1856PubMedCrossRefGoogle Scholar
  46. 46.
    Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G et al (2009) Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361(24):2330–3241PubMedCrossRefGoogle Scholar
  47. 47.
    Huang J, Driscoll EM, Gonzales ML, Park AM, Lucchesi BR (2000) Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model. J Pharmacol Exp Ther 295(2):492–429PubMedGoogle Scholar
  48. 48.
    Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM et al (2009) Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361(24):2318–2329PubMedCrossRefGoogle Scholar
  49. 49.
    Berger JS, Roe MT, Gibson CM, Kilaru R, Green CL, Melton L et al (2009) Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 158(6):998–1004, e1PubMedCrossRefGoogle Scholar
  50. 50.
    Leonardi S, Rao SV, Harrington RA, Bhatt DL, Gibson CM, Roe MT et al (2010) Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI). Am Heart J 160(1):65–72PubMedCrossRefGoogle Scholar
  51. 51.
    The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) (2010) Guidelines on Myocardial Revascularization. Eur Heart J 31:2051–2555Google Scholar
  52. 52.
    Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH et al (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373(9665):723–731PubMedCrossRefGoogle Scholar
  53. 53.
    Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP et al (2010) Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis. Circulation 122(21):2131–2141PubMedCrossRefGoogle Scholar
  54. 54.
    Bellemain-Appaix A, Brieger D, Beygui F, Silvain J, Pena A, Cayla G et al (2010) New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol 56(19):1542–1551PubMedCrossRefGoogle Scholar
  55. 55.
    James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH et al (2010) Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 122:1056–1067PubMedCrossRefGoogle Scholar
  56. 56.
    Mehta S, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB et al (2010) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376:1233–1243PubMedCrossRefGoogle Scholar
  57. 57.
    Mahoney EM, Wang K, Arnold SV, Proskorovsky I, Wiviott S, Antman E et al (2009) Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38. Circulation 121(1):71–79PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Stephen O’Connor
    • 1
  • Gilles Montalescot
    • 1
  • Jean-Philippe Collet
    • 1
  1. 1.Institut de Cardiologie-Inserm UMR_S 937-Hôpital Pitié-Salpêtrière (APHP), UPMC (Paris 6)ParisFrance

Personalised recommendations