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Thromb Haemost 2010; 103(03): 535-544
DOI: 10.1160/TH09-07-0491
Theme Issue Article
Schattauer GmbH

Platelet P2Y12 receptor antagonist pharmacokinetics and pharmaco -dynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies

Richard C. Becker
1   Duke University School of Medicine, Durham, North Carolina, United States
,
Paul A. Gurbel
2   Sinai Center for Thrombosis Research, Baltimore, Maryland, United States
› Author Affiliations Financial support: Editorial assistance for this paper was provided by BioScience Communications, funded by AstraZeneca.
Further Information

Publication History

Received: 29 July 2009

Accepted after major revision: 13 February 2009

Publication Date:
22 November 2017 (online)

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Summary

The platelet P2Y12 receptor is involved in all aspects of arterial thrombosis, including adhesion, activation, aggregation, secretion and development of a stable aggregate on which coagulation proteins can assemble and fibrin strands can mesh. Inhibition of the P2Y12 receptor has been shown convincingly to reduce cardiovascular events among patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous intervention (PCI). Current studies are exploring whether there is a threshold of platelet aggregation below which only more bleeding occurs, without a concomitant reduction in clinical events. The following review considers the potential relevance of reversible and irreversible mechanisms of P2Y12 inhibition to bleeding risk, posing the question, “Is it not only how much but how a platelet P2Y12 receptor is inhibited that determines the attributable safety profile?”

Keywords

Platelet P2Y12 receptor - clopidogrel - prasugrel - ticagrelor - cangrelor
 

  • References

  • 1 Yusuf S, Zhao F, Mehta SR. et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
    CrossrefPubMedGoogle Scholar
  • 2 Steinhubl SR, Berger PB, Mann JT III. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
    CrossrefPubMedGoogle Scholar
  • 3 Sabatine MS, Cannon CP, Gibson CM. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
    CrossrefPubMedGoogle Scholar
  • 4 Sabatine MS, Cannon CP, Gibson CM. et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. J Am Med Assoc 2005; 294: 1224-1232.
    CrossrefPubMedGoogle Scholar
  • 5 Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J 2009; 30: 1964-1977.
    CrossrefPubMedGoogle Scholar
  • 6 Gurbel PA, Tantry US. Drug insight: Clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006; 3: 387-395.
    CrossrefPubMedGoogle Scholar
  • 7 Smid J, Braun-Dullaeus R, Gawaz M. et al. Platelet interactions as therapeutic targets for prevention of atherothrombosis. Future Cardiol 2009; 5: 285-296.
    CrossrefPubMedGoogle Scholar
  • 8 Gurbel PA. The relationship of platelet reactivity to the occurrence of post-stenting ischemic events: emergence of a new cardiovascular risk factor. Rev Cardiovasc Med 2006; 7 (Suppl. 04) S20-28.
    PubMedGoogle Scholar
  • 9 Gurbel PA, Bliden KP, Hayes KM. et al. Platelet activation in myocardial ischemic syndromes. Expert Rev Cardiovasc Ther 2004; 2: 535-545.
    CrossrefPubMedGoogle Scholar
  • 10 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174-183.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Cattaneo M, Akkawat B, Leechi A. et al. Ticlopidine selectively inhibits human platelet responses to adenosine diphosphate. Thromb Haemost 1991; 66: 694-699.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Gachet C, Savi P, Ohlmann P. et al. ADP receptor induced activation of guanine nucleotide binding proteins in rat platelet membranes—an effect selectively blocked by the thienopyridine clopidogrel. Thromb Haemost 1992; 68: 79-83.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Ding Z, Kim S, Dorsam RT. et al. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 2003; 101: 3908-3914.
    CrossrefPubMedGoogle Scholar
  • 15 Cattaneo M. ADP receptor antagonists. In: Platelets. San Diego, CA, Academic Press;; 2007: pp. 1127-1144.
    Google Scholar
  • 16 Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993; 4: 252-261.
    CrossrefPubMedGoogle Scholar
  • 17 Thebault J-J, Kieffer G, Lowe GDO. et al. Repeated dose pharmacodynamics of clopidogrel in healthy subjects. Semin Thromb Hemost 1999; 25 (Suppl. 02) 9-14.
    PubMedGoogle Scholar
  • 18 Gurbel PA, Cummings CC, Bell CR. et al. Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial. Am Heart J 2003; 145: 239-247.
    CrossrefPubMedGoogle Scholar
  • 19 Anderson JL, Adams CD, Antman EM. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol 2007; 50: e1-157.
    CrossrefPubMedGoogle Scholar
  • 20 Bassand J-P, Hamm CW, Ardissino D. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
    CrossrefPubMedGoogle Scholar
  • 21 Becker RC. Focus on thrombosis: applying management guidelines in clinical practice. J Thromb Thrombolysis 2007; 24: 183-222.
    CrossrefPubMedGoogle Scholar
  • 22 Niitsu Y, Jakubowski JA, Sugidachi A. et al. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost 2005; 31: 184-194.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Gurbel PA, Tantry US. Prasugrel, a third generation thienopyridine and potent platelet inhibitor. Curr Opin Invest Drugs 2008; 9: 324-336.
    PubMedGoogle Scholar
  • 24 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
    PubMedGoogle Scholar
  • 25 Sugidachi A, Asai F, Ogawa T. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-1446.
    CrossrefPubMedGoogle Scholar
  • 26 Wiviott SD, Braunwald E, McCabe CH. et al, for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2015-2021.
    PubMedGoogle Scholar
  • 27 van Giezen JJJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31: 195-204.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
    CrossrefPubMedGoogle Scholar
  • 29 Springthorpe B, Bailey A, Barton P. et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 2007; 17: 6013-6018.
    CrossrefPubMedGoogle Scholar
  • 30 Husted S. Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents. Fundam Clin Pharmacol 2009; 23: 1-9.
    PubMedGoogle Scholar
  • 31 van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl 2008; 10: D23-29.
    CrossrefPubMedGoogle Scholar
  • 32 van Giezen JJJ, Nilsson L, Berntsson P. et al. Ticagrelor binds to the human P2Y12 receptor independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-1565.
    CrossrefPubMedGoogle Scholar
  • 33 Peters G, Robbie G. Single dose pharmacokinetics and pharmacodynamics of AZD6140. Haematologica 2004; 89 (Suppl. 07) 14-15.
    PubMedGoogle Scholar
  • 34 Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009; 27: 259-274.
    CrossrefPubMedGoogle Scholar
  • 35 Nilsson L, van Giezen JJJ, Greasley PJ. Evidence for distinct ligand binding sites on recombinant P2Y12 receptors. Circulation. 2006 114. (Suppl II): II-248. Abstract 1313.
    PubMedGoogle Scholar
  • 36 van Giezen JJJ, Berntsson P, Zachrisson H. et al. Comparison of ticagrelor and thienopyridine P2Y12 binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res 2009; 124: 565-571.
    CrossrefPubMedGoogle Scholar
  • 37 Storey RF, Husted S, Harrington RA. et al. 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 2007; 50: 1852-1856.
    CrossrefPubMedGoogle Scholar
  • 38 Cannon CP, Husted S, Harrington RA. et al for the DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non–ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007; 50: 1844-1851. Correction in J Am Coll Cardiol 2007; 50; 2196.
    CrossrefPubMedGoogle Scholar
  • 39 Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndrome. Thromb Haemost 2001; 85: 401-407.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 2002; 13: 407-413.
    CrossrefPubMedGoogle Scholar
  • 41 Nassim MA, Sanderson JB, Clarke C. et al. Investigation of the novel P2T receptor antagonist AR-C69931MX on ex vivo adenosine diphosphate-induced platelet aggregation and bleeding time in healthy volunteers. J Am Coll Cardiol. 1999 33 225 (Abstract).
    PubMedGoogle Scholar
  • 42 Greenbaum AB, Grimes C, Bittl JA. et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo-and active-controlled trial. Am Heart J 2006; 151: 689.e1-e10.
    CrossrefPubMedGoogle Scholar
  • 43 Ingall AH, Dixon J, Bailey A. et al. Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999; 42: 213-220.
    CrossrefPubMedGoogle Scholar
  • 44 Huang J, Driscoll EM, Gonzales ML. et al. Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model. J Pharmacol Exp Ther 2000; 295: 492-499.
    PubMedGoogle Scholar
  • 45 Humphries RG, Tomlinson W, Ingall AH. et al. Effect of the novel P2T receptor antagonist, AR-C69931MX, on thrombosis and hemostasis in the dog: comparison with GPIIb/IIIa antagonists. Haematologica 2000; 85 (Suppl) 91-92 (Abstract).
    PubMedGoogle Scholar
  • 46 Dovlatova NL, Jakubowski JA, Sugidachi A. et al. The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2008; 6: 1153-1159.
    CrossrefPubMedGoogle Scholar
  • 47 Eikelboom JW, Mehta SR, Anand SS. et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.
    CrossrefPubMedGoogle Scholar
  • 48 de Winter RJ, Windhausen F, Cornel JH. et al Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators.. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005; 353: 1095-1104.
    CrossrefPubMedGoogle Scholar
  • 49 Fox KA, Anderson Jr, FA, Dabbous OH. et al GRACE investigators.. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart 2007; 93: 177-182.
    CrossrefPubMedGoogle Scholar
  • 50 Koch CG, Li L, Duncan AI. et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006; 34: 1608-1616.
    CrossrefPubMedGoogle Scholar
  • 51 Koch CG, Li L, Van Wagoner DR. et al. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006; 82: 1747-1756.
    CrossrefPubMedGoogle Scholar
  • 52 Kuduvalli M, Oo AY, Newall N. et al. Effect of peri-operative red blood cell transfusion on 30-day and 1-year mortality following coronary artery bypass surgery. Eur J Cardiothorac Surg 2005; 27: 592-598.
    CrossrefPubMedGoogle Scholar
  • 53 Surgenor SD, DeFoe GR, Fillinger MP. et al. Intraoperative red blood cell transfusion during coronary artery bypass graft surgery increases the risk of postoperative low-output heart failure. Circulation 2006; 114 Suppl I I43-48.
    PubMedGoogle Scholar
  • 54 Purkayastha S, Athanasiou T, Malinovski V. et al. Does clopidogrel affect outcome after coronary artery bypass grafting? A meta-analysis. Heart 2006; 92: 531-532.
    PubMedGoogle Scholar
  • 55 Pickard AS, Becker RC, Schumock GT. et al. Clopidogrel associated bleeding and related complications among patients undergoing coronary artery bypass graft surgery. Pharmacotherapy 2008; 28: 376-392.
    CrossrefPubMedGoogle Scholar
  • 56 Fox KAA, Mehta SR, Peters R. et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110: 1202-1208.
    CrossrefPubMedGoogle Scholar
  • 57 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
    CrossrefPubMedGoogle Scholar
  • 58 Andre P, Delaney SM, LaRocca T. et al. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest 2003; 112: 398-406.
    CrossrefPubMedGoogle Scholar
  • 59 van Gestel MA, Reitsma S, Slaaf DW. et al. Both ADP and thrombin regulate arteriolar thrombus stabilization and embolization, but are not involved in initial hemostasis as induced by micropuncture. Microcirculation 2007; 14: 193-205.
    CrossrefPubMedGoogle Scholar
  • 60 Stafford NP, Pink AE, White AE. et al. Mechanisms involved in adenosine triphosphate-induced platelet aggregation in whole blood. Arterioscler Thromb Vasc Biol 2003; 23: 1928-1933.
    CrossrefPubMedGoogle Scholar
  • 61 Baurand A, Eckly A, Hechler B. et al. Differential regulation and relocalization of the platelet P2Y receptors after activation: a way to avoid loss of hemostatic properties?. Mol Pharmacol 2005; 67: 721-733.
    PubMedGoogle Scholar
  • 62 O’Brien JR, Etherington M, Jamieson S. Refractory state of platelet aggregation with major operations. Lancet 1971; 2: 741-743.
    PubMedGoogle Scholar
  • 63 Enjyoji K, Sévigny J, Lin Y. et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 1999; 5: 1010-1017.
    CrossrefPubMedGoogle Scholar
  • 64 Mamedova LK, Gao ZG, Jacobson KA. Regulation of death and survival in astrocytes by ADP activating P2Y1 and P2Y12 receptors. Biochem Pharmacol 2006; 72: 1031-1041.
    CrossrefPubMedGoogle Scholar
  • 65 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
    CrossrefPubMedGoogle Scholar
  • 66 Gurbel PA, Bliden KP, Butler K. et al. Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease. Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Cornonary Disease: The ONSET/OFFSET Study. Circulation 2009; 120: 2577-2585.
    CrossrefPubMedGoogle Scholar
  • 67 Gurbel PA, Tantry US. Selecting optimal antiplatelet therapy based on platelet function monitoring in patients with coronary artery disease. Curr Treat Options Cardiovasc Med 2009; 11: 22-32.
    CrossrefPubMedGoogle Scholar