Bleeding manifestations of congenital and drug-induced defects of the platelet P2Y12 receptor for adenosine diphosphate

 

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Summary

P2Y12, one of the two platelet receptors for adenosine diphosphate (ADP), plays a central role in platelet function. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥10 μM), is unable to induce full, irreversible platelet aggregation. Patients with congenital P2Y12 defects display a mild-to-moderate bleeding diathesis of variable severity, characterised by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA). Its most important drawback is the inability to inhibit adequately P2Y12-dependent platelet function in about 1/3 of patients, at the recommended therapeutic doses. The incidence of bleeding events is similar in ASA-treated and clopidogrel-treated patients; however, the combination of ASA and clopidogrel causes more bleeding than each drug in monotherapy. Compared to clopidogrel, new drugs inhibiting P2Y12, such as prasugrel and ticagrelor, decrease the risk of cardiovascular events and increase the risk of bleeding complications, because they adequately inhibit P2Y12-dependent platelet function in the vast majority of treated patients.

• References

• 1 Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol 1999; 19: 2281-2285.
  CrossrefPubMedGoogle Scholar
• 2 Jin J, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA 1998; 95: 8070-8074.
  CrossrefPubMedGoogle Scholar
• 3 Savi P, Zachayus JL, Delesque-Touchard N. et al. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci USA 2006; 103: 11069-11074.
  CrossrefPubMedGoogle Scholar
• 4 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
• 5 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
• 6 Cattaneo M. The platelet P2 receptors. In: Platelets. San Diego, CA: Academic Press; 2006. pp. 201-220.
  Google Scholar
• 7 Cattaneo M. The P2 receptors and congenital platelet function defects. Sem Thromb Hemost 2005; 31: 168-173.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Cattaneo M, Lombardi R, Zighetti ML. et al. Deficiency of [33P]2MeS-ADP binding sites on platelets with secretion defect, normal granule stores and normal thromboxane A2 production. Evidence that ADP potentiates platelet secretion independently of the formation of large platelet aggregates and thromboxane A2 production. Thromb Haemost 1997; 77: 986-990.
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Cattaneo M, Lecchi A, Lombardi R. et al. Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet ‘primary secretion defect’ are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol 2000; 20: E101-106.
  CrossrefPubMedGoogle Scholar
• 10 Lecchi A, Cattaneo M, Mannucci PM. ADP potentiates platelet dense granule secretion induced by U46619 or TRAP through its interaction with the P2cyc receptor [abstract]. Haematologica 2000; 85 (Suppl. 05) 83.
  PubMedGoogle Scholar
• 11 Cattaneo M, Canciani MT, Lecchi A. et al. Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood 1990; 75: 1081-1086.
  PubMedGoogle Scholar
• 12 Cattaneo M, Akkawat B, Kinlough-Rathbone RL. et al. Ticlopidine facilitates the deaggregation of human platelets aggregated by thrombin. Thromb Haemost 1994; 71: 91-94.
  Article in Thieme ConnectPubMedGoogle Scholar
• 13 Trumel C, Payrastre B, Plantavid M. et al. 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 1999; 94: 4156-4165.
  PubMedGoogle Scholar
• 14 Li Z, Zhang G, Le Breton GC. et al. Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. J Biol Chem 2003; 278: 30725-30731.
  CrossrefPubMedGoogle Scholar
• 15 Cattaneo M, Lombardi R, Bettega D. et al. Shear-induced platelet aggregation is potentiated by desmopressin (DDAVP) and inhibited by ticlopidine. Arterioscl Thromb Vasc Biol 1993; 13: 393-397.
  CrossrefPubMedGoogle Scholar
• 16 Cattaneo M, Zighetti ML, Lombardi R. et al. Role of ADP in platelet aggregation at high shear: studies in a patient with congenital defect of platelet responses to ADP. Br J Haematol 1994; 88: 826-829.
  CrossrefPubMedGoogle Scholar
• 17 Resendiz JC, Feng S, Ji G. et al. Purinergic P2Y12 receptor blockade inhibits shear-induced platelet phosphatidylinositol 3-kinase activation. Mol Pharmacol 2003; 63: 639-645.
  CrossrefPubMedGoogle Scholar
• 18 Cattaneo M, Lecchi A. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J Thromb Haemost 2007; 5: 577-582.
  CrossrefPubMedGoogle Scholar
• 19 Leon C, Alex M, Klocke A. et al. Platelet ADP receptors contribute to the initiation of intravascular coagulation. Blood 2004; 103: 594-600.
  CrossrefPubMedGoogle Scholar
• 20 Takano K, Asazuma N, Satoh K. et al. Collagen-induced generation of platelet-derived microparticles in whole blood is dependent on ADP released from red blood cells and calcium ions. Platelets 2004; 15: 223-229.
  CrossrefPubMedGoogle Scholar
• 21 Leon C, Ravanat C, Freund M. et al. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 2003; 23: 1941-1947.
  CrossrefPubMedGoogle Scholar
• 22 Storey RF, Judge HM, Wilcox RG. et al. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002; 88: 488-494.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Dorsam RT, Tuluc M, Kunapuli SP. Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb Haemost 2004; 2: 804-812.
  CrossrefPubMedGoogle Scholar
• 24 van der Meijden PE, Feijge MA, Giesen PL. et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 2005; 93: 1128-1136.
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Cattaneo M, Lecchi A, Randi AM. et al. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood 1992; 80: 2787-2796.
  PubMedGoogle Scholar
• 26 Gachet C, Cattaneo M, Ohlmann P. et al. Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors. Br J Haematol 1995; 91: 434-444.
  CrossrefPubMedGoogle Scholar
• 27 Cattaneo M, Zighetti ML, Lombardi R. et al. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci USA 2003; 100: 1978-1983.
  CrossrefPubMedGoogle Scholar
• 28 Nurden P, Savi P, Heilmann E. et al. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function. J Clin Invest 1995; 95: 1612-1622.
  CrossrefPubMedGoogle Scholar
• 29 Shiraga M, Miyata S, Kato H. et al. Impaired platelet function in a patients with P2Y12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost 2005; 3: 2315-2323.
  CrossrefPubMedGoogle Scholar
• 30 Dawood BB, Daly M, Makris M. et al. Identification of a novel homozygous P2Y12 mutation in a patient with a mild platelet-based bleeding disorder [abstract]. J Thromb Haemost. 2009 7. (Suppl 2): Abstract PP-MO-076.
  PubMedGoogle Scholar
• 31 Remijn JA, IJsseldijk MJ, Strunk AL. et al. Novel molecular defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis. Clin Chem Lab Med 2007; 45: 187-189.
  PubMedGoogle Scholar
• 32 Daly ME, Dawood BB, Lester WA. et al. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study. Blood 2009; 113: 4110-4113.
  CrossrefPubMedGoogle Scholar
• 33 Zighetti ML, Carpani G, Sinigaglia E. et al. Usefulness of a flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of patients with genetic defects of the platelet P2Y12 receptor for ADP. J Thromb Haemost. 2011 in press.
  PubMedGoogle Scholar
• 34 Conley PB, Jurek MM, Vincent D. et al. Unique mutations in the P2Y12 locus of patients with previously described defects in ADP-dependent aggregation. Blood 2001; 98: 43b (abstract).
  PubMedGoogle Scholar
• 35 Fontana G, Ware J, Cattaneo M. Haploinsufficiency of the platelet P2Y12 gene in a family with congenital bleeding diathesis. Haematologica 2009; 94: 581-584.
  CrossrefPubMedGoogle Scholar
• 36 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
  CrossrefPubMedGoogle Scholar
• 37 Tosetto A, Rodeghiero F, Castaman G. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4: 766-773.
  CrossrefPubMedGoogle Scholar
• 38 Cattaneo M, Mannucci PM. Desmopressin. In: Platelets. San Diego, CA: Academic Press; 2002. pp. 855-866.
  Google Scholar
• 39 Cattaneo M. ADP receptors antagonists. In: Platelets. San Diego, CA: Academic Press; 2006. pp. 1127-1144.
  Google Scholar
• 40 Bouman HJ, Schömig E, van Werkum JW. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2010 epub ahead of print.
  PubMedGoogle Scholar
• 41 Cattaneo M. The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects. Blood. 2010 epub ahead of print.
  PubMedGoogle Scholar
• 42 Gent M, Blakely JA, Easton JD. et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-1220.
  PubMedGoogle Scholar
• 43 Hass WK, Easton JD, Adams Jr HP et al.. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321: 501-507.
  CrossrefPubMedGoogle Scholar
• 44 Cattaneo M. New P2Y(12) inhibitors. Circulation 2010; 121: 171-179.
  CrossrefPubMedGoogle Scholar
• 45 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
  CrossrefPubMedGoogle Scholar
• 46 Cuisset T, Frere C, Poyet R. et al. Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting. Arch Cardiovasc Dis 2010; 103: 39-45.
  CrossrefPubMedGoogle Scholar
• 47 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
  Article in Thieme ConnectPubMedGoogle Scholar
• 48 Paniccia R, Antonucci E, Maggini N. et al. Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 2010; 104: 287-292.
  Article in Thieme ConnectPubMedGoogle Scholar
• 49 Kim IS, Jeong YH, Kang MK. et al. Correlation of high post-treatment platelet reactivity assessed by light transmittance aggregometry and the VerifyNow P2Y(12) assay. J Thromb Thrombolysis. 2010 epub ahead of print.
  PubMedGoogle Scholar
• 50 Madsen EH, Saw J, Kristensen SR. et al. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem 2010; 56: 839-847.
  CrossrefPubMedGoogle Scholar
• 51 Aleil B, Léon C, Cazenave JP. et al. CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring. J Thromb Haemost 2009; 7: 1747-1749.
  CrossrefPubMedGoogle Scholar
• 52 Hochholzer W, Trenk D, Fromm MF. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010; 55: 2427-2434.
  CrossrefPubMedGoogle Scholar
• 53 Bonello L, Armero S, Ait Mokhtar O. et al. Clopidogrel Loading Dose Adjustment According to Platelet Reactivity Monitoring in Patients Carrying the 2C19*2 Loss of Function Polymorphism. J Am Coll Cardiol 2010; 56: 1630-1636.
  CrossrefPubMedGoogle Scholar
• 54 Bonello L, Tantry US, Marcucci R. et al. Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate. J Amer Coll Cardiol 2010; 56: 919-933.
  CrossrefPubMedGoogle Scholar
• 55 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: 2001-2015.
  CrossrefPubMedGoogle Scholar
• 56 van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31: 195-204.
  Article in Thieme ConnectPubMedGoogle Scholar
• 57 Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2010; 66: 487-496.
  CrossrefPubMedGoogle Scholar
• 58 van Giezen JJ, Nilsson L, Berntsson P. et al. Ticagrelor binds to the human P2Y receptor independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-1565.
  CrossrefPubMedGoogle Scholar
• 59 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
• 60 Cannon CP, Husted S, Harrington RA. et al. 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.
  CrossrefPubMedGoogle Scholar
• 61 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: the ONSET/OFFSET study. Circulation 2009; 120: 2577-2585.
  CrossrefPubMedGoogle Scholar
• 62 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
• 63 Bhatt DL, Lincoff AM, Gibson CM. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
  CrossrefPubMedGoogle Scholar
• 64 Harrington RA, Stone GW, McNulty S. et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318-2329.
  CrossrefPubMedGoogle Scholar
• 65 Mehran R, Pocock SJ, Nikolsky E. et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55: 2556-2566.
  CrossrefPubMedGoogle Scholar
• 66 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
• 67 Pocock SJ, Mehran R, Clayton TC. et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2010; 121: 43-51.
  CrossrefPubMedGoogle Scholar
• 68 van Hattum ES, Algra A, Lawson JA. et al. Bleeding increases the risk of ischemic events in patients with peripheral arterial disease. Circulation 2009; 120: 1569-1576.
  CrossrefPubMedGoogle Scholar
• 69 Diener HC, Bogousslavsky J, Brass LM. et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331-337.
  CrossrefPubMedGoogle Scholar
• 70 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-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.
  CrossrefPubMedGoogle Scholar
• 71 Sugidachi A, Ogawa T, Kurihara A. et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel‘s active metabolite. J Thromb Haemost 2007; 5: 1545-1551.
  CrossrefPubMedGoogle Scholar
• 72 CURRENT-OASIS 7 Investigators.. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
  CrossrefPubMedGoogle Scholar
• 73 Mehta SR, Tanguay JF, Eikelboom JW. et al. 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 2010; 376: 1233-1243.
  CrossrefPubMedGoogle Scholar
• 74 European Association for Percutaneous Cardiovascular Interventions.. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010; 31: 2501-2555.
  CrossrefPubMedGoogle Scholar