Skip to main content
SpringerLink
Log in

Genetically Determined Platelet Reactivity and Related Clinical Implications

  • Original Article
  • Published:
High Blood Pressure & Cardiovascular Prevention Aims and scope Submit manuscript

Abstract

Many drugs are nowadays available to inhibit platelet activation and aggregation, especially in patients with acute coronary syndromes and undergoing percutaneous coronary intervention with stent implantation. Primary targets are represented by enzymes or receptors involved in platelet activation. Genetic mutations in these targets contribute to the inter-individual variability in platelet responses therefore weakening the efficacy of antiplatelet agents. High on treatment platelet reactivity is a condition characterized by low levels of platelet inhibition despite the use of antiplatelet drugs. This could be responsible for re-infarction, stent-thrombosis and strokes, affecting short and long-term prognosis after coronary revascularization. So far, to test antiplatelet resistance either the assessment of platelet function or the identification of genetic carriers of poly morphisms have been pursued. Although several methods are now available to test platelet reactivity, it is still debated whether its routine assessment gives real benefits in clinical practice. The present review aims at examining current evidences on genetic polymorphisms affecting optimal platelet inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mangiacapra F, Barbato E. Individual variability of response to antiplatelet therapy is an important determinant of adverse outcome. High Blood Press Cardiovasc Prev. 2010;17(3):121–30.

    Article  CAS  Google Scholar 

  2. Kunicki TJ. The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol. 2002;22(1):14–20.

    Article  CAS  PubMed  Google Scholar 

  3. Esen FI, Hancer VS, Küçükkaya RD, et al. Glycoprotein Ib-alpha Kozak polymorphism in ischemic stroke. Neurol Res. 2012;34(1):68–71.

    Article  CAS  PubMed  Google Scholar 

  4. Zotz RB, Winkelmann BR, Müller C, et al. Association of polymorphisms of platelet membrane integrins alpha IIb(beta)3 (HPA-1b/Pl) and alpha2(beta)1 (alpha807TT) with premature myocardial infarction. J Thromb Haemost. 2005;3(7):1522–9.

    Article  CAS  PubMed  Google Scholar 

  5. Croft SA, Samani NJ, Teare MD, et al. Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation. 2001;104(13):1459–63.

    Article  CAS  PubMed  Google Scholar 

  6. Ollikainen E, Mikkelsson J, Perola M, et al. Platelet membrane collagen receptor glycoprotein VI polymorphism is associated with coronary thrombosis and fatal myocardial infarction in middle-aged men. Atherosclerosis. 2004;176(1):95–9.

    Article  CAS  PubMed  Google Scholar 

  7. Rosenberg N, Zivelin A, Chetrit A, et al. Effects of platelet membrane glycoprotein polymorphisms on the risk of myocardial infarction in young males. Isr Med Assoc J. 2002;4(6):411–4.

    CAS  PubMed  Google Scholar 

  8. O’Connor FF, Shields DC, Fitzgerald A, et al. Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes. Blood. 2001;98(12):3256–60.

    Article  PubMed  Google Scholar 

  9. Galasso G, Santulli G, Piscione F, et al. The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events. BMC Cardiovasc Disord. 2010;16(10):41.

    Article  Google Scholar 

  10. Kucharska-Newton AM, Monda KL, Campbell S, et al. Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2011;216(1):151–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Queen LR, Xu B, Horinouchi K, et al. Beta(2)-adrenoceptors activate nitric oxide synthase in human platelets. Circ Res. 2000;87(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  12. Peace AJ, Mangiacapra F, Bailleul E, et al. α2A-adrenergic receptor polymorphism potentiates platelet reactivity in patients with stable coronary artery disease carrying the cytochrome P450 2C19*2 genetic variant. Arterioscler Thromb Vasc Biol. 2014;34(6):1314–9.

    Article  CAS  PubMed  Google Scholar 

  13. Marketou ME, Kintsurashvili E, Androulakis NE, et al. Blockade of platelet alpha2B-adrenergic receptors: a novel antiaggregant mechanism. Int J Cardiol. 2013;168(3):2561–6.

    Article  PubMed  Google Scholar 

  14. Snapir A, Heinonen P, Tuomainen TP, et al. An insertion/deletion polymorphism in the alpha2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001;37(6):1516–22.

    Article  CAS  PubMed  Google Scholar 

  15. Barbato E, Berger A, Delrue L, et al. GLU-27 variant of beta2-adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease. Atherosclerosis. 2007;194(2):e80–6.

    Article  CAS  PubMed  Google Scholar 

  16. Piscione F, Iaccarino G, Galasso G, et al. Effects of Ile164 polymorphism of beta2-adrenergic receptor gene on coronary artery disease. J Am Coll Cardiol. 2008;52(17):1381–8.

    Article  CAS  PubMed  Google Scholar 

  17. Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002;347(24):1916–23.

    Article  CAS  PubMed  Google Scholar 

  18. Casas JP, Bautista LE, Humphries SE, et al. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation. 2004;109(11):1359–65.

    Article  CAS  PubMed  Google Scholar 

  19. Fatini C, Sticchi E, Bolli P, et al. eNOS gene influences platelet phenotype in acute coronary syndrome patients on dual antiplatelet treatment. Platelets. 2009;20(8):548–54.

    Article  CAS  PubMed  Google Scholar 

  20. Smith SM, Judge HM, Peters G, et al. PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets. 2005;16(6):340–5.

    Article  CAS  PubMed  Google Scholar 

  21. Dupont A, Fontana P, Bachelot-Loza C, et al. An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN. Blood. 2003;101(5):1833–40.

    Article  CAS  PubMed  Google Scholar 

  22. Gigante B, Vikström M, Meuzelaar LS, et al. Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels. Thromb Haemost. 2009;101(5):943–53.

    CAS  PubMed  Google Scholar 

  23. Edelstein LC, Simon LM, Lindsay CR, et al. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood. 2014;124(23):3450–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003;108(8):989–95.

    Article  CAS  PubMed  Google Scholar 

  25. Fontana P, Gaussem P, Aiach M, et al. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation. 2003;108(24):2971–3.

    Article  PubMed  Google Scholar 

  26. Ziegler S, Schillinger M, Funk M, et al. Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease. Stroke. 2005;36(7):1394–9.

    Article  CAS  PubMed  Google Scholar 

  27. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res. 2005;116(6):491–7.

    Article  CAS  PubMed  Google Scholar 

  28. Cuisset T, Frere C, Quilici J, et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Thromb Res. 2007;120(6):893–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hetherington SL, Singh RK, Lodwick D, et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol. 2005;25(1):252–7.

    CAS  PubMed  Google Scholar 

  30. Kim KA, Song WG, Lee HM, et al. Effect of P2Y1 and P2Y12 genetic polymorphisms on the ADP-induced platelet aggregation in a Korean population. Thromb Res. 2013;132(2):221–6.

    Article  CAS  PubMed  Google Scholar 

  31. Fontana P, Gandrille S, Remones V, et al. Identification of functional polymorphisms of the thromboxane A2 receptor gene in healthy volunteers. Thromb Haemost. 2006;96(3):356–60.

    CAS  PubMed  Google Scholar 

  32. Shao J, Fu Y, Yang W, et al. Thromboxane A2 receptor polymorphism in association with cerebral infarction and its regulation on platelet function. Curr Neurovasc Res. 2015;12(1):15–24.

    Article  CAS  PubMed  Google Scholar 

  33. Cuisset T, Quilici J. CYP-mediated pharmacologic interference with optimal platelet inhibition. J Cardiovasc Transl Res. 2013;6(3):404–10.

    Article  PubMed  Google Scholar 

  34. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925–34.

    Article  CAS  PubMed  Google Scholar 

  35. Arima Y, Hokimoto S, Akasaka T, et al. Comparison of the effect of CYP2C19 polymorphism on clinical outcome between acute coronary syndrome and stable angina. J Cardiol. 2014. doi:10.1016/j.jjcc.2014.07.016.

    Google Scholar 

  36. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376(9749):1312–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Jaitner J, Morath T, Byrne RA, et al. No association of ABCB1 C3435T genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting. Circ Cardiovasc Interv. 2012;5(1):82–8.

    Article  CAS  PubMed  Google Scholar 

  38. Bouman HJ, Schömig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011;17(1):110–6.

    Article  CAS  PubMed  Google Scholar 

  39. Paré G, Ross S, Mehta SR, et al. Effect of PON1 Q192R genetic polymorphism on clopidogrel efficacy and cardiovascular events in the Clopidogrel in the Unstable Angina to Prevent Recurrent Events trial and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. Circ Cardiovasc Genet. 2012;5(2):250–6.

    Article  PubMed  Google Scholar 

  40. Hulot JS, Collet JP, Cayla G, et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011;4(5):422–8.

    Article  CAS  PubMed  Google Scholar 

  41. Park KW, Park JJ, Kang J, et al. Paraoxonase 1 gene polymorphism does not affect clopidogrel response variability but is associated with clinical outcome after PCI. PLoS One. 2013;8(2):e52779.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. 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 Am Coll Cardiol. 2010;56(12):919–33.

    Article  CAS  PubMed  Google Scholar 

  43. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305(11):1097–105.

    Article  CAS  PubMed  Google Scholar 

  44. Legrand V, Cuisset T, Chenu P, et al. Platelet reactivity and cardiovascular events after percutaneous coronary intervention in patients with stable coronary artery disease: the Stent Thrombosis In Belgium (STIB) trial. EuroIntervention. 2014;10(2):204–11.

    Article  PubMed  Google Scholar 

  45. Cuisset T, Hamilos M, Delrue M, et al. Adrenergic receptor polymorphisms and platelet reactivity after treatment with dual antiplatelet therapy with aspirin and clopidogrel in acute coronary syndrome. Thromb Haemost. 2010;103(4):774–9.

    Article  CAS  PubMed  Google Scholar 

  46. Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015. doi:10.1093/eurheartj/ehv104.

    PubMed  Google Scholar 

  47. De Luca L, Bolognese L, Valgimigli M, et al. ANMCO/SICI-GISE document on antiplatelet therapy in patients with acute coronary syndrome. G Ital Cardiol. 2013;14(12):839–66.

    Google Scholar 

  48. Saucedo JF, Angiolillo DJ, DeRaad R, et al. Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: insights from the switching anti-platelet (SWAP) study. Thromb Haemost. 2013;109(2):347–55.

    Article  CAS  PubMed  Google Scholar 

  49. Cuisset T, Gaborit B, Dubois N, et al. Platelet reactivity in diabetic patients undergoing coronary stenting for acute coronary syndrome treated with clopidogrel loading dose followed by prasugrel maintenance therapy. Int J Cardiol. 2013;168(1):523–8.

    Article  PubMed  Google Scholar 

  50. Cayla G, Cuisset T, Silvain J, et al. Prasugrel monitoring and bleeding in real world patients. Am J Cardiol. 2013;111(1):38–44.

    Article  PubMed  Google Scholar 

  51. Franken CC, Kaiser AF, Krüger JC, et al. Cytochrome P450 2B6 and 2C9 genotype polymorphism–a possible cause of prasugrel low responsiveness. Thromb Haemost. 2013;110(1):131–40.

    Article  CAS  PubMed  Google Scholar 

  52. Neubauer H, Kaiser A, Busse B, et al. Identification, evaluation and treatment of prasugrel low-response after coronary stent implantation–a preliminary study. Thromb Res. 2010;126(5):e389–91.

    Article  CAS  PubMed  Google Scholar 

  53. Bassez C, Deharo P, Pankert M, et al. Effectiveness of switching ‘low responders’ to prasugrel to ticagrelor after acute coronary syndrome. Int J Cardiol. 2014;176(3):1184–5.

    Article  PubMed  Google Scholar 

  54. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS 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)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541–619.

    Article  PubMed  Google Scholar 

  55. Lhermusier T, Baker NC, Waksman R. Overview of the 2014 food and drug administration cardiovascular and renal drugs advisory committee meeting regarding cangrelor. Am J Cardiol. 2015;115(8):1154–61.

    Article  PubMed  Google Scholar 

  56. Food and Drug Administration: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. FDA drug safety communication. http://www.fda.gov/drugs/drugsafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm.

  57. Viviani Anselmi C, Briguori C, Roncarati R, et al. Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in predicting clinical outcome following drug-eluting stent implantation in patients with stable coronary artery disease. JACC Cardiovasc Interv. 2013;6(11):1166–75.

    Article  PubMed  Google Scholar 

  58. Palmerini T, Calabrò P, Piscione F, et al. Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: the GEPRESS study. JACC Cardiovasc Interv. 2014;7(10):1117–27.

    Article  PubMed  Google Scholar 

  59. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62(24):2261–73.

    Article  CAS  PubMed  Google Scholar 

  60. Frelinger AL 3rd, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisione di Cardiologia, Dipartimento di Scienze Biomediche Avanzate, Università Federico II Napoli, Naples, Italy

    Teresa Strisciuglio, Giuseppe Di Gioia, Chiara De Biase, Massimiliano Esposito, Danilo Franco, Bruno Trimarco & Emanuele Barbato

  2. Cardiovascular Research Center Aalst, Aalst, Belgium

    Emanuele Barbato

Authors
  1. Teresa Strisciuglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe Di Gioia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara De Biase
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimiliano Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Danilo Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Trimarco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emanuele Barbato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emanuele Barbato.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strisciuglio, T., Di Gioia, G., De Biase, C. et al. Genetically Determined Platelet Reactivity and Related Clinical Implications. High Blood Press Cardiovasc Prev 22, 257–264 (2015). https://doi.org/10.1007/s40292-015-0104-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40292-015-0104-5

Keywords

Search

Navigation