Skip to main content
SpringerLink
Log in

The value of using polymorphisms in anti-platelet therapy

  • Review
  • Published:
Frontiers in Biology

Abstract

Objectives and Backgrounds

Cardiovascular events occure as a result of various risk factors, such as uric acid (UA), inflammation, hormones and other materials that induce C- reactive protein (CRP) expression. These factors lead to complement activation, and endothelial damages. Damaged endothelial cells release heparan sulfate which inhibits tissue factor activity and von Willed brand factor (VWVF) and causes aggregation. Finally this cascade of events cause platelets aggregation and leads to heart ischemia and cardiovascular events.

Discussion

Anti-platelet therapy is an interesting premise. Anti-platelet resistance patients and bleeding as a result of using ticagrelor and prasugrel should be considered in this treatment methods. Anti-platelet drugs such as clopidogrel are prescribed in cardiovascular events. Platelets have VWF receptors and P2Y12 receptors on their surface, and thus, targeting these receptors can be useful in treatment. The active metabolites of clopidogrel bind to P2Y12R and inhibit ADP binding; thus, clopidogrel inhibits aggregation by interfering in several events as a result of the inhibition of ADP attachment to P2Y12R of the platelet. However, the polymorphisms of P2Y12 and other genes mentioned in Table 1 showed treatment resistance in anti-platelet therapy, highlighting that these SNPs can be helpful in anti-platelet therapy.

Conclusion

The knowledge of these SNPs may decrease the number of unwanted effects that endanger patients with cardiovascular diseases and avoids ineffective anti-platelet therapy in several patients. Clopidogrel, ticagrelor, prasugrel, and aspirin and CYP2C19 and their SNPs are very important subjects in anti-platelet therapy. To present the importance of using pharmacogenetics in anti-platelet therapy, we discuss here the association between these drugs and the SNPs for therapeutic resistance.

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

Similar content being viewed by others

References

  • Amarenco P, Albers G W, Denison H, Easton J D, Evans S R, Held P, Hill MD, Jonasson J, Kasner S E, Ladenvall P, Minematsu K, Molina C A, Wang Y, Wong K S L, Johnston S C, and the SOCRATES Steering Committee and Investigators (2017). Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol, 16(4): 301–310

    Article  CAS  PubMed  Google Scholar 

  • Andersson HM, Siegerink B, Luken BM, Crawley J T, Algra A, Lane D A, Rosendaal F R (2012). High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women. Blood, 119(6): 1555–1560

    Article  CAS  PubMed  Google Scholar 

  • Andreadou I, Iliodromitis E K, Lazou A, Görbe A, Giricz Z, Schulz R, Ferdinandy P (2017). Effect of hypercholesterolaemia on myocardial function, ischaemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. Br J Pharmacol, 174(12): 1555–1569

    Article  CAS  PubMed  Google Scholar 

  • Angiolillo D J, Suryadevara S, Capranzano P, Bass T A (2008). Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development. Expert Opin Pharmacother, 9(16): 2893–2900

    Article  CAS  PubMed  Google Scholar 

  • Armstrong P C, Hoefer T, Knowles R B, Tucker A T, Hayman M A, Ferreira P M, Chan M V, Warner T D (2017). Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies. Arterioscler Thromb Vasc Biol, 37(5): 949–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonaca M P, Wiviott S D (2016). Prasugrel Versus Ticagrelor. Circulation, 134(21): 1613–1616

    Article  PubMed  Google Scholar 

  • Bozzi LM, Mitchell B D, Lewis J P, Ryan K A, Herzog WR, O’Connell J R, Horenstein R B, Shuldiner A R, Yerges-Armstrong L M (2016). The pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: variation in platelet response to clopidogrel and aspirin. Curr Vasc Pharmacol, 14(1): 116–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bro-Jeppesen J, Johansson P I, Hassager C, Wanscher M, Ostrowski S R, Bjerre M, Kjaergaard J (2016). Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest. Resuscitation, 107: 71–79

    Article  PubMed  Google Scholar 

  • Capodanno D, Dharmashankar K, Angiolillo D J (2010). Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist. Expert Rev Cardiovasc Ther, 8(2): 151–158

    Article  CAS  PubMed  Google Scholar 

  • Castellano G, Melchiorre R, Loverre A, Ditonno P, Montinaro V, Rossini M, Divella C, Battaglia M, Lucarelli G, Annunziata G, Palazzo S, Selvaggi F P, Staffieri F, Crovace A, Daha MR, Mannesse M, van Wetering S, Paolo Schena FGrandaliano G, (2010). Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. Am J Pathol, 176(4): 1648–1659

    Article  PubMed  PubMed Central  Google Scholar 

  • Cavallari L H, Obeng A O (2017). Genetic Determinants of P2Y12 Inhibitors and Clinical Implications. Interv Cardiol Clin, 6(1): 141–149

    PubMed  PubMed Central  Google Scholar 

  • Chan N C, Eikelboom J W, Ginsberg J S, Lauw M N, Vanassche T, Weitz J I, Hirsh J (2014). Role of phenotypic and genetic testing in managing clopidogrel therapy. Blood, 124(5): 689–699

    Article  CAS  PubMed  Google Scholar 

  • Cohen M V, Downey J M (2014). Combined cardioprotectant and antithrombotic actions of platelet P2Y12 receptor antagonists in acute coronary syndrome: just what the doctor ordered. J Cardiovasc Pharmacol Ther, 19(2): 179–190

    Article  CAS  PubMed  Google Scholar 

  • Cui H, Lin S, Chen X, Gao W, Li X, Zhou H, Du W, Wang S, Zhao R (2015). Correlation between SNPs in candidate genes and Verify-Now-detected platelet responsiveness to aspirin and clopidogrel treatment. Cardiovasc Drugs Ther, 29(2): 137–146

    Article  CAS  PubMed  Google Scholar 

  • Daly P L, Becker R C (2014). Pharmacogenetics of antiplatelet therapy. Curr Atheroscler Rep, 16(5): 411

    Article  PubMed  Google Scholar 

  • Donato R, Cannon B R, Sorci G, Riuzzi F, Hsu K, Weber D J, Geczy C L (2013). Functions of S100 proteins. Curr Mol Med, 13(1): 24–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farthing D E, Farthing C A, Xi L (2015). Inosine and hypoxanthine as novel biomarkers for cardiac ischemia: from bench to point-of-care. Exp Biol Med (Maywood), 240(6): 821–831

    Article  CAS  Google Scholar 

  • Fontana P, Cattaneo M, Combescure C, Reny J L (2013). Tailored Thienopyridine therapy: no urgency for CYP2C19 genotyping. J Am Heart Assoc, 2(2): e000131

    Article  PubMed  PubMed Central  Google Scholar 

  • Friede K, Li J, Voora D (2017). Use of pharmacogenetic information in the treatment of cardiovascular disease. Clin Chem, 63(1): 177–185

    Article  CAS  PubMed  Google Scholar 

  • Gajda S N, Koltowski L, Tomaniak M (2014). Most recent evidence behind aggregometry and genotyping methods as platelet function testing for tailored anti-platelet treatment among PCI patients. Adv Clin Exp Med, 24(4): 687–693

    Article  Google Scholar 

  • Golukhova E Z, Ryabinina M N, Bulaeva N I, Grigorian M V, Kubova M Ch, Serebruany V L (2015). Clopidogrel response variability: impact of genetic polymorphism and platelet biomarkers for predicting adverse outcomes poststenting. Am J Ther, 22(3): 222–230

    Article  PubMed  Google Scholar 

  • Gorsuch W B, Chrysanthou E, Schwaeble W J, Stahl G L (2012). The complement system in ischemia-reperfusion injuries. Immunobiology, 217(11): 1026–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasan M S, Basri H B, Hin L P, Stanslas J (2013). Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci, 123(3): 143–154

    Article  CAS  PubMed  Google Scholar 

  • Hurst N L, Nooney V B, Raman B, Chirkov Y Y, De Caterina R, Horowitz J D (2013). Clopidogrel “resistance”: prevs post-receptor determinants. Vascul Pharmacol, 59(5-6): 152–161

    Article  CAS  PubMed  Google Scholar 

  • Jahn K, Suchodolski K, Schäfer A, Sahlmann B, Küster U, Echtermeyer F, Calmer S, Theilmeier G, Johanning K (2017). Effect of Clopidogrel on Thrombus Formation in an Ex Vivo Parallel Plate Flow Chamber Model Cannot Be Reversed by Addition of Platelet Concentrates or vWF Concentrate. Anesth Analg, 124(4): 1091–1098

    Article  CAS  PubMed  Google Scholar 

  • Jian L, Lu Y, Lu S, Lu C (2016). Chemical Chaperone 4-Phenylbutyric Acid Reduces Cardiac Ischemia/Reperfusion Injury by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress. Med Sci Monit, 22: 5218–5227

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiménez-Brítez G, Freixa X, Flores-Umanzor E, San Antonio R, Caixal G, Garcia J, Hernandez-Enriquez M, Andrea R, Regueiro A, Masotti M, Brugaletta S, Martin V, Sabaté M (2017). Out-of-hospital cardiac arrest and stent thrombosis: Ticagrelor versus clopidogrel in patients with primary percutaneous coronary intervention under mild therapeutic hypothermia. Resuscitation, 114: 141–145

    Article  PubMed  Google Scholar 

  • Kaikita K, Ono T, Iwashita S, Nakayama N, Sato K, Horio E, Nakamura S, Tsujita K, Tayama S, Hokimoto S, Sakamoto T, Nakao K, Oshima S, Sugiyama S, Ogawa H (2014). Impact of CYP2C19 polymorphism on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing percutaneous coronary intervention. J Atheroscler Thromb, 21(1): 64–76

    Article  PubMed  Google Scholar 

  • Kosacka M, Brzecka A, Piesiak P, Korzeniewska A, Jankowska R (2015). Soluble ligand CD40 and uric acid as markers of atheromatosis in patients with obstructive sleep apnea. Adv Exp Med Biol, 839: 55–60

    Article  CAS  PubMed  Google Scholar 

  • Kubo T, Ino Y, Matsuo Y, Shiono Y, Kameyama T, Yamano T, Katayama Y, Taruya A, Nishiguchi T, Satogami K, Kashiyama K, Orii M, Kuroi A, Yamaguchi T, Tanaka A, Hozumi T, Akasaka T (2017). Reduction of in-stent thrombus immediately after percutaneous coronary intervention by pretreatment with prasugrel compared with clopidogrel: An optical coherence tomography study. J Cardiol, 69(2): 436–441

    Article  PubMed  Google Scholar 

  • Lippi G, Franchini M, Cervellin G (2013). Diagnosis and management of ischemic heart disease. Semin Thromb Hemost, 39(2): 202–213

    Article  CAS  PubMed  Google Scholar 

  • Lowe G, Rumley A (2014). The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us? Thromb Haemost, 112(5): 860–867

    Article  PubMed  Google Scholar 

  • Majumdar S, Rustagi S, Mondal S, Rijhwani V, Kaur J, Sharma P (2014). Aspirin resistance: An emerging clinical predicament is associated with single nucleotide polymorphisms. Int J Basic Appl Biol, 2(2): 63–68

    Google Scholar 

  • Malhotra N, Abunassar J, Wells G A, McPherson R, Fu A, Hibbert B, Labinaz M, Le May M, Dick A, Glover C, Froeschl M, Marquis J F, Tran L, Bernick J, Chong A Y, So D Y, and the CArdiovascular Percutaneous Intervention TriAL (CAPITAL) investigators (2015). A pharmacodynamic comparison of a personalized strategy for antiplatelet therapy versus ticagrelor in achieving a therapeutic window. Int J Cardiol, 197: 318–325

    Article  PubMed  Google Scholar 

  • Martínez-Quintana E, Tugores A (2015). Clopidogrel: A multifaceted affair. J Clin Pharmacol, 55(1): 1–9

    Article  PubMed  Google Scholar 

  • Men J L, Ren J, Ma R, Wang Z X (2015). High Level of vonWillebrand Factor in Non-ST Segment Elevation Myocardial Infarction Patients Predicted Cardiovascular Ischemic Events After Off-Pump Coronary Artery Bypass Surgery. Int Heart J, 56(3): 298–302

    Article  CAS  PubMed  Google Scholar 

  • Nadir Y (2014). Heparanase and coagulation-new insights. Rambam Maimonides Med J, 5(4): e0031

    Article  PubMed  PubMed Central  Google Scholar 

  • Nie X Y, Li J L, Zhang Y, Xu Y, Yang X L, Fu Y, Liang G K, Lu Y, Liu J, Shi L W (2017). Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity. J Zhejiang Univ Sci B, 18(1): 37–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olechowski B, Ashby A, Mariathas M, Khanna V, Mahmoudi M, Curzen N (2017). Is arachidonic acid stimulation really a test for the response to aspirin? Time to think again? Expert Rev Cardiovasc Ther, 15(1): 35–46

    Article  CAS  PubMed  Google Scholar 

  • Ou W, He Y, Li A, Liu B, Jin L (2016). Genotype Frequencies of CYP2C19, P2Y12 and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness. Int Heart J, 57(5): 586–592

    Article  PubMed  Google Scholar 

  • Perry C G, Shuldiner A R (2013). Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation? J Hum Genet, 58(6): 339–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu L N, Sun Y, Wang L, Han R F, Xia X S, Liu J, Li X (2015). Influence of CYP2C19 polymorphisms on platelet reactivity and clinical outcomes in ischemic stroke patients treated with clopidogrel. Eur J Pharmacol, 747: 29–35

    Article  CAS  PubMed  Google Scholar 

  • Rao H, et al (2016). Polymorphism of platelet collagen receptor glycoprotein VI is associated with aspirin response in patients with unstable angina. Int J Clin Exp Pathol, 9(1): 275–281

    Google Scholar 

  • Ray S (2014). Clopidogrel resistance: the way forward. Indian Heart J, 66(5): 530–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Razzaghi H, Tempczyk-Russell A, Haubold K, Santorico S A, Shokati T, Christians U, Churchill M E (2013). Genetic and structure-function studies of missense mutations in human endothelial lipase. PLoS One, 8(3): e55716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rollini F, Franchi F, Angiolillo D J (2017). Drug-drug interactions when switching between intravenous and Oral P2Y 12 receptor inhibitors. JACC Cardiovasc Interv, 10(2): 130–132

    Article  PubMed  Google Scholar 

  • Scott S A, Sangkuhl K, Gardner E E, Stein C M, Hulot J S, Johnson J A, Roden D M, Klein T E, Shuldiner A R, and the Clinical Pharmacogenetics Implementation Consortium (2011). Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther, 90(2): 328–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen H M, Silan F, Silan C, Degirmenci Y, Ozisik Kamaran H I (2015). Effects of CYP2C19 and P2Y12 gene polymorphisms on clinical results of patients using clopidogrel after acute Ischemic cerebrovascular disease. Balkan J Med Genet, 17(2): 37–41

    PubMed  PubMed Central  Google Scholar 

  • Sharma M Mascarenhas D A (2017). Ticagrelor associated heart block: The need for close and continued monitoring. Case Rep Cardiol, 2017; 5074891

    PubMed  PubMed Central  Google Scholar 

  • Sheikh Rezaei S, Geroldinger A, Heinze G, Reichardt B, Wolzt M (2017). Clopidogrel, prasugrel, or ticagrelor use and clinical outcome in patients with acute coronary syndrome: A nationwide long-term registry analysis from 2009 to 2014. Int J Cardiol, 235: 61–66

    Article  PubMed  Google Scholar 

  • Shuldiner A R, Palmer K, Pakyz R E, Alestock T D, Maloney K A, O'Neill C, Bhatty S, Schub J, Overby C L, Horenstein R B, Pollin T I, Kelemen M D, Beitelshees A L, Robinson S W, Blitzer M G, McArdle P F, Brown L, Jeng L J, Zhao RY, Ambulos N, Vesely MR, et alImplementation of pharmacogenetics: The Universityof Maryland personalized anti-platelet pharmacogenetics program. in American Journal of Medical Genetics Part C:Seminars in Medical Genetics. 2014. Wiley Online Library.

    Google Scholar 

  • Spiel A O, Gilbert J C, Jilma B (2008). von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation, 117(11): 1449–1459

    Article  CAS  PubMed  Google Scholar 

  • Stone G W, Witzenbichler B, Weisz G, Rinaldi M J, Neumann F J, Metzger D C, Henry T D, Cox D A, Duffy P L, Mazzaferri E, Gurbel P A, Xu K, Parise H, Kirtane A J, Brodie B R, Mehran R, Stuckey T D, and the ADAPT-DES Investigators (2013). Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet, 382(9892): 614–623

    Article  PubMed  Google Scholar 

  • Sumaya W, Storey R F (2017). Ticagrelor: Effects Beyond the P2Y12 Receptor. Interv Cardiol Clin, 6(1): 49–55

    PubMed  Google Scholar 

  • Tekin G, Tekin Y K, Erbay A R, Turhan H, Yetkin E (2013). Serum uric acid levels are associated with atrial fibrillation in patients with ischemic heart failure. Angiology, 64(4): 300–303

    Article  CAS  PubMed  Google Scholar 

  • Thomas M R, Lip G Y (2017). Novel Risk Markers and Risk Assessments for Cardiovascular Disease. Circ Res, 120(1): 133–149

    Article  CAS  PubMed  Google Scholar 

  • Thomas M R, Storey R F (2014). Impact of aspirin dosing on the effects of P2Y12 inhibition in patients with acute coronary syndromes. J Cardiovasc Transl Res, 7(1): 19–28

    Article  CAS  PubMed  Google Scholar 

  • Tough D F, Tak P P, Tarakhovsky A, Prinjha R K (2016). Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov, 15(12): 835–853

    Article  CAS  PubMed  Google Scholar 

  • Ulehlova J, Slavik L, Kucerova J, Krcova V, Vaclavik J, Indrak K (2014). Genetic polymorphisms of platelet receptors in patients with acute myocardial infarction and resistance to antiplatelet therapy. Genet Test Mol Biomarkers, 18(9): 599–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verlinden N J, Coons J C, Iasella C J, Kane-Gill S L (2017). Triple Antithrombotic Therapy With Aspirin, P2Y12 Inhibitor, and Warfarin After Percutaneous Coronary Intervention. J Cardiovasc Pharmacol Ther, doi: 10.117711074248417698042

    Google Scholar 

  • Wang K, Yuan Y, Liu X, Lau WB, Zuo L, Wang X, Ma L, Jiao K, Shang J, Wang W, Ma X, Liu H (2016). Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction. Sci Rep, 6(1): 37927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xin Y G, Zhang H S, Li Y Z, Guan Q G, Guo L, Gao Y, Yu H J, Zhang X G, Xu F, Zhang Y L, Jia D L, Sun Y X, Qi G X, Tian W (2017). Efficacy and safety of ticagrelor versus clopidogrel with different dosage in high-risk patients with acute coronary syndrome. Int J Cardiol, 228: 275–279

    Article  PubMed  Google Scholar 

  • Yang H H, Chen Y, Gao C Y (2016). Associations of P2Y12R gene polymorphisms with susceptibility to coronary heart disease and clinical efficacy of antiplatelet treatment with clopidogrel. Cardiovasc Ther, 34(6): 460–467

    Article  CAS  PubMed  Google Scholar 

  • Yi X, Lin J, Wang Y, Zhou Q, Wang C, Cheng W, Chi L (2016). Association of cytochrome P450 genetic variants with clopidogrel resistance and outcomes in acute ischemic stroke. J Atheroscler Thromb, 23(10): 1188–1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi X, Zhou Q, Wang C, Lin J, Liu P, Fu C (2017). Platelet receptor Gene (P2Y12, P2Y1) and platelet glycoprotein Gene (GPIIIa) polymorphisms are associated with antiplatelet drug responsiveness and clinical outcomes after acute minor ischemic stroke. Eur J Clin Pharmacol, 73 (4): 437–443

    Article  CAS  PubMed  Google Scholar 

  • Yip V L M, Pirmohamed M (2013). Expanding role of pharmacogenomics in the management of cardiovascular disorders. Am J Cardiovasc Drugs, 13(3): 151–162

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank all our colleagues in Golestan Hospital clinical research development unit, Ahvaz Jundishapur University of Medical Sciences.

Author information

Authors and Affiliations

  1. Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Habib Haybar & Zeinab Deris Zayeri

Authors
  1. Habib Haybar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeinab Deris Zayeri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zeinab Deris Zayeri.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haybar, H., Zayeri, Z.D. The value of using polymorphisms in anti-platelet therapy. Front. Biol. 12, 349–356 (2017). https://doi.org/10.1007/s11515-017-1456-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-017-1456-0

Keywords

Search

Navigation