Download PDF
Thromb Haemost 2006; 95(02): 253-259
DOI: 10.1160/TH05-07-0516
Platelets and Blood Cells
Schattauer GmbH

Polymorphisms of COX-1 and GP VI associate with the antiplatelet effect of aspirin in coronary artery disease patients

Aino Lepäntalo
1   Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland
,
Jussi Mikkelsson
2   Research Unit, Laboratory Centre, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
,
Julio C. Reséndiz
3   Wihuri Research Institute, Helsinki, Finland
,
Leena Viiri
2   Research Unit, Laboratory Centre, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
,
Janne T. Backman
4   Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland
,
Esko Kankuri
5   Institute of Biomedicine, University of Helsinki, Helsinki, Finland
,
Pekka J. Karhunen
2   Research Unit, Laboratory Centre, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
,
Riitta Lassila
1   Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland
› Author AffiliationsFinancial support: This study was supported financially by the Helsinki University Central Hospital research funds, Finnish Society of Angiology, Einar and Karin Stoems fund, Duodecim Medical Society, Paavo Nurmi Foundation and Yrjö Jahnsson Foundation.
Further Information

Publication History

Received 24 July 2005

Accepted after resubmission 16 January 2005

Publication Date:
28 November 2017 (online)

    Permissions and Reprints

Summary

The antiplatelet effect of aspirin varies individually. This study evaluated whether the antiplatelet effect of aspirin associates with polymorphisms in the genes coding for cyclo-oxygenase-1 (COX-1) and several platelet glycoprotein (GP) receptors in patients with stable coronary artery disease (CAD). Blood samples were collected from 101 aspirin-treated (mean 100 mg/d) patients. Compliance to treatment was assessed by plasma salicylate measurement. Platelet functions were assessed by two methods: 1) Response to arachidonic acid (AA, 1.5 mmol/L in aggregometry, and 2) PFA-100, evaluating platelet activation under high shear stress in the presence of collagen and epinephrine (CEPI). Aspirin non-response was defined as: 1) slope steeper than 12%/min in AA-aggregations,and 2) by closure time shorter than 170 s in PFA-100. The methods used detected different individuals as being aspirin non-responders. Five and 21 patients, respectively, were non-responders according to AA-induced aggregation and PFA-100. Increased plasma thromboxane B2 levels correlated with poor aspirin-response measured with both AA-induced aggregations and PFA-100 (P=0.02 and P=0.003, respectively). Of the non-responders detected by AA, 3 of5 (60%) carried the rareG allele for the -A842G polymorphism of COX-1 in contrast to 16 of 96 (17%) responders (P=0.016). Diabetes was associated with poor response. Aspirin non-response detected by PFA-100 associated with C13254T polymorphism of GP VI and female gender (P=0.012 and P=0.019, respectively). Although two patients were possibly non-compliant, this did not effect present conclusions. Evaluation of aspirin efficacy by AA-induced aggregation and PFA-100 detected different individuals, with different genotypic profiles, as being aspirin non-responders.

Keywords

Aspirin - cyclo-oxygenase-1 - genotype - glycoprotein VI - coronary artery disease
 

  • References

  • 1 Antithrombotic Trialists Collaboration. Collaborative meta-analyses of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86.
    CrossrefPubMedGoogle Scholar
  • 2 Zimmermann N, Wenk A, Kim U. et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003; 108: 542-7.
    CrossrefPubMedGoogle Scholar
  • 3 Gum P, Kottke-Marchant K, Poggio E. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-5.
    CrossrefPubMedGoogle Scholar
  • 4 Gum P, Kottke-Marchant K, Welsh P. et al. A prospective blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-5.
    CrossrefPubMedGoogle Scholar
  • 5 Buchanan MR, Schwartz L, Bourassa M. et al. Results of the BRAT study--a pilot study investigating the possible significance of ASA nonresponsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Canadian Journal of Cardiology 2000; 16: 1385-90.
    PubMedGoogle Scholar
  • 6 Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003; 01: 1710-3.
    CrossrefPubMedGoogle Scholar
  • 7 Cattaneo M. Aspirin and clopidogrel efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-7.
    CrossrefPubMedGoogle Scholar
  • 8 Alberts M, Bergman D, Molner E. et al. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004; 35: 175-8.
    PubMedGoogle Scholar
  • 9 Eikelboom J, Hirsh J, Weitz J. et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke or cardiovascular death in patients at the high risk for cardiovascular events. Circulation 2002; 105: 1650-5.
    CrossrefPubMedGoogle Scholar
  • 10 Catella-Lawson F, Reilly M, Kapoor S. et al. Cyclooxygenase inhibitors and the antiplatelet affects of aspirin. N Eng J Med 2001; 345: 1809-17.
    CrossrefPubMedGoogle Scholar
  • 11 Cipollone F, Ciabattoni G, Patrignani P. et al. Oxidant stress and aspirin insensitive thromboxane biosynthesis in severe unstable angina. Circulation 2000; 102: 1007-13.
    CrossrefPubMedGoogle Scholar
  • 12 Weber AA, Zimmermann KC, Meyer-Kirchrath J. et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet. 1999 353. 900 letter.
    PubMedGoogle Scholar
  • 13 Halushka M, Walker L, Halushka P. Genetic variation in cyclooxygenase 1: Effects on response to aspirin. Clin Pharmacol Ther 2003; 73: 122-30.
    CrossrefPubMedGoogle Scholar
  • 14 Hillarp A, Palmqvist B, Lethagen S. et al. Mutations within the cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke. Thromb Res 2001; 112: 275-83.
    PubMedGoogle Scholar
  • 15 Maree AO, Curtin RJ, Chubb A. et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 03: 2340-5.
    CrossrefPubMedGoogle Scholar
  • 16 Macchi L, Christiaens L, Brabant S. et al. Resistance in vitro to low-dose aspirin is associated with platelet Pla1 (GP IIIa) polymorphism but not with C807T (GP Ia/IIa) and C-5T Kozak (GP Iba) polymorphisms. J Am Coll Cardiol 2003; 42: 1115-9.
    CrossrefPubMedGoogle Scholar
  • 17 Szczeklik A, Undas A, Sanak M. et al. Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa. Br J Haematol 2000; 110: 965-7.
    CrossrefPubMedGoogle Scholar
  • 18 Croft SA, Samani NJ, Teare MC. et al. Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation 2001; 104: 1459-63.
    CrossrefPubMedGoogle Scholar
  • 19 Mikkelsson J, Perola M, Penttilä A. et al. Platelet glycoprotein Iba HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation 2001; 104: 876-80.
    CrossrefPubMedGoogle Scholar
  • 20 Mikkelsson J, Perola M. Laippala et al. The Glycoprotein IIIa PlA polymorphism associates with progression of coronary artery disease and with myocardial infarction in an autopsy series of middle-aged men who died suddenly. Arterioscler Thromb Vasc Biol 1999; 19: 2573-8.
    CrossrefPubMedGoogle Scholar
  • 21 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: 95-9.
    CrossrefPubMedGoogle Scholar
  • 22 Moshfegh K, Wuillemin WA, Redondo M. et al. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353: 351-4.
    CrossrefPubMedGoogle Scholar
  • 23 Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Research 1991; 19: 5444.
    CrossrefPubMedGoogle Scholar
  • 24 Mikkelsson J, Perola M, Penttilä A. et al. Platelet collagen receptor GPIa (C807T/HPA-5) haplotype is not associated with an increased risk of fatal coronary events in middle-aged men. Atherosclerosis 2002; 165: 111-8.
    CrossrefPubMedGoogle Scholar
  • 25 Siljander P, Lassila R. Studies of adhesion-dependent platelet activation: distinct roles for different participating receptors can be dissociated by proteolysis of collagen. Arterioscler Thromb Vasc Biol 1999; 19: 3033-43.
    CrossrefPubMedGoogle Scholar
  • 26 Lepäntalo A, Virtanen K, Heikkilä J. et al. Limited early antiplatelet effect of 300mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004; 25: 476-83.
    CrossrefPubMedGoogle Scholar
  • 27 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24: 195-202.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Favaloro EJ. Clinical application of the PFA-100®. Curr Opin Hematol 2002; 09: 407-15.
    CrossrefPubMedGoogle Scholar
  • 29 Homoncik M, Jilma B, Hergovich N. et al. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83: 316-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Ojanen R, Kaukinen L, Seppälä E. et al. Single dose of acetylsalicylic acid prevents thromboxane release after tourniquet ischemia. J Trauma 2003; 54: 986-9.
    CrossrefPubMedGoogle Scholar
  • 31 Brandon RA, Eadie MJ, Smith MT. A sensitive liquid chromatography assay for plasma aspirin and salicylate concentrations after low doses of aspirin. Ther Drug Monit 1985; 07: 216-21.
    CrossrefPubMedGoogle Scholar
  • 32 Cerletti C, Dell’Elba G, Manarini S. et al. Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may effect therapeutic outcomes. Clin Pharmacokinet 2003; 42: 1059-70.
    CrossrefPubMedGoogle Scholar
  • 33 Schwertner HA, McGlasson D, Christopher M. et al. Effects of different aspirin formulations on platelet aggregation times and on plasma salicylate concentration. Thromb Res. 2005 prepublished online doi:10.1016/j.thromres.2005.10.001.
    PubMedGoogle Scholar
  • 34 Tantry UA, Bliden KP, Gurbel PA. et al. Overestimation of platelet aspirin resistance detection by thromboelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 2005; 46: 1705-9.
    CrossrefPubMedGoogle Scholar
  • 35 Weber AA, Przytulski B, Schanz A. et al. Towards a definition of aspirin resistance: a typological approach. Platelets 2002; 13: 37-40.
    CrossrefPubMedGoogle Scholar
  • 36 Topol EJ, Gum P, Kottke-Marchant K. Determination of the natural history of aspirin resistance among stable patients with cardiovascular disease: Reply. JACC 2003; 42: 1336-7. letter.
    PubMedGoogle Scholar
  • 37 Chakroun T, Gerotziafas G, Francoise R. et al. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willerand factor. BrJ Haematol 2004; 124: 80-5.
    CrossrefPubMedGoogle Scholar
  • 38 Poujol C. Ultrastructural analysis of the distribution of von Willebrand factor and fibrinogen in platelet aggregates formed in the PFA-100. Platelets 1998; 09: 381-9.
    CrossrefPubMedGoogle Scholar
  • 39 Michelson A, Furman M, Goldschmidt-Clermont P. et al. Platelet GP IIIa PlA polymorphism display different sensitivities to agonists. Circulation 2000; 101: 1013-8.
    CrossrefPubMedGoogle Scholar
  • 40 Joutsi-Korhonen L, Smethurst PA, Rankin A. et al. The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression. Blood 2003; 101: 4372-9.
    CrossrefPubMedGoogle Scholar
  • 41 Heemskerk JW, Siljander P, Vuist WM. et al. Function of glycoprotein VI and integrin α2β1 in the pro-coagulant response of single, collagen-adherent platelets. Thromb Haemost 1999; 81: 782-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Macchi L, Christiaens L, Brabant S. et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107: 151-5.
    CrossrefPubMedGoogle Scholar
  • 43 Westerbacka J, Yki-Jarvinen H, Turpeinen A. et al. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 167-72.
    CrossrefPubMedGoogle Scholar
  • 44 Tamminen M, Lassila R, Westerbacka J. et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes 2003; 27: 907-11.
    CrossrefPubMedGoogle Scholar
  • 45 Davi G, Ciabattoni G, Consoli A. et al. In vivo formation of 8-iso-prostaglandin F 2α and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 1999; 99: 224-9.
    CrossrefPubMedGoogle Scholar
  • 46 Buchanan MR, Rischke JA, Butt R. et al. The sexrelated differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res 1983; 29: 125-39.
    CrossrefPubMedGoogle Scholar
  • 47 Spranger M, Aspey BS, Harrison MJ. Sex difference in antithrombotic effect of aspirin. Stroke 1989; 20: 34-7.
    CrossrefPubMedGoogle Scholar
  • 48 Chen W-H, Lee P-Y, Ng W. et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004; 43: 1122-6.
    CrossrefPubMedGoogle Scholar
  • 49 Gurbel P, Blinde K, Hiatt B. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-13.
    CrossrefPubMedGoogle Scholar
  • 50 Patrono C, Coller B, FitzGerald GA. et al. Platelet active drugs: the relationships among dose, effectiveness, and side effects: the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 234S-264S.
    CrossrefPubMedGoogle Scholar