Download PDF
Thromb Haemost 2009; 101(01): 123-133
DOI: 10.1160/TH08-05-0287
Platelets and Blood Cells
Schattauer GmbH

Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease

Thomas J. Kunicki
1   Division of Experimental Hemostasis and Thrombosis, of the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Shirley A. Williams
2   Division of Hematology, The Children’s Hospital of Orange County, Orange, California, USA
,
Diane J. Nugent
2   Division of Hematology, The Children’s Hospital of Orange County, Orange, California, USA
,
Paul Harrison
3   Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK
,
Helen C. Segal
3   Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK
,
Anila Syed
4   Stroke Prevention Research Unit, Department of Clinical Neurology, University of Oxford, Oxford, UK
,
Peter M. Rothwell
5   University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK
› Author AffiliationsFinancial support: This study was supported by R01 Grant HL075821 from the NHLBI awarded to TJK and funding provided to DJN from The CHOC Foundation.
Further Information

Publication History

Received: 06 May 2008

Accepted after major revision: 20 October 2008

Publication Date:
23 November 2017 (online)

    Permissions and Reprints

Summary

We studied the effect of prophylactic aspirin (ASA) ingestion on platelet function in 463 patients with stroke, transient ischemic attack (TIA) or acute coronary disease (ACD), using the Platelet Function Analyzer-100 (PFA-100). We correlated ASA responsiveness with haplotypes of seven candidate genes, selected for their documented role in platelet function, namely, the genes for integrins α2β1and αIIbβ3 (ITGA2, ITGA2B, and ITGB3), platelet glycoproteins Ibα and VI (GPIBA and GP6), the purinergic receptor P2Y1 (P2RY1), and prostaglandin H synthase 1 (PTGS1 = COX1). Non-responsiveness to ASA was defined as the failure of prior ASA ingestion to prolong the PFA-100 closure time (CT) when blood was perfused through cartridges coated with collagen plus epinephrine (CEPI-CT). ASA non-responsiveness was observed in 114 of 463 patients (24.6 %), but was not associated with haplotypes of any of the seven candidate genes. There was also no association between any haplotypes and the CT when blood was perfused through cartridges coated with collagen plus ADP (CADP-CT). The ASA non-responsive cohort had significantly increased whole blood platelet counts (p = 0.03) and plasma von Willebrand Factor antigen levels (p<0.001), which likely contributes to resistance to the inhibitory effects of ASA in the PFA-100.

Keywords

Aspirin - PFA-100 - platelet - SNP - VWF
 

  • References

  • 1 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86.
    CrossrefPubMedGoogle Scholar
  • 2 Gum PA, Kottke-Marchant K, Poggio ED. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-235.
    CrossrefPubMedGoogle Scholar
  • 3 Cattaneo M. Aspirin and Clopidogrel. Efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
    CrossrefPubMedGoogle Scholar
  • 4 Eikelboom JW, Hankey GJ. Failure of aspirin to prevent atherothrombosis: potential mechanisms and implications for clinical practice. Am J Cardiovasc Drugs 2004; 04: 57-67.
    CrossrefPubMedGoogle Scholar
  • 5 Gum PA, Kottke-Marchant K, Welsh PA. 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: 961-965.
    CrossrefPubMedGoogle Scholar
  • 6 Eikelboom JW, Hankey GJ. Aspirin resistance: a new independent predictor of vascular events?. J Am Coll Cardiol 2003; 41: 966-968.
    CrossrefPubMedGoogle Scholar
  • 7 Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006; 367: 606-617.
    CrossrefPubMedGoogle Scholar
  • 8 Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol 2008; 51: 1829-1843.
    CrossrefPubMedGoogle Scholar
  • 9 Tran HA, Anand SS, Hankey GJ. et al. Aspirin resistance. Thromb Res 2007; 120: 337-346.
    CrossrefPubMedGoogle Scholar
  • 10 Harrison P, Segal H, Silver L. et al. Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests. Platelets 2008; 19: 119-124.
    CrossrefPubMedGoogle Scholar
  • 11 Homoncik M, Jilma B, Hergovich N. et al. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83: 316-321.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Rothwell PM, Coull AJ, Giles MF. et al. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet 2004; 363: 1925-1933.
    CrossrefPubMedGoogle Scholar
  • 13 Rothwell PM, Coull AJ, Silver LE. et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 2005; 366: 1773-1783.
    CrossrefPubMedGoogle Scholar
  • 14 Coull AJ, Silver LE, Bull LM. et al. Direct assessment of completeness of ascertainment in a stroke incidence study. Stroke 2004; 35: 2041-2045.
    CrossrefPubMedGoogle Scholar
  • 15 Harrison P, Segal H, Blasbery K. et al. Screening for aspirin responsiveness after transient ischemic attack and stroke: comparison of 2 point-of-care platelet function tests with optical aggregometry. Stroke 2005; 36: 1001-1005.
    CrossrefPubMedGoogle Scholar
  • 16 Harrison P, Robinson MS, Mackie IJ. et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 1999; 10: 25-31.
    CrossrefPubMedGoogle Scholar
  • 17 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-163.
    CrossrefPubMedGoogle Scholar
  • 18 Crescente M, Di CA, Lacoviello L. et al. Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100. A systematic review. Thromb Haemost 2008; 99: 14-26.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Jacquelin B, Tarantino MD, Kritzik M. et al. Allele-dependent transcriptional regulation of the human integrin alpha 2 gene. Blood 2001; 97: 1721-1726.
    CrossrefPubMedGoogle Scholar
  • 20 Kritzik M, Savage B, Nugent DJ. et al. Nucleotide polymorphisms in the alpha 2 gene define multiple alleles which are associated with differences in platelet alpha 2 beta 1. Blood 1998; 92: 2382-2388.
    PubMedGoogle Scholar
  • 21 Kalb R, Santoso S, Unkelbach K. et al. Localization of the Br polymorphism on a 144 bp Exon of the GPIa gene and its application in platelet DNA typing. Thromb Haemost 1994; 71: 651-654.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Di Paola J, Jugessur A, Goldman T. et al. Platelet glycoprotein Ibalpha and integrin alphabeta polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel. J Thromb Haemost 2005; 03: 1511-1521.
    CrossrefPubMedGoogle Scholar
  • 23 Reiner AP, Kumar PN, Schwartz SM. et al. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000; 31: 1628-1633.
    CrossrefPubMedGoogle Scholar
  • 24 Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PLA1 and PLA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989; 83: 1778-1781.
    CrossrefPubMedGoogle Scholar
  • 25 Afshar-Kharghan V, Li CQ, Khoshnevis-Asl M. et al. Kozak sequence polymorphism of the glycoprotein (GP) Ibalpha gene is a major determinant of the plasma membrane levels of the platelet GP Ib- IX-V complex. Blood 1999; 94: 186-191.
    PubMedGoogle Scholar
  • 26 Kaski S, Kekomaki R, Partanen J. Systematic screening for genetic polymorphism in human platelet glycoprotein Ib alpha. Immunogenetics 1996; 44: 170-176.
    CrossrefPubMedGoogle Scholar
  • 27 Kuijpers RWAM, Faber NM, Cuypers HTM. et al. NH2-Terminal globular domain of human platelet glycoprotein Iba has a methionine145/threonine145 amino acid polymorphism, which is associated with the HPA-2 (Ko) alloantigens. J Clin Invest 1992; 89: 381-384.
    CrossrefPubMedGoogle Scholar
  • 28 Murata M, Furihata K, Ishida F. et al. Genetic and structural characterization of an amino acid dimorphism in glycoprotein Iba involved in platelet transfusion refractoriness. Blood 1992; 79: 3086-3090.
    PubMedGoogle Scholar
  • 29 Kunicki TJ, Federici AB, Salomon DR. et al. An association of candidate gene haplotypes and bleeding severity in Von Willebrand Disease (VWD) type 1 pedigrees. Blood 2004; 104: 2359-2367.
    CrossrefPubMedGoogle Scholar
  • 30 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: 4372-4379.
    CrossrefPubMedGoogle Scholar
  • 31 Jefferson BK, Foster JH, McCarthy JJ. et al. Aspirin resistance and a single gene. Am J Cardiol 2005; 95: 805-808.
    CrossrefPubMedGoogle Scholar
  • 32 Maree AO, Curtin RJ, Chubb A. et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 03: 2340-2345.
    CrossrefPubMedGoogle Scholar
  • 33 Chakroun T, Gerotziafas G, Robert F. et al. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor. Br J Haematol 2004; 124: 80-85.
    CrossrefPubMedGoogle Scholar
  • 34 Reny JL, de MP, Dauzat M. et al. Use of the PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 06: 444-450.
    CrossrefPubMedGoogle Scholar
  • 35 Krasopoulos G, Brister SJ, Beattie WS. et al. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008; 336: 195-198.
    CrossrefPubMedGoogle Scholar
  • 36 Snoep JD, Hovens MM, Eikenboom JC. et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 1593-1599.
    CrossrefPubMedGoogle Scholar
  • 37 Crescente M, Di CA, Lacoviello L. et al. PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: A meta-analysis of 19 studies comprising 3,003 patients. Thromb Haemost 2008; 99: 1129-1131.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Ye Z, Liu EH, Higgins JP. et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
    CrossrefPubMedGoogle Scholar
  • 39 Kunicki TJ, Nugent DJ. The influence of platelet glycoprotein polymorphisms on receptor function and risk for thrombosis. Vox Sang 2002; 83: 85-90.
    CrossrefPubMedGoogle Scholar
  • 40 Vijayan KV, Goldschmidt-Clermont PJ, Roos C. et al. The P1(A2) polymorphism of integrin beta(3) enhances outdie-in signaling and adhesive functions. J Clin Invest 2000; 105: 793-802.
    CrossrefPubMedGoogle Scholar
  • 41 Michelson AD, Furman MI, Goldschmidt-Clermont P. et al. Platelet GP IIIa PI(A) polymorphisms display different sensitivities to agonists. Circulation 2000; 101: 1013-1018.
    CrossrefPubMedGoogle Scholar
  • 42 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: 965-967.
    CrossrefPubMedGoogle Scholar
  • 43 Szczeklik A, Sanak M, Undas A. Platelet glycoprotein IIIa pl(a) polymorphism and effects of aspirin on thrombin generation. Circulation 2001; 103: E33-E34.
    CrossrefPubMedGoogle Scholar
  • 44 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 Ibalpha) polymorphisms. J Am Coll Cardiol 2003; 42: 1115-1119.
    CrossrefPubMedGoogle Scholar
  • 45 Cooke GE, Liu-Stratton Y, Ferketich AK. et al. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination. J Am Coll Cardiol 2006; 47: 541-546.
    CrossrefPubMedGoogle Scholar
  • 46 Cooke GE, Bray PF, Hamlington JD. et al. PIA2 polymorphism and efficacy of aspirin. Lancet 1998; 351: 1253-1253.
    CrossrefPubMedGoogle Scholar
  • 47 Lev EI, Patel RT, Guthikonda S. et al. Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Thromb Res 2007; 119: 355-360.
    CrossrefPubMedGoogle Scholar
  • 48 Bernardo E, Angiolillo DJ, Ramirez C. et al. Lack of association between gene sequence variations of platelet membrane receptors and aspirin responsiveness detected by the PFA-100 system in patients with coronary artery disease. Platelets 2006; 17: 586-590.
    CrossrefPubMedGoogle Scholar
  • 49 Kunicki TJ, Kritzik M, Annis DS. et al. Hereditary variation in platelet integrin α2β1 copy number is associated with two silent polymorphisms in the a2 gene coding sequence. Blood 1997; 89: 1939-1943.
    PubMedGoogle Scholar
  • 50 Gonzalez-Conejero R, Rivera J, Corral J. et al. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure?. Stroke 2005; 36: 276-280.
    CrossrefPubMedGoogle Scholar
  • 51 Lepantalo A, Mikkelsson J, Resendiz JC. et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95: 253-259.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Takahashi S, Ushida M, Komine R. et al. Platelet responsiveness to in vitro aspirin is independent of COX-1 and COX-2 protein levels and polymorphisms. Thromb Res 2008; 121: 509-517.
    CrossrefPubMedGoogle Scholar
  • 53 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: 45-49.
    CrossrefPubMedGoogle Scholar
  • 54 Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive systematic review. Br J Clin Pharmacol 2008; 66: 222-232.
    CrossrefPubMedGoogle Scholar