Platelet reactivity is a stable and global phenomenon in aspirin-treated cardiovascular patients

 

 Buy Article Permissions and Reprints

Summary

In healthy subjects, platelet hyperreactivity is a global phenomenon – as opposed to agonist-specific – and epinephrine-induced platelet aggregation (EPA) is a reliable marker of this phenotype. Few data are available on platelet reactivity and the relationship between EPA and aggregation induced by other agonists in cardiovascular patients. It was the objective of this study to characterise platelet reactivity in stable cardiovascular patients treated with aspirin and to derive a composite index integrating several aggregation pathways, suitable for selecting patients with extreme phenotypes for further proteomics analysis. Platelet reactivity to agonists was assessed in 110 patients twice, two weeks apart. Factorial analysis was used to determine whether the results obtained with the different agonists could be summarised in a single composite index. EPA correlated with the aggregation values obtained with each of the other agonists, with correlation coefficients of 0.44 to 0.55 (p<0.001). We constructed a composite “platelet reactivity” index that included 60% of the information provided by each agonist. The results obtained at the first patient visit were consistent with those obtained at the second visit (r=0.78, p<0.01). No clinical or biological parameters correlated with the composite index. The extreme phenotypes of six selected subjects were confirmed 12 months after the second visit. In conclusion, platelet reactivity in aspirin-treated cardiovascular patients is a global phenomenon that can be summarised by a composite index based on the aggregation responses to various agonists and integrating several activation pathways. This index is not dependent on clinical or biological variables, suggesting that genetic factors regulate platelet reactivity in these patients.

• References

• 1 Patrono C, Rocca B. Aspirin, 110 years later. J Thromb Haemost 2009; 7 (Suppl. 01) 258-261
  CrossrefPubMedGoogle Scholar
• 2 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
• 3 Breet NJ, van Werkum JW, Bouman HJ. et al. High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. J Thromb Haemost 2010; 8: 2140-2148.
  CrossrefPubMedGoogle Scholar
• 4 Combescure C, Fontana P, Mallouk N. et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2009; 8: 923-933.
  PubMedGoogle Scholar
• 5 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Gori AM, Marcucci R, Migliorini A. et al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents. J Am Coll Cardiol 2008; 52: 734-739.
  CrossrefPubMedGoogle Scholar
• 7 Reny JL, Bonvini RF, Bonvini JM. et al. Poor Responsiveness to Antiplatelet Drugs in Acute Coronary Syndromes: Clinical Relevance and Management. Cardiovasc Ther. 2011 in press.
  PubMedGoogle Scholar
• 8 Gori AM, Marcucci R, Paniccia R. et al. Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function. Thromb Haemost 2008; 100: 1136-1145.
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Yee DL, Sun CW, Bergeron AL. et al. Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106: 2723-2729.
  CrossrefPubMedGoogle Scholar
• 10 Yee DL, Bergeron AL, Sun CW. et al. Platelet hyperreactivity generalizes to multiple forms of stimulation. J Thromb Haemost 2006; 4: 2043-2050.
  CrossrefPubMedGoogle Scholar
• 11 Guthikonda S, Mangalpally K, Vaduganathan M. et al. Increased platelet sensitivity among individuals with aspirin resistance – platelet aggregation to submaximal concentration of arachidonic acid predicts response to antiplatelet therapy. Thromb Haemost 2008; 100: 83-89.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Faraday N, Yanek LR, Mathias R. et al. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1. Circulation 2007; 115: 2490-2496.
  CrossrefPubMedGoogle Scholar
• 13 Bray PF, Mathias RA, Faraday N. et al. Heritability of platelet function in families with premature coronary artery disease. J Thromb Haemost 2007; 5: 1617-1623.
  CrossrefPubMedGoogle Scholar
• 14 Kunicki TJ, Nugent DJ. The genetics of normal platelet reactivity. Blood 2010; 116: 2627-2634.
  CrossrefPubMedGoogle Scholar
• 15 Williams MS, Weiss EJ, Sabatine MS. et al. Genetic regulation of platelet receptor expression and function: application in clinical practice and drug development. Arterioscler Thromb Vasc Biol 2010; 30: 2372-2384.
  CrossrefPubMedGoogle Scholar
• 16 Jaitner J, Stegherr J, Morath T. et al. Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients. Thromb Haemost 2011; 105: 107-112.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Peace AJ, Tedesco AF, Foley DP. et al. Dual antiplatelet therapy unmasks distinct platelet reactivity in patients with coronary artery disease. J Thromb Haemost 2008; 6: 2027-2034.
  CrossrefPubMedGoogle Scholar
• 18 Fontana P, de Moerloose P, Reny JL. Platelet hyperreactivity and dual antiplatelet therapy: can biases be avoided?. J Thromb Haemost 2009; 7: 363-364.
  CrossrefPubMedGoogle Scholar
• 19 Cazenave JP, Ohlmann P, Cassel D. et al. Preparation of washed platelet suspensions from human and rodent blood. Methods Mol Biol 2004; 272: 13-28.
  PubMedGoogle Scholar
• 20 Dayon L, Turck N, Kienle S. et al. Isobaric tagging-based selection and quantitation of cerebrospinal fluid tryptic peptides with reporter calibration curves. Anal Chem 2010; 82: 848-858.
  CrossrefPubMedGoogle Scholar
• 21 Patrono C, Ciabattoni G, Pinca E. et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327.
  CrossrefPubMedGoogle Scholar
• 22 Cuzick J. A Wilcoxon-type test for trend. Stat Med 1985; 4: 87-90.
  CrossrefPubMedGoogle Scholar
• 23 Ohmori T, Yatomi Y, Nonaka T. et al. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost 2006; 4: 1271-1278.
  CrossrefPubMedGoogle Scholar
• 24 Gorsuch RL. Factor analysis.. 2nd Edition Hillsdale, NJ: 1983
• 25 Lanza F, Beretz A, Stierle A. et al. Epinephrine potentiates human platelet activation but is not an aggregating agent. Am J Physiol 1988; 255: H1276-1288.
  PubMedGoogle Scholar
• 26 Trip MD, Cats VM, van Capelle FJ. et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554.
  CrossrefPubMedGoogle Scholar
• 27 Kabbani SS, Watkins MW, Ashikaga T. et al. Platelet reactivity characterized prospectively: a determinant of outcome 90 days after percutaneous coronary intervention. Circulation 2001; 104: 181-186.
  CrossrefPubMedGoogle Scholar
• 28 Frossard M, Fuchs I, Leitner JM. et al. Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation 2004; 110: 1392-1397.
  CrossrefPubMedGoogle Scholar
• 29 Bray PF. Platelet hyperreactivity: predictive and intrinsic properties. Hematol Oncol Clin North Am 2007; 21: 633-645.
  CrossrefPubMedGoogle Scholar
• 30 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: 989-995.
  CrossrefPubMedGoogle Scholar
• 31 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: 1833-1840.
  CrossrefPubMedGoogle Scholar
• 32 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: 252-257.
  PubMedGoogle Scholar
• 33 Jones CI, Garner SF, Angenent W. et al. Mapping the platelet profile for functional genomic studies and demonstration of the effect size of the GP6 locus. J Thromb Haemost 2007; 5: 1756-1765.
  CrossrefPubMedGoogle Scholar
• 34 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: 356-360.
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 Jones CI, Bray S, Garner SF. et al. A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways. Blood 2009; 114: 1405-1416.
  CrossrefPubMedGoogle Scholar
• 36 O’Donnell CJ, Larson MG, Feng D. et al. Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation 2001; 103: 3051-3056.
  CrossrefPubMedGoogle Scholar
• 37 Gaxiola B, Friedl W, Propping P. Epinephrine-induced platelet aggregation. A twin study. Clin Genet 1984; 26: 543-548.
  PubMedGoogle Scholar
• 38 Fontana P, Nolli S, Reber G. et al. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost 2006; 4: 813-819.
  CrossrefPubMedGoogle Scholar
• 39 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
• 40 Fontana P, Berdague P, Castelli C. et al. Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study. J Thromb Haemost 2010; 8: 2614-2623.
  CrossrefPubMedGoogle Scholar
• 41 Frelinger AL, 3rd Furman MI, Linden MD. et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclo-oxygenase-1– and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006; 113: 2888-2896.
  CrossrefPubMedGoogle Scholar
• 42 Reny JL, De Moerloose P, 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; 6: 444-450.
  CrossrefPubMedGoogle Scholar
• 43 Crescente M, Di Castelnuovo A, Iacoviello 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
• 44 Geisler T, Gawaz M. Editorial on “Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy” by Marcucci et al. Thromb Haemost 2007; 98: 705-706.
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Marcucci R, Paniccia R, Antonucci E. et al. Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy. Thromb Haemost 2007; 98: 844-851.
  Article in Thieme ConnectPubMedGoogle Scholar
• 46 Mateos-Caceres PJ, Macaya C, Azcona L. et al. Different expression of proteins in platelets from aspirin-resistant and aspirin-sensitive patients. Thromb Haemost 2010; 103: 160-170.
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 Johnson AD, Yanek LR, Chen MH. et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet 2010; 42: 608-613.
  CrossrefPubMedGoogle Scholar
• 48 Kondkar AA, Bray MS, Leal SM. et al. VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J Thromb Haemost 2010; 8: 369-378.
  CrossrefPubMedGoogle Scholar