Platelet turnover predicts outcome after coronary intervention

Summary

Elevated platelet turnover contributes to high platelet reactivity. High platelet reactivity after percutaneous coronary intervention (PCI) is associated with major adverse cardiovascular events (MACE). The purpose of this study was to determine the prognostic value of platelet turnover and function with regard to MACE after PCI with stent implantation. In this prospective observational study, 486 consecutive patients after PCI on aspirin and clopidogrel were included to determine platelet turnover (mean platelet volume (MPV), reticulated platelet fraction (RPF)) and platelet function (multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay). At six-months follow-up, MACE occurred in 10.7 % of patients. RPF (odds ratio [OR]=1.173 (95% confidence interval [CI 95 %] 1.040–1.324), p=0.009) and MPV (OR=1.459 (CI 95 % 1.059–2.008), p=0.021) were univariable predictors of MACE, whereas VASP-P (OR=1.016 (CI 95 % 1.000–1.032), p=0.052) and MEA (OR=0.999 (CI 95 % 0.980–1.017), p=0.895) failed to predict MACE. RPF remained the only platelet variable independently associated with MACE. The best model to predict MACE included: troponin I (OR=1.007 (CI 95 % 1.002–1.012), p=0.009), RPF (OR=1.136 (CI 95 % 1.001–1.288), p=0.048), CRP (OR=1.008 (CI 95 % 1.001–1.014), p=0.023) and history of myocardial infarction (OR=2.039 (CI 95 % 1.093–3.806), p=0.025). RPF (OR=1.211 (CI 95 % 1.042–1.406), p=0.012) was also independently associated with in-hospital bleedings. In conclusion, RPF as index of platelet turnover is an independent predictor of MACE and bleeding events in PCI patients on dual antiplatelet therapy. Since RPF can reliably be quantified along with routine haemograms, RPF might easily be applied in the setting of cardiovascular risk prediction.

Keywords

Reticulated platelets - mean platelet volume - Multiplate - VASP-P - dual antiplatelet therapy

• References

• 1 Freynhofer MK, Bruno V, Wojta J. et al. The Role of Platelets in Athero-Thrombotic Events. Curr Pharm Des 2012; 18: 5197-5214.
• 2 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 3 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
• 4 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 5 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; 36: 1762-1771.
• 6 Guthikonda S, Alviar CL, Vaduganathan M. et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52: 743-749.
• 7 Freynhofer MK, Gruber SC, Grove EL. et al. Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing. Thromb Haemost 2015; 114: 459-468.
• 8 Kristensen SD, Bath PM, Martin JF. Differences in bleeding time, aspirin sensitivity and adrenaline between acute myocardial infarction and unstable angina. Cardiovasc Res 1990; 24: 19-23.
• 9 Chu SG, Becker RC, Berger PB. et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2010; 08: 148-156.
• 10 Martin JF, Kristensen SD, Mathur A. et al. The causal role of megakaryocyte-platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 09: 658-670.
• 11 Ingram M, Coopersmith A. Reticulated platelets following acute blood loss. Br J Haematol 1969; 17: 225-229.
• 12 Grove EL, Hvas AM, Mortensen SB. et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 09: 185-191.
• 13 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
• 14 Ritchie JL, Harker LA. Platelet and fibrinogen survival in coronary atherosclerosis. Response to medical and surgical therapy. Am J Cardiol 1977; 39: 595-598.
• 15 Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156.
• 16 McBane RD. Gonzalez C, Hodge DO. et al. Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 2014; 37: 148-154.
• 17 Lev EI. Immature Platelets: Clinical Relevance and Research Perspectives. Circulation 2016; 134: 987-988.
• 18 Freynhofer MK, Brozovic I, Bruno V. et al. Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Haemost 2011; 106: 230-239.
• 19 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 20 Easton JD, Saver JL, Albers GW. et al. Definition and evaluation of transient ischaemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009; 40: 2276-2293
• 21 Briggs C, Kunka S, Hart D. et al. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol 2004; 126: 93-99.
• 22 Cesari F, Marcucci R, Gori AM. et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 2013; 109: 846-853.
• 23 Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood 2008; 111: 981-986.
• 24 Trowbridge EA, Slater DN, Kishk YT. et al. Platelet production in myocardial infarction and sudden cardiac death. Thromb Haemost 1984; 52: 167-171.
• 25 Bath PM, Gladwin AM, Carden N. et al. Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis. Cardiovasc Res 1994; 28: 1348-1352.
• 26 Dalby Kristensen S, Bath PM, Martin JF. The bleeding time is inversely related to megakaryocyte nuclear DNA content and size in man. Thromb Haemost 1988; 59: 357-359.
• 27 Martin JF, Trowbridge EA, Salmon G. et al. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32: 443-460.
• 28 Perneby C, Wallen NH, Rooney C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
• 29 Henry P, Vermillet A, Boval B. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105: 336-344.
• 30 Dragani A, Pascale S, Recchiuti A. et al. The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy. Blood 2010; 115: 1054-1061.
• 31 Wurtz M, Hvas AM, Jensen LO. et al. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol 2014; 175: 274-279.
• 32 Guthikonda S, Lev EI, Patel R. et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 05: 490-496.
• 33 Kieffer N, Guichard J, Farcet JP. et al. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem 1987; 164: 189-195.
• 34 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
• 35 Stratz C, Nuhrenberg T, Amann M. et al. Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. Thromb Haemost 2016; 116: 941-948.
• 36 Stratz C, Bomicke T, Younas I. et al. Comparison of Immature Platelet Count to Established Predictors of Platelet Reactivity During Thienopyridine Therapy. J Am Coll Cardiol 2016; 68: 286-293.
• 37 Wurtz M, Grove EL, Wulff LN. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. JACC Cardiovasc Interv 2010; 03: 828-835.
• 38 Ibrahim H, Schutt RC, Hannawi B. et al. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014; 64: 2122-2129.
• 39 De Labriolle A, Bonello L, Lemesle G. et al. Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors. Eur Heart J 2010; 31: 1079-1087.
• 40 Perl L, Lerman-Shivek H, Rechavia E. et al. Response to Prasugrel and Levels of Circulating Reticulated Platelets in Patients with ST-Elevation Myocardial Infarction. J Am Coll Cardiol 2014; 63: 513-517.