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Journal of Thrombosis and Thrombolysis

, Volume 41, Issue 4, pp 663–670 | Cite as

Immature platelet fraction and high-on treatment platelet reactivity with ticagrelor in patients with acute coronary syndromes

  • Monica Verdoia
  • Chiara Sartori
  • Patrizia Pergolini
  • Matteo Nardin
  • Roberta Rolla
  • Lucia Barbieri
  • Alon Schaffer
  • Paolo Marino
  • Giorgio Bellomo
  • Harry Suryapranata
  • Giuseppe De Luca
Article

Abstract

Residual high-on treatment platelet reactivity (HRPR) has been associated with a 2–9 fold increased risk of acute ischemic events in patients with acute coronary syndromes or coronary stenting. However, the mechanism of suboptimal platelet inhibition are still poorly understood. Aim of present study was to evaluate the role of the percentage of reticulated platelets on HRPR with ticagrelor. In patients treated with ASA (100–160 mg) and ticagrelor (90 mg twice a day) platelet reactivity and the reticulated platelets fraction (immature platelets fraction, IPF) were assessed at 30–90 days after acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined as ADP test >417 AU*min. Our population is represented by 190 patients, divided according to tertiles values of IPF (<2.5; 2.5–3.99; ≥4 %). Higher IPF was associated to a larger platelet volume and lower platelets count (p < 0.001), and inversely related with a history of previous coronary revascularization (p = 0.03). Twenty-one out of 190 (11.0 %) patients displayed HRPR. No difference in the levels of circulating IPF was found in patients with or without HRPR (p = 0.25), with no correlation between the rate of reticulated platelets and platelet reactivity at ADP test (r = −0.084, p = 0.26). In fact no association was observed between high levels of IPF and the occurrence of HRPR (adjusted OR[95 % CI] = 0.69[0.34–1,37], p = 0.28), even after correction for baseline differences. In patients treated with ticagrelor, the levels of circulating reticulated platelets assessed at 30–90 days post-ACS are not associated with platelet reactivity or the occurrence of HRPR.

Keywords

Ticagrelor High-on treatment platelet reactivity Immature platelets fraction 

Notes

Compliance with ethical standards

Conflict of interest

The Authors declare no conflict of interest or funding source to disclose.

References

  1. 1.
    De Luca G, Marino P (2008) Advances in antithrombotic therapy as adjunct to reperfusion therapies for ST-segment elevation myocardial infarction. Thromb Haemost 100:184–195PubMedGoogle Scholar
  2. 2.
    De Luca G, Dirksen MT, Spaulding C, Kelbæk H, Schalij M, Thuesen L, van der Hoeven B, Vink MA, Kaiser C, Musto C, Chechi T, Spaziani G, Diaz de la Llera LS, Pasceri V, Di Lorenzo E, Violini R, Suryapranata H, Stone GW, DESERT cooperation (2013) Time course, predictors and clinical implications of stent thrombosis following primary angioplasty. Insights from the DESERT cooperation. Thromb Haemost 110:826–833CrossRefPubMedGoogle Scholar
  3. 3.
    Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, Siller-Matula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, et al; Working Group on On-Treatment Platelet Reactivity (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol, 62:2261–2273Google Scholar
  4. 4.
    Siller-Matula JM, Trenk D, Schrör K, Gawaz M, Kristensen SD, Storey RF, Huber K, EPA (European Platelet Academy) (2013) Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv 6:1111–1128CrossRefPubMedGoogle Scholar
  5. 5.
    Montalescot G, Rangé G, Silvain J, Bonnet JL, Boueri Z, Barthélémy O, Cayla G, Belle L, Van Belle E, Cuisset T, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Beygui F, Vicaut E, Collet JP, ARCTIC Investigators (2014) High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the ARCTIC study. Circulation 129:2136–2143CrossRefPubMedGoogle Scholar
  6. 6.
    Windecker S, Hernández-Antolín RA, Stefanini GG, Wijns W, Zamorano JL (2014) Management of ST-elevation myocardial infarction according to European and American guidelines. EuroIntervention. doi: 10.4244/EIJV10STA5 Google Scholar
  7. 7.
    Nguyen TA, Diodati JG, Pharand C (2005) Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 45:1157–1164CrossRefPubMedGoogle Scholar
  8. 8.
    Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D (2013) Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol. 61:1601–1606CrossRefPubMedGoogle Scholar
  9. 9.
    Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G (2012) Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 5:797–804CrossRefPubMedGoogle Scholar
  10. 10.
    De Luca G, Verdoia M, Suryapranata H (2012) Benefits from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: a meta-analysis of 8 randomized trials. Atherosclerosis 222:426–433CrossRefPubMedGoogle Scholar
  11. 11.
    De Luca G, Bellandi F, Huber K, Noc M, Petronio AS, Arntz HR, Maioli M, Gabriel HM, Zorman S, DE Carlo M, Rakowski T, Gyongyosi M, Dudek D (2011) Early glycoprotein IIb-IIIa inhibitors in primary angioplasty-abciximab long-term results (EGYPT-ALT) cooperation: individual patient’s data meta-analysis. J Thromb Haemost 9:2361–2370CrossRefGoogle Scholar
  12. 12.
    Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS (1992) The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 98:637–646CrossRefPubMedGoogle Scholar
  13. 13.
    Machin SJ (2013) Development of a consensus standard reference method for immature platelets. Int J Lab Hematol 35:26CrossRefGoogle Scholar
  14. 14.
    Pons I, Monteagudo M, Lucchetti G, Muñoz L, Perea G, Colomina I, Guiu J, Obiols J (2010) Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. Eur J Haematol 85(2):158–163PubMedGoogle Scholar
  15. 15.
    Cesari F, Marcucci R, Gori AM, Caporale R, Fanelli A, Casola G, Balzi D, Barchielli A, Valente S, Giglioli C, Gensini GF, Abbate R (2013) Reticulated platelets predict cardiovascular death in acute coronary syndrome patients: insights from the AMIflorence 2 study. Thromb Haemost 109:846–853CrossRefPubMedGoogle Scholar
  16. 16.
    Grove EL, Hvas A-M, Kristensen SD (2009) Immature platelets in patients with acute coronary syndromes. Thromb Haemost 101:151–156PubMedGoogle Scholar
  17. 17.
    Ibrahim H, Nadipalli S, Delao T, Paranilam J, Barker C, Kleiman N (2013) Immature platelets for prediction of clinical events: a possible future target for antiplatelet therapy. Cathet Cardiovasc Intervent 81:S108–S109Google Scholar
  18. 18.
    De Luca G, Secco GG, Santagostino M, Venegoni L, Iorio S, Cassetti E, Verdoia M, Coppo L, Di Mario C, Bellomo G, Marino P, Novara Atherosclerosis Study Group (NAS) (2012) Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study. Nutr Metab Cardiovasc Dis 22:426–433CrossRefPubMedGoogle Scholar
  19. 19.
    De Luca G, Secco GG, Verdoia M, Cassetti E, Schaffer A, Coppo L, Marino P (2014) Combination between mean platelet volume and platelet distribution width to predict the prevalence and extent of coronary artery disease: results from a large cohort study. Blood Coagul Fibrinolysis 25:86–91CrossRefPubMedGoogle Scholar
  20. 20.
    Verdoia M, Pergolini P, Camaro C, Restifo M, Rolla R, Schaffer A, Di Giovine G, Marino P, Bellomo G, Suryapranata H, De Luca G (2013) Novara Atherosclerosis Study Group (NAS). PlA(1)/PlA(2) polymorphism does not influence response to Gp IIb-IIIa inhibitors in patients undergoing coronary angioplasty. Blood Coagul Fibrinolysis 24:411–418CrossRefPubMedGoogle Scholar
  21. 21.
    Vidali M, Rolla R, Parrella M, Cassani C, Manzini M, Portalupi MR, Serino R, Prando MD, Bellomo G, Pergolini P (2012) Role of the laboratory in monitoring patients receiving dual antiplatelet therapy. Int J Lab Hematol 34:484–494CrossRefPubMedGoogle Scholar
  22. 22.
    Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R et al (2010) Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933CrossRefPubMedGoogle Scholar
  23. 23.
    De Luca G, Navarese EP, Suryapranata H (2013) A meta-analytic overview of thrombectomy during primary angioplasty. Int J Cardiol 166:606–612CrossRefPubMedGoogle Scholar
  24. 24.
    De Luca G, Dirksen MT, Spaulding C, Kelbæk H, Schalij M, Thuesen L, van der Hoeven B, Vink MA, Kaiser C, Musto C, Chechi T, Spaziani G, Diaz de la Llera LS, Pasceri V, Di Lorenzo E, Violini R, Cortese G, Suryapranata H, Stone GW, Drug-Eluting Stent in Primary Angioplasty (DESERT) Cooperation (2012) Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level meta-analysis of randomized trials. Arch Intern Med 172:611–621CrossRefPubMedGoogle Scholar
  25. 25.
    Capozzolo C, Piscione F, De Luca G, Cioppa A, Mazzarotto P, Leosco D, Golino P, Indolfi C, Chiariello M (2001) Direct coronary stenting: effect on coronary blood flow, immediate and late clinical results. Catheter Cardiovasc Interv 53:464–473CrossRefPubMedGoogle Scholar
  26. 26.
    De Luca G, Marino P (2009) Facilitated angioplasty with combo therapy among patients with ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. Am J Emerg Med 27:683–690CrossRefPubMedGoogle Scholar
  27. 27.
    De Luca G, Smit JJ, Ernst N, Suryapranata H, Ottervanger JP, Hoorntje JC, Dambrink JH, Gosslink AT, de Boer MJ, van’t Hof AW (2005) Impact of adjunctive tirofiban administration on myocardial perfusion and mortality in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Thromb Haemost 93:820–823PubMedGoogle Scholar
  28. 28.
    Verdoia M, Schaffer A, Barbieri L, Cassetti E, Piccolo R, Galasso G, Marino P, Sinigaglia F, De Luca G (2014) Benefits from new ADP antagonists as compared with clopidogrel in patients with stable angina or acute coronary syndrome undergoing invasive management: a meta-analysis of randomized trials. J Cardiovasc Pharmacol 63:339–350CrossRefPubMedGoogle Scholar
  29. 29.
    De Luca G, Suryapranata H, Marino P (2008) Reperfusion strategies in acute ST-elevation myocardial infarction: an overview of current status. Prog Cardiovasc Dis 50:352–382CrossRefPubMedGoogle Scholar
  30. 30.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516CrossRefPubMedGoogle Scholar
  31. 31.
    Migliorini A, Valenti R, Marcucci R, Parodi G, Giuliani G, Buonamici P, Cerisano G, Carrabba N, Gensini GF, Abbate R, Antoniucci D (2009) High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation 120:2214–2221CrossRefPubMedGoogle Scholar
  32. 32.
    Breet NJ, Van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, Deneer VH, Harmsze AM, van der Heyden JA, Rensing BJ, Suttorp MJ, Hackeng CM, ten Berg JM (2010) Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303:754–762CrossRefPubMedGoogle Scholar
  33. 33.
    Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schömig A, Kastrati A, von Beckerath N (2009) Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 53:849–856CrossRefPubMedGoogle Scholar
  34. 34.
    Siller-Matula JM, Delle-Karth G, Lang IM, Neunteufl T, Kozinski M, Kubica J, Maurer G, Linkowska K, Grzybowski T, Huber K, Jilma B (2012) Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost 10(4):529–542CrossRefPubMedGoogle Scholar
  35. 35.
    Siller-Matula JM, Gruber C, Francesconi M, Dechant C, Jilma B, Delle-Karth G, Grohs K, Podczeck-Schweighofer A, Christ G (2015) The net clinical benefit of personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention. Clin Sci (Lond). 128:121–130CrossRefPubMedGoogle Scholar
  36. 36.
    Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ, GRAVITASInvestigators (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–1105CrossRefPubMedGoogle Scholar
  37. 37.
    Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Müller U, Richardt G, Jakubowski JA, Neumann FJ (2012) A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 59:2159–2164CrossRefPubMedGoogle Scholar
  38. 38.
    McBane RD 2nd, Gonzalez C, Hodge DO, Wysokinski WE (2014) Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 37:148–154CrossRefPubMedGoogle Scholar
  39. 39.
    Hoffmann JJ (2014) Reticulated platelets: analytical aspects and clinical utility. Clin Chem Lab Med 52:1107–1117CrossRefPubMedGoogle Scholar
  40. 40.
    Guthikonda S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, DeLao T, Granada JF, Dong JF, Kleiman NS, Lev EI (2008) 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 52:743–749CrossRefPubMedGoogle Scholar
  41. 41.
    Ibrahim H, Nadipalli S, DeLao T, Guthikonda S, Kleiman NS (2012) Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness. J Thromb Thrombolysis 33:137–142CrossRefPubMedGoogle Scholar
  42. 42.
    Perl L, Lerman-Shivek H, Rechavia E, Vaduganathan M, Leshem-Lev D, Zemer-Wassercug N, Dadush O, Codner P, Bental T, Battler A, Kornowski R, Lev EI (2014) Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 63:513–517CrossRefPubMedGoogle Scholar
  43. 43.
    Sillén H, Cook M, Davis P (2011) Determination of unbound ticagrelor and its active metabolite (AR-C124910XX) in human plasma by equilibrium dialysis and LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 879:2315–2322CrossRefPubMedGoogle Scholar
  44. 44.
    Nylander S, Femia EA, Scavone M, Berntsson P, Asztély AK, Nelander K, Löfgren L, Nilsson RG, Cattaneo M (2013) Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. J Thromb Haemost 11:1867–1876PubMedGoogle Scholar
  45. 45.
    Guthikonda S, Lev EI, Patel R, DeLao T, Bergeron AL, Dong JF, Kleiman NS (2007) Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 5:490–496CrossRefPubMedGoogle Scholar
  46. 46.
    Larsen SB, Grove EL, Hvas AM, Kristensen SD (2014) Platelet turnover in stable coronary artery disease - influence of thrombopoietin and low-grade inflammation. PLoS One 9:e85566CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    McCabe DJ, Harrison P, Sidhu PS, Brown MM, Machin SJ (2004) Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack. Br J Haematol 126:861–869CrossRefPubMedGoogle Scholar
  48. 48.
    Lakkis N, Dokainish H, Abuzahra M, Tsyboulev V, Jorgensen J, De Leon AP, Saleem A (2004) Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 44:2091–2093CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Monica Verdoia
    • 1
  • Chiara Sartori
    • 1
  • Patrizia Pergolini
    • 2
  • Matteo Nardin
    • 1
  • Roberta Rolla
    • 2
  • Lucia Barbieri
    • 1
  • Alon Schaffer
    • 1
  • Paolo Marino
    • 1
  • Giorgio Bellomo
    • 2
  • Harry Suryapranata
    • 3
  • Giuseppe De Luca
    • 1
  1. 1.Division of CardiologyAzienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont UniversityNovaraItaly
  2. 2.Clinical ChemistryAzienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont UniversityNovaraItaly
  3. 3.Department of CardiologyUMC St RadboudNijmegenThe Netherlands

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