Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing

Summary

Platelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y₁₂-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

Keywords

Platelet turnover - reticulated platelets - mean platelet volume - P2Y₁₂ inhibitors - aspirin

• References

• 1 Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 (Suppl. 01) S13-33.
• 2 Freynhofer MK. et al. The role of platelets in athero-thrombotic events. Curr Pharm Des 2012; 18: 5197-5214.
• 3 Virchow R. Phlogose und Thrombose im Gefäßsystem. Frankfurt am Main: Meidinger Sohn; 1856
• 4 Farb A. et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93: 1354-1363.
• 5 Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50: 127-134.
• 6 Nesbitt WS. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009; 15: 665-673.
• 7 Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolisation culminating in total vascular occlusion. Circulation 1985; 71: 699-708.
• 8 Fitzgerald DJ. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989.
• 9 Martin JF. et al. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-1411.
• 10 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
• 11 Chen ZM. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 12 Yusuf S. 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.
• 13 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-20015.
• 14 Cannon CP. et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-293.
• 15 Wurtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18: 5344-5361.
• 16 Bonello L. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
• 17 Freynhofer MK. et al. Vasodilator-stimulated phosphoprotein-phosphorylation assay in patients on clopidogrel: does standardisation matter?. Thromb Haemost 2012; 107: 538-544.
• 18 Freynhofer MK. 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 Aradi D. 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 Epub ahead of print.
• 20 Freynhofer MK. et al. Is increased platelet turnover responsible for low responsiveness to different thienopyridienes? A case report of recurrent stent thromboses. Thromb Haemost 2011; 106: 182-184.
• 21 Guthikonda S. 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.
• 22 Perl L. et al. Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2013; 63: 513-517.
• 23 Martin JF. et al. The causal role of megakaryocyte-platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 09: 658-670.
• 24 Italiano Jr., JE, Shivdasani RA. Megakaryocytes and beyond: the birth of platelets. J Thromb Haemost 2003; 01: 1174-1182.
• 25 Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood 2008; 111: 981-986.
• 26 Kaushansky K. Thrombopoiesis. Semin Hematol 2015; 52: 4-11.
• 27 Martin JF. et al. The relationship between platelet and megakaryocyte volumes. Thromb Res 1982; 28: 447-459.
• 28 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339-3347.
• 29 Kaushansky K. et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994; 369: 568-571.
• 30 Podolak-Dawidziak M. et al. The expression of mRNA for fibrinogen in megakaryocytes isolated from patients with T-cell lymphoma. Br J Haematol 1995; 91: 362-366.
• 31 Gladwin AM. et al. Identification of mRNA for PDGF B-chain in human megakaryocytes isolated using a novel immunomagnetic separation method. Br J Haematol 1990; 76: 333-339.
• 32 Hancock V. et al. The relationship between human megakaryocyte nuclear DNA content and gene expression. Br J Haematol 1993; 85: 692-697.
• 33 Radley JM, Scurfield G. The mechanism of platelet release. Blood 1980; 56: 996-999.
• 34 Junt T. et al. Dynamic visualisation of thrombopoiesis within bone marrow. Science 2007; 317: 1767-1770.
• 35 Ault KA. et al. The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 1992; 98: 637-646.
• 36 Ault KA, Knowles C. In vivo biotinylation demonstrates that reticulated platelets are the youngest platelets in circulation. Exp Hematol 1995; 23: 996-1001.
• 37 Lordkipanidze M. Platelet turnover in atherothrombotic disease. Curr Pharm Des 2012; 18: 5328-5343.
• 38 Briggs C. et al. Continuing developments with the automated platelet count. Int J Lab Hematol 2007; 29: 77-91.
• 39 Overgaard CB. et al. Thrombocytopenia at baseline is a predictor of inhospital mortality in patients undergoing percutaneous coronary intervention. Am Heart J 2008; 156: 120-124.
• 40 Nikolsky E. et al. Impact of in-hospital acquired thrombocytopenia in patients undergoing primary angioplasty for acute myocardial infarction. Am J Cardiol 2005; 96: 474-481.
• 41 De Labriolle A. 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.
• 42 Nikolsky E. et al. Impact of baseline platelet count in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction (from the CADILLAC trial). Am J Cardiol 2007; 99: 1055-1061.
• 43 Ly HQ. et al. Association of platelet counts on presentation and clinical outcomes in ST-elevation myocardial infarction (from the TIMI Trials). Am J Cardiol 2006; 98: 1-5.
• 44 Thaulow E. et al. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991; 84: 613-617.
• 45 Ingram M, Coopersmith A. Reticulated platelets following acute blood loss. Br J Haematol 1969; 17: 225-229.
• 46 Martin JF. 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.
• 47 Mazur EM. et al. Evaluation of bone marrow megakaryocyte ploidy distributions in persons with normal and abnormal platelet counts. J Lab Clin Med 1988; 111: 194-202.
• 48 Gladwin AM, Martin JF. The control of megakaryocyte ploidy and platelet production: biology and pathology. Int J Cell Cloning 1990; 08: 291-298.
• 49 Dalby Kristensen S. et al. The bleeding time is inversely related to megakaryocyte nuclear DNA content and size in man. Thromb Haemost 1988; 59: 357-359.
• 50 Bessman JD. The relation of megakaryocyte ploidy to platelet volume. Am J Hematol 1984; 16: 161-170.
• 51 Giles H. et al. Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur J Clin Invest 1994; 24: 69-72.
• 52 Martin JF. et al. Changes in volume and density of platelets in myocardial infarction. Br Med J 1983; 287: 456-459.
• 53 Cameron HA. et al. Platelet size in myocardial infarction. Br Med J 1983; 287: 449-451.
• 54 Pizzulli L. et al. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998; 19: 80-84.
• 55 Kristensen SD. et al. Differences in bleeding time, aspirin sensitivity and adrenaline between acute myocardial infarction and unstable angina. Cardiovasc Res 1990; 24: 19-23.
• 56 Chu SG. et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2010; 08: 148-156.
• 57 Choi SW. et al. Clinical outcome prediction from mean platelet volume in patients undergoing percutaneous coronary intervention in Korean cohort: Implications of more simple and useful test than platelet function testing. Platelets 2014; 25: 322-327.
• 58 Berny-Lang MA. et al. Do immature platelet levels in chest pain patients presenting to the emergency department aid in the diagnosis of acute coronary syndrome?. Int J Lab Hematol 2015; 37: 112-119.
• 59 De Luca G. et al. Mean platelet volume and the extent of coronary artery disease: results from a large prospective study. Atherosclerosis 2009; 206: 292-297.
• 60 Klovaite J. et al. High platelet volume and increased risk of myocardial infarction: 39,531 participants from the general population. J Thromb Haemost 2011; 09: 49-56.
• 61 Trowbridge EA. et al. Platelet production in myocardial infarction and sudden cardiac death. Thromb Haemost 1984; 52: 167-171.
• 62 van der Meer PF. et al. In vivo tracking of transfused platelets for recovery and survival studies: an appraisal of labeling methods. Transfus Apher Sci 2010; 42: 53-61.
• 63 D’Souza C, Briggs C, Machin SJ. Platelets: The Few, the Young, and the Active. Clin Lab Med 2015; 35: 123-131.
• 64 Kienast J, Schmitz G. Flow cytometric analysis of thiazole orange uptake by platelets: a diagnostic aid in the evaluation of thrombocytopenic disorders. Blood 1990; 75: 116-121.
• 65 Briggs C. et al. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol 2004; 126: 93-99.
• 66 Freynhofer MK. et al. Reticulated Platelets as Index of Platelet Turnover Predict Outcome after Coronary Intervention. GTH;; 2014. Vienna; 2014.
• 67 Pons I. et al. Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. Eur J Haematol 2010; 85: 158-163.
• 68 Hirsh J. et al. The effect of platelet age on platelet adherence to collagen. J Clin Invest 1968; 47: 466-473.
• 69 Grove EL. et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 09: 185-191.
• 70 Cesari F. 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.
• 71 Ritchie JL, Harker LA. Platelet and fibrinogen survival in coronary atherosclerosis. Response to medical and surgical therapy. Am J Cardiol 1977; 39: 595-598.
• 72 Kutti J, Weinfeld A. Platelet survival and platelet production in acute myocardial infarction. Acta Med Scand 1979; 205: 501-504.
• 73 Abrahamsen AF. Platelet survival studies in man. With special reference to thrombosis and atherosclerosis. Scand J Haematol Suppl 1968; 03: 1-53.
• 74 Grove EL. et al. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156.
• 75 Gonzalez-Porras JR. et al. The role of immature platelet fraction in acute coronary syndrome. Thromb Haemost 2010; 103: 247-249.
• 76 Lakkis N. et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004; 44: 2091-2093.
• 77 Wurtz M. 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.
• 78 Freynhofer MK. et al. Variability of on-treatment platelet reactivity in patients on clopidogrel. Platelets 2014; 25: 328-336.
• 79 McBane 2nd RD. et al. Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 2014; 37: 148-154.
• 80 Cesari F. et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Hae-most 2013; 109: 846-853.
• 81 Ibrahim H. et al. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014; 64: 2122-2129.
• 82 Patrono C. et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932.
• 83 Windecker S. et al. 2014 ESC/EACTS Guidelines on myocardial revascularisation: The Task Force on Myocardial Revascularisation of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619.
• 84 Krasopoulos G. et al. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
• 85 Wurtz M. et al. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol 2014; 175: 274-279.
• 86 Henry P. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105: 336-344.
• 87 Christensen KH. et al. Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes. Platelets 2014; 26: 230-235.
• 88 Henry P. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105: 336-344.
• 89 Capodanno D. et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv 2011; 04: 180-187.
• 90 Grove EL. et al. Can we improve the efficacy of low-dose aspirin?. Thromb Hae-most 2014; 112: 1077-1078.
• 91 Bonello L. et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 05: 1630-1636.
• 92 Marcucci R. et al. Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay. A 12-Month Follow-Up. Circulation 2009; 119: 237-242.
• 93 Breet NJ. 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.
• 94 Sibbing D. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 95 Price MJ. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
• 96 Grove EL. et al. Platelet function testing in atherothrombotic disease. Curr Pharm Des 2012; 18: 5379-5391.
• 97 Price MJ. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
• 98 Trenk D. et al. 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 2012; 59: 2159-2164.
• 99 Collet JP. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
• 100 Bonello L. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
• 101 Bonello L. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multi-centre randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
• 102 Welsh RC. et al. A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y₁₂ Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention: The INNOVATE-PCI Trial. Circ Cardiovasc Interv 2012; 05: 336-346.
• 103 White HD. et al. Reduced immediate ischemic events with cangrelor in PCI: a pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction. Am Heart J 2012; 163: 182-190e4.
• 104 Bonello L. et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011; 58: 467-473.
• 105 Hedegaard SS. et al. Optical platelet aggregation versus thromboxane metabolites in healthy individuals and patients with stable coronary artery disease after low-dose aspirin administration. Thromb Res 2009; 124: 96-100.
• 106 Patrono C. et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327.
• 107 Lordkipanidze M. Why an aspirin a day no longer keeps the doctor away. Thromb Haemost 2011; 105: 209-210.
• 108 Moncada S. Adventures in vascular biology: a tale of two mediators. Philos Trans R Soc Lond B Biol Sci 2006; 361: 735-759.
• 109 Perneby C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
• 110 Dragani 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.
• 111 DiMinno G. et al. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68: 886-891.
• 112 Guthikonda S. et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 05: 490-496.
• 113 Kieffer N. et al. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem 1987; 164: 189-195.
• 114 Rocca B. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
• 115 Spectre G. et al. Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. Thromb Haemost 2011; 106: 491-499.
• 116 Dillinger JG. et al. Twice daily aspirin to improve biological aspirin efficacy in patients with essential thrombocythemia. Thromb Res 2012; 129: 91-94.
• 117 Murugappa S, Kunapuli SP. The role of ADP receptors in platelet function. Front Biosci 2006; 11: 1977-1986.
• 118 Bal Dit Sollier C. et al. Functional variability of platelet response to clopidogrel correlates with P2Y(12) receptor occupancy. Thromb Haemost 2009; 101: 116-122.
• 119 Tucker EI. et al. Safety and antithrombotic efficacy of moderate platelet count reduction by thrombopoietin inhibition in primates. Sci Transl Med 2010; 02: 37ra45.
• 120 Mijovic R. et al. Reticulated platelets and antiplatelet therapy response in diabetic patients. J Thromb Thrombolysis 2015; 40: 203-210.
• 121 Wurtz M. et al. Influence of renal function and platelet turnover on the antiplatelet effect of aspirin. Thromb Res 2012; 129: 434-440.
• 122 Zanazzi M. et al. Reticulated platelets and platelet reactivity in renal transplant recipients receiving antiplatelet therapy. Transplant Proc 2010; 42: 1156-1157.
• 123 Funck-Jensen KL. et al. Increased platelet aggregation and turnover in the acute phase of ST-elevation myocardial infarction. Platelets 2012; 24: 528-537.
• 124 Vaduganathan M. et al. Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-ST elevation acute coronary syndromes. J Thromb Thrombolysis 2015; 40: 211-217.
• 125 Ibrahim H. et al. Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness. J Thromb Thrombolysis 2012; 33: 137-142.
• 126 Eisen A. et al. Circulating reticulated platelets over time in patients with myocardial infarction treated with prasugrel or ticagrelor. J Thromb Thrombolysis 2015; 40: 70-75.
• 127 Verdoia M. et al. Mean platelet volume and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. Expert Opin Pharmacother 2015; 1-9.
• 128 Motovska Z. et al. Selection of P2Y₁₂ antagonist, treatment initiation, and predictors of high on-treatment platelet reactivity in a “Real World” registry. Thromb Res 2015; 135: 1093-1099.
• 129 Koh YY. et al. Relation between the Change in Mean Platelet Volume and Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Intervention. Curr Vasc Pharmacol. 2014 Epub ahead of print.
• 130 Kubica A. et al. Time-related changes in determinants of antiplatelet effect of clopidogrel in patients after myocardial infarction. Eur J Pharmacol 2014; 742: 47-54.
• 131 Asher E. et al. Increased mean platelet volume is associated with non-responsiveness to clopidogrel. Thromb Haemost 2014; 112: 137-141.
• 132 Uzel H. et al. Diagnostic accuracy of mean platelet volume in prediction of clopidogrel resistance in patients with acute coronary syndrome. Anadolu Kardiyol Derg 2014; 14: 134-139.
• 133 Kim YG. et al. Platelet volume indices are associated with high residual platelet reactivity after antiplatelet therapy in patients undergoing percutaneous coronary intervention. J Atheroscler Thromb 2014; 21: 445-453.
• 134 Akturk IF. et al. Hypertension as a risk factor for aspirin and clopidogrel resistance in patients with stable coronary artery disease. Clin Appl Thromb He-most 2014; 20: 749-754.
• 135 De Luca G. et al. Short-term effects of aspirin and clopidogrel on mean platelet volume among patients with acute coronary syndromes. A single-centre prospective study. Blood Coagul Fibrinolysis 2012; 23: 756-759.
• 136 Huczek Z. et al. Baseline platelet size is increased in patients with acute coronary syndromes developing early stent thrombosis and predicts future residual platelet reactivity. A case-control study. Thromb Res 2010; 125: 406-412.
• 137 Aksu HU. et al. Aspirin resistance in patients with impaired renal functions. Kardiol Pol MPV 72: 331-338.
• 138 Shah B. et al. Mean platelet volume reproducibility and association with platelet activity and anti-platelet therapy. Platelets 2014; 25: 188-192.
• 139 Sanioglu S. et al. Aspirin resistance after CABG. Thorac Cardiovasc Surg 2009; 57: 281-285.
• 140 Durmaz T. et al. Heart rate variability in patients with stable coronary artery disease and aspirin resistance. Int Heart J 2008; 49: 413-422.