Increased mean platelet volume is associated with non-responsiveness to clopidogrel

Elad Asher; Paul Fefer; Michael Shechter; Roy Beigel; David Varon; Boris Shenkman; Naphtali Savion; Hanoch Hod; Shlomi Matetzky

doi:10.1160/TH13-10-0845

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(01): 137-141
DOI: 10.1160/TH13-10-0845

Platelets and Blood Cells

Schattauer GmbH

Increased mean platelet volume is associated with non-responsiveness to clopidogrel

Elad Asher

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Paul Fefer

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Michael Shechter

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Roy Beigel

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

David Varon

²Coagulation Unit, Dept. of Hematology, Hadassah Medical Center, Hebrew University Medical Center, Jerusalem, Israel

,

Boris Shenkman

³Hematology Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Naphtali Savion

⁴Goldschleger Eye Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Hanoch Hod

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Shlomi Matetzky

¹Heart Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

› Author Affiliations

Abstract

Summary

Prior studies have demonstrated significant individual variability of platelet response to clopidogrel, which affects clinical outcome. In patients with stable coronary artery disease (CAD) smoking, diabetes mellitus, elevated body mass index and renal insufficiency, significantly impact response to clopidogrel. The determinants of platelet response to clopidogrel in patients with acute coronary syndrome are unknown. Adenosine diphosphate (ADP)-induced platelet aggregation (PA), hs C-reactive protein, platelet count and mean platelet volume (MPV) were determined 72 hours post clopidogrel loading in 276 consecutive acute myocardial infarction (AMI) patients. Patients with ADP-platelet aggregation ≥ 70% were considered to be clopidogrel non-responders. Eighty-four patients (30%) were clopidogrel non-responders and 192 (70%) were responders (ADP-induced PA: 81 ± 17% vs 49 ± 17%, respectively, p<0.001). Both study groups were comparable with respect to age, gender, prior cardiovascular history, prior aspirin use and risk factors for CAD, including smoking (42% for both groups) and diabetes mellitus (26% vs 22%, respectively, p=0.4). Responders and non-responders had similar angiographic characteristics, indices of infarct size, and similar hs-CRP (29 ± 34 vs 28 ± 34 mg/l, p=0.7) and creatinine (1.08 ± 0.4 mg% vs 1.07 ± 0.4, p=0.9) levels. On the contrary non-responders had significantly larger mean MPV (9 ± 1.2 fl vs 8 ± 1 fl, respectively, p=0.0018), and when patients were stratified into quartiles based on MPV, ADP-induced PA increased gradually and significantly across the quartiles of MPV (p<0.001). In conclusion, increased MPV associated with platelet activation, predicts non-responsiveness to clopidogrel among patients with acute coronary syndrome.

Keywords

Acute coronary syndrome - platelet activation - response to clopidogrel - mean platelet volume

Full Text

References

References
1 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
2 Gurbel PA, Samara WM, Bliden KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets 2004; 15: 95-99.
3 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3064-3067.
4 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 04: 542-549.
5 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
6 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 2010; 08: 923-933.
7 Bliden KP, Dichiara J, Lawal L. et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52: 531-533.
8 Price MJ, Nayak KR, Barker CM. et al. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 103: 1339-1343.
9 Angiolillo DJ, Bernardo E, Ramírez C. et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral anti-platelet treatment. J Am Coll Cardiol 2006; 48: 298-304.
10 Angiolillo DJ, Shoemaker SB, Desai B. et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708-716.
11 Cuisset T, Frere C, Quilici J. et al. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597-603.
12 Park SH, Kim W, Park CS. et al. A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure. Am J Cardiol 2009; 104: 1292-1295.
13 Beinart R, Abu Sham’a R, Segev A. et al. The incidence and clinical predictors of early stent thrombosis in patients with acute coronary syndrome. Am Heart J 2010; 159: 118-124.
14 Bonello L, Tantry US, Marucci R. et al. 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 2010; 56: 919-933.
15 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007; 97: 282-287.
16 Frere C, Cuisset T, Quilici J. et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-843.
17 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
18 Shenkman B, Matetzky S, Fefer P. et al. Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests. Thromb Res 2008; 122: 336-345.
19 Tsiara S, Elisaf M, Jagroop IA. et al. Platelets and stroke. Vasc Med 1999; 04: 165-172.
20 Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-1411.
21 Park Y, Schoene N, Harris W. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets 2002; 13: 301-306.
22 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 2009; 08: 148-156.
23 Karpatkin S. Heterogeneity of human platelets II Functional evidence suggestive of young and old platelets. J Clin Invest 1969; 48: 1083-1087.
24 Kamath S, Blann AD, Lip GY. Platelet activation: assessment and quantification. Eur Heart J 2001; 22: 1561-1571.
25 Bostan F, Coban E. The relationship between levels of von Willebrand factor and mean platelet volume in subjects with isolated impaired fasting glucose. Med Sci Monit 2011; 17: PR1-PR4.
26 Endler G, Klimesch A, Sunder-Plassmann H. et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002; 117: 399-404.
27 Estévez-Loureiro R, Salgado-Fernández J, Marzoa-Rivas R. et al. Mean platelet volume predicts patency of the infarct-related artery before mechanical reperfusion and short-term mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Thromb Res 2009; 124: 536-540.
28 Fabregat-Andrés Ó, Cubillos A, Ferrando-Beltrán M. et al. Mean platelet volume is associated with infarct size and microvascular obstruction estimated by cardiac magnetic resonance in ST segment elevation myocardial infarction. Blood Coagul Fibrinolysis 2013; 24: 424-427.
29 Huczek Z, Kochman J, Filipiak KJ. et al. Mean platelet volume on admission predicts impaired reperfusion and long-term mortality in acute myocardial infarction treated with primary percutaneous coronary intervention. J Am Coll Cardiol 2005; 46: 284-290.
30 Sarli B, Baktir AO, Saglam H. et al. Mean platelet volume is associated with poor postinterventional myocardial blush grade in patients with ST-segment elevation myocardial infarction. Coron Artery Dis 2013; 24: 285-289.
31 Maden O, Kacmaz F, Selcuk H. et al. Relationship of admission hematological indexes with myocardial reperfusion abnormalities in acute ST segment elevation myocardial infarction patients treated with primary percutaneous coronary interventions. Can J Cardiol 2009; 25: e164-168.
32 Dogan A, Aksoy F, Icli A. et al. Mean platelet volume is associated with culprit lesion severity and cardiac events in acute coronary syndromes without ST elevation. Blood Coagul Fibrinolysis 2012; 23: 324-330.
33 Taglieri N, Saia F, Rapezzi C. et al. Prognostic significance of mean platelet volume on admission in an unselected cohort of patients with non ST-segment elevation acute coronary syndrome. Thromb Haemost 2011; 106: 132-140.
34 Goncalves SC, Labinaz M, Le May M. et al. Usefulness of mean platelet volume as a biomarker for long-term outcomes after percutaneous coronary intervention. Am J Cardiol 2011; 107: 204-209.
35 Aksu H, Ozer O, Unal H. et al. Significance of mean platelet volume on prognosis of patients with and without aspirin resistance in settings of non-ST-segment elevated acute coronary syndromes. Blood Coagul Fibrinolysis 2009; 20: 686-693.
36 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.
37 Vizioli L, Muscari S, Muscari A. The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases. Int J Clin Pract 2009; 63: 1509-1515.