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Platelet Function Profiles in Patients with Diabetes Mellitus

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Abstract

Patients with diabetes mellitus (DM) are at high risk for several cardiovascular disorders such as coronary heart disease, stroke, peripheral arterial disease, and congestive heart failure. DM has reached epidemic proportions and its strong association with coronary artery disease is responsible for increased cardiovascular morbidity and mortality. DM patients are characterized by platelet hyperreactivity, which contribute to the enhanced atherothrombotic risk of these subjects. Several mechanisms are involved in the hyperreactive platelet phenotype characterizing DM patients. Furthermore, a large proportion of DM patients show inadequate response to standard antiplatelet treatments and high rate of adverse recurrent cardiovascular events despite compliance with standard antiplatelet treatment regimens. Therefore, new antiplatelet treatment regimens are warranted in DM patients to reduce their atherothrombotic risk. The present manuscript provides an overview on the current status of knowledge on platelet function profiles in patients with DM and therapeutic considerations.

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References

  1. Inzucchi, S. E. (2012). Diagnosis of diabetes. The New England Journal of Medicine, 367, 542–550.

    Article  CAS  PubMed  Google Scholar 

  2. Morel, O., Kessler, L., Ohlmann, P., & Bareiss, P. (2010). Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis, 212, 367–376.

    Article  CAS  PubMed  Google Scholar 

  3. Webster MW, Scott RS (1997) What cardiologists need to know about diabetes. Lancet 350 Suppl 1:SI23–8.

    Google Scholar 

  4. Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998). Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. The New England Journal of Medicine, 339, 229–234.

    Article  CAS  PubMed  Google Scholar 

  5. Malmberg, K., Yusuf, S., Gerstein, H. C., Brown, J., Zhao, F., Hunt, D., et al. (2000). Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation, 102, 1014–1019.

    Article  CAS  PubMed  Google Scholar 

  6. Roffi, M., Chew, D. P., Mukherjee, D., Bhatt, D. L., White, J. A., Heeschen, C., et al. (2001). Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation, 104, 2767–2771.

    Article  CAS  PubMed  Google Scholar 

  7. Creager, M. A., Lüscher, T. F., Cosentino, F., & Beckman, J. A. (2003). Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation, 108, 1527–1532.

    Article  PubMed  Google Scholar 

  8. Stratmann, B., & Tschoepe, D. (2005). Pathobiology and cell interactions of platelets in diabetes. Diabetes & Vascular Disease Research, 2, 16–23.

    Article  Google Scholar 

  9. Angiolillo, D. J., Fernandez-Ortiz, A., Bernardo, E., Ramírez, C., Sabaté, M., Jimenez-Quevedo, P., et al. (2005). Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes, 54, 2430–2435.

    Article  CAS  PubMed  Google Scholar 

  10. Vinik, A. I., Erbas, T., Park, T. S., Nolan, R., & Pittenger, G. L. (2001). Platelet dysfunction in type 2 diabetes. Diabetes Care, 24, 1476–1485.

    Article  CAS  PubMed  Google Scholar 

  11. Ferroni, P., Basili, S., Falco, A., & Davì, G. (2004). Platelet activation in type 2 diabetes mellitus. Journal of Thrombosis and Haemostasis, 2, 1282–1291.

    Article  CAS  PubMed  Google Scholar 

  12. Ferreiro, J. L., & Angiolillo, D. J. (2011). Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation, 123, 798–813.

    Article  PubMed  Google Scholar 

  13. Geisler, T., Anders, N., Paterok, M., Langer, H., Stellos, K., Lindemann, S., et al. (2007). Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care, 30, 372–374.

    Article  PubMed  Google Scholar 

  14. Davì, G., & Patrono, C. (2007). Platelet activation and atherothrombosis. The New England Journal of Medicine, 357, 2482–2494.

    Article  PubMed  Google Scholar 

  15. Fuster, V., Moreno, P. R., Fayad, Z. A., Corti, R., & Badimon, J. J. (2005). Atherothrombosis and high-risk plaque: part I: evolving concepts. Journal of the American College of Cardiology, 46, 937–954.

    Article  PubMed  Google Scholar 

  16. Schneider, D. J. (2009). Factors contributing to increased platelet reactivity in people with diabetes. Diabetes Care, 32, 525–527.

    Article  CAS  PubMed  Google Scholar 

  17. Lemkes, B. A., Hermanides, J., Devries, J. H., Holleman, F., Meijers, J. C., & Hoekstra, J. B. (2010). Hyperglycaemia, a prothrombotic factor? Journal of Thrombosis and Haemostasis, 8, 1663–1669.

    Article  CAS  PubMed  Google Scholar 

  18. Ferreiro, J. L., & Angiolillo, D. J. (2012). Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. Current Pharmaceutical Design, 1, 5273–5293.

    Article  Google Scholar 

  19. Winocour, P. D., Watala, C., Perry, D. W., & Kinlough-Rathbone, R. L. (1992). Decreased platelet membrane fluidity due to glycation or acetylation of membrane proteins. Thrombosis and Haemostasis, 68, 577–582.

    CAS  PubMed  Google Scholar 

  20. Watala, C., Golański, J., Boncler, M. A., Pietrucha, T., & Gwoździński, K. (1998). Membrane lipid fluidity of blood platelets: a common denominator that underlies the opposing actions of various agents that affect platelet activation in whole blood. Platelets, 9, 315–327.

    Article  CAS  PubMed  Google Scholar 

  21. Chappey, O., Dosquet, C., Wautier, M. P., & Wautier, J. L. (1997). Advanced glycation end products, oxidant stress and vascular lesions. European Journal of Clinical Investigation, 27, 97–108.

    Article  CAS  PubMed  Google Scholar 

  22. Assert, R., Scherk, G., Bumbure, A., Pirags, V., Schatz, H., & Pfeiffer, A. F. (2001). Regulation of protein kinase C by short term hyperglycaemia in human platelets in vivo and in vitro. Diabetologia, 44, 188–195.

    Article  CAS  PubMed  Google Scholar 

  23. Xia, P., Inoguchi, T., Kern, T. S., Engerman, R. L., Oates, P. J., & King, G. L. (1994). Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes, 43, 1122–1129.

    Article  CAS  PubMed  Google Scholar 

  24. Ferretti, G., Rabini, R. A., Bacchetti, T., Vignini, A., Salvolini, E., Ravaglia, F., et al. (2002). Glycated low density lipoproteins modify platelet properties: a compositional and functional study. Journal of Clinical Endocrinology and Metabolism, 87, 2180–2184.

    Article  CAS  PubMed  Google Scholar 

  25. Williams, S. B., Goldfine, A. B., Timimi, F. K., Ting, H. H., Roddy, M. A., Simonson, D. C., et al. (1998). Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation, 97, 1695–1701.

    Article  CAS  PubMed  Google Scholar 

  26. Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S., Matsumura, T., Kaneda, Y., et al. (2000). Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 404, 787–790.

    Article  CAS  PubMed  Google Scholar 

  27. Keating, F. K., Sobel, B. E., & Schneider, D. J. (2003). Effects of increased concentrations of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes mellitus. The American Journal of Cardiology, 92, 1362–1365.

    Article  CAS  PubMed  Google Scholar 

  28. Takada, Y., Urano, T., Watanabe, I., Taminato, A., Yoshimi, T., & Takada, A. (1993). Changes in fibrinolytic parameters in male patients with type 2 (non-insulin-dependent) diabetes mellitus. Thrombosis Research, 71, 405–415.

    Article  CAS  PubMed  Google Scholar 

  29. Kessler, L., Wiesel, M. L., Attali, P., Mossard, J. M., Cazenave, J. P., & Pinget, M. (1998). Von Willebrand factor in diabetic angiopathy. Diabetes & Metabolism, 24, 327–336.

    CAS  Google Scholar 

  30. Boden, G., & Rao, A. K. (2007). Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood coagulation. Current Diabetes Reports, 7, 223–227.

    Article  CAS  PubMed  Google Scholar 

  31. Eibl, N., Krugluger, W., Streit, G., Schrattbauer, K., Hopmeier, P., & Schernthaner, G. (2004). Improved metabolic control decreases platelet activation markers in patients with type-2 diabetes. European Journal of Clinical Investigation, 34, 205–209.

    Article  CAS  PubMed  Google Scholar 

  32. Vivas, D., García-Rubira, J. C., Bernardo, E., Angiolillo, D. J., Martín, P., Calle-Pascual, A., et al. (2011). Effects of intensive glucose control on platelet reactivity in patients with acute coronary syndromes. Results of the CHIPS Study ("Control de Hiperglucemia y Actividad Plaquetaria en Pacientes con Sindrome Coronario Agudo"). Heart, 97, 803–809.

    Article  CAS  PubMed  Google Scholar 

  33. Malmberg, K. (1997). Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ, 314, 1512–1515.

    Article  CAS  PubMed  Google Scholar 

  34. Malmberg, K., Rydén, L., Wedel, H., Birkeland, K., Bootsma, A., Dickstein, K., et al. (2005). Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. European Heart Journal, 26, 650–661.

    Article  CAS  PubMed  Google Scholar 

  35. Gerstein, H. C., Miller, M. E., Byington, R. P., Goff, D. C., Jr., Bigger, J. T., Buse, J. B., et al. (2008). Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of Medicine, 358, 2545–2559.

    Article  CAS  PubMed  Google Scholar 

  36. Finfer, S., Chittock, D. R., Su, S. Y., Blair, D., Foster, D., Dhingra, V., et al. (2009). Intensive versus conventional glucose control in critically ill patients. The New England Journal of Medicine, 360, 1283–1297.

    Article  PubMed  Google Scholar 

  37. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care (2010) 33:S62-S69.

    Google Scholar 

  38. Hajek, A. S., & Joist, J. H. (1992). Platelet insulin receptor. Methods in Enzymology, 215, 398–403.

    Article  CAS  PubMed  Google Scholar 

  39. Hunter, R. W., & Hers, I. (2009). Insulin/IGF-1 hybrid receptor expression on human platelets: consequences for the effect of insulin on platelet function. Journal of Thrombosis and Haemostasis, 7, 2123–2130.

    Article  CAS  PubMed  Google Scholar 

  40. Kahn, N. N. (1998). Insulin-induced expression of prostacyclin receptors on platelets is mediated through ADP-ribosylation of Gi alpha protein. Life Sciences, 63, 2031–2038.

    Article  CAS  PubMed  Google Scholar 

  41. Randriamboavonjy, V., & Fleming, I. (2009). Insulin, insulin resistance, and platelet signaling in diabetes. Diabetes Care, 32, 528–530.

    Article  CAS  PubMed  Google Scholar 

  42. Westerbacka, J., Yki-Järvinen, H., Turpeinen, A., Rissanen, A., Vehkavaara, S., Syrjälä, M., et al. (2002). Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 167–172.

    Article  CAS  PubMed  Google Scholar 

  43. Angiolillo, D. J., Bernardo, E., Zanoni, M., Vivas, D., Capranzano, P., Malerba, G., et al. (2011). Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. Journal of the American College of Cardiology, 58, 30–39.

    Article  CAS  PubMed  Google Scholar 

  44. Ishida, M., Ishida, T., Ono, N., Matsuura, H., Watanabe, M., Kajiyama, G., et al. (1996). Effects of insulin on calcium metabolism and platelet aggregation. Hypertension, 28, 209–212.

    Article  CAS  PubMed  Google Scholar 

  45. Betteridge, D. J., El Tahir, K. E., Reckless, J. P., & Williams, K. I. (1982). Platelets from diabetic subjects show diminished sensitivity to prostacyclin. European Journal of Clinical Investigation, 12, 395–398.

    Article  CAS  PubMed  Google Scholar 

  46. Anfossi, G., Mularoni, E. M., Burzacca, S., Ponziani, M. C., Massucco, P., Mattiello, L., et al. (1998). Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care, 21, 121–126.

    Article  CAS  PubMed  Google Scholar 

  47. Russo, I., Traversa, M., Bonomo, K., De Salve, A., Mattiello, L., Del Mese, P., et al. (2010). In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity (Silver Spring), 18, 788–797.

    Article  CAS  Google Scholar 

  48. Randriamboavonjy, V., Pistrosch, F., Bölck, B., Schwinger, R. H., Dixit, M., Badenhoop, K., et al. (2008). Platelet sarcoplasmic endoplasmic reticulum Ca2 + −ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation, 117, 52–60.

    Article  CAS  PubMed  Google Scholar 

  49. Sidhu, J. S., Cowan, D., Tooze, J. A., & Kaski, J. C. (2004). Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. American Heart Journal, 147, e25.

    Article  PubMed  CAS  Google Scholar 

  50. Nissen, S. E., Nicholls, S. J., Wolski, K., Nesto, R., Kupfer, S., Perez, A., et al. (2008). Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. Journal of the American Medical Association, 299, 1561–1573.

    Article  CAS  PubMed  Google Scholar 

  51. McGuire, D. K., Newby, L. K., Bhapkar, M. V., Moliterno, D. J., Hochman, J. S., Klein, W. W., et al. (2004). Association of diabetes mellitus and glycemic control strategies with clinical outcomes after acute coronary syndromes. American Heart Journal, 147, 246–252.

    Article  CAS  PubMed  Google Scholar 

  52. Gerstein, H. C., Ratner, R. E., Cannon, C. P., Serruys, P. W., García-García, H. M., van Es, G. A., et al. (2010). Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation, 121, 1176–1187.

    Article  CAS  PubMed  Google Scholar 

  53. Suryadevara, S., Ueno, M., Tello-Montoliu, A., Ferreiro, J. L., Desai, B., Rollini, F., et al. (2012). Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus. Thrombosis and Haemostasis, 108, 930–936.

    Article  CAS  PubMed  Google Scholar 

  54. Muscari, A., De Pascalis, S., Cenni, A., Ludovico, C., Castaldini, N., Antonelli, S., et al. (2008). Determinants of mean platelet volume (MPV) in an elderly population: relevance of body fat, blood glucose and ischaemic electrocardiographic changes. Thrombosis and Haemostasis, 99, 1079–1084.

    CAS  PubMed  Google Scholar 

  55. Sugiyama, C., Ishizawa, M., Kajita, K., Morita, H., Uno, Y., Matsubara, K., et al. (2007). Platelet aggregation in obese and diabetic subjects: association with leptin level. Platelets, 18, 128–134.

    Article  CAS  PubMed  Google Scholar 

  56. Scherrer, U., Nussberger, J., Torriani, S., Waeber, B., Darioli, R., Hofstetter, J. R., et al. (1991). Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium. Circulation, 83, 552–558.

    Article  CAS  PubMed  Google Scholar 

  57. Anfossi, G., Russo, I., & Trovati, M. (2009). Platelet dysfunction in central obesity. Nutrition, Metabolism, and Cardiovascular Diseases, 19, 440–449.

    Article  CAS  PubMed  Google Scholar 

  58. Angiolillo, D. J., Fernández-Ortiz, A., Bernardo, E., Barrera Ramírez, C., Sabaté, M., Fernandez, C., et al. (2004). Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? The Journal of Invasive Cardiology, 16, 169–174.

    PubMed  Google Scholar 

  59. Sibbing, D., von Beckerath, O., Schömig, A., Kastrati, A., & von Beckerath, N. (2007). Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. The American Journal of Cardiology, 100, 203–205.

    Article  CAS  PubMed  Google Scholar 

  60. Hochholzer, W., Trenk, D., Fromm, M. F., Valina, C. M., Stratz, C., Bestehorn, H. P., et al. (2010). Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. Journal of the American College of Cardiology, 55, 2427–2434.

    Article  CAS  PubMed  Google Scholar 

  61. Olufadi, R., & Byrne, C. D. (2006). Effects of VLDL and remnant particles on platelets. Pathophysiology of Haemostasis and Thrombosis, 35, 281–291.

    Article  CAS  PubMed  Google Scholar 

  62. Pedreño, J., Hurt-Camejo, E., Wiklund, O., Badimón, L., & Masana, L. (2000). Platelet function in patients with familial hypertriglyceridemia: evidence that platelet reactivity is modulated by apolipoprotein E content of very-low-density lipoprotein particles. Metabolism, 49, 942–949.

    Article  PubMed  Google Scholar 

  63. Kuhn, F. E., Mohler, E. R., Satler, L. F., Reagan, K., Lu, D. Y., & Rackley, C. E. (1991). Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity. The American Journal of Cardiology, 68, 1425–1430.

    Article  CAS  PubMed  Google Scholar 

  64. Calkin, A. C., Drew, B. G., Ono, A., Duffy, S. J., Gordon, M. V., Schoenwaelder, S. M., et al. (2009). Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation, 120, 2095–2104.

    Article  CAS  PubMed  Google Scholar 

  65. Li, Y., Woo, V., & Bose, R. (2001). Platelet hyperactivity and abnormal Ca(2+) homeostasis in diabetes mellitus. American Journal of Physiology. Heart and Circulatory Physiology, 280, H1480–489.

    CAS  PubMed  Google Scholar 

  66. Mazzanti, L., Rabini, R. A., Faloia, E., Fumelli, P., Bertoli, E., & De Pirro, R. (1990). Altered cellular Ca2+ and Na + transport in diabetes mellitus. Diabetes, 39, 850–854.

    Article  CAS  PubMed  Google Scholar 

  67. Schaeffer, G., Wascher, T. C., Kostner, G. M., & Graier, W. F. (1999). Alterations in platelet Ca2+ signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. Diabetologia, 42, 167–176.

    Article  CAS  PubMed  Google Scholar 

  68. Ishii, H., Umeda, F., Hashimoto, T., & Nawata, H. (1991). Increased intracellular calcium mobilization in platelets from patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 34, 332–336.

    Article  CAS  PubMed  Google Scholar 

  69. Freedman, J. E. (2008). Oxidative stress and platelets. Arteriosclerosis, Thrombosis, and Vascular Biology, 28, s11–16.

    Article  CAS  PubMed  Google Scholar 

  70. Seghieri, G., Di Simplicio, P., Anichini, R., Alviggi, L., De Bellis, A., Bennardini, F., et al. (2001). Platelet antioxidant enzymes in insulin-dependent diabetes mellitus. Clinica Chimica Acta, 309, 19–23.

    Article  CAS  Google Scholar 

  71. Jardín, I., Redondo, P. C., Salido, G. M., Pariente, J. A., & Rosado, J. A. (2006). Endogenously generated reactive oxygen species reduce PMCA activity in platelets from patients with non-insulin-dependent diabetes mellitus. Platelets, 17, 283–288.

    Article  PubMed  CAS  Google Scholar 

  72. Redondo, P. C., Jardin, I., Hernández-Cruz, J. M., Pariente, J. A., Salido, G. M., & Rosado, J. A. (2005). Hydrogen peroxide and peroxynitrite enhance Ca2+ mobilization and aggregation in platelets from type 2 diabetic patients. Biochemical and Biophysical Research Communications, 333, 794–802.

    Article  CAS  PubMed  Google Scholar 

  73. Ahmed, N. (2005). Advanced glycation endproducts-role in pathology of diabetic complications. Diabetes Research and Clinical Practice, 67, 3–21.

    Article  CAS  PubMed  Google Scholar 

  74. Hasegawa, Y., Suehiro, A., Higasa, S., Namba, M., & Kakishita, E. (2002). Enhancing effect of advanced glycation end products on serotonin-induced platelet aggregation in patients with diabetes mellitus. Thrombosis Research, 107, 319–323.

    Article  CAS  PubMed  Google Scholar 

  75. Schmidt, A. M., Yan, S. D., Wautier, J. L., & Stern, D. (1999). Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circulation Research, 84, 489–497.

    Article  CAS  PubMed  Google Scholar 

  76. Schäfer, A., & Bauersachs, J. (2008). Endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation in diabetes and atherosclerosis. Current Vascular Pharmacology, 6, 52–60.

    Article  PubMed  Google Scholar 

  77. Kario, K., Matsuo, T., Kobayashi, H., Matsuo, M., Sakata, T., & Miyata, T. (1995). Activation of tissue factor-induced coagulation and endothelial cell dysfunction in non-insulin-dependent diabetic patients with microalbuminuria. Arteriosclerosis, Thrombosis, and Vascular Biology, 15, 1114–1120.

    Article  CAS  PubMed  Google Scholar 

  78. Tschoepe, D., Roesen, P., Esser, J., Schwippert, B., Nieuwenhuis, H. K., Kehrel, B., et al. (1991). Large platelets circulate in an activated state in diabetes mellitus. Seminars in Thrombosis and Hemostasis, 17, 433–438.

    Article  CAS  PubMed  Google Scholar 

  79. Levine, G. N., Bates, E. R., Blankenship, J. C., et al. (2011). American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Journal of the American College of Cardiology, 58, e44–122.

    Article  PubMed  Google Scholar 

  80. Feit, F., Manoukian, S. V., Ebrahimi, R., Pollack, C. V., Ohman, E. M., Attubato, M. J., et al. (2008). Safety and efficacy of bivalirudin monotherapy in patients with diabetes mellitus and acute coronary syndromes: a report from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. Journal of the American College of Cardiology, 51, 1645–1652.

    Article  CAS  PubMed  Google Scholar 

  81. Davì, G., Catalano, I., Averna, M., Notarbartolo, A., Strano, A., Ciabattoni, G., et al. (1990). Thromboxane biosynthesis and platelet function in type II diabetes mellitus. The New England Journal of Medicine, 322, 1769–1774.

    Article  PubMed  Google Scholar 

  82. Investigators, E. T. D. R. S. (1992). Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. Journal of the American Medical Association, 268, 1292–300.

    Article  Google Scholar 

  83. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O'Brien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh (2008) The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 337:a1840.

  84. Ogawa, H., Nakayama, M., Morimoto, T., Uemura, S., Kanauchi, M., Doi, N., et al. (2008). Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. Journal of the American Medical Association, 300, 2134–141.

    Article  CAS  PubMed  Google Scholar 

  85. Rydén, L., Standl, E., Bartnik, M., et al. (2007). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). European Heart Journal, 28, 88–136.

    Article  PubMed  Google Scholar 

  86. Pignone, M., Alberts, M. J., Colwell, J. A., Cushman, M., Inzucchi, S. E., Mukherjee, D., et al. (2010). Aspirin for primary prevention of cardiovascular events in people with diabetes. Journal of the American College of Cardiology, 55, 2878–2886.

    Article  CAS  PubMed  Google Scholar 

  87. O’Gara, P. T., Kushner, F. G., Ascheim, D. D., et al. (2013). ACCF/AHA guideline for the management of ST-elevation myocardial infarction. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. doi:10.1016/j.jacc.2012.11.019. 2012.

  88. Anderson, J. L., Adams, C. D., Antman, E. M., et al. (2011). ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 123, e426–579.

    Article  PubMed  Google Scholar 

  89. Roux, S., Christeller, S., & Lüdin, E. (1992). Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. Journal of the American College of Cardiology, 19, 671–677.

    Article  CAS  PubMed  Google Scholar 

  90. Antithrombotic Trialists' Collaboration. (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ, 324, 71–86.

    Article  Google Scholar 

  91. Snoep, J. D., Hovens, M. M., Eikenboom, J. C., van der Bom, J. G., & Huisman, M. V. (2007). Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Archives of Internal Medicine, 167, 1593–1599.

    Article  PubMed  Google Scholar 

  92. Krasopoulos, G., Brister, S. J., Beattie, W. S., & Buchanan, M. R. (2008). Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ, 336, 195–198.

    Article  PubMed  CAS  Google Scholar 

  93. Grove, E. L., Hvas, A. M., Johnsen, H. L., Hedegaard, S. S., Pedersen, S. B., Mortensen, J., et al. (2010). A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thrombosis and Haemostasis, 103, 1245–1253.

    Article  CAS  PubMed  Google Scholar 

  94. Guthikonda, S., Lev, E. I., Patel, R., DeLao, T., Bergeron, A. L., Dong, J. F., et al. (2007). Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. Journal of Thrombosis and Haemostasis, 5, 490–496.

    Article  CAS  PubMed  Google Scholar 

  95. Cox, D., Maree, A. O., Dooley, M., Conroy, R., Byrne, M. F., & Fitzgerald, D. J. (2006). Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke, 37, 2153–2158.

    Article  CAS  PubMed  Google Scholar 

  96. Maree, A. O., Curtin, R. J., Chubb, A., Dolan, C., Cox, D., O'Brien, J., et al. (2005). Cyclooxygenase-1 haplotype modulates platelet response to aspirin. Journal of Thrombosis and Haemostasis, 3, 2340–2345.

    Article  CAS  PubMed  Google Scholar 

  97. Catella-Lawson, F., Reilly, M. P., Kapoor, S. C., Cucchiara, A. J., DeMarco, S., Tournier, B., et al. (2001). Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. The New England Journal of Medicine, 345, 1809–1817.

    Article  CAS  PubMed  Google Scholar 

  98. Cerbone, A. M., Macarone-Palmieri, N., Saldalamacchia, G., Coppola, A., Di Minno, G., & Rivellese, A. A. (2009). Diabetes, vascular complications and antiplatelet therapy: open problems. Acta Diabetologica, 46, 253–261.

    Article  CAS  PubMed  Google Scholar 

  99. Storey, R. F., Newby, L. J., & Heptinstall, S. (2001). Effects of P2Y(1) and P2Y(12) receptor antagonists on platelet aggregation induced by different agonists in human whole blood. Platelets, 12, 443–447.

    Article  CAS  PubMed  Google Scholar 

  100. Gachet, C. (2001). ADP receptors of platelets and their inhibition. Thrombosis and Haemostasis, 86, 222–232.

    CAS  PubMed  Google Scholar 

  101. Turner, N. A., Moake, J. L., & McIntire, L. V. (2001). Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood, 98, 3340–3345.

    Article  CAS  PubMed  Google Scholar 

  102. Steering Committee, C. A. P. R. I. E. (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet, 348, 1329–1339.

    Article  Google Scholar 

  103. Bhatt, D. L., Marso, S. P., Hirsch, A. T., Ringleb, P. A., Hacke, W., & Topol, E. J. (2002). Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. The American Journal of Cardiology, 90, 625–628.

    Article  PubMed  Google Scholar 

  104. Bhatt, D. L., Fox, K. A., Hacke, W., Berger, P. B., Black, H. R., Boden, W. E., et al. (2006). Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. The New England Journal of Medicine, 354, 1706–1717.

    Article  CAS  PubMed  Google Scholar 

  105. Yusuf, S., Zhao, F., Mehta, S. R., Chrolavicius, S., Tognoni, G., Fox, K. K., et al. (2001). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England Journal of Medicine, 345, 494–502.

    Article  CAS  PubMed  Google Scholar 

  106. Mehta, S. R., Yusuf, S., Peters, R. J., Bertrand, M. E., Lewis, B. S., Natarajan, M. K., et al. (2001). Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet, 358, 527–533.

    Article  CAS  PubMed  Google Scholar 

  107. Steinhubl, S. R., Berger, P. B., Mann, J. T., 3rd, Fry, E. T., DeLago, A., Wilmer, C., et al. (2002). Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. Journal of the American Medical Association, 288, 2411–2420.

    Article  CAS  PubMed  Google Scholar 

  108. Chen, Z. M., Jiang, L. X., Chen, Y. P., Xie, J. X., Pan, H. C., Peto, R., et al. (2005). Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet, 366, 1607–1621.

    Article  CAS  PubMed  Google Scholar 

  109. Sabatine, M. S., Cannon, C. P., Gibson, C. M., López-Sendón, J. L., Montalescot, G., Theroux, P., et al. (2005). Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. The New England Journal of Medicine, 352, 1179–1189.

    Article  CAS  PubMed  Google Scholar 

  110. Sabatine, M. S., Cannon, C. P., Gibson, C. M., López-Sendón, J. L., Montalescot, G., Theroux, P., et al. (2005). Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. Journal of the American Medical Association, 294, 1224–1232.

    Article  CAS  PubMed  Google Scholar 

  111. Angiolillo, D. J., Fernandez-Ortiz, A., Bernardo, E., Alfonso, F., Macaya, C., Bass, T. A., et al. (2007). Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. Journal of the American College of Cardiology, 49, 1505–1516.

    Article  CAS  PubMed  Google Scholar 

  112. Ferreiro, J. L., & Angiolillo, D. J. (2009). Clopidogrel response variability: current status and future directions. Thrombosis and Haemostasis, 102, 7–14.

    CAS  PubMed  Google Scholar 

  113. Angiolillo, D. J., & Ferreiro, J. L. (2010). Platelet adenosine diphosphate P2Y12 receptor antagonism: benefits and limitations of current treatment strategies and future directions. Revista Española de Cardiología, 63, 60–76.

    Article  PubMed  Google Scholar 

  114. Serebruany, V., Pokov, I., Kuliczkowski, W., Chesebro, J., & Badimon, J. (2008). Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thrombosis and Haemostasis, 100, 76–82.

    CAS  PubMed  Google Scholar 

  115. Angiolillo, D. J. (2009). Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care, 32, 531–40.

    Article  CAS  PubMed  Google Scholar 

  116. Matsuno, H., Tokuda, H., Ishisaki, A., Zhou, Y., Kitajima, Y., & Kozawa, O. (2005). P2Y12 receptors play a significant role in the development of platelet microaggregation in patients with diabetes. Journal of Clinical Endocrinology and Metabolism, 90, 920–927.

    Article  CAS  PubMed  Google Scholar 

  117. Ueno, M., Ferreiro, J. L., Tomasello, S. D., Capodanno, D., Tello-Montoliu, A., Kodali, M., et al. (2011). Functional profile of the platelet P2Y12 receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease. Thrombosis and Haemostasis, 105, 730–732.

    Article  CAS  PubMed  Google Scholar 

  118. Erlinge, D., Varenhorst, C., Braun, O. O., James, S., Winters, K. J., Jakubowski, J. A., et al. (2008). Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. Journal of the American College of Cardiology, 52, 1968–1977.

    Article  CAS  PubMed  Google Scholar 

  119. Ueno, M., Ferreiro, J. L., Desai, B., Tomasello, S. D., Tello-Montoliu, A., Capodanno, D., et al. (2012). Cigarette smoking is associated with a dose–response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC. Cardiovascular Interventions, 5, 293–300.

    Article  PubMed  Google Scholar 

  120. Angiolillo, D. J., Bernardo, E., Ramírez, C., Costa, M. A., Sabaté, M., Jimenez-Quevedo, P., et al. (2006). Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. Journal of the American College of Cardiology, 48, 298–304.

    Article  CAS  PubMed  Google Scholar 

  121. Angiolillo, D. J., Bernardo, E., Capodanno, D., Vivas, D., Sabaté, M., Ferreiro, J. L., et al. (2010). Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease on dual antiplatelet therapy. Journal of the American College of Cardiology, 55, 1139–1146.

    Article  CAS  PubMed  Google Scholar 

  122. Angiolillo, D. J., Bernardo, E., Sabaté, M., Jimenez-Quevedo, P., Costa, M. A., Palazuelos, J., et al. (2007). Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. Journal of the American College of Cardiology, 50, 1541–1547.

    Article  PubMed  Google Scholar 

  123. Iakovou, I., Schmidt, T., Bonizzoni, E., Ge, L., Sangiorgi, G. M., Stankovic, G., et al. (2005). Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. Journal of the American Medical Association, 293, 2126–2130.

    Article  CAS  PubMed  Google Scholar 

  124. Urban, P., Gershlick, A. H., Guagliumi, G., Guyon, P., Lotan, C., Schofer, J., et al. (2006). Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry. Circulation, 113, 1434–1441.

    Article  CAS  PubMed  Google Scholar 

  125. Kuchulakanti, P. K., Chu, W. W., Torguson, R., Ohlmann, P., Rha, S. W., Clavijo, L. C., et al. (2006). Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation, 113, 1108–1113.

    Article  CAS  PubMed  Google Scholar 

  126. Michno, A., Bielarczyk, H., Pawełczyk, T., Jankowska-Kulawy, A., Klimaszewska, J., & Szutowicz, A. (2007). Alterations of adenine nucleotide metabolism and function of blood platelets in patients with diabetes. Diabetes, 56, 462–467.

    Article  CAS  PubMed  Google Scholar 

  127. Guthikonda, S., Alviar, C. L., Vaduganathan, M., Arikan, M., Tellez, A., DeLao, T., et al. (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. Journal of the American College of Cardiology, 52, 743–749.

    Article  CAS  PubMed  Google Scholar 

  128. DiChiara, J., Bliden, K. P., Tantry, U. S., Hamed, M. S., Antonino, M. J., Suarez, T. A., et al. (2007). The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes, 56, 3014–3019.

    Article  CAS  PubMed  Google Scholar 

  129. CURRENT-OASIS 7 Investigators, Mehta, S. R., Bassand, J. P., Chrolavicius, S., Diaz, R., Eikelboom, J. W., et al. (2010). Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. The New England Journal of Medicine, 363, 930–942.

    Article  PubMed  Google Scholar 

  130. Angiolillo, D. J. (2009). Variability in responsiveness to oral antiplatelet therapy. The American Journal of Cardiology, 103(3 Suppl), 27A–34A.

    Article  CAS  PubMed  Google Scholar 

  131. Capodanno, D., Patel, A., Dharmashankar, K., Ferreiro, J. L., Ueno, M., Kodali, M., et al. (2011). Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circulation. Cardiovascular Interventions, 4, 180–187.

    Article  CAS  PubMed  Google Scholar 

  132. Rocca, B., Santilli, F., Pitocco, D., Mucci, L., Petrucci, G., Vitacolonna, E., et al. (2012). The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. Journal of Thrombosis and Haemostasis, 10, 1220–1230.

    Article  CAS  PubMed  Google Scholar 

  133. Di Minno, G., Silver, M. J., Cerbone, A. M., & Murphy, S. (1986). Trial of repeated low-dose aspirin in diabetic angiopathy. Blood, 68, 886–891.

    Google Scholar 

  134. Angiolillo, D. J., Shoemaker, S. B., Desai, B., Yuan, H., Charlton, R. K., Bernardo, E., et al. (2007). 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, 115, 708–716.

    Article  CAS  PubMed  Google Scholar 

  135. Mehta, S. R., Tanguay, J. F., Eikelboom, J. W., Jolly, S. S., Joyner, C. D., Granger, C. B., et al. (2010). Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet, 376, 1233–1243.

    Article  CAS  PubMed  Google Scholar 

  136. Price, M. J., Berger, P. B., Teirstein, P. S., Tanguay, J. F., Angiolillo, D. J., Spriggs, D., et al. (2011). Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. Journal of the American Medical Association, 305, 1097–1105.

    Article  CAS  PubMed  Google Scholar 

  137. Collet, J. P., Cuisset, T., Rangé, G., Cayla, G., Elhadad, S., Pouillot, C., et al. (2012). Bedside monitoring to adjust antiplatelet therapy for coronary stenting. The New England Journal of Medicine, 367, 2100–2109.

    Article  CAS  PubMed  Google Scholar 

  138. Angiolillo, D. J., Capodanno, D., & Goto, S. (2010). Platelet thrombin receptor antagonism and atherothrombosis. European Heart Journal, 31, 17–28.

    Article  CAS  PubMed  Google Scholar 

  139. Mortensen, S. B., Larsen, S. B., Grove, E. L., Kristensen, S. D., & Hvas, A. M. (2010). Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus. Thrombosis Research, 126, e318–322.

    Article  CAS  PubMed  Google Scholar 

  140. Fontana, P., Alberts, P., Sakariassen, K. S., Bounameaux, H., Meyer, J. P., & Santana Sorensen, A. (2011). The dual thromboxane receptor antagonist and thromboxane synthase inhibitor EV-077 is a more potent inhibitor of platelet function than aspirin. Journal of Thrombosis and Haemostasis, 9, 2109–2111.

    Article  CAS  PubMed  Google Scholar 

  141. American Heart Association (1994) Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. The Ridogrel Versus Aspirin Patency Trial (RAPT). Circulation 89:588–595.

    Google Scholar 

  142. Gresele, P., Migliacci, R., Procacci, A., De Monte, P., & Bonizzoni, E. (2007). Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication. Thrombosis and Haemostasis, 97, 444–450.

    CAS  PubMed  Google Scholar 

  143. Kariyazono, H., Nakamura, K., Arima, J., Ayukawa, O., Onimaru, S., Masuda, H., et al. (2004). Evaluation of anti-platelet aggregatory effects of aspirin, cilostazol and ramatroban on platelet-rich plasma and whole blood. Blood Coagulation & Fibrinolysis, 15, 157–167.

    Article  CAS  Google Scholar 

  144. Neri Serneri, G. G., Coccheri, S., Marubini, E., & Violi, F. (2004). Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. European Heart Journal, 25, 1845–1852.

    Article  CAS  PubMed  Google Scholar 

  145. Angiolillo, D. J., & Capranzano, P. (2008). Pharmacology of emerging novel platelet inhibitors. American Heart Journal, 156(2 Suppl), S10–15.

    Article  PubMed  CAS  Google Scholar 

  146. Angiolillo, D. J., Badimon, J. J., Saucedo, J. F., Frelinger, A. L., Michelson, A. D., Jakubowski, J. A., et al. (2011). A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. European Heart Journal, 32, 838–846.

    Article  CAS  PubMed  Google Scholar 

  147. Wiviott, S. D., Braunwald, E., McCabe, C. H., Montalescot, G., Ruzyllo, W., Gottlieb, S., et al. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine, 357, 2001–2015.

    Article  CAS  PubMed  Google Scholar 

  148. Montalescot, G., Wiviott, S. D., Braunwald, E., Murphy, S. A., Gibson, C. M., McCabe, C. H., et al. (2009). Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet, 373, 723–731.

    Article  CAS  PubMed  Google Scholar 

  149. Wiviott, S. D., Braunwald, E., Angiolillo, D. J., Meisel, S., Dalby, A. J., Verheugt, F. W., et al. (2008). Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation, 118, 1626–1636.

    Article  CAS  PubMed  Google Scholar 

  150. Capodanno, D., Dharmashankar, K., & Angiolillo, D. J. (2010). Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist. Expert Review of Cardiovascular Therapy, 8, 151–158.

    Article  CAS  PubMed  Google Scholar 

  151. Angiolillo, D. J., & Ueno, M. (2011). Optimizing platelet inhibition in clopidogrel poor metabolizers: therapeutic options and practical considerations. JACC. Cardiovascular Interventions, 4, 411–414.

    Article  PubMed  Google Scholar 

  152. Gurbel, P. A., Bliden, K. P., Butler, K., Tantry, U. S., Gesheff, T., Wei, C., et al. (2009). Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation, 120, 2577–2585.

    Article  CAS  PubMed  Google Scholar 

  153. Storey, R. F., Husted, S., Harrington, R. A., Heptinstall, S., Wilcox, R. G., Peters, G., et al. (2007). Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. Journal of the American College of Cardiology, 50, 1852–1856.

    Article  CAS  PubMed  Google Scholar 

  154. Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., et al. (2009). Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. The New England Journal of Medicine, 361, 1–13.

    Article  Google Scholar 

  155. James, S., Angiolillo, D. J., Cornel, J. H., Erlinge, D., Husted, S., Kontny, F., et al. (2010). Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. European Heart Journal, 31, 3006–3116.

    Article  CAS  PubMed  Google Scholar 

  156. Ferreiro, J. L., Ueno, M., & Angiolillo, D. J. (2009). Cangrelor: a review on its mechanism of action and clinical development. Expert Review of Cardiovascular Therapy, 7, 1195–1201.

    Article  CAS  PubMed  Google Scholar 

  157. Storey, R. F., Wilcox, R. G., & Heptinstall, S. (2002). Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets, 13, 407–413.

    Article  CAS  PubMed  Google Scholar 

  158. Ferreiro JL, Ueno M, Tello-Montoliu A, Tomasello SD, Capodanno D, Capranzano P, Dharmashankar K, Darlington A, Desai B, Rollini F, Guzman LA, Bass TA, Angiolillo DJ (2012) Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation. Journal of Thrombosis and Thrombolysis, 35, 155–164.

    Google Scholar 

  159. Harrington, R. A., Stone, G. W., McNulty, S., White, H. D., Lincoff, A. M., Gibson, C. M., et al. (2009). Platelet inhibition with Cangrelor in patients undergoing PCI. The New England Journal of Medicine, 361, 2318–2329.

    Article  CAS  PubMed  Google Scholar 

  160. Bhatt, D. L., Lincoff, A. M., Gibson, C. M., Stone, G. W., McNulty, S., Montalescot, G., et al. (2009). Intravenous Platelet Blockade with Cangrelor during PCI. The New England Journal of Medicine, 361, 2330–2341.

    Article  CAS  PubMed  Google Scholar 

  161. Berger, J. S., Roe, M. T., Gibson, C. M., Kilaru, R., Green, C. L., Melton, L., et al. (2009). Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. American Heart Journal, 158, 998–1004.

    Article  CAS  PubMed  Google Scholar 

  162. Ueno, M., Rao, S. V., & Angiolillo, D. J. (2010). Elinogrel: pharmacological principles, preclinical and early phase clinical testing. Future Cardiology, 6, 445–453.

    Article  CAS  PubMed  Google Scholar 

  163. Welsh, R. C., Rao, S. V., Zeymer, U., Thompson, V. P., Huber, K., Kochman, J., et al. (2012). 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. Circulation. Cardiovascular Interventions, 5, 336–346.

    Article  CAS  PubMed  Google Scholar 

  164. Angiolillo, D. J., Welsh, R. C., Trenk, D., Neumann, F. J., Conley, P. B., McClure, M. W., et al. (2012). Pharmacokinetic and pharmacodynamic effects of elinogrel: results of the platelet function substudy from the intravenous and oral administration of elinogrel to evaluate tolerability and efficacy in nonurgent percutaneous coronary intervention patients (INNOVATE-PCI) trial. Circulation. Cardiovascular Interventions, 5, 347–356.

    Article  CAS  PubMed  Google Scholar 

  165. Angiolillo, D. J., Capranzano, P., Ferreiro, J. L., Ueno, M., Capodanno, D., Dharmashankar, K., et al. (2011). Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. Thrombosis and Haemostasis, 106, 253–262.

    Article  CAS  PubMed  Google Scholar 

  166. Jeong, Y. H., Lee, S. W., Choi, B. R., Kim, I. S., Seo, M. K., Kwak, C. H., et al. (2009). Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. Journal of the American College of Cardiology, 53, 1101–1109.

    Article  CAS  PubMed  Google Scholar 

  167. Ferreiro, J. L., Ueno, M., Desai, B., Capranzano, P., Capodanno, D., & Angiolillo, D. J. (2012). Impact of adjunctive cilostazol therapy versus high maintenance dose of clopidogrel in suboptimal responders with diabetes mellitus. Rev Esp Cardiol (Engl)., 65, 105–106.

    Article  Google Scholar 

  168. Capranzano, P., Ferreiro, J. L., Ueno, M., Capodanno, D., Dharmashankar, K., Darlington, A., et al. (2012). Pharmacodynamic effects of adjunctive cilostazol therapy in patients with coronary artery disease on dual antiplatelet therapy: Impact of high on-treatment platelet reactivity and diabetes mellitus status. Catheterization and Cardiovascular Interventions. doi:10.1002/ccd.24416.

  169. Angiolillo, D. J., Capranzano, P., Goto, S., Aslam, M., Desai, B., Charlton, R. K., et al. (2008). A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. European Heart Journal, 29, 2202–2211.

    Article  CAS  PubMed  Google Scholar 

  170. Lee, S. W., Park, S. W., Kim, Y. H., Yun, S. C., Park, D. W., Lee, C. W., et al. (2008). Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). Journal of the American College of Cardiology, 51, 1181–1187.

    Article  CAS  PubMed  Google Scholar 

  171. Morrow, D. A., Braunwald, E., Bonaca, M. P., Ameriso, S. F., Dalby, A. J., Fish, M. P., et al. (2012). Vorapaxar in the secondary prevention of atherothrombotic events. The New England Journal of Medicine, 366, 1404–413.

    Article  CAS  PubMed  Google Scholar 

  172. Tricoci, P., Huang, Z., Held, C., The TRACER Investigators, et al. (2012). Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. The New England Journal of Medicine, 366, 20–33.

    Article  CAS  PubMed  Google Scholar 

  173. De Caterina, R., Husted, S., Wallentin, L., Andreotti, F., Arnesen, H., Bachmann, F., et al. (2012). New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. Journal of the American College of Cardiology, 59, 1413–1425.

    Article  PubMed  CAS  Google Scholar 

  174. Mega, J. L., Braunwald, E., Wiviott, S. D., Bassand, J. P., Bhatt, D. L., Bode, C., et al. (2012). Rivaroxaban in patients with a recent acute coronary syndrome. The New England Journal of Medicine, 366, 9–19.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The text and outline of the present manuscript have been adapted with permission from (1) Ferreiro JL, Angiolillo DJ (2011) Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798–813 [reference 12] and (2) Ferreiro JL, Angiolillo DJ (2012) Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. Curr Pharm Des 1:5273–5293 [reference 18].

Dr. Ana Muñiz-Lozano is recipient of the Research grant from the Spanish Society of Cardiology. (“Beca de la Sección de Cardiopatía Isquémica de la Sociedad Española de Cardiología para Formación e Investigación Post Residencia en el extranjero”): “Comparación farmacodinámica de Prasugrel versus Ticagrelor en pacientes con diabetes mellitus tipo 2 y enfermedad coronaria”.

Disclosures

Dr. Angiolillo has received honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, and Sanofi-Aventis; has received consulting fees from Abbott Vascular, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, Medicure, Novartis, Portola, Sanofi-Aventis and The Medicines Company; and has received research grants from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, Eisai, GlaxoSmithKline, Otsuka, Portola, Sanofi-Aventis, and The Medicines Company.

Conflict of Interest

All other authors have no conflict of interest to report.

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Authors and Affiliations

  1. University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA

    Fabiana Rollini, Francesco Franchi, Ana Muñiz-Lozano & Dominick J Angiolillo

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  1. Fabiana Rollini
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  2. Francesco Franchi
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  3. Ana Muñiz-Lozano
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  4. Dominick J Angiolillo
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Correspondence to Dominick J Angiolillo.

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Rollini, F., Franchi, F., Muñiz-Lozano, A. et al. Platelet Function Profiles in Patients with Diabetes Mellitus. J. of Cardiovasc. Trans. Res. 6, 329–345 (2013). https://doi.org/10.1007/s12265-013-9449-0

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