Patients with diabetes mellitus presenting with acute coronary syndrome have a higher risk of cardiovascular complications and recurrent ischemic events when compared to nondiabetic counterparts. Different mechanisms including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrinolysis have been implicated for this increased atherothrombotic risk. Platelets play an important role in atherogenesis and its thrombotic complications in diabetic patients with acute coronary syndrome. Hence, potent platelet inhibition is of paramount importance in order to optimise outcomes of diabetic patients with acute coronary syndrome. The aim of this paper is to provide an overview of the increased thrombotic burden in diabetes and acute coronary syndrome, the underlying pathophysiology focussing on endothelial and platelet abnormalities, currently available antiplatelet therapies, their benefits and limitations in diabetic patients, and to describe potential future therapeutic strategies to overcome these limitations. 1. Introduction A PubMed (Medline) search was performed using the following terms either singly or in combination: diabetes, type 2 diabetes mellitus, cardiovascular risk, hypercoagulability, prothrombotic, acute coronary syndrome, endothelial dysfunction, antiplatelet, platelet dysfunction, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitor. All papers relevant to platelet and endothelial abnormalities in diabetes mellitus, acute coronary syndrome, and current antiplatelet therapies were considered. Diabetes mellitus (DM) can be described as a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or a combination of both [1]. The world prevalence of diabetes among adults (aged 20–79 years) was approximately 6.4%, affecting 285 million adults in 2010 and is predicted to rise to 7.7%, affecting 439 million adults by 2030 [2]. Between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries. Globally, diabetes is likely to be the fifth leading cause of death [3]. The most prevalent form of DM is type 2 diabetes mellitus (T2DM). Insulin resistance usually precedes the onset of T2DM and is commonly accompanied by other related metabolic abnormalities such as hyperglycaemia, dyslipidaemia, hypertension, and prothrombotic factors, all of which contribute to the increased
References
[1]
R. A. DeFronzo, International Textbook of Diabetes Mellitus, Wiley Reference Series in Biostatistics, John Wiley & Sons, Chichester, UK, 3rd edition, 2004.
[2]
J. E. Shaw, R. A. Sicree, and P. Z. Zimmet, “Global estimates of the prevalence of diabetes for 2010 and 2030,” Diabetes Research and Clinical Practice, vol. 87, no. 1, pp. 4–14, 2010.
[3]
G. Roglic, N. Unwin, P. H. Bennett et al., “The burden of mortality attributable to diabetes: realistic estimates for the year 2000,” Diabetes Care, vol. 28, no. 9, pp. 2130–2135, 2005.
[4]
P. N. Hopkins, S. C. Hunt, L. L. Wu, G. H. Williams, and R. R. Williams, “Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel?” Current Opinion in Lipidology, vol. 7, no. 4, pp. 241–253, 1996.
[5]
R. S. Gray, R. R. Fabsitz, L. D. Cowan, E. T. Lee, B. V. Howard, and P. J. Savage, “Risk factor clustering in the insulin resistance syndrome. The Strong Heart Study,” American Journal of Epidemiology, vol. 148, no. 9, pp. 869–878, 1998.
[6]
P. W. F. Wilson, R. B. D'Agostino, D. Levy, A. M. Belanger, H. Silbershatz, and W. B. Kannel, “Prediction of coronary heart disease using risk factor categories,” Circulation, vol. 97, no. 18, pp. 1837–1847, 1998.
[7]
P. W. F. Wilson, “Diabetes mellitus and coronary heart disease,” American Journal of Kidney Diseases, vol. 32, no. 5, supplement 3, pp. S89–S100, 1998.
[8]
H. C. McGill Jr. and C. A. McMahan, “Determinants of atherosclerosis in the young. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group,” The American Journal of Cardiology, vol. 82, no. 10B, pp. 30T–36T, 1998.
[9]
S. M. Haffner, S. Lehto, T. R？nnemaa, K. Py？r？l？, and M. Laakso, “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, vol. 339, no. 4, pp. 229–234, 1998.
[10]
M. Laakso, “Hyperglycemia and cardiovascular disease in type 2 diabetes,” Diabetes, vol. 48, no. 5, pp. 937–942, 1999.
[11]
V. Brezinka and I. Padmos, “Coronary heart disease risk factors in women,” European Heart Journal, vol. 15, no. 11, pp. 1571–1584, 1994.
[12]
P. H. Stone, J. E. Muller, T. Hartwell et al., “The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group,” Journal of the American College of Cardiology, vol. 14, no. 1, pp. 49–57, 1989.
[13]
D. E. Singer, A. W. Moulton, and D. M. Nathan, “Diabetic myocardial infarction: interaction of diabetes with other preinfarction risk factors,” Diabetes, vol. 38, no. 3, pp. 350–357, 1989.
[14]
J. W. Smith, F. I. Marcus, and R. Serokman, “Prognosis of patients with diabetes mellitus after acute myocardial infarction,” The American Journal of Cardiology, vol. 54, no. 7, pp. 718–721, 1984.
[15]
“Third report of the National Cholestrol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholestrol in adults (adult treatment panel III) final report,” Circulation, vol. 106, pp. 3143–3421, 2002.
[16]
K. Malmberg, “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,” British Medical Journal, vol. 314, no. 7093, pp. 1512–1515, 1997.
[17]
H. C. Gerstein, M. E. Miller, R. P. Byington, et al., “Effects of intensive glucose lowering in type 2 diabetes,” The New England Journal of Medicine, vol. 358, no. 24, pp. 2545–2559, 2008.
[18]
A. Patel, S. MacMahon, J. Chalmers et al., “Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes,” The New England Journal of Medicine, vol. 358, no. 24, pp. 2560–2572, 2008.
[19]
W. Duckworth, C. Abraira, T. Moritz et al., “Glucose control and vascular complications in veterans with type 2 diabetes,” The New England Journal of Medicine, vol. 360, no. 2, pp. 129–139, 2009.
[20]
K. E. Kip, D. P. Faxon, K. M. Detre, W. Yeh, S. F. Kelsey, and J. W. Currier, “Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry,” Circulation, vol. 94, no. 8, pp. 1818–1825, 1996.
[21]
B. Stein, W. S. Weintraub, S. S. P. Gebhart et al., “Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty,” Circulation, vol. 91, no. 4, pp. 979–989, 1995.
[22]
S. Yusuf, F. Zhao, S. R. Mehta, S. Chrolavicius, G. Tognoni, and K. K. Fox, “Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation,” The New England Journal of Medicine, vol. 345, no. 7, pp. 494–502, 2001.
[23]
K.-H. Mak, D. J. Moliterno, C. B. Granger et al., “Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries,” Journal of the American College of Cardiology, vol. 30, no. 1, pp. 171–179, 1997.
[24]
M. Roffi and E. J. Topol, “Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes,” European Heart Journal, vol. 25, no. 3, pp. 190–198, 2004.
[25]
J. D. Flaherty and C. J. Davidson, “Diabetes and coronary revascularization,” The Journal of the American Medical Association, vol. 293, no. 12, pp. 1501–1508, 2005.
[26]
C. Cola, S. Brugaletta, V. M. Yuste, B. Campos, D. J. Angiolillo, and M. Sabaté, “Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization,” Vascular Health and Risk Management, vol. 5, pp. 101–119, 2009.
[27]
M. A. Creager, T. F. Lüscher, F. Cosentino, and J. A. Beckman, “Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I,” Circulation, vol. 108, no. 12, pp. 1527–1532, 2003.
[28]
M. E. Widlansky, N. Gokce, J. F. Keaney Jr., and J. A. Vita, “The clinical implications of endothelial dysfunction,” Journal of the American College of Cardiology, vol. 42, no. 7, pp. 1149–1160, 2003.
[29]
J. A. Vita and J. F. Keaney Jr., “Endothelial function: a barometer for cardiovascular risk?” Circulation, vol. 106, no. 6, pp. 640–642, 2002.
[30]
R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999.
[31]
P. Libby, P. M. Ridker, and A. Maseri, “Inflammation and atherosclerosis,” Circulation, vol. 105, no. 9, pp. 1135–1143, 2002.
[32]
H. Li, M. I. Cybulsky, M. A. Gimbrone Jr., and P. Libby, “An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium,” Arteriosclerosis & Thrombosis, vol. 13, no. 2, pp. 197–204, 1993.
[33]
S. B. Wheatcroft, I. L. Williams, A. M. Shah, and M. T. Kearney, “Pathophysiological implications of insulin resistance on vascular endothelial function,” Diabetic Medicine, vol. 20, no. 4, pp. 255–268, 2003.
[34]
R. Stocker and J. F. Keaney Jr., “Role of oxidative modifications in atherosclerosis,” Physiological Reviews, vol. 84, no. 4, pp. 1381–1478, 2004.
[35]
A. San Martín, P. Du, A. Dikalova et al., “Reactive oxygen species-selective regulation of aortic inflammatory gene expression in type 2 diabetes,” American Journal of Physiology, vol. 292, no. 5, pp. H2073–H2082, 2007.
[36]
L. Gao and G. E. Mann, “Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling,” Cardiovascular Research, vol. 82, no. 1, pp. 9–20, 2009.
[37]
E. Maloney, I. R. Sweet, D. M. Hockenbery et al., “Activation of NF-κB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 9, pp. 1370–1375, 2009.
[38]
S. Rajagopalan and D. G. Harrison, “Reversing endothelial dysfunction with ACE inhibitors: a new trend,” Circulation, vol. 94, no. 3, pp. 240–243, 1996.
[39]
E. J. Henriksen, “Improvement of insulin sensitivity by antagonism of the renin-angiotensin system,” American Journal of Physiology, vol. 293, no. 3, pp. R974–R980, 2007.
[40]
J. H. Oak and H. Cai, “Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice,” Diabetes, vol. 56, no. 1, pp. 118–126, 2007.
[41]
J. A. Beckman, M. A. Creager, and P. Libby, “Diabetes and atherosclerosis epidemiology, pathophysiology, and management,” The Journal of the American Medical Association, vol. 287, no. 19, pp. 2570–2581, 2002.
[42]
G. M. Pieper and H. Riaz ul, “Activation of nuclear factor-κB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C,” Journal of Cardiovascular Pharmacology, vol. 30, no. 4, pp. 528–532, 1997.
[43]
R. Piga, Y. Naito, S. Kokura, O. Handa, and T. Yoshikawa, “Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells,” Atherosclerosis, vol. 193, no. 2, pp. 328–334, 2007.
[44]
J. F. Keaney Jr., J. M. Massaro, M. G. Larson et al., “Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study,” Journal of the American College of Cardiology, vol. 44, no. 1, pp. 168–173, 2004.
[45]
A. Festa, R. D'Agostino Jr., G. Howard, L. Mykk？nen, R. P. Tracy, and S. M. Haffner, “Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS),” Circulation, vol. 102, no. 1, pp. 42–47, 2000.
[46]
P. Dandona, R. Weinstock, K. Thusu, E. Abdel-Rahman, A. Aljada, and T. Wadden, “Tumor necrosis factor-α in sera of obese patients: fall with weight loss,” The Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 8, pp. 2907–2910, 1998.
[47]
B. Vozarova, C. Weyer, K. Hanson, P. A. Tataranni, C. Bogardus, and R. E. Pratley, “Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion,” Obesity Research, vol. 9, no. 7, pp. 414–417, 2001.
[48]
M. B. Schulze, E. B. Rimm, T. Li, N. Rifai, M. J. Stampfer, and F. B. Hu, “C-reactive protein and incident cardiovascular events among men with diabetes,” Diabetes Care, vol. 27, no. 4, pp. 889–894, 2004.
[49]
Z. He and G. L. King, “Protein kinase Cβ isoform inhibitors: a new treatment for diabetic cardiovascular diseases,” Circulation, vol. 110, no. 1, pp. 7–9, 2004.
[50]
T. Inoguchi, R. Battan, E. Handler, J. R. Sportsman, W. Heath, and G. L. King, “Preferential elevation of protein kinase C isoform βII and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 22, pp. 11059–11063, 1992.
[51]
P. Xia, T. Inoguchi, T. S. Kern, R. L. Engerman, P. J. Oates, and G. L. King, “Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia,” Diabetes, vol. 43, no. 9, pp. 1122–1129, 1994.
[52]
B. Tesfamariam, M. L. Brown, and R. A. Cohen, “Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C,” Journal of Clinical Investigation, vol. 87, no. 5, pp. 1643–1648, 1991.
[53]
A. Goel, Y. Zhang, L. Anderson, and R. Rahimian, “Gender difference in rat aorta vasodilation after acute exposure to high glucose: involvement of protein kinase C β and superoxide but not of Rho kinase,” Cardiovascular Research, vol. 76, no. 2, pp. 351–360, 2007.
[54]
C. Rask-Madsen and G. L. King, “Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 3, pp. 487–496, 2005.
[55]
S. I. Itani, N. B. Ruderman, F. Schmieder, and G. Boden, “Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α,” Diabetes, vol. 51, no. 7, pp. 2005–2011, 2002.
[56]
J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, and M. A. Creager, “Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans,” Circulation Research, vol. 90, no. 1, pp. 107–111, 2002.
[57]
N. N. Mehta, M. Sheetz, K. Price et al., “Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus,” Cardiovascular Drugs and Therapy, vol. 23, no. 1, pp. 17–24, 2009.
[58]
B. B. Lowell and G. I. Shulman, “Mitochondrial dysfunction and type 2 diabetes,” Science, vol. 307, no. 5708, pp. 384–387, 2005.
[59]
J. A. Kim, Y. Wei, and J. R. Sowers, “Role of mitochondrial dysfunction in insulin resistance,” Circulation Research, vol. 102, no. 4, pp. 401–414, 2008.
[60]
A. Zorzano, M. Liesa, and M. Palacín, “Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1846–1854, 2009.
[61]
S. Goldman, Y. Zhang, and S. Jin, “Autophagy and adipogenesis: implications in obesity and type II diabetes,” Autophagy, vol. 6, no. 1, pp. 179–181, 2010.
[62]
C. E. Tabit, W. B. Chung, N. M. Hamburg, and J. A. Vita, “Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications,” Reviews in Endocrine and Metabolic Disorders, vol. 11, no. 1, pp. 61–74, 2010.
[63]
J. J. Badimon, A. Zaman, G. Helft, Z. Fayad, and V. Fuster, “Acute coronary syndromes: pathophysiology and preventive priorities,” Thrombosis and Haemostasis, vol. 82, no. 2, pp. 997–1004, 1999.
[64]
P. V. Halushka, R. C. Rogers, C. B. Loadholt, and J. A. Colwell, “Increased platelet thromboxane synthesis in diabetes mellitus,” Journal of Laboratory and Clinical Medicine, vol. 97, no. 1, pp. 87–96, 1981.
[65]
N. Eibl, W. Krugluger, G. Streit, K. Schrattbauer, P. Hopmeier, and G. Schernthaner, “Improved metabolic control decreases platelet activation markers in patients with type-2 diabetes,” European Journal of Clinical Investigation, vol. 34, no. 3, pp. 205–209, 2004.
[66]
J. Lefkovits, E. F. Plow, and E. J. Topol, “Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine,” The New England Journal of Medicine, vol. 332, no. 23, pp. 1553–1559, 1995.
[67]
J. A. Colwell and R. W. Nesto, “The platelet in diabetes: focus on prevention of ischemic events,” Diabetes Care, vol. 26, no. 7, pp. 2181–2188, 2003.
[68]
P. Ferroni, S. Basili, A. Falco, and G. Davì, “Platelet activation in type 2 diabetes mellitus,” Journal of Thrombosis and Haemostasis, vol. 2, no. 8, pp. 1282–1291, 2004.
[69]
Y. Li, V. Woo, and R. Bose, “Platelet hyperactivity and abnormal Ca2+ homeostasis in diabetes mellitus,” American Journal of Physiology, vol. 280, no. 4, pp. H1480–H1489, 2001.
[70]
M. Gawaz, I. Ott, A. J. Reininger, and F. J. Neumann, “Effects of magnesium on platelet aggregation and adhesion. Magnesium modulates surface expression of glycoproteins on platelets in vitro and ex vivo,” Thrombosis and Haemostasis, vol. 72, no. 6, pp. 912–918, 1994.
[71]
S. Lindemann, N. D. Tolley, D. A. Dixon et al., “Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis,” Journal of Cell Biology, vol. 154, no. 3, pp. 485–490, 2001.
[72]
F. Cipollone, A. Mezzetti, E. Porreca et al., “Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy,” Circulation, vol. 106, no. 4, pp. 399–402, 2002.
[73]
A. S. Weyrich, S. Lindemann, and G. A. Zimmerman, “The evolving role of platelets in inflammation,” Journal of Thrombosis and Haemostasis, vol. 1, no. 9, pp. 1897–1905, 2003.
[74]
J. L. Ferreiro and D. J. Angiolillo, “Diabetes and antiplatelet therapy in acute coronary syndrome,” Circulation, vol. 123, no. 7, pp. 798–813, 2011.
[75]
L. Burnier, P. Fontana, B. R. Kwak, and A. Angelillo-Scherrer, “Cell-derived microparticles in haemostasis and vascular medicine,” Thrombosis and Haemostasis, vol. 101, no. 3, pp. 439–451, 2009.
[76]
O. Morel, L. Kessler, P. Ohlmann, and P. Bareiss, “Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis,” Atherosclerosis, vol. 212, no. 2, pp. 367–376, 2010.
[77]
F. D. George, “Microparticles in vascular diseases,” Thrombosis Research, vol. 122, supplement 1, pp. S55–S59, 2008.
[78]
O. Morel, N. Morel, J. M. Freyssinet, and F. Toti, “Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses,” Platelets, vol. 19, no. 1, pp. 9–23, 2008.
[79]
H. Schwertz, N. D. Tolley, J. M. Foulks et al., “Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets,” Journal of Experimental Medicine, vol. 203, no. 11, pp. 2433–2440, 2006.
[80]
A. S. Leroyer, A. Tedgui, and C. M. Boulanger, “Role of microparticles in atherothrombosis,” Journal of Internal Medicine, vol. 263, no. 5, pp. 528–537, 2008.
[81]
S. P. Ardoin, J. C. Shanahan, and D. S. Pisetsky, “The role of microparticles in inflammation and thrombosis,” Scandinavian Journal of Immunology, vol. 66, no. 2-3, pp. 159–165, 2007.
[82]
S. Nomura, M. Suzuki, K. Katsura et al., “Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus,” Atherosclerosis, vol. 116, no. 2, pp. 235–240, 1995.
[83]
M. Diamant, R. Nieuwland, R. F. Pablo, A. Sturk, J. W. A. Smit, and J. K. Radder, “Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus,” Circulation, vol. 106, no. 19, pp. 2442–2447, 2002.
[84]
T. Ueba, T. Haze, M. Sugiyama et al., “Level, distribution and correlates of platelet-derived microparticles in healthy individuals with special reference to the metabolic syndrome,” Thrombosis and Haemostasis, vol. 100, no. 2, pp. 280–285, 2008.
[85]
S. Omoto, S. Nomura, A. Shouzu, M. Nishikawa, S. Fukuhara, and T. Iwasaka, “Detection of monocyte-derived microparticles in patients with type II diabetes mellitus,” Diabetologia, vol. 45, no. 4, pp. 550–555, 2002.
[86]
S. Nomura, A. Shouzu, S. Omoto, M. Nishikawa, T. Iwasaka, and S. Fukuhara, “Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes,” Clinical and Applied Thrombosis/Hemostasis, vol. 10, no. 3, pp. 205–215, 2004.
[87]
S. Bernard, R. Loffroy, A. Sérusclat et al., “Increased levels of endothelial microparticles CD144 (VE-Cadherin) positives in type 2 diabetic patients with coronary noncalcified plaques evaluated by multidetector computed tomography (MDCT),” Atherosclerosis, vol. 203, no. 2, pp. 429–435, 2009.
[88]
O. Morel, B. Pereira, G. Averous et al., “Increased levels of procoagulant tissue factor-bearing microparticles within the occluded coronary artery of patients with ST-segment elevation myocardial infarction: role of endothelial damage and leukocyte activation,” Atherosclerosis, vol. 204, no. 2, pp. 636–641, 2009.
[89]
A. J. Gerrits, C. A. Koekman, C. Yildirim, R. Nieuwland, and J. W. N. Akkerman, “Insulin inhibits tissue factor expression in monocytes,” Journal of Thrombosis and Haemostasis, vol. 7, no. 1, pp. 198–205, 2009.
[90]
D. W. Sommeijer, K. Joop, A. Leyte, P. H. Reitsma, and H. Ten Cate, “Pravastatin reduces fibrinogen receptor gpIIIa on platelet-derived microparticles in patients with type 2 diabetes,” Journal of Thrombosis and Haemostasis, vol. 3, no. 6, pp. 1168–1171, 2005.
[91]
S. Nomura, N. Inami, A. Shouzu et al., “The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients,” Platelets, vol. 20, no. 1, pp. 16–22, 2009.
[92]
K. K. Koh, M. J. Quon, S. H. Han, J. Y. Ahn, Y. Lee, and E. K. Shin, “Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1？+？2 in patients with type 2 diabetes,” Atherosclerosis, vol. 194, no. 1, pp. 230–237, 2007.
[93]
M. Diamant, M. E. Tushuizen, M. N. Abid-Hussein et al., “Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent,” Thrombosis and Haemostasis, vol. 100, no. 3, pp. 489–497, 2008.
[94]
E. R. Vandendries, B. C. Furie, and B. Furie, “Role of P-selectin and PSGL-I in coagulation and thrombosis,” Thrombosis and Haemostasis, vol. 92, no. 3, pp. 459–466, 2004.
[95]
H. M. Rinder, J. L. Bonan, C. S. Rinder, K. A. Ault, and B. R. Smith, “Activated and unactivated platelet adhesion to monocytes and neutrophils,” Blood, vol. 78, no. 7, pp. 1760–1769, 1991.
[96]
K. I. Hidari, A. S. Weyrich, G. A. Zimmerman, and R. P. McEver, “Engagement of P-selectin glycoprotein ligand, 1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils,” Journal of Biological Chemistry, vol. 272, no. 45, pp. 28750–28756, 1997.
[97]
I. Elalamy, T. Chakroun, G. T. Gerotziafas et al., “Circulating platelet-leukocyte aggregates: a marker of microvascular injury in diabetic patients,” Thrombosis Research, vol. 121, no. 6, pp. 843–848, 2008.
[98]
H. Hu, N. Li, M. Yngen, C.-G. ？stenson, N. H. Wallén, and P. Hjemdahl, “Enhanced leukocyte-platelet cross-talk in type 1 diabetes mellitus: relationship to microangiopathy,” Journal of Thrombosis and Haemostasis, vol. 2, no. 1, pp. 58–64, 2004.
[99]
S. H. Alzahrani and R. A. Ajjan, “Coagulation and fibrinolysis in diabetes,” Diabetes and Vascular Disease Research, vol. 7, no. 4, pp. 260–273, 2010.
[100]
A. Breitenstein, F. C. Tanner, and T. F. Lüscher, “Tissue factor and cardiovascular disease: quo vadis?” Circulation, vol. 74, no. 1, pp. 3–12, 2010.
[101]
B. H. Annex, S. M. Denning, K. M. Channon et al., “Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes,” Circulation, vol. 91, no. 3, pp. 619–622, 1995.
[102]
H. Suefuji, H. Ogawa, H. Yasue et al., “Increased plasma tissue factor levels in acute myocardial infarction,” American Heart Journal, vol. 134, no. 2, part 1, pp. 253–259, 1997.
[103]
H. Soejima, H. Ogawa, H. Yasue et al., “Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina,” Circulation, vol. 99, no. 22, pp. 2908–2913, 1999.
[104]
G. Boden, V. R. Vaidyula, C. Homko, P. Cheung, and A. K. Rao, “Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 11, pp. 4352–4358, 2007.
[105]
J. Heinrich, L. Balleisen, H. Schulte, G. Assmann, and J. van de Loo, “Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men,” Arteriosclerosis & Thrombosis, vol. 14, no. 1, pp. 54–59, 1994.
[106]
A. R. Folsom, K. K. Wu, C. E. Davis, M. G. Conlan, P. D. Sorlie, and M. Szklo, “Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors,” Atherosclerosis, vol. 91, no. 3, pp. 191–205, 1991.
[107]
P.-Y. Scarabin, M.-F. Aillaud, P. Amouyel et al., “Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction—the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction.,” Thrombosis and Haemostasis, vol. 80, no. 5, pp. 749–756, 1998.
[108]
D. M. Heywood, M. W. Mansfield, and P. J. Grant, “Factor VII gene polymorphisms, factor VII:C levels and features of insulin resistance in non-insulin-dependent diabetes mellitus,” Thrombosis and Haemostasis, vol. 75, no. 3, pp. 401–406, 1996.
[109]
R. A. Karatela and G. S. Sainani, “Interrelationship between coagulation factor VII and obesity in diabetes mellitus (type 2),” Diabetes Research and Clinical Practice, vol. 84, no. 3, pp. e41–e44, 2009.
[110]
A. S. Wolberg and R. A. Campbell, “Thrombin generation, fibrin clot formation and hemostasis,” Transfusion and Apheresis Science, vol. 38, no. 1, pp. 15–23, 2008.
[111]
A. Ceriello, K. Esposito, M. Ihnat, J. Zhang, and D. Giugliano, “Simultaneous control of hyperglycemia and oxidative stress normalizes enhanced thrombin generation in type 1 diabetes,” Journal of Thrombosis and Haemostasis, vol. 7, no. 7, pp. 1228–1230, 2009.
[112]
E. Corrado, M. Rizzo, G. Coppola et al., “An update on the role of markers of inflammation in atherosclerosis,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 1, pp. 1–11, 2010.
[113]
R. Guardado-Mendoza, L. Jimenez-Ceja, M. F. Pacheco-Carrasco et al., “Fibrinogen is associated with silent myocardial ischaemia in type 2 diabetes mellitus,” Acta Cardiologica, vol. 64, no. 4, pp. 523–530, 2009.
[114]
R. Ajjan and P. J. Grant, “Coagulation and atherothrombotic disease,” Atherosclerosis, vol. 186, no. 2, pp. 240–259, 2006.
[115]
R. Barazzoni, E. Kiwanuka, M. Zanetti, M. Cristini, M. Vettore, and P. Tessari, “Insulin acutely increases fibrinogen production in individuals with type 2 diabetes but not in individuals without diabetes,” Diabetes, vol. 52, no. 7, pp. 1851–1856, 2003.
[116]
P. Tessari, E. Kiwanuka, R. Millioni et al., “Albumin and fibrinogen synthesis and insulin effect in type 2 diabetic patients with normoalbuminuria,” Diabetes Care, vol. 29, no. 2, pp. 323–328, 2006.
[117]
I. Seljeflot, J. R. Larseb, K. Dahl-J？rgensen, K. F. Hanssen, and H. Arnesen, “Fibrinolytic activity is highly influenced by long-term glycemic control in type 1 diabetic patients,” Journal of Thrombosis and Haemostasis, vol. 4, no. 3, pp. 686–688, 2006.
[118]
M. E. Stegenga, S. N. van der Crabben, M. C. Dessing et al., “Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans,” Diabetic Medicine, vol. 25, no. 2, pp. 157–164, 2008.
[119]
M.-C. Alessi and I. Juhan-Vague, “Metabolic syndrome, haemostasis and thrombosis,” Thrombosis and Haemostasis, vol. 99, no. 6, pp. 995–1000, 2008.
[120]
E. J. Dunn, R. A. S. Ari？ns, and P. J. Grant, “The influence of type 2 diabetes on fibrin structure and function,” Diabetologia, vol. 48, no. 6, pp. 1198–1206, 2005.
[121]
A. Natarajan, A. G. Zaman, J. J. Badimon, and S. M. Marshall, “Platelet-dependent thrombosis in patients with type 2 diabetes and coronary artery disease,” Diabetes, vol. 56, Article ID A181, 2007.
[122]
A. Natarajan, S. M. Marshall, S. G. Worthley, J. J. Badimon, and A. G. Zaman, “The presence of coronary artery disease increases platelet-dependent thrombosis in patients with type 2 diabetes mellitus,” Journal of Thrombosis and Haemostasis, vol. 6, no. 12, pp. 2210–2213, 2008.
[123]
J. I. Osende, J. J. Badimon, V. Fuster et al., “Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control,” Journal of the American College of Cardiology, vol. 38, no. 5, pp. 1307–1312, 2001.
[124]
G. N. Viswanathan, A. Natarajan, S. M. Marshall, J. J. Badimon, and A. G. Zaman, “Higher thrombus burden and impaired clot kinetics in patients with type 2 diabetes mellitus following non St-elevation acute coronary syndrome,” Circulation, vol. 122, Article ID A17675, 2010.
[125]
G. N. Viswanathan, A. G. Zaman, and S. M. Marshall, “Thrombus burden, clot kinetics and response to anti-platelet therapy in type 2 diabetes,” Diabetic Medicine, vol. 28, supplement 1, pp. 1–2, 2011.
[126]
J. L. Anderson, C. D. Adams, E. M. Antman et al., “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/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine,” Circulation, vol. 116, no. 7, pp. e148–e304, 2007.
[127]
E. M. Antman, D. T. Anbe, P. W. Armstrong et al., “ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction),” Circulation, vol. 110, no. 5, pp. 588–636, 2004.
[128]
A. I. Schafer, “Antiplatelet therapy,” American Journal of Medicine, vol. 101, pp. 199–209, 1996.
[129]
H. Ogawa, M. Nakayama, T. Morimoto et al., “Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial,” The Journal of the American Medical Association, vol. 300, no. 18, pp. 2134–2141, 2008.
[130]
G. De Berardis, M. Sacco, G. F. Strippoli et al., “Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials,” British Medical Journal, vol. 339, Article ID b4531, 2009.
[131]
C. Baigent, L. Blackwell, R. Collins, et al., “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials,” The Lancet, vol. 373, no. 9678, pp. 1849–1860, 2009.
[132]
C. Patrono, L. A. García Rodríguez, R. Landolfi, and C. Baigent, “Low-dose aspirin for the prevention of atherothrombosis,” The New England Journal of Medicine, vol. 353, no. 22, pp. 2373–2383, 2005.
[133]
J. A. Colwell, “Aspirin therapy in diabetes,” Diabetes Care, vol. 27, supplement 1, pp. S72–S73, 2004.
[134]
S. B. King III, S. C. Smith Jr., J. W. Hirshfeld Jr. et al., “2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee,” Circulation, vol. 117, no. 2, pp. 261–295, 2008.
[135]
“Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group,” The Lancet, vol. 336, no. 8719, pp. 827–830, 1990.
[136]
P. Theroux, H. Ouimet, J. McCans et al., “Aspirin, heparin, or both to treat acute unstable angina,” The New England Journal of Medicine, vol. 319, no. 17, pp. 1105–1111, 1988.
[137]
H. D. Lewis Jr., J. W. Davis, D. G. Archibald, et al., “Protective effects of aspirin against acute myocardial infarction and death in mean with unstable angina. Results of a Veterans Administration Cooperative Study,” The New England Journal of Medicine, vol. 309, no. 7, pp. 396–403, 1983.
[138]
S. Roux, S. Christeller, and E. Ludin, “Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis,” Journal of the American College of Cardiology, vol. 19, no. 3, pp. 671–677, 1992.
[139]
“Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.ISIS-2 (Second International Study of Infarct Survival) Collaborative Group,” The Lancet, vol. 2, no. 8607, pp. 349–360, 1988.
[140]
K. Senior, “Aspirin withdrawal increases risk of heart problems,” The Lancet, vol. 362, no. 9395, p. 1558, 2003.
[141]
“Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration,” British Medical Journal, vol. 308, no. 6921, pp. 81–106, 1994.
[142]
“Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients,” British Medical Journal, vol. 324, no. 7329, pp. 71–86, 2002.
[143]
S. R. Mehta, J. P. Bassand, S. Chrolavicius et al., “Dose comparisons of clopidogrel and aspirin in acute coronary syndromes,” The New England Journal of Medicine, vol. 363, no. 10, pp. 930–942, 2010.
[144]
S. R. Mehta, J. F. Tanguay, J. W. Eikelboom et al., “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,” The Lancet, vol. 376, no. 9748, pp. 1233–1243, 2010.
[145]
R. F. Storey, L. J. Newby, and S. Heptinstall, “Effects of P2Y 1 and P2Y 12 receptor antagonists on platelet aggregation induced by different agonists in human whole blood,” Platelets, vol. 12, no. 7, pp. 443–447, 2001.
[146]
C. Gachet, “ADP receptors of platelets and their inhibition,” Journal of Thrombosis and Haemostasis, vol. 86, no. 1, pp. 222–232, 2001.
[147]
A. Schomig, F. J. Neumann, A. Kastrati, et al., “A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents,” The New England Journal of Medicine, vol. 334, no. 17, pp. 1084–1089, 1996.
[148]
M. B. Leon, D. S. Baim, J. J. Popma, et al., “A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators,” The New England Journal of Medicine, vol. 339, no. 23, pp. 1665–1671, 1998.
[149]
M. E. Bertrand, V. Legrand, J. Boland et al., “Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study,” Circulation, vol. 98, no. 16, pp. 1597–1603, 1998.
[150]
P. Urban, C. Macaya, H. J. Rupprecht et al., “Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS),” Circulation, vol. 98, no. 20, pp. 2126–2132, 1998.
[151]
M. E. Bertrand, H. J. Rupprecht, P. Urban, and A. H. Gershlick, “Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS),” Circulation, vol. 102, no. 6, pp. 624–629, 2000.
[152]
Y. Cadroy, J. P. Bossavy, C. Thalamas, L. Sagnard, K. Sakariassen, and B. Boneu, “Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans,” Circulation, vol. 101, no. 24, pp. 2823–2828, 2000.
[153]
“A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee,” The Lancet, vol. 348, no. 9038, pp. 1329–1339, 1996.
[154]
D. L. Bhatt, S. P. Marso, A. T. Hirsch, P. A. Ringleb, W. Hacke, and E. J. Topol, “Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus,” The American Journal of Cardiology, vol. 90, no. 6, pp. 625–628, 2002.
[155]
M. S. Sabatine, C. P. Cannon, C. M. Gibson et al., “Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study,” The Journal of the American Medical Association, vol. 294, no. 10, pp. 1224–1232, 2005.
[156]
M. S. Sabatine, C. P. Cannon, C. M. Gibson et al., “Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation,” The New England Journal of Medicine, vol. 352, no. 12, pp. 1179–1189, 2005.
[157]
Z. Chen and L. Jiang, “Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial,” The Lancet, vol. 366, no. 9497, pp. 1607–1621, 2005.
[158]
S. R. Steinhubl, P. B. Berger, J. T. Mann III et al., “Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial,” The Journal of the American Medical Association, vol. 288, no. 19, pp. 2411–2420, 2002.
[159]
S. R. Mehta, S. Yusuf, R. J. G. Peters et al., “Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study,” The Lancet, vol. 358, no. 9281, pp. 527–533, 2001.
[160]
D. L. Bhatt, K. A. A. Fox, W. Hacke et al., “Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events,” The New England Journal of Medicine, vol. 354, no. 16, pp. 1706–1717, 2006.
[161]
D. J. Angiolillo and P. Capranzano, “Pharmacology of emerging novel platelet inhibitors,” American Heart Journal, vol. 156, no. 2, supplement, pp. 10S–15S, 2008.
[162]
S. D. Wiviott, D. Trenk, A. L. Frelinger et al., “Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 trial,” Circulation, vol. 116, no. 25, pp. 2923–2932, 2007.
[163]
S. D. Wiviott, E. Braunwald, C. H. McCabe et al., “Prasugrel versus clopidogrel in patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 357, no. 20, pp. 2001–2015, 2007.
[164]
S. D. Wiviott, E. Braunwald, C. H. McCabe et al., “Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial,” The Lancet, vol. 371, no. 9621, pp. 1353–1363, 2008.
[165]
S. D. Wiviott, E. Braunwald, D. J. Angiolillo et al., “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, vol. 118, no. 16, pp. 1626–1636, 2008.
[166]
D. J. Angiolillo, J. J. Badimon, J. F. Saucedo et al., “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, vol. 32, no. 7, pp. 838–846, 2011.
[167]
D. J. Angiolillo, S. B. Shoemaker, B. Desai 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, vol. 115, no. 6, pp. 708–716, 2007.
[168]
D. J. Angiolillo, P. Capranzano, S. Goto et al., “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, vol. 29, no. 18, pp. 2202–2211, 2008.
[169]
R. F. Storey, S. Husted, R. A. Harrington et al., “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, vol. 50, no. 19, pp. 1852–1856, 2007.
[170]
L. Wallentin, R. C. Becker, A. Budaj, et al., “Ticagrelor versus clopidogrel in patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 361, no. 11, pp. 1045–1057, 2009.
[171]
S. James, D. J. Angiolillo, J. H. Cornel et al., “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, vol. 31, no. 24, pp. 3006–3016, 2010.
[172]
M. Roffi, D. P. Chew, D. Mukherjee et al., “Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes,” Circulation, vol. 104, no. 23, pp. 2767–2771, 2001.
[173]
J. Mehilli, A. Kastrati, H. Schuhlen, et al., “Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel,” Circulation, vol. 110, no. 24, pp. 3627–3635, 2004.
[174]
A. Kastrati, J. Mehilli, F. J. Neumann, et al., “Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial,” The Journal of the American Medical Association, vol. 295, no. 13, pp. 1531–1538, 2006.
[175]
G. De Luca, E. Navarese, and P. Marino, “Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials,” European Heart Journal, vol. 30, no. 22, pp. 2705–2713, 2009.
[176]
S. V. Rao, J. A. Eikelboom, C. B. Granger, R. A. Harrington, R. M. Califf, and J. P. Bassand, “Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes,” European Heart Journal, vol. 28, no. 10, pp. 1193–1204, 2007.
[177]
J. W. Eikelboom, S. R. Mehta, S. S. Anand, C. Xie, K. A. A. Fox, and S. Yusuf, “Adverse impact of bleeding on prognosis in patients with acute coronary syndromes,” Circulation, vol. 114, no. 8, pp. 774–782, 2006.
[178]
G. W. Stone, B. T. McLaurin, D. A. Cox et al., “Bivalirudin for patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 355, no. 21, pp. 2203–2216, 2006.
[179]
S. V. Manoukian, “Predictors and impact of bleeding complications in percutaneous coronary intervention, acute coronary syndromes, and ST-segment elevation myocardial infarction,” The American Journal of Cardiology, vol. 104, no. 5, supplement, pp. 9C–15C, 2009.
[180]
D. J. Angiolillo, “Variability in responsiveness to oral antiplatelet therapy,” The American Journal of Cardiology, vol. 103, no. 3, supplement, pp. 27A–34A, 2009.
[181]
J. D. Snoep, M. M. C. Hovens, J. C. J. Eikenboom, J. G. van der Bom, and M. V. Huisman, “Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis,” Archives of Internal Medicine, vol. 167, no. 15, pp. 1593–1599, 2007.
[182]
G. Krasopoulos, S. J. Brister, W. S. Beattie, and M. R. Buchanan, “Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis,” British Medical Journal, vol. 336, no. 7637, pp. 195–198, 2008.
[183]
A. D. Michelson, M. Cattaneo, J. W. Eikelboom, et al., “Aspirin resistance: position paper of the Working Group on Aspirin Resistance,” Journal of Thrombosis and Haemostasis, vol. 3, no. 6, pp. 1309–1311, 2005.
[184]
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, et al., “Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment,” Diabetes, vol. 54, no. 8, pp. 2430–2435, 2005.
[185]
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, et al., “Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention,” The American Journal of Cardiology, vol. 97, no. 1, pp. 38–43, 2006.
[186]
A. L. Frelinger III, M. I. Furman, M. D. Linden et al., “Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance,” Circulation, vol. 113, no. 25, pp. 2888–2896, 2006.
[187]
C. Watala, J. Pluta, J. Golanski et al., “Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin,” Journal of Molecular Medicine, vol. 83, no. 2, pp. 148–158, 2005.
[188]
G. Davi, I. Catalano, M. Averna et al., “Thromboxane biosynthesis and platelet function in type II diabetes mellitus,” The New England Journal of Medicine, vol. 322, no. 25, pp. 1769–1774, 1990.
[189]
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo et al., “Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives,” Journal of the American College of Cardiology, vol. 49, no. 14, pp. 1505–1516, 2007.
[190]
J. L. Ferreiro and D. J. Angiolillo, “Clopidogrel response variability: current status and future directions,” Journal of Thrombosis and Haemostasis, vol. 102, no. 1, pp. 7–14, 2009.
[191]
T. Geisler, N. Anders, M. Paterok et al., “Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation,” Diabetes Care, vol. 30, no. 2, pp. 372–374, 2007.
[192]
V. Serebruany, I. Pokov, W. Kuliczkowski, J. Chesebro, and J. Badimon, “Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease,” Thrombosis and Haemostasis, vol. 100, no. 1, pp. 76–82, 2008.
[193]
D. J. Angiolillo, E. Bernardo, C. Ramirez, et al., “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, vol. 48, no. 2, pp. 298–304, 2006.
[194]
D. J. Angiolillo, E. Bernardo, D. Capodanno et al., “Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy,” Journal of the American College of Cardiology, vol. 55, no. 11, pp. 1139–1146, 2010.
[195]
I. Iakovou, T. Schmidt, E. Bonizzoni et al., “Incidence, predictors and outcome of thrombosis after succesful implantation of drug-eluting stents,” The Journal of the American Medical Association, vol. 293, no. 17, pp. 2126–2130, 2005.
[196]
P. Urban, A. H. Gershlick, G. Guagliumi et al., “Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry,” Circulation, vol. 113, no. 11, pp. 1434–1441, 2006.
[197]
P. K. Kuchulakanti, W. W. Chu, R. Torguson et al., “Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents,” Circulation, vol. 113, no. 8, pp. 1108–1113, 2006.
[198]
M. J. Price, P. B. Berger, P. S. Teirstein et al., “Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial,” The Journal of the American Medical Association, vol. 305, no. 11, pp. 1097–1105, 2011.
[199]
D. J. Angiolillo, M. Roffi, and A. Fernandez-Ortiz, “Tackling the thrombotic burden in patients with acute coronary syndrome and diabetes mellitus,” Expert Review of Cardiovascular Therapy, vol. 9, no. 6, pp. 697–710, 2011.
[200]
G. G. Neri Serneri, S. Coccheri, E. Marubini, and F. Violi, “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, vol. 25, no. 20, pp. 1845–1852, 2004.
[201]
“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, vol. 89, no. 2, pp. 588–595, 1994.
[202]
P. Gresele, R. Migliacci, A. Procacci, P. De Monte, and E. Bonizzoni, “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, vol. 97, no. 3, pp. 444–450, 2007.
[203]
H. Kariyazono, K. Nakamura, J. Arima et al., “Evaluation of anti-platelet aggregatory effects of aspirin, cilostazol and ramatroban on platelet-rich plasma and whole blood,” Blood Coagulation and Fibrinolysis, vol. 15, no. 2, pp. 157–167, 2004.
[204]
A. Chamorro, “TP receptor antagonism: a new concept in atherothrombosis and stroke prevention,” Cerebrovascular Diseases, vol. 27, supplement 3, pp. 20–27, 2009.
[205]
D. J. Angiolillo and L. A. Guzman, “Clinical overview of promising nonthienopyridine antiplatelet agents,” American Heart Journal, vol. 156, no. 2, supplement, pp. S23–S28, 2008.
[206]
R. F. Storey, R. G. Wilcox, and S. Heptinstall, “Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease,” Platelets, vol. 13, no. 7, pp. 407–413, 2002.
[207]
R. A. Harrington, G. W. Stone, S. McNulty et al., “Platelet inhibition with cangrelor in patients undergoing PCI,” The New England Journal of Medicine, vol. 361, no. 24, pp. 2318–2329, 2009.
[208]
D. L. Bhatt, A. M. Lincoff, C. M. Gibson et al., “Intravenous platelet blockade with cangrelor during PCI,” The New England Journal of Medicine, vol. 361, no. 24, pp. 2330–2341, 2009.
[209]
S. W. Lee, S. W. Park, M. K. Hong et al., “Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis,” Journal of the American College of Cardiology, vol. 46, no. 10, pp. 1833–1837, 2005.
[210]
S. W. Lee, S. W. Park, Y. H. Kim et al., “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, vol. 51, no. 12, pp. 1181–1187, 2008.
[211]
G. G. L. Biondi-Zoccai, M. Lotrionte, M. Anselmino et al., “Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention,” American Heart Journal, vol. 155, no. 6, pp. 1081–1089, 2008.
[212]
Y. Han, Y. Li, S. Wang et al., “Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: a randomized, controlled study,” American Heart Journal, vol. 157, no. 4, pp. 733–739, 2009.
[213]
D. J. Angiolillo, D. Capodanno, and S. Goto, “Platelet thrombin receptor antagonism and atherothrombosis,” European Heart Journal, vol. 31, no. 1, pp. 17–28, 2010.
[214]
R. C. Becker, D. J. Moliterno, L. K. Jennings et al., “Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study,” The Lancet, vol. 373, no. 9667, pp. 919–928, 2009.
[215]
S. Goto, H. Ogawa, M. Takeuchi, M. D. Flather, and D. L. Bhatt, “Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease,” European Heart Journal, vol. 31, no. 21, pp. 2601–2613, 2010.
[216]
A. K. Wittkowsky, “New oral anticoagulants: a practical guide for clinicians,” Journal of Thrombosis and Thrombolysis, vol. 29, no. 2, pp. 182–191, 2010.
[217]
S. J. Connolly, M. D. Ezekowitz, S. Yusuf et al., “Dabigatran versus warfarin in patients with atrial fibrillation,” The New England Journal of Medicine, vol. 361, no. 12, pp. 1139–1151, 2009.
[218]
E. Lonn, S. Yusuf, B. Hoogwerf et al., “Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy,” Diabetes Care, vol. 25, no. 11, pp. 1919–1927, 2002.
[219]
“MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial,” The Lancet, vol. 360, no. 9326, pp. 23–33, 2002.
[220]
T. Münzel and J. F. Keaney Jr., “Are ACE inhibitors a “magic bullet” against oxidative stress?” Circulation, vol. 104, no. 13, pp. 1571–1574, 2001.
