The influence of low-grade inflammation on platelets in patients with stable coronary artery disease

Summary

Inflammation is likely to be involved in all stages of atherosclerosis. Numerous inflammatory biomarkers are currently being studied, and even subtle increases in inflammatory biomarkers have been associated with increased risk of cardiovascular events in patients with coronary artery disease (CAD). Low-grade inflammation may influence both platelet production and platelet activation potentially leading to enhanced platelet aggregation. Thrombopoietin is considered the primary regulator of platelet production, but it likely acts in conjunction with numerous cytokines, of which many have altered levels in CAD. Previous studies have shown that high-sensitive C-reactive protein (CRP) independently predicts increased platelet aggregation in stable CAD patients. Increased levels of CRP, fibrinogen, interleukin-6, stromal cell-derived factor-1, CXC motif ligand 16, macrophage migration inhibitory factor, RANTES, calprotectin, and copeptin have been associated with increased risk of cardiovascular events in CAD patients. Additionally, some of these inflammatory markers have been associated with enhanced platelet activation and aggregation. However, CRP and other inflammatory markers provide only limited additional predictive value to classical risk factors such as smoking, blood pressure, and cholesterol levels. Existing data do not clarify whether inflammation simply accompanies CAD and increased production and aggregation of platelets, or whether a causal relationship exists. In this review, we provide a comprehensive overview of inflammatory markers in stable CAD with particular emphasis on platelet production, activation, and aggregation in CAD patients.

Keywords

Inflammation - platelet aggregation - platelet production - antiplatelet therapy - coronary artery disease

• References

• 1 Lozano R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095-2128.
• 2 Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 2045-2051.
• 3 Kaptoge S. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014; 35: 578-589.
• 4 Moreira DM. et al. Role of Vascular Inflammation in Coronary Artery Disease: Potential of Anti-inflammatory Drugs in the Prevention of Atherothrombosis: Inflammation and Anti-Inflammatory Drugs in Coronary Artery Disease. Am J Cardiovasc Drugs 2015; 15: 1-11.
• 5 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
• 6 Marini MG. et al. Targeting inflammation: impact on atherothrombosis. J Cardiovasc Transl Res 2014; 07: 9-18.
• 7 Tsaknis G. et al. Clinical usefulness of novel serum and imaging biomarkers in risk stratification of patients with stable angina. Dis Markers 2014; 2014: 831364.
• 8 Bisoendial RJ. et al. C-reactive protein is a mediator of cardiovascular disease. Eur Heart J 2010; 31: 2087-2091.
• 9 Kaptoge S. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132-140.
• 10 Ridker PM. et al. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 2008; 118: 2243-2251.
• 11 Arroyo-Espliguero R. et al. Predictive value of coronary artery stenoses and C-reactive protein levels in patients with stable coronary artery disease. Atherosclerosis 2009; 204: 239-243.
• 12 Sabatine MS. et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation 2007; 115: 1528-1536.
• 13 Zebrack JS. et al. Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol 2002; 89: 145-149.
• 14 Biasucci LM. et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999; 99: 855-860.
• 15 Liuzzo G. et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331: 417-424.
• 16 Niccoli G. et al. Independent prognostic value of C-reactive protein and coronary artery disease extent in patients affected by unstable angina. Atherosclerosis 2008; 196: 779-785.
• 17 Haverkate F. et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349: 462-466.
• 18 Zacho J. et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359: 1897-1908.
• 19 Pearson TA. et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499-511.
• 20 Zebrack JS. et al. C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina. J Am Coll Cardiol 2002; 39: 632-637.
• 21 Cheng JM. et al. Relation of C-Reactive Protein to Coronary Plaque Characteristics on Grayscale, Radiofrequency Intravascular Ultrasound, and Cardiovascular Outcome in Patients With Acute Coronary Syndrome or Stable Angina Pectoris (from the ATHEROREMO-IVUS Study). Am J Cardiol 2014; 114: 1497-1503.
• 22 Kubo T. et al. High-sensitivity C-reactive protein and plaque composition in patients with stable angina pectoris: a virtual histology intravascular ultrasound study. Coron Artery Dis 2009; 20: 531-535.
• 23 Perk J. et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33: 1635-1701.
• 24 Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 2011; 105 (Suppl. 01) S43-S54.
• 25 Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89: 601-609.
• 26 Danesh J. et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. J Am Med Assoc 1998; 279: 1477-1482.
• 27 Neergaard-Petersen S. et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PLoS One 2013; 08: e71150.
• 28 Neergaard-Petersen S. et al. The influence of type 2 diabetes on fibrin clot properties in patients with CAD. Thromb Haemost 2014; 112: 1142-1150.
• 29 Lowe GD. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 2005; 03: 1618-1627.
• 30 Heinrich PC. et al. Interleukin-6 and the acute phase response. Biochem J 1990; 265: 621-636.
• 31 Loppnow H, Libby P. Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1. Cell Immunol 1989; 122: 493-503.
• 32 Seino Y. et al. Interleukin 6 gene transcripts are expressed in human athero-sclerotic lesions. Cytokine 1994; 06: 87-91.
• 33 Ridker PM. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772.
• 34 Volpato S. et al. Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women’s health and aging study. Circulation 2001; 103: 947-953.
• 35 Harris TB. et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999; 106: 506-512.
• 36 Ikeda U. et al. Interleukin-6 and acute coronary syndrome. Clin Cardiol 2001; 24: 701-704.
• 37 Wang XH. et al. Correlation of serum high-sensitivity C-reactive protein and interleukin-6 in patients with acute coronary syndrome. Genet Mol Res 2014; 13: 4260-4266.
• 38 De Gennaro L. et al. Subacute inflammatory activation in subjects with acute coronary syndrome and left ventricular dysfunction. Inflammation 2012; 35: 363-370.
• 39 Lai CL. et al. Relationship between coronary atherosclerosis plaque characteristics and high sensitivity C-reactive proteins, interleukin-6. Chin Med J 2011; 124: 2452-2456.
• 40 Mazzone A. et al. Plasma levels of interleukin 2, 6, 10 and phenotypic characterisation of circulating T lymphocytes in ischemic heart disease. Atherosclerosis 1999; 145: 369-374.
• 41 Fisman EZ. et al. Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol 2006; 98: 14-18.
• 42 Hoffmeister A. et al. Prognostic value of inflammatory markers alone and in combination with blood lipids in patients with stable coronary artery disease. Eur J Intern Med 2005; 16: 47-52.
• 43 von Hundelshausen P, Schmitt MM. Platelets and their chemokines in atherosclerosis-clinical applications. Front Physiol 2014; 05: 294.
• 44 Stellos K. et al. Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells. Eur Heart J 2009; 30: 584-593.
• 45 Stellos K. et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 2008; 117: 206-215.
• 46 Wurster T. et al. Platelet expression of stromal-cell-derived factor-1 (SDF-1): an indicator for ACS?. Int J Cardiol 2013; 164: 111-115.
• 47 Geisler T. et al. Association of platelet-SDF-1 with hemodynamic function and infarct size using cardiac MR in patients with AMI. Eur J Radiol 2012; 81: e486-e490.
• 48 Rath D. et al. Platelet surface expression of SDF-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease. J Thromb Haemost. 2015 In press.
• 49 Sheikine Y, Sirsjo A. CXCL16/SR-PSOX--a friend or a foe in atherosclerosis?. Atherosclerosis 2008; 197: 487-495.
• 50 Petit SJ. et al. The CXCL16 A181V mutation selectively inhibits monocyte adhesion to CXCR6 but is not associated with human coronary heart disease. Arterioscler Thromb Vasc Biol 2011; 31: 914-920.
• 51 Lehrke M. et al. CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans. J Am Coll Cardiol 2007; 49: 442-449.
• 52 Mitsuoka H. et al. Circulating soluble SR-PSOX/CXCL16 as a biomarker for acute coronary syndrome -comparison with high-sensitivity C-reactive protein. J Atheroscler Thromb 2009; 16: 586-593.
• 53 Jansson AM. et al. Soluble CXCL16 predicts long-term mortality in acute coronary syndromes. Circulation 2009; 119: 3181-3188.
• 54 Doring Y. et al. The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease. Front Physiol 2014; 05: 212.
• 55 Bernhagen J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007; 13: 587-596.
• 56 Herder C. et al. Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Atherosclerosis 2008; 200: 380-388.
• 57 Boekholdt SM. et al. Macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without prior myocardial infarction or stroke: the EPIC-Norfolk Prospective Population study. Am J Med 2004; 117: 390-397.
• 58 Muller II. et al. Impact of counterbalance between macrophage migration inhibitory factor and its inhibitor Gremlin-1 in patients with coronary artery disease. Atherosclerosis 2014; 237: 426-432.
• 59 Muller II. et al. Macrophage migration inhibitory factor is enhanced in acute coronary syndromes and is associated with the inflammatory response. PLoS One 2012; 07: e38376.
• 60 Makino A. et al. High plasma levels of macrophage migration inhibitory factor are associated with adverse long-term outcome in patients with stable coronary artery disease and impaired glucose tolerance or type 2 diabetes mellitus. Atherosclerosis 2010; 213: 573-578.
• 61 Gear AR, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 2003; 10: 335-350.
• 62 Veillard NR. et al. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res 2004; 94: 253-261.
• 63 von Hundelshausen P. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777.
• 64 Schober A. et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 2002; 106: 1523-1529.
• 65 Kraaijeveld AO. et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms. Circulation 2007; 116: 1931-1941.
• 66 Rothenbacher D. et al. Differential expression of chemokines, risk of stable coronary heart disease, and correlation with established cardiovascular risk markers. Arterioscler Thromb Vasc Biol 2006; 26: 194-199.
• 67 de Jager SC. et al. Chemokines CCL3/MIP1alpha, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes. PLoS One 2012; 07: e45804.
• 68 Herder C. et al. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One 2011; 06: e25734.
• 69 Cavusoglu E. et al. Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography. Arterioscler Thromb Vasc Biol 2007; 27: 929-935.
• 70 Boger CA. et al. RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis 2005; 183: 121-129.
• 71 Edgeworth J. et al. Identification of p8, 14 as a highly abundant heterodimeric calcium binding protein complex of myeloid cells. J Biol Chem 1991; 266: 7706-7713.
• 72 de Seny D. et al. Monomeric calgranulins measured by SELDI-TOF mass spec-trometry and calprotectin measured by ELISA as biomarkers in arthritis. Clin Chem 2008; 54: 1066-1075.
• 73 Ho GT. et al. Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis. Am J Gastroenterol 2009; 104: 673-678.
• 74 Morrow DA. et al. Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial. Am Heart J 2008; 155: 49-55.
• 75 Healy AM. et al. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 2006; 113: 2278-2284.
• 76 Altwegg LA. et al. Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes. Eur Heart J 2007; 28: 941-948.
• 77 Cotoi OS. et al. Plasma S100A8/A9 Correlates With Blood Neutrophil Counts, Traditional Risk Factors, and Cardiovascular Disease in Middle-Aged Healthy Individuals. Arterioscler Thromb Vasc Biol 2014; 34: 202-210.
• 78 Larsen SB. et al. Calprotectin and platelet aggregation in patients with stable coronary artery disease. PLoS One. 2015 In press.
• 79 Santilli F. et al. Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment. J Am Heart Assoc. 2014 Epub ahead of print.
• 80 Morgenthaler NG. et al. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab 2008; 19: 43-49.
• 81 Keller T. et al. Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol 2010; 55: 2096-2106.
• 82 Voors AA. et al. C-terminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction: results from the OPTIMAAL study. Eur Heart J 2009; 30: 1187-1194.
• 83 von Haehling S. et al. Copeptin as a prognostic factor for major adverse cardiovascular events in patients with coronary artery disease. Int J Cardiol 2012; 162: 27-32.
• 84 May AE. et al. Platelets: inflammatory firebugs of vascular walls. Arterioscler Thromb Vasc Biol 2008; 28: s5-10.
• 85 Abi-Younes S. et al. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res 2000; 86: 131-138.
• 86 Gear AR. et al. Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function. Blood 2001; 97: 937-945.
• 87 Kowalska MA. et al. Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. Br J Haematol 1999; 104: 220-229.
• 88 Chatterjee M. et al. SDF-1alpha induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. FASEB J 2014; 28: 2864-2878.
• 89 Seizer P. et al. CXCL16 is a novel scavenger receptor on platelets and is associated with acute coronary syndrome. Thromb Haemost 2011; 105: 1112-1114.
• 90 Borst O. et al. The inflammatory chemokine CXC motif ligand 16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling. Circ Res 2012; 111: 1297-1307.
• 91 Huo Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
• 92 Combadiere C. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008; 117: 1649-1657.
• 93 Deutsch VR, Tomer A. Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside. Br J Haematol 2013; 161: 778-793.
• 94 Ault KA. et al. The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 1992; 98: 637-646.
• 95 Grove EL. et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 09: 185-191.
• 96 Larsen SB. et al. Platelet turnover in stable coronary artery disease – influence of thrombopoietin and low-grade inflammation. PLoS One 2014; 09: e85566.
• 97 Lupia E. et al. Thrombopoietin contributes to enhanced platelet activation in patients with unstable angina. J Am Coll Cardiol 2006; 48: 2195-2203.
• 98 Senaran H. et al. Thrombopoietin and mean platelet volume in coronary artery disease. Clin Cardiol 2001; 24: 405-408.
• 99 Ishibashi T. et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 1989; 86: 5953-5957.
• 100 Kaushansky K. Determinants of platelet number and regulation of thrombopoiesis. Hematology Am Soc Hematol Educ Program 2009; 147-152.
• 101 Laterveer L. et al. Continuous infusion of interleukin-6 in sublethally irradiated mice accelerates platelet reconstitution and the recovery of myeloid but not of megakaryocytic progenitor cells in bone marrow. Exp Hematol 1993; 21: 1621-1627.
• 102 Ceresa IF. et al. Thrombopoietin is not uniquely responsible for thrombocytosis in inflammatory disorders. Platelets 2007; 18: 579-582.
• 103 Sahin DY. et al. Mean Platelet Volume Associated With Aortic Distensibility, Chronic Inflammation, and Diabetes in Patients With Stable Coronary Artery Disease. Clin Appl Thromb Hemost 2012; 20: 416-421.
• 104 Baigent C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
• 105 Schror K. Acetylsalicylic Acid. Chapter 2.2. 2009. Wiley-Blackwell.;
• 106 Larsen SB. et al. Determinants of reduced antiplatelet effect of aspirin in patients with stable coronary artery disease. PLoS One. 2015 In press.
• 107 Wurtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18: 5344-5361.
• 108 Blann AD. et al. Vascular and platelet responses to aspirin in patients with coronary artery disease. Eur J Clin Invest 2013; 43: 91-99.
• 109 Dotsenko O. et al. Platelet and leukocyte activation, atherosclerosis and inflammation in European and South Asian men. J Thromb Haemost 2007; 05: 2036-2042.
• 110 Gremmel T. et al. Differential impact of inflammation on six laboratory assays measuring residual arachidonic acid-inducible platelet reactivity during dual antiplatelet therapy. J Atheroscler Thromb 2013; 20: 630-645.
• 111 Karolczak K. et al. Homocysteine is a novel risk factor for suboptimal response of blood platelets to acetylsalicylic acid in coronary artery disease: a randomized multicenter study. Pharmacol Res 2013; 74: 7-22.
• 112 Larsen SB. et al. Reduced antiplatelet effect of aspirin is associated with low-grade inflammation in patients with coronary artery disease. Thromb Haemost 2013; 109: 920-929.
• 113 Markuszewski L. et al. Reduced blood platelet sensitivity to aspirin in coronary artery disease: are dyslipidaemia and inflammatory states possible factors pre-disposing to sub-optimal platelet response to aspirin?. Basic Clin Pharmacol Toxicol 2006; 98: 503-509.
• 114 Pettersen AA. et al. Markers of endothelial and platelet activation are associated with high on-aspirin platelet reactivity in patients with stable coronary artery disease. Thromb Res 2012; 130: 424-428.
• 115 Hanriot D. et al. C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor alpha, on human monocytes. Thromb Haemost 2008; 99: 558-569.
• 116 Nakagomi A. et al. Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age, sex, and hormone replacement treatment. Circulation 2000; 101: 1785-1791.
• 117 Gori AM. et al. The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis 2009; 202: 255-262.
• 118 Obradovic SD. et al. Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention. Blood Coagul Fibrinolysis 2009; 20: 283-289.
• 119 Gurbel PA. et al. The link between heightened thrombogenicity and inflammation: pre-procedure characterisation of the patient at high risk for recurrent events after stenting. Platelets 2009; 20: 97-104.
• 120 Prasad KS. et al. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 2003; 100: 12367-12371.
• 121 Cipollone F. et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106: 399-402.
• 122 Pamukcu B. et al. Relationship between the serum sCD40L level and aspirin-resistant platelet aggregation in patients with stable coronary artery disease. Circ J 2008; 72: 61-66.
• 123 Aitken AE, Morgan ET. Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos 2007; 35: 1687-1693.
• 124 Bernlochner I. et al. Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. Thromb Haemost 2010; 104: 1193-1200.
• 125 Geisler T. et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol 2010; 99: 743-752.
• 126 Muller K. et al. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis 2010; 213: 256-262.
• 127 Ang L. et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol 2008; 52: 1052-1059.
• 128 Gaborit B. et al. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. J Thromb Haemost 2009; 07: 1939-1941.
• 129 Storey RF. et al. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002; 88: 488-494.
• 130 Evangelista V. et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost 2005; 94: 568-577.
• 131 Angiolillo DJ. et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006; 55: 780-784.
• 132 Gori AM. et al. The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis 2009; 202: 255-262.
• 133 Osmancik P. et al. High leukocyte count and interleukin-10 predict high on-treatment-platelet-reactivity in patients treated with clopidogrel. J Thromb Thrombolysis 2012; 33: 349-354.
• 134 Everett BM. et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J 2013; 166: 199-207.
• 135 Ridker PM. et al. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605.
• 136 Cushman M. et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005; 112: 25-31.
• 137 Lindmark E. et al. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. J Am Med Assoc 2001; 286: 2107-2113.
• 138 Vita JA. et al. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation 2004; 110: 1134-1139.
• 139 Ndrepepa G. et al. Myeloperoxidase level in patients with stable coronary artery disease and acute coronary syndromes. Eur J Clin Invest 2008; 38: 90-96.
• 140 Morrow DA. et al. Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18. Eur Heart J 2008; 29: 1096-1102.
• 141 Jonsson S. et al. Increased levels of leukocyte-derived MMP-9 in patients with stable angina pectoris. PLoS One 2011; 06: e19340.
• 142 Ikeda U, Shimada K. Matrix metalloproteinases and coronary artery diseases. Clin Cardiol 2003; 26: 55-59.
• 143 Nanni S. et al. Matrix metalloproteinases in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms. Transl Res 2007; 149: 137-144.
• 144 Silva IT. et al. Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)): a review. Lipids Health Dis 2011; 10: 170.
• 145 Serruys PW. et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118: 1172-1182.
• 146 Sabatine MS. et al. Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol 2007; 27: 2463-2469.
• 147 Maiolino G. et al. Lipoprotein-associated phospholipase A2 activity predicts cardiovascular events in high risk coronary artery disease patients. PLoS One 2012; 07: e48171.
• 148 Anderson JL. Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol 2008; 101: 23F-33F.
• 149 Bogaty P. et al. Clinical utility of C-reactive protein measured at admission, hospital discharge, and 1 month later to predict outcome in patients with acute coronary disease. The RISCA (recurrence and inflammation in the acute coronary syndromes) study. J Am Coll Cardiol 2008; 51: 2339-2346.
• 150 He LP. et al. Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010; 96: 339-346.
• 151 van Loon JE. et al. Prognostic markers in young patients with premature coronary heart disease. Atherosclerosis 2012; 224: 213-217.
• 152 Jensen LJ. et al. Plasma calprotectin predicts mortality in patients with ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention. J Interv Cardiol 2010; 23: 123-129.