Thromb Haemost 2015; 114(03): 498-518
DOI: 10.1160/TH14-11-0947
Theme Issue Article
Schattauer GmbH

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Karin A. L. Müller
1   Medizinische Klinik III, Abteilung für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tübingen, Germany
2   La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
,
Madhumita Chatterjee
1   Medizinische Klinik III, Abteilung für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tübingen, Germany
,
Dominik Rath
1   Medizinische Klinik III, Abteilung für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tübingen, Germany
,
Tobias Geisler
1   Medizinische Klinik III, Abteilung für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tübingen, Germany
› Author Affiliations
Further Information

Publication History

Received: 15 November 2014

Accepted after major revision: 05 June 2015

Publication Date:
01 December 2017 (online)

Summary

Platelets play a pivotal role in chronic inflammation leading to progression of atherosclerosis and acute coronary events. Recent discoveries on novel mechanisms and platelet-dependent inflammatory targets underpin the role of platelets to maintain a chronic inflammatory condition in cardiovascular disease. There is strong and clinically relevant crosslink between chronic inflammation and platelet activation. Antiplatelet therapy is a cornerstone in the prevention and treatment of acute cardiovascular events. The benefit of antiplatelet agents has mainly been attributed to their direct anti-aggregatory impact. Some anti-inflammatory off-target effects have also been described. However, it is unclear whether these effects are secondary due to inhibition of platelet activation or are caused by direct distinct mechanisms interfering with inflammatory pathways. This article will highlight novel platelet associated targets that contribute to inflammation in cardiovascular disease and elucidate mechanisms by which currently available antiplatelet agents evolve anti-inflammatory capacities, in particular by carving out the differential mechanisms directly or indirectly affecting platelet mediated inflammation. It will further illustrate the prognostic impact of antiplatelet therapies by reducing inflammatory marker release in recent cardiovascular trials.

 
  • References

  • 1 Weyrich AS, Zimmerman GA. Platelets: signaling cells in the immune continuum. Trends Immunol 2004; 25: 489-495.
  • 2 Weyrich AS. et al. The evolving role of platelets in inflammation. J Thromb Hae-most 2003; 01: 1897-1905.
  • 3 de Boer HC. et al. Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell pheno-type. Arterioscl Thromb Vasc Biol 2006; 26: 1653-1659.
  • 4 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischaemic myocardium. Cardiovasc Res 2004; 61: 498-511.
  • 5 Gawaz M. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148: 75-85.
  • 6 Ross R. et al. Platelets, macrophages, endothelium, and growth factors. Their effects upon cells and their possible roles in atherogenesis. Ann NY Acad Sci 1985; 454: 254-260.
  • 7 Hawrylowicz CM. et al. Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production. J Exp Med 1991; 174: 785-790.
  • 8 Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 2005; 96: 612-616.
  • 9 von Hundelshausen P. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777.
  • 10 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.
  • 11 Scheuerer B. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95: 1158-1166.
  • 12 Sachais BS. et al. Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic machinery, resulting in retention of low-density lipoprotein on the cell surface. Blood 2002; 99: 3613-3622.
  • 13 Pitsilos S. et al. Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. Thromb Haemost 2003; 906: 1112-1120.
  • 14 Nassar T. et al. Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells. J Biol Chem 2003; 278: 6187-6193.
  • 15 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
  • 16 Gawaz M. et al. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
  • 17 Fernandez-Patron C. et al. Differential regulation of platelet aggregation by matrix metalloproteinases-9 and –2. Thromb Haemost 1999; 82: 1730-1735.
  • 18 May AE. et al. Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106: 2111-2117.
  • 19 Nannizzi-Alaimo L. et al. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation 2003; 107: 1123-1128.
  • 20 Bunting M. et al. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol 2002; 09: 30-35.
  • 21 Danese S. et al. Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol 2007; 178: 6017-6022.
  • 22 Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nature Rev Immunol 2007; 07: 803-815.
  • 23 Chatterjee M. et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 2011; 117: 3907-3911.
  • 24 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.
  • 25 Massberg S. et al. Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 2006; 203: 1221-1233.
  • 26 Stellos K. et al. Platelet aggregates-induced human CD34+ progenitor cell proliferation and differentiation to macrophages and foam cells is mediated by stromal cell derived factor 1 in vitro. Semin Thromb Hemost 2010; 36: 139-145.
  • 27 Thelen M, Thelen S. CXCR7, CXCR4 and CXCL12: an eccentric trio?. J Neuroimmunol 2008; 198: 9-13.
  • 28 Kraemer BF. et al. PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). J Mol Med 2010; 88: 1277-1288.
  • 29 Kraemer BF. et al. High shear flow induces migration of adherent human platelets. Platelets 2011; 22: 415-421.
  • 30 Rath D. et al. Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J 2014; 35: 386-394.
  • 31 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.
  • 32 Chatterjee M. et al. Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling. Circ Res 2014; 115: 939-949.
  • 33 Zernecke A. et al. Macrophage migration inhibitory factor in cardiovascular disease. Circulation 2008; 117: 1594-1602.
  • 34 Strussmann T. et al. Platelets are a previously unrecognised source of MIF. Thromb Haemost 2013; 110: 1004-1013.
  • 35 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.
  • 36 Seizer P. et al. Cyclophilin A and EMMPRIN (CD147) in cardiovascular diseases. Cardiovasc Res 2014; 102: 17-23.
  • 37 Wang L. et al. Cyclophilin A is an important mediator of platelet function by regulating integrin alphaIIbbeta3 bidirectional signalling. Thromb Haemost 2014; 111: 873-882.
  • 38 Elvers M. et al. Intracellular cyclophilin A is an important Ca(2+) regulator in platelets and critically involved in arterial thrombus formation. Blood 2012; 120: 1317-1326.
  • 39 Coppinger JA. et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 2004; 103: 2096-2104.
  • 40 Eisenhardt SU. et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localises inflammation to atherosclerotic plaques. Circ Res 2009; 105: 128-137.
  • 41 Venugopal SK. et al. Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: potential for paracrine/ autocrine effects. Am J Pathol 2005; 166: 1265-1271.
  • 42 Tsimikas S. et al. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006; 47 (Suppl. 08) C19-31.
  • 43 Koenig W. et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999; 99: 237-242.
  • 44 Ridker PM. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843.
  • 45 Yeh ET, Willerson JT. Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation 2003; 107: 370-371.
  • 46 Jialal I. et al. C-reactive protein: risk marker or mediator in atherothrombosis?. Hypertension 2004; 44: 6-11.
  • 47 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-1812.
  • 48 Devaraj S. et al. CRP promotes monocyte-endothelial cell adhesion via Fcgamma receptors in human aortic endothelial cells under static and shear flow conditions. Am J Physiol Heart Circ Physiol 2006; 291: H1170-1176.
  • 49 Inoue T. et al. Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting. J Am Coll Cardiol 2005; 46: 239-245.
  • 50 Meuwissen M. et al. Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction. J Clin Pathol 2006; 59: 196-201.
  • 51 Yasojima K. et al. Generation of C-reactive protein and complement components in atherosclerotic plaques. AmJ Pathol 2001; 158: 1039-1051.
  • 52 Ji SR. et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J 2007; 21: 284-294.
  • 53 Khreiss T. et al. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 2004; 109: 2016-2022.
  • 54 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.
  • 55 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.
  • 56 Khreiss T. et al. Loss of pentameric symmetry in C-reactive protein induces interleukin-8 secretion through peroxynitrite signaling in human neutrophils. Circ Res 2005; 97: 690-697.
  • 57 Zouki C. et al. Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion. J Immunol 2001; 167: 5355-5361.
  • 58 Singh U. et al. C-reactive protein decreases interleukin-10 secretion in activated human monocyte-derived macrophages via inhibition of cyclic AMP production. Arterioscl Thromb Vasc Biol 2006; 26: 2469-2475.
  • 59 Khreiss T. et al. Opposing effects of C-reactive protein isoforms on shear-induced neutrophil-platelet adhesion and neutrophil aggregation in whole blood. Circulation 2004; 110: 2713-2720.
  • 60 Teupser D. et al. No reduction of atherosclerosis in C-reactive protein (CRP)-deficient mice. J Biol Chem 2011; 286: 6272-6279.
  • 61 Simon LM. et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 2014; 123: e37-45.
  • 62 Dangwal S, Thum T. MicroRNAs in platelet biogenesis and function. Thromb Haemost 2012; 108: 599-604.
  • 63 Laffont B. et al. Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood 2013; 122: 253-261.
  • 64 Gatsiou A. et al. MicroRNAs in platelet biogenesis and function: implications in vascular homeostasis and inflammation. Curr Vasc Pharmacol 2012; 10: 524-531.
  • 65 Stakos DA. et al. Platelet microRNAs: From platelet biology to possible disease biomarkers and therapeutic targets. Platelets 2013; 24: 579-589.
  • 66 Kondkar AA. et al. VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J Thromb Haemost 2010; 08: 369-378.
  • 67 Osman A, Falker K. Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes. Platelets 2011; 22: 433-441.
  • 68 Sondermeijer BM. et al. Platelets in patients with premature coronary artery disease exhibit upregulation of miRNA340* and miRNA624*. PloS one 2011; 06: e25946.
  • 69 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
  • 70 Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. CurrPharm Design 2006; 12: 1255-1259.
  • 71 Patrono C, Andreotti F, Arnesen H. et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932.
  • 72 Panes O. et al. Human platelets synthesize and express functional tissue factor. Blood 2007; 109: 5242-5250.
  • 73 Brogren H. et al. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood 2004; 104: 3943-3948.
  • 74 Rinder HM. et al. Dynamics of leukocyte-platelet adhesion in whole blood. Blood 1991; 78: 1730-1737.
  • 75 Christersson C. et al. Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10. J Thromb Haemost 2008; 06: 986-994.
  • 76 Elstad MR. et al. P-selectin regulates platelet-activating factor synthesis and phagocytosis by monocytes. J Immunol 1995; 155: 2109-2122.
  • 77 Weyrich AS. et al. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 07: 241-246.
  • 78 Boilard E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
  • 79 Woo JS. et al. Effect of platelet reactivity, endothelial function, and inflammatory status on outcomes in patients with stable angina pectoris on clopidogrel therapy. Am J Cardiol 2014; 113: 786-792.
  • 80 Antonino MJ. et al. Effect of long-term clopidogrel treatment on platelet function and inflammation in patients undergoing coronary arterial stenting. Am J Cardiol 2009; 103: 1546-1550.
  • 81 Weber C. et al. Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation 1995; 91: 1914-1917.
  • 82 Fontana P. et al. Antiplatelet therapy: targeting the TxA2 pathway. J Cardiovasc Transl Res 2014; 07: 29-38.
  • 83 Otto GP. et al. Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets 2013; 24: 480-485.
  • 84 Birnbaum Y. et al. Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. Prostagland Other Lipid Med 2007; 83: 89-98.
  • 85 Birnbaum Y. et al. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation 2006; 114: 929-935.
  • 86 Passacquale G. et al. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PloS one 2011; 06: e25595.
  • 87 Machado FS. et al. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med 2008; 205: 1077-1086.
  • 88 Javeed A. et al. Aspirin significantly decreases the nonopsonic phagocytosis and immunogenicity of macrophages in mice. Inflam Res 2011; 60: 389-398.
  • 89 Ridker PM. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-979.
  • 90 Final report on the aspirin component of the ongoing Physicians’ Health Study.. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989; 321: 129-135.
  • 91 Antithrombotic Trialists C, Baigent C, Blackwell L. 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.
  • 92 Bartolucci AA. et al. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2011; 107: 1796-1801.
  • 93 Meade T. Primary prevention of ischaemic cardiovascular disorders with anti-platelet agents. Handb Exp Pharmacol 2012; 210: 565-605.
  • 94 Verheugt FW. The role of the cardiologist in the primary prevention of cardiovascular disease with aspirin. J Am Coll Cardiol 2015; 65: 122-124.
  • 95 Brotons C. et al. A Systematic Review of Aspirin in Primary Prevention: Is It Time for a New Approach?. Am J Cardiovasc Drugs. 2014 Epub ahead of print.
  • 96 Pasche B. et al. Prevention and treatment of cancer with aspirin: where do we stand?. Semin Oncol 2014; 41: 397-401.
  • 97 Ikonomidis I. et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 793-798.
  • 98 Chen YG. et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J 2006; 119: 32-36.
  • 99 Solheim S. et al. Influence of aspirin on inflammatory markers in patients after acute myocardial infarction. Am J Cardiol 2003; 92: 843-845.
  • 100 Solheim S. et al. No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease. Thromb Haemost 2006; 96: 660-664.
  • 101 Li N. et al. Aspirin treatment does not attenuate platelet or leukocyte activation as monitored by whole blood flow cytometry. Thromb Res 2003; 111: 165-170.
  • 102 Iyengar S, Rabbani LE. Beyond platelet inhibition: potential pleiotropic effects of ADP-receptor antagonists. J Thromb Thrombol 2009; 27: 300-306.
  • 103 Palabrica T. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-851.
  • 104 Klinkhardt U. et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Therap 2003; 73: 232-241.
  • 105 Klinkhardt U. et al. Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model. Clin Pharmacol Therap 2002; 71: 176-185.
  • 106 Xiao Z, Theroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 2004; 43: 1982-1988.
  • 107 Azar RR. et al. Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Am Heart J 2006; 151: 521e1-e4.
  • 108 Vavuranakis M. et al. Randomized comparison of the effects of ASA plus clopidogrel versus ASA alone on early platelet activation in acute coronary syndromes with elevated high-sensitivity C-reactive protein and soluble CD40 ligand levels. Clin Therap 2006; 28: 860-871.
  • 109 Quinn MJ. et al. Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol 2004; 93: 679-684.
  • 110 Harding SA. et al. Clopidogrel reduces platelet-leucocyte aggregation, monocyte activation and RANTES secretion in type 2 diabetes mellitus. Heart 2006; 92: 1335-1337.
  • 111 Sabatine MS. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
  • 112 Bhatt DL. et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706-1717.
  • 113 Bellemain-Appaix A. et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. J Am Med Assoc 2012; 308: 2507-2516.
  • 114 Mehta SR. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
  • 115 Dibra A. et al. Association between C-reactive protein levels and subsequent cardiac events among patients with stable angina treated with coronary artery stenting. Am J Med 2003; 114: 715-722.
  • 116 Toutouzas K. et al. Inflammation and restenosis after percutaneous coronary interventions. Eur Heart J 2004; 25: 1679-1687.
  • 117 Gurbel PA. et al. Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study. J Am Coll Cardiol 2006; 48: 2186-2191.
  • 118 Chew DP. et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol 2001; 88: 672-674.
  • 119 Bhatt DL. et al. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002; 90: 625-628.
  • 120 Meune C. et al. Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors. Eur J Heart Fail 2007; 09: 197-201.
  • 121 Willerson JT. et al. PROCLAIM: pilot study to examine the effects of clopidogrel on inflammatory markers in patients with metabolic syndrome receiving low-dose aspirin. Texas Heart Inst J 2009; 36: 530-539.
  • 122 Wang L. et al. P2 receptor mRNA expression profiles in human lymphocytes, monocytes and CD34+ stem and progenitor cells. BMC Immunol 2004; 05: 16.
  • 123 Wihlborg AK. et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscl Thromb Vasc Biol 2004; 24: 1810-1815.
  • 124 Ben Addi A. et al. Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. J Immunol 2010; 185: 5900-5906.
  • 125 Liverani E. et al. LPS-induced systemic inflammation is more severe in P2Y12 null mice. J Leukocyte Biol 2014; 95: 313-323.
  • 126 Storey RF. et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014; 25: 517-525.
  • 127 Husted S. et al. Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. Clin Cardiol 2010; 33: 206-212.
  • 128 Bonello L. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014; 63: 872-877.
  • 129 Armstrong D. et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 2014; 19: 209-219.
  • 130 Hasko G, Pacher P. A2A receptors in inflammation and injury: lessons learned from transgenic animals. J Leukocyte Biol 2008; 83: 447-455.
  • 131 Hasko G. et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nature Rev Drug Discov 2008; 07: 759-770.
  • 132 Hasko G, Cronstein BN. Adenosine: an endogenous regulator of innate immunity. Trends Immunol 2004; 25: 33-39.
  • 133 Rahman M. et al. Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis. Platelets 2014; 25: 257-263.
  • 134 Grzesk G. et al. Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats. Thromb Res 2012; 130: 65-69.
  • 135 Grzesk G. et al. High-dose, but not low-dose, aspirin impairs anticontractile effect of ticagrelor following ADP stimulation in rat tail artery smooth muscle cells. BioMed Res Intern 2013; 2013: 928271.
  • 136 Tunjungputri RN. et al. Differential effects of platelets and platelet inhibition by ticagrelor on TLR2– and TLR4-mediated inflammatory responses. Thromb Haemost 2015; 113: 1035-1045.
  • 137 Frelinger 3rd AL. et al. The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities. J Thromb Haemost 2008; 06: 359-365.
  • 138 Totani L. et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost 2012; 107: 1130-1140.
  • 139 Frelinger 3rd AL. et al. The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin. Thromb Haemost 2007; 98: 192-200.
  • 140 Judge HM. et al. The active metabolite of prasugrel effectively blocks the platelet P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets 2008; 19: 125-133.
  • 141 Serebruany VL. et al. Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study. Postgrad Med J 2006; 82: 404-410.
  • 142 Braun OO. et al. Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb Haemost 2008; 100: 626-633.
  • 143 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
  • 144 Liverani E. et al. Prasugrel metabolites inhibit neutrophil functions. J Pharmacol Exp Therap 2013; 344: 231-243.
  • 145 Mylotte D. et al. Clopidogrel discontinuation and platelet reactivity following coronary stenting. J Thromb Haemost 2011; 09: 24-32.
  • 146 Ho PM. et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. J Am Med Assoc 2008; 299: 532-539.
  • 147 Wykrzykowska JJ. et al. Effect of clopidogrel discontinuation at 1 year after drug eluting stent placement on soluble CD40L, P-selectin and C-reactive protein levels: DECADES (Discontinuation Effect of Clopidogrel After Drug Eluting Stent): a multicenter, open-label study. J Thromb Thrombol 2009; 28: 410-417.
  • 148 Obradovic S. et al. Men with Lower HDL Cholesterol Levels have Significant Increment of Soluble CD40 Ligand and High-sensitivity CRP Levels Following the Cessation of Long-term Clopidogrel Therapy. J Atheroscl Thromb. 2014 Epub ahead of print.
  • 149 Sambu N. et al. Clopidogrel withdrawal: is there a “rebound” phenomenon?. Thromb Haemost 2011; 105: 211-220.
  • 150 Hobson AR. et al. Effects of clopidogrel on “aspirin specific” pathways of platelet inhibition. Platelets 2009; 20: 386-390.
  • 151 Armstrong PC. et al. Reduction of platelet thromboxane A2 production ex vivo and in vivo by clopidogrel therapy. J Thromb Haemost 2010; 08: 613-615.
  • 152 Shankar H. et al. P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost 2006; 04: 638-647.
  • 153 Frelinger 3rd AL. 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 2006; 113: 2888-2896.
  • 154 Sibbing D. et al. A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment. J Am Coll Cardiol 2010; 55: 558-565.
  • 155 Fiedler KA. et al. Randomised, double-blind trial on the value of tapered discontinuation of clopidogrel maintenance therapy after drug-eluting stent implantation. Intracoronary Stenting and Antithrombotic Regimen: CAUTION in Discontinuing Clopidogrel Therapy--ISAR-CAUTION. Thromb Haemost 2014; 111: 1041-1049.
  • 156 Garratt KN. et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel-eluting coronary stent placement. Circulation 2015; 131: 62-73.
  • 157 Schror K, Weber AA. Comparative pharmacology of GP IIb/IIIa antagonists. J Thromb Thrombol 2003; 15: 71-80.
  • 158 Mascelli MA. et al. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 1998; 97: 1680-1688.
  • 159 Kereiakes DJ. Effects of GP IIb/IIIa inhibitors on vascular inflammation, coronary microcirculation, and platelet function. Rev Cardiovasc Med 2006; 07 (Suppl. 04) S3-11.
  • 160 Boersma E. et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002; 359: 189-198.
  • 161 Lincoff AM. et al. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001; 104: 163-167.
  • 162 James SK. et al. Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST-elevation acute coronary syndromes treated with dalteparin: a GUSTO IV sub-study. Am Heart J 2004; 147: 267-274.
  • 163 Steinhubl SR. et al. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007; 12: 113-122.
  • 164 Ercan E. et al. Decreased soluble cell adhesion molecules after tirofiban infusion in patients with unstable angina pectoris. Thromb J 2004; 02: 4.
  • 165 Akbulut M. et al. Effects of tirofiban on acute systemic inflammatory response in elective percutaneous coronary interventions. Curr Med Res Opin 2004; 20: 1759-1767.
  • 166 Bhatt DL. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
  • 167 Ueno M. et al. Update on the clinical development of cangrelor. Exp Rev Cardiovasc Ther 2010; 08: 1069-1077.
  • 168 Judge HM. et al. Glycoprotein IIb/IIIa and P2Y12 receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses. Platelets 2005; 16: 398-407.
  • 169 Jones WS. et al. Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER). Am Heart J 2014; 168: 588-596.
  • 170 Scirica BM. et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2 degrees P-TIMI 50 trial. Lancet 2012; 380: 1317-1324.
  • 171 Storey RF. et al. Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thromb Haemost 2014; 111: 883-891.
  • 172 O’Donoghue ML. et al. Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program. J Thromb Thrombol 2012; 34: 36-43.
  • 173 Rao AK. et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb Haemost 2006; 96: 738-743.
  • 174 Husted S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
  • 175 Pels K. et al. Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs. Eur J Clin Invest 2009; 39: 174-182.
  • 176 Salanova B. et al. Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperate in NF-kappaB activation of human neutrophils. J Biol Chem 2007; 282: 27960-27969.
  • 177 Molero L. et al. Effect of clopidogrel on the expression of inflammatory markers in rabbit ischaemic coronary artery. Br J Pharmacol 2005; 146: 419-424.
  • 178 Bhatt DL. et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982-1988.
  • 179 Ridker PM. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-2207.
  • 180 Obi C. et al. Inhibition of platelet-rich arterial thrombus in vivo: acute anti-thrombotic effect of intravenous HMG-CoA reductase therapy. Arterioscl Thromb Vasc Biol 2009; 29: 1271-1276.
  • 181 Coppinger JA. et al. Moderation of the platelet releasate response by aspirin. Blood 2007; 109: 4786-4792.
  • 182 Voora D. et al. Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events. J Am Coll Cardiol 2013; 62: 1267-1276.
  • 183 Vivekananthan DP. et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol 2004; 94: 358-360.
  • 184 Montalescot G. et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48: 931-938.
  • 185 Heitzer T. et al. Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscl Thromb Vasc Biol 2006; 26: 1648-1652.
  • 186 Merino A. et al. Platelet aggregation inhibition blocks C-reactive protein and interleukin-6 (IL-6) elevation after the coronary angioplasty: effect of the –174 G/C IL-6 gene polymorphism. Am J Cardiol 2004; 94: 1300-1303.
  • 187 Welt FG. et al. GP IIb/IIIa inhibition with eptifibatide lowers levels of soluble CD40L and RANTES after percutaneous coronary intervention. Catheter Cardiovasc Intervent 2004; 61: 185-189.
  • 188 Boilard E. et al. Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 2012; 08: 534-542.
  • 189 Langer HF. et al. Platelets contribute to the pathogenesis of experimental auto-immune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
  • 190 Verschoor A, Langer HF. Crosstalk between platelets and the complement system in immune protection and disease. Thromb Haemost 2013; 110: 910-919.
  • 191 Bonaca MP. et al. PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-1800.
  • 192 Mauri L. et al. DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-2166.