Biomarkers of platelet activation in acute coronary syndromes

Summary

The most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of antiplatelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of <i>in vivo</i>platelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of <i>in vivo</i>platelet activation should be specific, unaltered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet ac- tivation in the setting of ACS.

Keywords

Acute coronary syndromes - platelet-derived biomarkers - thromboxane - metabolites - P-selectin - CD40L

• References

• 1 Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998; 97: 211-218.
• 2 Heeschen C. et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
• 3 Gurbel PA. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
• 4 Chu SG. et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 1998; 8: 148-156.
• 5 Badimon L. et al. Pathogenesis of the acute coronary syndromes and therapeutic implications. Pathophysiol Haemost Thromb 2002; 32: 225-231.
• 6 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
• 7 Ferroni P. et al. Platelet Function in Health and Disease: from Molecular Mechanisms, Redox Considerations to Novel Therapeutic Opportunities. Antioxid Redox Signal 2012; 17: 1447-1485.
• 8 Massberg S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.
• 9 Gawaz M. et al. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
• 10 Varga-Szabo D. et al. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol 2008; 28: 403-412.
• 11 Goto S. et al. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101: 479-486.
• 12 Pabla R. et al. Integrin-dependent control of translation: engagement of integrin alphaIIbbeta3 regulates synthesis of proteins in activated human platelets. J Cell Biol 1999; 144: 175-184.
• 13 Colombo G. et al. Gene expression profiling reveals multiple differences in platelets from patients with stable angina or non-ST elevation acute coronary syndrome. Thromb Res 2011; 128: 161-168.
• 14 Sedky HA. et al. Clinical Significance of Baseline Platelet Reactivity in Patients With Acute Coronary Syndrome. Clin Appl Thromb Hemost. 2012 Epub ahead of print
• 15 Tantry US. et al. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets 2010; 21: 360-367.
• 16 Christenson RH. et al. Cardiac markers in the assessment of acute coronary syndromes. Md Med J 1997. Suppl 18-24
• 17 NIH Definitions Working Group. Biomarkers and surrogate endpoints in clinical research: definitions and conceptual model. In: Downing GJ (ed). Biomarkers and Surrogate Endpoints. Amsterdam: Elsevier; 2000: 1-9
• 18 Aronson JK. Research priorities in biomarkers and surrogate endpoints. Br J Clin Pharmacol 2012; 73: 900-907.
• 19 Kamath S. et al. Platelet activation: assessment and quantification. Eur Heart J 2001; 22: 1561-1571.
• 20 Gurney D. et al. A reliable plasma marker of platelet activation: does it exist?. Am J Hematol 2002; 70: 139-144.
• 21 Weber M. et al. Influence of sample type and storage conditions on soluble CD40 ligand assessment. Clin Chem 2006; 52: 888-891.
• 22 Varo N. et al. Influence of pre-analytical and analytical factors on soluble CD40L measurements. Clin Sci 2006; 111: 341-347.
• 23 Riondino S. et al. Increased plasma levels of soluble CD40 ligand correlate with platelet activation markers and underline the need for standardized pre-analytical conditions. Clin Biochem 2010; 43: 666-670.
• 24 Ivandic BT. et al. Increased plasma concentrations of soluble CD40 ligand in acute coronary syndrome depend on in vitro platelet activation. Clin Chem 2007; 53: 1231-1234.
• 25 Harrison P. et al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol 2011; 155: 30-44.
• 26 Bonello L. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
• 27 Sibbing D. et al. Role of platelet function testing in clinical practice: current concepts and future perspectives. Curr Drug Targets 2011; 12: 1836-1847.
• 28 Tantry US, Gurbel PA. Assessment of oral antithrombotic therapy by platelet function testing. Nat Rev Cardiol 2011; 8: 572-579.
• 29 Italiano Jr. JE. et al Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111: 1227-1233.
• 30 Lemons PP. et al. Regulated secretion in platelets: identification of elements of the platelet exocytosis machinery. Blood 1997; 90: 1490-1500.
• 31 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.
• 32 Berndt MC. et al. Programmed autologous cleavage of platelet receptors. J Thromb Haemost 2007; 5 (Suppl. 01) 212-219.
• 33 Coppinger JA, Maguire PB. Insights into the platelet releasate. Curr Pharm Des 2007; 13: 2640-2646.
• 34 Parguina AF. et al. Proteins involved in platelet signaling are differentially regulated in acute coronary syndrome: a proteomic study. PLoS One 2010; 5: e13404.
• 35 Parguina AF. et al. Variations in platelet proteins associated with ST-elevation myocardial infarction: novel clues on pathways underlying platelet activation in acute coronary syndromes. Arterioscler Thromb Vasc Biol 2011; 31: 2957-2964.
• 36 Banfi C. et al. Proteome of platelets in patients with coronary artery disease. Exp Hematol 2010; 38: 341-350.
• 37 Lopez-Farre AJ. et al. Proteomic changes related to „bewildered“circulating platelets in the acute coronary syndrome. Proteomics 2011; 11: 3335-3348.
• 38 Parguina AF. et al. Proteomics applied to the study of platelet-related diseases: Aiding the discovery of novel platelet biomarkers and drug targets. J Proteomics. 2012 Epub ahead of print
• 39 Shattil SJ. et al. Changes in the platelet membrane glycoprotein IIb. IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107-11114.
• 40 Fijnheer R. et al. The origin of P-selectin as a circulating plasma protein. Thromb Haemost 1997; 77: 1081-1085.
• 41 Dunlop LC. et al. Characterization of GMP-140 (P-selectin) as a circulating plasma protein. J Exp Med 1992; 175: 1147-1150.
• 42 Berger G. et al. P-Selectin and platelet clearance. Blood 1998; 92: 4446-4452.
• 43 Ferroni P. et al. Soluble P-selectin as a marker of in vivo platelet activation. Clin Chim Acta 2009; 399: 88-91.
• 44 Shimomura H. et al. Serial changes in plasma levels of soluble P-selectin in patients with acute myocardial infarction. Am J Cardiol 1998; 81: 397-400.
• 45 Sakurai S. et al. Soluble form of selectins in blood of patients with acute myocardial infarction and coronary intervention. Vasc Med 1997; 2: 163-168.
• 46 Ikeda H. et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92: 1693-1696.
• 47 Ridker PM. et al. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001; 103: 491-495.
• 48 Tsakiris DA. et al. Circulating cell adhesion molecules and endothelial markers before and after transluminal angioplasty in peripheral arterial occlusive disease. Atherosclerosis 1999; 142: 193-200.
• 49 Ishiwata S. et al. Postangioplasty restenosis: platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis. Am Heart J 1997; 133: 387-392.
• 50 Hillis GS. et al. Elevated soluble P-selectin levels are associated with an increased risk of early adverse events in patients with presumed myocardial ischemia. Am Heart J 2002; 143: 235-241.
• 51 Hollander JE. et al. Risk stratification of emergency department patients with acute coronary syndromes using P-selectin. J Am Coll Cardiol 1999; 34: 95-105.
• 52 Body R. et al. Low soluble P-selectin may facilitate early exclusion of acute myocardial infarction. Clin Chim Acta 2011; 412: 614-618.
• 53 Santilli F. et al. CD40/CD40L system and vascular disease. Intern Emerg Med 2007; 2: 256-268.
• 54 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
• 55 Aukrust P. et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100: 614-620.
• 56 Manenti ER. et al. Prognostic value of serum biomarkers in association with TIMI risk score for acute coronary syndromes. Clin Cardiol 2006; 29: 405-410.
• 57 Mason PJ. et al. Plasma, serum, and platelet expression of CD40 ligand in adults with cardiovascular disease. Am J Cardiol 2005; 96: 1365-1369.
• 58 Varo N. et al. Soluble CD40L: risk prediction after acute coronary syndromes. Circulation 2003; 108: 1049-1052.
• 59 Malarstig A. et al. Soluble CD40L levels are regulated by the -3459 A>G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 1667-1673.
• 60 Peng DQ. et al. Elevated soluble CD40 ligand is related to the endothelial adhesion molecules in patients with acute coronary syndrome. Clin Chim Acta 2002; 319: 19-26.
• 61 Wang Y. et al. Transcoronary concentration gradient of sCD40L and hsCRP in patients with coronary heart disease. Clin Cardiol 2007; 30: 86-91.
• 62 Ohashi Y. et al. Soluble CD40 ligand and interleukin-6 in the coronary circulation after acute myocardial infarction. Int J Cardiol 2006; 112: 52-58.
• 63 Antoniades C. et al. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009; 54: 669-677.
• 64 L’Allier PL. et al. Sustained elevation of serum CD40 ligand levels one month after coronary angioplasty predicts angiographic restenosis. Can J Cardiol 2005; 21: 495-500.
• 65 Santilli F. et al. Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol 2006; 47: 391-397.
• 66 Cipollone F. et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106: 399-402.
• 67 Ferroni P, Guadagni F. Soluble CD40L and its role in essential hypertension: diagnostic and therapeutic implications. Cardiovasc Hematol Disord Drug Targets 2008; 8: 194-202.
• 68 Desideri G, Ferri C. Effects of obesity and weight loss on soluble CD40L levels. J Am Med Assoc 2003; 289: 1781-1782.
• 69 Antoniades C. et al. Genetic polymorphisms of platelet glycoprotein Ia and the risk for premature myocardial infarction: effects on the release of sCD40L during the acute phase of premature myocardial infarction. J Am Coll Cardiol 2006; 47: 1959-1966.
• 70 Kaplan KL, Owen J. Plasma levels of beta-thromboglobulin and platelet factor 4 as indices of platelet activation in vivo. Blood 1981; 57: 199-202.
• 71 Ohkawa R. et al. Platelet release of beta-thromboglobulin and platelet factor 4 and serotonin in plasma samples. Clin Biochem 2005; 38: 1023-1026.
• 72 Baenziger NL. et al. Isolation and properties of a thrombin-sensitive protein of human platelets. J Biol Chem 1972; 247: 2723-2731.
• 73 Bonnefoy A. et al. The evolving role of thrombospondin-1 in hemostasis and vascular biology. Cell Mol Life Sci 2008; 65: 713-727.
• 74 Mikhailenko I. et al. Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein. J Biol Chem 1997; 272: 6784-6791.
• 75 Dawes J. et al. A radioimmunoassay for thrombospondin, used in a comparative study of thrombospondin, beta-thromboglobulin and platelet factor 4 in healthy volunteers. Thromb Res 1983; 29: 569-581.
• 76 Starlinger P. et al. Thrombospondin-1: a unique marker to identify in vitro platelet activation when monitoring in vivo processes. J Thromb Haemost 2010; 8: 1809-1819.
• 77 French P. et al. Comparative evaluation of plasma thrombospondin beta-thromboglobulin and platelet factor 4 in acute myocardial infarction. Thromb Res 1985; 39: 619-624.
• 78 Yang RB. et al. Identification of a novel family of cell-surface proteins expressed in human vascular endothelium. J Biol Chem 2002; 277: 46364-46373.
• 79 Tu CF. et al. Localization and characterization of a novel secreted protein SCUBE1 in human platelets. Cardiovasc Res 2006; 71: 486-495.
• 80 Dai DF. et al. Plasma concentration of SCUBE1, a novel platelet protein, is elevated in patients with acute coronary syndrome and ischemic stroke. J Am Coll Cardiol 2008; 51: 2173-2180.
• 81 Santos-Martinez MJ. et al. Role of metalloproteinases in platelet function. Thromb Res 2008; 121: 535-542.
• 82 Santos-Martinez L. et al. Profile of cytokine mRNA expression in spontaneous and UV-induced skin lesions from actinic prurigo patients. Exp Dermatol 1997; 6: 91-97.
• 83 Burnier L. et al. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009; 101: 439-451.
• 84 Busti C. et al. Matrix metalloproteinases and peripheral arterial disease. Intern Emerg Med 2010; 5: 13-25.
• 85 Thompson MM, Squire IB. Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological?. Cardiovasc Res 2002; 54: 495-498.
• 86 Gresele P. et al. Platelets release matrix metalloproteinase-2 in the coronary circulation of patients with acute coronary syndromes: possible role in sustained platelet activation. Eur Heart J 2011; 32: 316-325.
• 87 Blankenberg S. et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003; 107: 1579-1585.
• 88 Clemetson KJ. Platelet GPIb-V-IX complex. Thromb Haemost 1997; 78: 266-270.
• 89 Ravanat C. et al. GPV is a marker of in vivo platelet activation--study in a rat thrombosis model. Thromb Haemost 2000; 83: 327-333.
• 90 Blann AD. et al. Increased platelet glycoprotein V levels in patients with coronary and peripheral atherosclerosis--the influence of aspirin and cigarette smoking. Thromb Haemost 2001; 86: 777-783.
• 91 Huisse MG. et al. Prothrombotic markers and early spontaneous recanalization in ST-segment elevation myocardial infarction. Thromb Haemost 2007; 98: 420-426.
• 92 Aleil B. et al. Increased plasma levels of soluble platelet glycoprotein V in patients with acute myocardial infarction. J Thromb Haemost 2003; 1: 1846-1847.
• 93 Azorsa DO. et al. Measurement of GPV released by activated platelets using a sensitive immunocapture ELISA--its use to follow platelet storage in transfusion. Thromb Haemost 1999; 81: 131-138.
• 94 Serebruany VL. et al. Heterogeneity of platelet aggregation and major surface receptor expression in patients with acute myocardial infarction. Am Heart J 1998; 136: 398-405.
• 95 Michelson AD. et al. In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. Proc Natl Acad Sci USA 1996; 93: 11877-11882.
• 96 Ferroni P. et al. Platelet activation and cytokine production during hypothermic cardiopulmonary bypass--a possible correlation?. Thromb Haemost 1998; 80: 58-64.
• 97 Ferroni P. et al. Is soluble P-selectin determination a more reliable marker of in vivo platelet activation than CD62P flow cytometric analysis?. Thromb Haemost 1999; 81: 472-473.
• 98 Garlichs CD. et al. Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets. Heart 2001; 86: 649-655.
• 99 Abu el-Makrem MA. et al. The role of platelets CD40 ligand (CD154) in acute coronary syndromes. Thromb Res 2009; 124: 683-688.
• 100 Pignatelli P. et al. Ascorbic acid infusion blunts CD40L upregulation in patients undergoing coronary stent. Cardiovasc Ther 2011; 29: 385-394.
• 101 Basili S. et al. Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention: relationship with oxidative stress markers. JACC Cardiovasc Interv 2010; 3: 221-229.
• 102 Pamukcu B. et al. The CD40-CD40L system in cardiovascular disease. Ann Med 2011; 43: 331-340.
• 103 Tantry US, Gurbel PA. Platelet monitoring for PCI: is it really necessary?. Hamostaseologie 2009; 29: 368-375.
• 104 Bigalke B. et al. Platelet glycoprotein VI: a novel marker for acute coronary syndrome. Semin Thromb Hemost 2007; 33: 179-184.
• 105 Bigalke B. et al. Glycoprotein VI for diagnosis of acute coronary syndrome when ECG is ambiguous. Int J Cardiol 2010; 149: 164-168.
• 106 Bigalke B. et al. Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain. Thromb Res 2010; 125: e184-189.
• 107 Bigalke B. et al. Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke. Eur J Neurol 2010; 17: 111-117.
• 108 Bigalke B. et al. Glycoprotein VI as a prognostic biomarker for cardiovascular death in patients with symptomatic coronary artery disease. Clin Res Cardiol 2010; 99: 227-233.
• 109 Bigalke B. et al. Sandwich immunoassay for soluble glycoprotein VI in patients with symptomatic coronary artery disease. Clin Chem 2011; 57: 898-904.
• 110 Kowalska MA. et al. Stromal cell-derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets. Blood 2000; 96: 50-57.
• 111 Abi-Younes S. et al. The CC chemokines MDC and TARC induce platelet activation via CCR4. Thromb Res 2001; 101: 279-289.
• 112 Clemetson KJ. et al. Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood 2000; 96: 4046-4054.
• 113 Schafer A. et al. Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion. Blood 2004; 103: 407-412.
• 114 Flierl U. et al. Fractalkine Activates a Signal Transduction Pathway Similar to P2Y12 and Is Associated With Impaired Clopidogrel Responsiveness. Arterioscler Thromb Vasc Biol 2012; 32: 1832-1840.
• 115 Moatti D. et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-1928.
• 116 Shantsila E. et al. Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis. J Thromb Haemost 2010; 8: 2358-2368.
• 117 Lee YJ. et al. Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multiinfarct dementias. Thromb Res 1993; 72: 295-304.
• 118 Katopodis JN. et al. Platelet microparticles and calcium homeostasis in acute coronary ischemias. Am J Hematol 1997; 54: 95-101.
• 119 Tan KT, Lip GY. The potential role of platelet microparticles in atherosclerosis. Thromb Haemost 2005; 94: 488-492.
• 120 Aleman MM. et al. Differential contributions of monocyte- and platelet-derived microparticles towards thrombin generation and fibrin formation and stability. J Thromb Haemost 2011; 9: 2251-2261.
• 121 Van Der Meijden PE. et al. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10: 1355-1362.
• 122 Dey-Hazra E. et al. Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing. Vasc Health Risk Manag 2010; 6: 1125-1133.
• 123 Bevers EM. et al. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 1983; 736: 57-66.
• 124 Dachary-Prigent J. et al Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: a flow cytometry study showing a role for free sulfhydryl groups. Blood 1993; 81: 2554-2565.
• 125 Shantsila E, Lip GY. The role of monocytes in thrombotic disorders. Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thromb Haemost 2009; 102: 916-924.
• 126 Biasucci LM. et al. Differences in Microparticle Release in Patients With Acute Coronary Syndrome and Stable Angina. Circ J 2012; 76: 2174-2182.
• 127 Vidal C. et al. Flow cytometry detection of platelet procoagulation activity and microparticles in patients with unstable angina treated by percutaneous coronary angioplasty and stent implantation. Thromb Haemost 2001; 86: 784-790.
• 128 Evangelista V. et al. Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18. Blood 1996; 88: 4183-4194.
• 129 Yang J. et al. The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction. Thromb Haemost 1999; 81: 1-7.
• 130 Neumann FJ. et al. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999; 34: 1420-1426.
• 131 Michelson AD. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
• 132 Zarbock A. et al. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 2007; 21: 99-111.
• 133 Frenette PS. et al. P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med 2000; 191: 1413-1422.
• 134 Ott I. et al. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996; 94: 1239-1246.
• 135 Furman MI. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358.
• 136 Brambilla M. et al. Tissue factor in patients with acute coronary syndromes: expression in platelets, leukocytes, and platelet-leukocyte aggregates. Arterioscler Thromb Vasc Biol 2008; 28: 947-953.
• 137 Park Y. et al. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets 2002; 13: 301-306.
• 138 Gasparyan AY. et al. Mean platelet volume: a link between thrombosis and inflammation?. Curr Pharm Des 2011; 17: 47-58.
• 139 Tsiara S. et al. Platelets as predictors of vascular risk: is there a practical index of platelet activity?. Clin Appl Thromb Hemost 2003; 9: 177-190.
• 140 Endler G. et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002; 117: 399-404.
• 141 Martin JF. et al. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-1411.
• 142 Pizzulli L. et al. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998; 19: 80-84.
• 143 Sezer M. et al. Association of haematological indices with the degree of microvascular injury in patients with acute anterior wall myocardial infarction treated with primary percutaneous coronary intervention. Heart 2007; 93: 313-318.
• 144 Murat SN. et al. Relation Between Mean Platelet Volume and Severity of Atherosclerosis in Patients With Acute Coronary Syndromes. Angiology 2012; 10: 524-531.
• 145 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.
• 146 Harrison P, Goodall AH. „Message in the platelet“--more than just vestigial mRNA! Platelets. 2008; 19: 395-404.
• 147 Santilli F. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin „resistance“. J Am Coll Cardiol 2009; 53: 667-677.
• 148 Pons I. et al. Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. Eur J Haematol 2010; 85: 158-163.
• 149 Lakkis N. et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004; 44: 2091-2093.
• 150 Grove EL. et al. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156.
• 151 Guthikonda S. et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 5: 490-496.
• 152 Rocca B. et al. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost 2012; 10: 1220-1230.
• 153 Wurtz M. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. JACC Cardiovasc Interv 2010; 3: 828-835.
• 154 Cesari F. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
• 155 Guthikonda S. et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52: 743-749.
• 156 Davi G. et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 1769-1774.
• 157 Davi G. et al. Platelet activation in obese women: role of inflammation and oxidant stress. J Am Med Assoc 2002; 288: 2008-2014.
• 158 Patrono C. et al. Thromboxane biosynthesis in cardiovascular diseases. Stroke 1990; 21: IV130-133.
• 159 Ciabattoni G. et al. Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70.
• 160 Catella F. et al. 11-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulation. Proc Natl Acad Sci USA 1986; 83: 5861-5865.
• 161 McAdam BF. et al. Contribution of cyclooxygenase-2 to elevated biosynthesis of thromboxane A2 and prostacyclin in cigarette smokers. Circulation 2005; 112: 1024-1029.
• 162 Dragani A. et al. The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy. Blood 2010; 115: 1054-1061.
• 163 Fitzgerald DJ. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989.
• 164 Hamm CW. et al. Biochemical evidence of platelet activation in patients with persistent unstable angina. J Am Coll Cardiol 1987; 10: 998-1006.
• 165 Vejar M. et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990; 63: 163-168.
• 166 Group I- C. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360.
• 167 Eikelboom JW. et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-1655.
• 168 Eikelboom JW. et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
• 169 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.
• 170 Rowley JW. et al. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood 2011; 118: e101-111.
• 171 Freedman JE. et al. Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart study. Circulation 2010; 122: 119-129.
• 172 Fichtlscherer S. et al. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?. Arterioscler Thromb Vasc Biol 2011; 31: 2383-2390.
• 173 Landry P. et al. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16: 961-966.
• 174 Gatsiou A. et al. MicroRNAs in Platelet Biogenesis and Function: Implications in Vascular Homeostasis and Inflammation. Curr Vasc Pharmacol 2012 Feb 15 [Epub ahead of print]
• 175 De Rosa S. et al. Transcoronary concentration gradients of circulating microRNAs. Circulation 2011; 124: 1936-1944.
• 176 Sondermeijer BM. et al. Platelets in patients with premature coronary artery disease exhibit upregulation of miRNA340* and miRNA624*. PLoS One 2011; 6: e25946.
• 177 Tan KT, Lip GY. The assessment of platelet activation in antiplatelet drug development. Curr Med Chem 2005; 12: 3117-3125.
• 178 Breet NJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
• 179 deFilippi CR, Seliger SL. Biomarkers for prognostication after acute coronary syndromes: new times and statistics. J Am Coll Cardiol 2009; 54: 365-367.
• 180 Bigalke B. et al. Regulation of platelet glycoprotein VI (GPVI) surface expression and of soluble GPVI in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS). Basic Res Cardiol 2009; 104: 352-357.
• 181 Al-Tamimi M. et al. Focusing on plasma glycoprotein VI. Thromb Haemost 2012; 107: 648-655.
• 182 Morel O. et al. Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists. J Thromb Haemost 2004; 2: 1118-1126.
• 183 Dhillon OS. et al. Matrix metalloproteinase-2 predicts mortality in patients with acute coronary syndrome. Clin Sci 2009; 118: 249-257.
• 184 Postea O. et al. Contribution of platelet CX(3)CR1 to platelet-monocyte complex formation and vascular recruitment during hyperlipidemia. Arterioscler Thromb Vasc Biol 2012; 32: 1186-1193.
• 185 Furman MI. et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38: 1002-1006.