Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100

Marilena Crescente; Augusto Di Castelnuovo; Licia Iacoviello; Jos Vermylen; Chiara Cerletti; Giovanni de Gaetano

doi:10.1160/TH07-08-0530

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 99(01): 14-26
DOI: 10.1160/TH07-08-0530

Review Article

Schattauer GmbH

Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100

A systematic review

Marilena Crescente

¹Research Laboratories, ”John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Augusto Di Castelnuovo

¹Research Laboratories, ”John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Licia Iacoviello

¹Research Laboratories, ”John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Jos Vermylen

²Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium

,

Chiara Cerletti

¹Research Laboratories, ”John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Giovanni de Gaetano

¹Research Laboratories, ”John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

› Institutsangaben

Abstract

Summary

It was the aim of the present study to perform a systematic review of the published studies that estimated the prevalence of non-responders to aspirin, as assessed by the closure time of PFA-100^®, a point-of-care device, and to analyse: 1) some major clinical and methodological factors that can influence it and 2) its possible association with vascular outcomes. The prevalence of non-responders to aspirin in 64 populations from 53 studies, comprising 6,450 subjects, had a median value of 0.27.A higher number of aspirin non-responders was found among older patients, those with acute vascular events, or those treated for more than one month. Aspirin non-response was more frequently associated with the use of “home-established” cut-offs or when closure time was only assessed after aspirin (rather than both before and after).Among risk factors, type 2 diabetes appeared to be associated with a higher prevalence of aspirin non-responders. The latter was also higher in less recent publications and in studies that used 3.2% rather than 3.8% Na-citrate as an anticoagulant. In eight studies comprising 847 subjects, aspirin non-responders were more likely to have vascular events than responders (relative risk: 1.63; 95% CI 1.16–2.28). In conclusion, although there appears to be heterogeneity among the studies analysed, this review indicates that about one quarter of people receiving aspirin would be identified – as an average – as aspirin non-responders by PFA-100. As this is a simple, widely available point-of-care test, efforts to better standardize it and to control for its major methodological variables might be useful to improve monitoring of platelet performance under aspirin treatment and to firmly establish the observed association with clinical vascular events.

Keywords

Aspirin resistance - aspirin variability - PFA–100 - diabetes - pointofcare test - platelet function - clinical outcome

Volltext

Referenzen

References
1 Bartolucci AA, Howard G. Meta-analysis of data from the six primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2006; 98: 746-750.
2 Antithrombotic Trialists’ Collaboration.. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
3 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
4 Michelson AD, Cattaneo M, Eikelboom JW. et al; Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis; Working Group on Aspirin Resistance. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005; 3: 1309-1311.
5 Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006; 367: 606-617.
6 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 5 (Suppl. 01) 230-237.
7 Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004; 110: e489-493.
8 Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol 2005; 46: 986-993.
9 Hayward CP, Harrison P, Cattaneo M. et al. The Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4: 312-319.
10 Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003; 1: 1710-1713.
11 de Gaetano G, Cerletti C. Aspirin resistance: a revival of platelet aggregation tests?. J Thromb Haemost 2003; 1: 2048-2050.
12 Martin CP, Talbert RL. Aspirin resistance: an evaluation of current evidence and measurement methods. Pharmacotherapy 2005; 25: 942-953.
13 Sanderson S, Emery J, Baglin T. et al. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005; 142: 370-380.
14 Harrison P, Frelinger AL, 3rd Furman MI. et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120: 323-336.
15 Hovens MM, Snoep JD, Eikenboom JC. et al. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007; 153: 175-181.
16 Snoep JD, Hovens MM, Eikenboom JC. et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 1593-1599.
17 Marshall PW, Williams AJ, Dixon RM. et al. A comparison of the effects of aspirin on bleeding time measured using the Simplate method and closure time measured using the PFA-100, in healthy volunteers. Br J Clin Pharmacol 1997; 44: 151-155.
18 Feuring M, Haseroth K, Janson CP. et al. Inhibition of platelet aggregation after intake of acetylsalicylic acid detected by a platelet function analyzer (PFA-100). Int J Clin Pharmacol Ther 1999; 37: 584-588.
19 Golanski J, Chizynski K, Golanski R. et al. Use of platelet function analyzer PFA-100 and whole blood aggregometry to monitor blood platelet sensitivity to acetylsalicylic acid (aspirin). Is it possible to reliably monitor antiplatelet treatment using routine laboratory diagnostic methods? Pol Arch Med Wewn 2000; 104: 355-361.
20 Homoncik M, Jilma B, Hergovich N. et al. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83: 316-321.
21 Gum PA, Kottke-Marchant K, Poggio ED. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-235.
22 Kretschmer V, Bade S, Weippert-Kretschmer M. et al. Measurement of primary haemostasis using a pressure clamp technique. Platelets 2001; 12: 462-469.
23 Peters AJ, Borries M, Gradaus F. et al. In vitro bleeding test with PFA-100-aspects of controlling individual acetylsalicylic acid induced platelet inhibition in patients with cardiovascular disease. J Thromb Thrombolysis 2001; 12: 263-272.
24 Macchi L, Christiaens L, Brabant S. et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107: 45-49.
25 Roller RE, Dorr A, Ulrich S. et al. Effect of aspirin treatment in patients with peripheral arterial disease monitored with the platelet function analyzer PFA-100. Blood Coagul Fibrinolysis 2002; 13: 277-281.
26 Sane DC, McKee SA, Malinin AI. et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol 2002; 90: 893-895.
27 Ziegler S, Maca T, Alt E. et al. Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty patients. Platelets 2002; 13: 493-497.
28 Andersen K, Hurlen M, Arnesen H. et al. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2003; 108: 37-42.
29 Christiaens L, Macchi L, Herpin D. et al. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res 2003; 108: 115-119.
30 Grau AJ, Reiners S, Lichy C. et al. Platelet function under aspirin, clopidogrel, and both after ischemic stroke: acase-crossover study. Stroke 2003; 34: 849-854.
31 Grundmann K, Jaschonek K, Kleine B. et al. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003; 250: 63-66.
32 Macchi L, Christiaens L, Brabant S. et al. Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GPIIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms. J Am Coll Cardiol 2003; 42: 1115-1119.
33 Malinin AI, Atar D, Callahan KP. et al. Effect of a single dose aspirin on platelets in humans with multiple risk factors for coronary artery disease. Eur J Pharmacol 2003; 462: 139-143.
34 Mueller T, Haltmayer M, Poelz W. et al. Monitoring aspirin 100 mg and clopidogrel 75 mg therapy with the PFA-100 device in patients with peripheral arterial disease. Vasc Endovascular Surg 2003; 37: 117-123.
35 Alberts MJ, Bergman DL, Molner E. et al. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004; 35: 175-178.
36 Chakroun T, Gerotziafas G, Robert F. et al. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor. Br J Haematol 2004; 124: 80-85.
37 Golanski J, Nocuna M, Rozalski M. et al. An in vitro model for the detection of reduced platelet sensitivity to acetylsalicylic acid. Blood Coagul Fibrinolysis 2004; 15: 187-195.
38 Jimenez-Quevedo P, Angiolillo DJ, Bernardo E. et al. Late stent thrombosis (>1 year) following clopidogrel withdrawal after brachytherapy treatment: need to assess aspirin resistance?. Catheter Cardiovasc Interv 2004; 62: 39-42.
39 Lepantalo A, Virtanen KS, Heikkila J. et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004; 25: 476-483.
40 Macchi L, Petit E, Brizard A. et al. Aspirin resistance in vitro and hypertension in stroke patients. J Thromb Haemost 2004; 2: 2051-2053.
41 Sambola A, Heras M, Escolar G. et al. The PFA-100 detects sub-optimal antiplatelet responses in patients on aspirin. Platelets 2004; 15: 439-446.
42 Watala C, Golanski J, Pluta J. et al. Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control. Thromb Res 2004; 113: 101-113.
43 Abaci A, Yilmaz Y, Caliskan M. et al. Effect of increasing doses of aspirin on platelet function as measured by PFA-100 in patients with diabetes. Thromb Res 2005; 116: 465-470.
44 Borna C, Lazarowski E, van Heusden C. et al. Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels. Thromb J 2005; 3: 10.
45 Coakley M, Self R, Marchant W. et al. Use of the platelet function analyser (PFA-100) to quantify the effect of low dose aspirin in patients with ischaemic heart disease. Anaesthesia 2005; 60: 1173-1178.
46 Coma-Canella I, Velasco A, Castano S. Prevalence of aspirin resistance measured by PFA-100. Int J Cardiol 2005; 101: 71-76.
47 Crowe B, Abbas S, Meany B. et al. Detection of aspirin resistance by PFA-100: prevalence and aspirin compliance in patients with chronic stable angina. Semin Thromb Hemost 2005; 31: 420-425.
48 Falco A, Salvati F, Vitacolonna E. et al. Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus. Atherosclerosis 2005; 183: 329-335.
49 Fateh-Moghadam S, Plockinger U, Cabeza N. et al. Prevalence of aspirin resistance in patients with type 2 diabetes. Acta Diabetol 2005; 42: 99-103.
50 Golanski J, Chlopicki S, Golanski R. et al. Resistance to aspirin in patients after coronary artery bypass grafting is transient: impact on the monitoring of aspirin antiplatelet therapy. Ther Drug Monit 2005; 27: 484-490.
51 Gonzalez-Conejero R, Rivera J, Corral J. et al. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure?. Stroke 2005; 36: 276-280.
52 Harrison P, Mackie I, Mathur A. et al. Platelet hyper-function in acute coronary syndromes. Blood Coagul Fibrinolysis 2005; 16: 557-562.
53 Harrison P, Segal H, Blasbery K. et al. Screening for aspirin responsiveness after transient ischemic attack and stroke: comparison of 2 point-of-care platelet function tests with optical aggregometry. Stroke 2005; 36: 1001-1005.
54 Hobikoglu GF, Norgaz T, Aksu H. et al. High frequency of aspirin resistance in patients with acute coronarysyndrome. Tohoku J Exp Med 2005; 207: 59-64.
55 Maly’ J, Pecka M, Gregor J. et al. Acetylsalicylic acid (ASA) resistance in patients with ischemic heart disease (IHD) as bioindicator of the treatment strategy. Cas Lek Cesk 2005; 144 (Suppl. 03) 23-29.
56 McCabe DJ, Harrison P, Mackie IJ. et al. Assessment of the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischaemic stroke and TIA. Platelets 2005; 16: 269-280.
57 Pamukcu B, Oflaz H, Acar RD. et al. The role of exercise on platelet aggregation in patients with stable coronary artery disease: exercise induces aspirin resistant platelet activation. J Thromb Thrombolysis 2005; 20: 17-22.
58 Pamukcu B, Oflaz H, Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis. Am Heart J 2005; 149: 675-680.
59 von Pape KW, Strupp G, Bonzel T. et al. Effect of compliance and dosage adaptation of long term aspirin on platelet function with PFA-100 in patients after myocardial infarction. Thromb Haemost 2005; 94: 889-891.
60 Yilmaz MB, Balbay Y, Caldir V. et al. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Thromb Res 2005; 115: 25-29.
61 Abaci A, Caliskan M, Bayram F. et al. A new definition of aspirin non-responsiveness by platelet function analyzer-100 and its predictors. Platelets 2006; 17: 7-13.
62 Agarwal S, Coakley M, Reddy K. et al. Quantifying the effect of antiplatelet therapy: a comparison of the platelet function analyzer (PFA-100) and modified thromboelastography (mTEG) with light transmission platelet aggregometry. Anesthesiology 2006; 105: 676-683.
63 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. Am J Cardiol 2006; 97: 38-43.
64 Becker DM, Segal J, Vaidya D. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. J Am Med Assoc 2006; 295: 1420-1427.
65 Bernardo E, Angiolillo DJ, Ramirez C. et al. Lack of association between gene sequence variations of platelet membrane receptors and aspirin responsiveness detected by the PFA-100 system in patients with coronary artery disease. Platelets 2006; 17: 586-590.
66 Faraday N, Becker DM, Yanek LR. et al. Relation between atherosclerosis risk factors and aspirin resistance in a primary prevention population. Am J Cardiol 2006; 98: 774-779.
67 Fontana P, Nolli S, Reber G. et al. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Throm Haemost 2006; 4: 813-819.
68 Gresner P, Dolnik M, Waczulikova I. et al. Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases. Biochim Biophys Acta 2006; 1760: 207-215.
69 Konrad CJ, Schuepfer GK, Gerber H. et al. Duration of effects of aspirin on platelet function in healthy volunteers: an analysis using the PFA-100. J Clin Anesth 2006; 18: 12-17.
70 Lepantalo A, Mikkelsson J, Resendiz JC. et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95: 253-259.
71 Mani H, Linnemann B, Luxembourg B. et al. Response to aspirin and clopidogrel monitored with different platelet function methods. Platelets 2006; 17: 303-310.
72 Marcucci R, Paniccia R, Antonucci E. et al. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol 2006; 98: 1156-1159.
73 Pamukcu B, Oflaz H, Oncul A. et al. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events. J Thromb Thrombolysis 2006; 22: 103-110.
74 Williams MS, Kickler TS, Vaidya D. et al. Evaluation of platelet function in aspirin treated patients with CAD. J Thromb Thrombolysis 2006; 21: 241-247.
75 Wong S, Ward CM, Appleberg M. et al. Point of care testing of aspirin resistance in patients with vascular disease. ANZ J Surg 2006; 76: 873-877.
76 Atiemo AD, Ng’alla LS, Vaidya D. et al. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain. J Thromb Thrombolysis. 2007 epub ahead of print.
77 Dichiara J, Bliden KP, Tantry US. et al. The Effect of Aspirin Dosing on Platelet Function in Diabetic and Non-Diabetic Patients: An Analysis from the ASpirin- Induced Platelet EffeCT (ASPECT) Study. Diabetes. 2007 epub ahead of print.
78 Faraday N, Yanek LR, Mathias R. et al. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxyge- nase-1. Circulation 2007; 115: 2490-2496.
79 Gulmez O, Yildirir A, Bal U. et al. Assessment of biochemical aspirin resistance at rest and immediately after exercise testing. Blood Coagul Fibrinolysis 2007; 18: 9-13.
80 Gurbel PA, Bliden KP, DiChiara J. et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115: 3156-3164.
81 Hobikoglu GF, Norgaz T, Aksu H. et al. The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy. Can J Cardiol 2007; 23: 201-206.
82 Kahraman G, Sahin T, Kilic T. et al. The frequency of aspirin resistance and its risk factors in patients with metabolic syndrome. Int J Cardiol 2007; 115: 391-396.
83 Lordkipanidze M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
84 Malek LA, Spiewak M, Filipiak KJ. et al. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes. Kardiol Pol 2007; 65: 40-45.
85 Modica A, Karlsson F, Mooe T. Platelet aggregation and aspirin non-responsiveness increase when an acute coronary syndrome is complicated by an infection. J Thromb Haemost 2007; 5: 507-511.
86 Narvaez I, Sagastagoitia JD, Vacas M. et al. Prevalence and biologic profile of aspirin resistance in patients with angiographically proven coronary artery disease. Thromb Res 2007; 120: 671-677.
87 Pamukcu B, Oflaz H, Onur I. et al. Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR). Blood Coagul Fibrinolysis 2007; 18: 187-192.
88 Pamukcu B, Oflaz H, Onur I. et al. Aspirin-resistant platelet aggregation in a cohort of patients with coronary heart disease. Blood Coagul Fibrinolysis 2007; 18: 461-465.
89 Poulsen TS, Mickley H, Korsholm L. et al. Using the Platelet Function Analyzer-100 for monitoring aspirin therapy. Thromb Res 2007; 120: 161-172.
90 Wang JS, Jen CJ, Kung HC. et al. Different effects of strenuous exercise and moderate exercise on platelet function in men. Circulation 1994; 90: 2877-2885.
91 Hurlen M, Seljeflot I, Arnesen H. Increased platelet aggregability during exercise in patients with previous myocardial infarction. Lack of inhibition by aspirin. Thromb Res 2000; 99: 487-494.
92 Andreotti F, Lanza GA, Sciahbasi A. et al. Low- grade exercise enhances platelet aggregability in patients with obstructive coronary disease independently of myocardial ischemia. Am J Cardiol 2001; 87: 16-20.
93 Martin DO, Austin H. Exact estimates for a rate ratio. Epidemiology 1996; 7: 29-33.
94 Caruso V, Iacoviello L, Di Castelnuovo A. et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108: 2216-2222.
95 Bock M, De Haan J, Beck KH. et al. Standardization of the PFA-100® platelet function test in 105 mmol/l buffered citrate: effect of gender, smoking, and oral contraceptives. Br J Haematol 1999; 106: 898-904.
96 Thompson SG, Kienast J, Pyke SD. et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-641.
97 Danesh J, Wheeler JG, Hirschfield GM. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-1397.
98 Pulcinelli FM, Pignatelli P, Celestini A. et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. J Am Coll Cardiol 2004; 43: 979-984.
99 Levine PH. An acute effect of cigarette smoking on platelet function. A possible link between smoking and arterial thrombosis. Circulation 1973; 48: 619-623.
100 Weber AA, Liesener S, Schanz A. et al. Habitual smoking causes an abnormality in platelet thromboxane A2 metabolism and results in an altered susceptibility to aspirin effects. Platelets 2000; 11: 177-182.
101 Ridker PM, Cook NR, Lee IM. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-1304.
102 de Gaetano G. Aspirin resistance in diabetic patients. Diabetes Care 2004; 27: 1244-1245.
103 Drzewoski J, Watala C. Is aspirin resistance a real problem in people with type 2 diabetes?. Diabetes Care 2004; 27: 1245-1246.
104 Collaborative Group of the Primary Prevention Project.. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general pratice. Lancet 2001; 357: 89-95.
105 Swamy-Mruthinti S, Carter AL. Acetyl- L -carnitine decreases glycation of lens proteins: in vitro studies. Exp Eye Res 1999; 69: 109-115.
106 Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26: 2181-2188.
107 Davi G, Ciabattoni G, Consoli A. et al. In vivo formation of 8-iso-prostaglandin F2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 1999; 99: 224-229.
108 Evangelista V, De Berardis G, Totani L. et al. Persistent platelet activation in patients with type 2 diabetes treated with low doses of aspirin. J Thromb Haemost 2007; 5: 2197-2203.
109 Maclouf J, Folco G, Patrono C. Eicosanoids and iso-eicosanoids: constitutive, inducible and transcellular biosynthesis in vascular disease. Thromb Haemost 1998; 79: 691-705.
110 Cipollone F, Rocca B, Patrono C. Cyclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol 2004; 24: 246-255.
111 Di Minno G, Silver MJ, Cerbone AM. et al. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68: 886-891.
112 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclo-oxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
113 Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. Br Med J 2000; 321: 13-17.
114 Friend M, Vucenik I, Miller M. Research pointers: Platelet responsiveness to aspirin in patients with hyperlipidaemia. Br Med J 2003; 326: 82-83.
115 Mirkhel A, Peyster E, Sundeen J. et al. Frequency of aspirin resistance in a community hospital. Am J Cardiol 2006; 98: 577-579.
116 von Pape KW, Aland E, Bohner J. Platelet function analysis with PFA-100 in patients medicated with acetylsalicylic acid strongly depends on concentration of sodium citrate used for anticoagulation of blood sample. Thromb Res 2000; 98: 295-299.
117 Packham MA, Rand ML, Kinlough-Rathbone RL. Aggregation. Gresele P, Page C, Fuster V, Vermylen J. Platelets in thrombotic and non thrombotic disorders.. Cambridge University Press; Cambridge, UK: 2002: 338-356.
118 Schwartz KA, Schwartz DE, Ghosheh K. et al. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol 2005; 95: 973-975.
119 Hohlfeld T, Weber AA, Junghans U. et al. Variable platelet response to aspirin in patients with ischemic stroke. Cerebrovasc Dis 2007; 24: 43-50.
120 de Gaetano G, Cerletti C, Iacoviello L. et al. The epidemiological night where all patients are black: will pharmacogenetics shed some light?. Thromb Res 2003; 112: 273-274.
121 Maseri A. Antibiotics for acute coronary syndromes: are we ready for megatrials?. Eur Heart J 1999; 20: 89-92.
122 de Gaetano G, Cerletti C. Platelet function, antiplatelet therapy and clinical outcomes: test or not to test?. J Thromb Haemost 2007; 5: 1835-1838.
123 Paniccia R, Antonucci E, Gori AM. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 5: 1839-1847.