Background: A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis. Methods: We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects. Results: Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals. Conclusion: Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

Keywords:
Aspirin, Stroke, Platelets, Aggregation, Thromboxane
1.
Yip HK, Liou CW, Chang HW, Lan MY, Liu JS, Chen MC: Link between platelet activity and outcomes after an ischemic stroke. Cerebrovasc Dis 2005;20:120–128.
2.
Antithrombotic Trialist’s Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002;324:71–86.
3.
Junghans U, Siebler M: Cerebral microembolism is blocked by tirofiban, a selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist. Circulation 2003;107:2717–2721.
4.
Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB: Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233–2240.
5.
Forbes CD: Secondary stroke prevention with low-dose aspirin, sustained release dipyridamole alone and in combination. ESPS Investigators. European Stroke Prevention Study. Thromb Res 1998;92:S1–S6.
6.
Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ: Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–337.
7.
Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, Brace LD: Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994;25:2331–2336.
8.
Alberts MJ, Bergman DL, Molner E, Jovanovic BD, Ushiwata I, Teruya J: Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004;35:175–178.
9.
Pongracz E: Measurement of platelet aggregation during antiplatelet therapy in ischemic stroke. Clin Hemorheol Microcirc 2004;30:237–242.
10.
McCabe DJ, Harrison P, Mackie IJ, Sidhu PS, Lawrie AS, Purdy G, Machin SJ, Brown MM: 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.
11.
Sztriha LK, Sas K, Vecsei L: Aspirin resistance in stroke: 2004. J Neurol Sci 2005;229–230:163–169.
12.
Berrouschot J, Schwetlick B, Twickel G, Fischer C, Uhlemann H, Siegemund T, Siegemund A, Roessler A: Aspirin resistance in secondary stroke prevention. Acta Neurol Scand 2006;113:31–35.
13.
Uchiyama S, Nakamura T, Yamazaki M, Kimura Y, Iwata M: New modalities and aspects of antiplatelet therapy for stroke prevention. Cerebrovasc Dis 2006;21(suppl 1): 7–16.
14.
Hankey GJ, Eikelboom JW: Aspirin resistance. Lancet 2006;367:606–617.
15.
Schrör K, Weber AA, Hohlfeld T: Aspirin ‘resistance’. Blood Cells Mol Dis 2006;36:171–176.
16.
Hayward CP, Harrison P, Cattaneo M, Ortel TL, Rao AK: Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006;4:312–319.
17.
Weber A-A, Przytulski B, Schanz A, Hohlfeld T, Schrör K: Towards a definition of aspirin resistance: a typological approach. Platelets 2002;13:37–40.
18.
Weber A-A, Liesener S, Schanz A, Hohlfeld T, Schrör K: Habitual smoking causes an abnormality in platelet thromboxane A2 metabolism and results in an altered susceptibility to aspirin effects. Platelets 2000;11:177–182.
19.
Bretschneider E, Glusa E, Schrör K: ADP-, PAF- and adrenaline-induced platelet aggregation and thromboxane formation are not affected by a thromboxane receptor antagonist at physiological external Ca2+ concentrations. Thromb Res 1994;75:233–242.
20.
Schrör K, Seidel H: Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system. Naunyn-Schmiedeberg’s Arch Pharmacol 1988;337:177–182.
21.
Mayeux PR, Morton HE, Gillard J, Lord A, Morinelli TA, Boehm A, Mais DE, Halushka PV: The affinities of prostaglandin H2 and thromboxane A2 for their receptor are similar in washed human platelets. Biochem Biophys Res Commun 1988;157:733–739.
22.
Weber AA, Liesener S, Hohlfeld T, Schrör K: 40 mg of aspirin are not sufficient to inhibit platelet function under conditions of limited compliance. Thromb Res 2000;97:365–367.
23.
Hamann GF, Weimar C, Glahn J, Busse O, Diener HC: Adherence to secondary stroke prevention strategies – Results from the German Stroke Data Bank. Cerebrovasc Dis 2003;15:282–288.
24.
Lago A, Tembl JI, Pareja A, Ponz A, Ferrer JM, Valles J, Santos MT: Adherence to aspirin in secondary prevention of ischemic stroke. Cerebrovasc Dis 2006;21:353–356.
25.
Crowe B, Abbas S, Meany B, de Haan J, Cahill MR: Detection of aspirin resistance by PFA-100: prevalence and aspirin compliance in patients with chronic stable angina. Semin Thromb Hemost 2005;31:420–425.
26.
Benedek IH, Joshi AS, Pieniaszek HJ, King SYP, Kornhauser DM: Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. J Clin Pharmacol 1995;35:1181–1186.
27.
Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA: Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809–1817.
28.
Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P: Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol 2005;45:1295–1301.
29.
Weber AA, Zimmermann K, Meyer-Kirchrath J, Schrör K: Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999;353:900.
30.
Rocca B, Secchiero P, Ciabattoni G, Ranelletti FO, Catani L, Guidotti L, Melloni E, Maggiano N, Zauli G, Patrono C: Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002;99:7634–7639.
31.
Warner TD, Mitchell JA: Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18:790–804.
32.
Zimmermann N, Wenk A, Kim U, Kienzle P, Weber AA, Gams E, Schrör K, Hohlfeld T: Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003;108:542–547.
33.
Halushka MK, Walker LP, Halushka PV: Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 2003;73:122–130.
34.
Hillarp A, Palmqvist B, Lethagen S, Villoutreix BO, Mattiasson I: Mutations within the cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke. Thromb Res 2003;112:275–283.
35.
Kawasaki T, Ozeki Y, Igawa T, Kambayashi J: Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke 2000;31:591–595.
36.
Nieswandt B, Watson SP: Platelet-collagen interaction: is GPVI the central receptor? Blood 2003;102:449–461.
37.
Calverley DC, Brass E, Hacker MR, Tsao-Wei DD, Espina BM, Pullarkat VA, Hodis HN, Groshen S: Potential role of platelet FcγRIIA in collagen-mediated platelet activation associated with atherothrombosis. Atherosclerosis 2002;164:261–267.
38.
Carlsson LE, Santoso S, Spitzer C, Kessler C, Greinacher A: The α2 gene coding sequence T807/A873 of the platelet collagen receptor integrin α2β1 might be a genetic risk factor for the development of stroke in younger patients. Blood 1999;93:3583–3586.
39.
Watson S, Berlanga O, Best D, Frampton J: Update on collagen receptor interactions in platelets: is the two-state model still valid? Platelets 2000;11:252–258.
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2007
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