Dose- and time-dependent antiplatelet effects of aspirin

 

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Summary

Aspirin is widely used, but dosages in different clinical situations and the possible importance of “aspirin resistance” are debated. We performed an open cross-over study comparing no treatment (baseline) with three aspirin dosage regimens – 37.5 mg/ day for 10 days, 320 mg/day for 7 days, and, finally, a single 640 mg dose (cumulative dose 960 mg) – in 15 healthy male volunteers. Platelet aggregability was assessed in whole blood (WB) and platelet rich plasma (PRP).The urinary excretions of stable thromboxane (TxM) and prostacyclin (PGI-M) metabolites, and bleeding time were also measured. Platelet COX inhibition was nearly complete already at 37.5 mg aspirin daily, as evidenced by >98 % suppression of serum thromboxane B2 and almost abolished arachidonic acid (AA) induced aggregation in PRP 2–6 h after dosing. Bleeding time was similarly prolonged by all dosages of as- pirin. Once daily dosing was associated with considerable recovery of AA induced platelet aggregation inWB after 24 hours, even after 960 mg aspirin. Collagen induced aggregation in WB with normal extracellular calcium levels (hirudin anticoagulated) was inhibited <40% at all dosages. TxM excretion was incompletely suppressed, and increased <24 hours after the cumulative 960 mg dose. Aspirin treatment reduced PGI-M already at the lowest dosage (by ≈25%), but PGI-M excretion and platelet aggregability were not correlated. Antiplatelet effects of aspirin are limited in WB with normal calcium levels. Since recovery of COX-dependent platelet aggregation occurred within 24 hours, once daily dosing of aspirin might be insufficient in patients with increased platelet turnover.

• References

• 1 Antithrombotic Trialists´ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-8.
  CrossrefPubMedGoogle Scholar
• 2 Patrono C, Coller B, Fitzgerald GA. et al. Plateletactive drugs: the relationships among dose, effectiveness, and side-effects. Chest 2004; 126: 234S-264S.
  CrossrefPubMedGoogle Scholar
• 3 Sanderson S, Emery J, Baglin T. et al. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005; 142: 370-80.
  CrossrefPubMedGoogle Scholar
• 4 Cattaneo M. Aspirin and clopidogrel - efficacy, safety, and the issue of drug resistance. Arterioscl Thromb Vasc Biol 2004; 24: 1980-7.
  CrossrefPubMedGoogle Scholar
• 5 Rihal CS, Flather M, Hirsch J. et al. Advances in antithrombotic drug therapy for coronary artery disease. Eur Heart J 1995; 16 (Suppl D): 10-21.
  PubMedGoogle Scholar
• 6 Reilly IAG, Fitzgerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-6.
  PubMedGoogle Scholar
• 7 Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61: 1081-5.
  PubMedGoogle Scholar
• 8 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-72.
  CrossrefPubMedGoogle Scholar
• 9 Quinn MJ, Aronow HD, Califf RM. et al. Aspirin dose and six-month outcome after an acute coronary syndrome. J Am Coll Cardiol 2004; 43: 972-8.
  CrossrefPubMedGoogle Scholar
• 10 Peters RJG, Mehta SR, Fox KAA. et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes; observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682-7.
  CrossrefPubMedGoogle Scholar
• 11 Juul-Möller S, Edvardsson N, Jahnmatz B. et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 1992; 340: 1421-5.
  CrossrefPubMedGoogle Scholar
• 12 The RISC group. Risk of myocardial infraction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827-30.
  CrossrefPubMedGoogle Scholar
• 13 Fitzgerald DJ, Roy L, Catella F. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
  CrossrefPubMedGoogle Scholar
• 14 Hamsten A, Svensson J, Waldius G. et al. Shortened megakaryocyte-platelet regeneration time in young survivors of myocardial infarction. Am Heart J 1985; 110: 1154-60.
  CrossrefPubMedGoogle Scholar
• 15 Wallenburg HCS, van Kessel PH. Platelet life span in pregnancies resulting in small-for gestational age infants. Am J Obstet Gynecol 1979; 134: 739-42.
  CrossrefPubMedGoogle Scholar
• 16 Tschoepe D. The activated megacaryocyte-plateletsystem in vascular disease: focus on diabetes. Sem Thromb Hemost 1995; 21: 152-60.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Clarke RJ, Mayo G, Price P. et al. Supression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991; 325: 1137-41.
  CrossrefPubMedGoogle Scholar
• 18 Fitzgerald GA, Oates JA, Hawiger J. et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71: 676-88.
  CrossrefPubMedGoogle Scholar
• 19 Kobayashi T, Tahara Y, Matsumoto M. et al. Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest 2004; 114: 784-94.
  CrossrefPubMedGoogle Scholar
• 20 Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005; 112: 759-70.
  CrossrefPubMedGoogle Scholar
• 21 Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709-11.
  CrossrefPubMedGoogle Scholar
• 22 Packham MA, Kinlough-Rathbone RL, Mustard JF. Thromboxane A2 causes feedback amplification involving extensive thromboxane A2 formation on close contact of human platelets in media with a low concentration of ionized calcium. Blood 1987; 70: 647-51.
  PubMedGoogle Scholar
• 23 Bretschneider E, Glusa E, Schrör K. ADP-, PAFand adrenaline-induced platelet aggregation and thromboxane formation are not affected by a thromboxane receptor antagonist at physiological external Ca++ concentrations. Thromb Res 1994; 75: 233-42.
  CrossrefPubMedGoogle Scholar
• 24 Wallén N, Ladjevardi M, Albert J. et al. Influence of different anticoagulants on platelet aggregation in whole blood; a comparison between citrate, low molecular mass heparin and hirudin. Thromb Res 1997; 87: 151-7.
  CrossrefPubMedGoogle Scholar
• 25 Albert J, Norman M, Wallén NH. et al. Inhaled nitric oxide does not influence bleeding time or platelet function in healthy volunteers. Eur J Clin Invest 1999; 29: 953-9.
  CrossrefPubMedGoogle Scholar
• 26 Catella F, Healy D, Lawson J A. et al. 11-dehydrothromboxane B2:a quantitave index of thromboxane A2 formation in the human circulation. Proc Natl Acad Sci 1986; 83: 5861-5.
  CrossrefPubMedGoogle Scholar
• 27 Perneby C, Granström E, Beck O. et al. Optimization of an enzyme immunoassay for 11-dehydrothromboxane B2 in urine: comparison with GC-MS. Thromb Res 1999; 96: 427-36.
  CrossrefPubMedGoogle Scholar
• 28 Fitzgerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174-7.
  CrossrefPubMedGoogle Scholar
• 29 Harrison P, Robinson MSC, Mackie IJ. et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coag Fibrinol 1999; 10: 25-31.
  CrossrefPubMedGoogle Scholar
• 30 Wallén NH, Held C, Rehnqvist N. et al. Impact of treatment with acetylsalicylic acid on the proaggregatory effects of adrenaline in vitro in patients with stable angina pectoris: influence of the anticoagulant. Clin Sci (Lond) 1993; 85: 577-83.
  CrossrefPubMedGoogle Scholar
• 31 Valles J, Santos T, Aznar J. et al. Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality. Circulation 1998; 97: 350-5.
  CrossrefPubMedGoogle Scholar
• 32 Li N, Hu H, Lindqvist M. et al. Platelet-leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol 2000; 20: 2702-8.
  CrossrefPubMedGoogle Scholar
• 33 Camacho M, Vila L. Transcellular formation of thromboxane A2 in mixed incubations of endothelial cells and aspirin treated platelets strongly depends on the prostaglandin I-synthase activity. Thromb Res 2000; 99: 155-64.
  CrossrefPubMedGoogle Scholar
• 34 Karim S, Habib A, Lévy-Toledano S. et al. Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem 1996; 271: 12042-8.
  CrossrefPubMedGoogle Scholar
• 35 Cipollone F, Patrignani P, Greco A. et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation 2001; 96: 1109-19.
  PubMedGoogle Scholar
• 36 Eikelboom JW, Hirsh J, Weitz JI. 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: 1650-5.
  CrossrefPubMedGoogle Scholar
• 37 Chamorro A, Escolar G, Revilla M. et al. Ex vivo response to aspirin differs in stroke patient with single or recurrent events: a pilot study. J Neurol Sci 1999; 171: 110-4.
  CrossrefPubMedGoogle Scholar
• 38 Vesterqvist O. Rapid recovery of in vivo prostacyclin formation after inhibition by aspirin. Eur J Clin Pharmacol 1986; 30: 69-73.
  CrossrefPubMedGoogle Scholar
• 39 Toghi H, Konno S, Tamura K. et al. Effects of lowto-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke 1992; 23: 1400-3.
  CrossrefPubMedGoogle Scholar
• 40 Ridker PM, Cook N, I-Min L. et al. A randomised trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-304.
  CrossrefPubMedGoogle Scholar