Functional and Biochemical Evaluation of Platelet Aspirin Resistance After Coronary Artery Bypass Surgery

Abstract

Background-Aspirin inhibits platelet activation and reduces atherothrombotic complications in patients at risk of myocardial infarction and stroke. However, a sufficient inhibition of platelet function by aspirin is not always achieved. The causes of this aspirin resistance are unknown. Methods and Results-Patients undergoing coronary artery bypass grafting (CABG) have a high incidence of aspirin resistance. To evaluate functional and biochemical responses to aspirin, platelet-rich plasma was obtained before and at days 1, 5, and 10 after CABG. Thromboxane formation, aggregation, and ␣-granule secretion were effectively inhibited by 30 or 100 mol/L aspirin in vitro before CABG, but this inhibition was prevented or attenuated after CABG. Whereas the inhibition of thromboxane formation and aggregation by aspirin in vitro partly recovered at day 10 after CABG, oral aspirin (100 mg/d) remained ineffective. The inducible isoform of cyclooxygenase in platelets, COX-2, has been suggested to confer aspirin resistance. In fact, immunoreactive COX-2 was increased 16-fold in platelets at day 5 after CABG, but the COX-2 selective inhibitor celecoxib did not alter aspirin-resistant thromboxane formation. By contrast, the combined inhibitor of thromboxane synthase and thromboxane receptor antagonist terbogrel equally prevented thromboxane formation of platelets obtained before (control) and after CABG. Conclusions-Platelet aspirin resistance involves an impairment of both in vivo and in vitro inhibition of platelet functions and is probably due to a disturbed inhibition of platelet COX-1 by aspirin. (Circulation. 2003;108:542-547.)

Incidence of Venous Thromboembolism and Benefits and Risks of Thromboprophylaxis After Cardiac Surgery: A Systematic Review and Meta‐Analysis

“…Our results showed that aspirin appears to be effective in reducing VTE after cardiac surgery in the pediatric population (using 5 mg/kg/day)45 or when a higher dose of aspirin is used in adults (>300 mg/day) 68. Evidence suggests that aspirin resistance is common within the first week after cardiac surgery and the standard low‐dose aspirin (100 mg/day) would not be adequate to exert its full antiplatelet effects in many patients 11, 12, 13. Because cardiac surgical patients are also prothrombotic postsurgery (up to 30 days),6, 7, 8, 9 use of low‐dose antiplatelet agents alone would not be sufficient in preventing VTE during this high‐risk period if the patients have multiple risk factors for VTE (Table 3).…”

Aspirin and Clopidogrel

“…The same effect can be progressively achieved with the chronic administration of daily doses of 30 to 50 mg. 1 COX has 2 isoforms with different tissue distribution and susceptibility to inhibition by NSAID. COX-2 in not inhibited by therapeutic doses of aspirin and, under physiological conditions, is present in a small fraction of platelets, [3][4][5] but the number of COX-2-expressing platelets may increase in conditions of high platelet regeneration. 5 Because aspirin acetylates COX-1 in all tissues, including endothelial cells, where the enzyme converts arachidonic acid into the vasodilator and natural platelet antagonist prostacyclin, for several years there has been the concern that the potential antithrombotic effect of aspirin could be blunted, or even overcome, by the theoretical prothrombotic effect associated with the parallel inhibition of prostacyclin.…”

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

“…The relative ineffectiveness of aspirin as an anti-inflammatory drug is mirrored at the cellular level by the demonstration that aspirin is 166 times more potent in inhibiting PGHS activity in the platelet than in the J774.2 macrophage cell line [8], leading to consideration that the action of aspirin might be selective for the PGHS-1 isoform. However, the potency of inhibition of PGHS-1 by aspirin ex vivo observed in normal platelets is lost in platelets of patients after coronary artery bypass grafting [9], and PGHS-1 from platelet homogenates is poorly acetylated by aspirin [10], suggesting differences in acetylation that can not be attributed to isoform selectivity. Collectively, these observations reflect considerable variability in acetylation of the PGHSs by aspirin, a variability that implies a mechanistic basis for regulating the action of the drug.…”