Residual Arachidonic Acid–Induced Platelet Activation via an Adenosine Diphosphate–Dependent but Cyclooxygenase-1– and Cyclooxygenase-2–Independent Pathway

Abstract

Background-Thrombotic events still occur in aspirin-treated patients with coronary artery disease. Methods and Results-To better understand aspirin "resistance," serum thromboxane B 2 (TXB 2 ) and flow cytometric measures of arachidonic acid-induced platelet activation (before and after the ex vivo addition of aspirin and indomethacin) were analyzed in 700 consecutive aspirin-treated patients undergoing cardiac catheterization. In 680 of 682 evaluable patients, serum TXB 2 concentrations were reduced compared with nonaspirinated healthy donors. Twelve patients had serum TXB 2 that was lower than nonaspirinated healthy donors but Ͼ10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum TXB 2 (Ͼ10 ng/mL) than in patients with low serum TXB 2 . Addition of ex vivo aspirin reduced arachidonic acid-induced platelet activation to similar levels regardless of serum TXB 2 concentrations, which suggests that patients with high residual serum TXB 2 concentrations were either noncompliant or underdosed with aspirin. Among the remaining 98% of patients, ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation across all degrees of arachidonic acid-induced platelet activation and aspirin doses. Although the patients were not randomized with respect to clopidogrel treatment, multivariate analysis showed that arachidonic acid-induced platelet activation was less in patients receiving clopidogrel. Conclusions-There is a residual arachidonic acid-induced platelet activation in aspirin-treated patients that (1) is caused by underdosing and/or noncompliance in only Ϸ2% of patients and (2) in the remaining patients, occurs via a cyclooxygenase-1 and cyclooxygenase-2 independent pathway, in direct proportion to the degree of baseline platelet activation, and is mediated in part by adenosine diphosphate-induced platelet activation. (Circulation. 2006;113:2888-2896.)

Aspirin Resistance: Current Status and Role of Tailored Therapy

“…Conversely, there was a dose-dependent inhibition of platelet function as assessed by non-COX-1 pathways because aspirin at doses of 162 mg and 325 mg was more effective at reducing ADP-and collagen-mediated aggregation as well at prolonging CT as measured by PFA-100 than 81 mg of aspirin. 74 This interplay between COX-1-dependent and ADP-dependent pathways was also described by Frelinger et al, 6 who showed that residual arachidonic acid-induced platelet activation was less in patients taking clopidogrel, an ADP receptor antagonist, compared to controls. Adjunctive clopidogrel, in addition to low-dose aspirin, has been shown to be more effective at inhibiting platelet aggregation to ADP or collagen than high-dose aspirin (300 mg) monotherapy in diabetic patients with coronary artery disease who were resistant to low-dose aspirin.…”

“…10 Fortunately, for the great majority of patients, standard doses of aspirin, even low-dose aspirin, leads to significant and near complete inhibition of COX-1 and thromboxane A2. Frelinger et al 6 followed 700 consecutive aspirin-treated patients undergoing cardiac catheterization and found that only 1.8% of patients had thromboxane B2 levels, a stable metabolite of thromboxane A2, greater than 10 ng/mL (∼5% of intrinsic activity, as validated above). Platelets from this population also had more arachidonic acid-induced platelet activation as measured by P-selectin surface positivity on flow cytometry.…”

“…39 Furthermore, arachidonic acid appears to be able to incompletely activate platelets through an ADP-dependent and COX-independent pathway in COX-inhibited cells, suggesting some overlap in these pathways. 6 …”

“…In this population of aspirin-resistant patients, the addition of ex vivo aspirin reduced platelet activation to levels similar to those seen in patients with more complete inhibition of COX-1, suggesting that the aspirin nonresponders may simply have been underdosed with aspirin. Interestingly, 75% of these aspirin-resistant patients were receiving low-dose (81 mg) aspirin, 6 suggesting the dose of aspirin may be a factor.…”

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…In order to differentiate mechanisms of ASA hyporesponse, measurements of serum thromboxane B 2 and arachidonic acid-induced platelet activation were assessed in 700 ASA-treated patients undergoing cardiac catheterization. 9 The ASA reduced thromboxane B 2 levels in all but two evaluable patients compared with untreated controls; these patients were deemed noncompliant and not included in analyses. The major finding was that there is residual arachidonic acid-induced platelet activation in patients who receive ASA.…”