Evaluation of Dose-Related Effects of Aspirin on Platelet Function

Abstract

Background-The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition. Methods and Results-We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, PՅ0.05), and urinary 11-dehydrothromboxane B 2 was dose-related (81 mg versus 325 mg, Pϭ0.003). No carryover effects were observed. Conclusions-The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation. (Circulation. 2007;115:3156-3164.)

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.…”

“…It appears that the dose-dependent effect of aspirin in aspirin-resistant patients may be mediated by non-COX-1 pathways. Gurbel et al 74 showed that aspirin at doses of 81 mg, 162 mg, and 325 mg all had near total inhibition of arachidonic acid-induced platelet aggregation with no difference seen among dose. 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.…”

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…10 In this double-blind, double-crossover investigation of 3 commonly used ASA doses (81, 162, and 325 mg/d), arachidonic acid-induced aggregation was suppressed in a dose-independent fashion whereas collagen-induced platelet aggregation and shear-induced platelet aggregation were significantly affected by dose. Moreover, the prevalence of resistance measured by COX-1 nonspecific methods such as ADP-, collagen-and shear-induced aggregation, was also significantly affected by dose.…”

Fish Oil Metabolites: Translating Promising Findings from Bench to bedside to Reduce Cardiovascular Disease

“…Aspirin acetylates COX and blocks the metabolism of arachidonic acid (an omega 6 polyunsaturated fatty acid) into a variety of proinflammatory and thrombosis-enhancing mediators including thromboxane [32][33][34][35] . The omega 3 fatty acids EPA and DHA compete with arachidonic acid for the same COX pathways and can also inhibit the production of inflammatory mediators.…”