Evaluation of Dose-Related Effects of Aspirin on Platelet Function Results From the Aspirin-Induced Platelet Effect (ASPECT) Study

University of Maryland, Baltimore County, Baltimore, Maryland, United States
Circulation (Impact Factor: 14.43). 06/2007; 115(25):3156-64. DOI: 10.1161/CIRCULATIONAHA.106.675587
Source: PubMed


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.
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, P < or = 0.05), and urinary 11-dehydrothromboxane B2 was dose-related (81 mg versus 325 mg, P = 0.003). No carryover effects were observed.
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.

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    • "Platelet aggregation was measured by LTA method to assess 0.5 mg/ml AA-mediated platelet aggregation (LTA AA ) as described (Angiolillo et al., 2005, 2006, 2007). Aggregation was expressed as maximum percentage change in light transmittance from baseline, while PPP were used as a reference (Gurbel et al., 2007). A 20 μmol/l ADP-induced platelet aggregation (LTA ADP ) was used to evaluate clopidogrel response, and the low clopidogrel response was defined as LTA ADP ≥70%. "
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    ABSTRACT: Aspirin is widely used in the primary and secondary prevention of cardiovascular diseases. The aim of our study was to compare between two established methods of aspirin response, urinary 11-dehydrothromboxane B2 (11dhTXB2) and platelet Light Transmission Aggregometry (LTA) assays in elderly Chinese patients with coronary artery disease (CAD), and to investigate the clinical significance of both methods in predicting cardiovascular events. Urinary 11dhTxB2 assay and arachidonic acid-induced (AA, 0.5mg/ml) platelet aggregation by Light Transmission Aggregometry (LTAAA) assay were measured to evaluate aspirin responses. High-on aspirin platelet reactivity (HAPR) was defined as urinary 11dhTxB2>1500pg/mg or AA-induced platelet aggregation≥15.22%-the upper quartile of our enrolled population. The two tests showed a poor correlation for aspirin inhibition (r=0.063) and a poor agreement in classifying HAPR (kappa=0.053). With a mean follow-up time of 12months, cardiovascular events occurred more frequently in HAPR patients who were diagnosed by LTA assay as compared with no-HAPR patients (22.5% versus 10.6%, P=0.039, OR=2.45, 95%CI=1.06~5.63). However, the HAPR status, as determined by urinary 11dTXB2 measurement, did not show a significant correlation with outcomes. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Gene
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    • "In contrast, with 500 μM ASA added ex vivo, 49 of 66 determinations of R COX b 1 demonstrated most subjects had platelets that were sensitive to ASA inhibition of platelet TXA 2 (Fig. 5C). The 17 determinations of R COX where R COX N 1 with 500 μM ASA added ex vivo could be due to non COX-1 mediated ASA effects on platelets when they are activated by collagen with autocrinic ADP present [15]. Such blood samples may be worthy of further study with respect to the phenotype of functional insensitivity to ASA despite COX-1 acetylation. "
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    ABSTRACT: Microfluidic devices recreate the hemodynamic conditions of thrombosis. Whole blood inhibited with PPACK was treated ex vivo with inhibitors and perfused over collagen for 300s (wall shear rate=200s(-1)) using a microfluidic flow assay. Platelet accumulation was measured in the presence of COX-1 inhibitor (aspirin, ASA), P2Y1 inhibitor (MRS 2179), P2Y12 inhibitor (2MeSAMP) or combined P2Y1 and P2Y12 inhibitors. High dose ASA (500μM), 2MeSAMP (100μM), MRS 2179 (10μM), or combined 2MeSAMP and MRS 2179 decreased total platelet accumulation by 27.5%, 75.6%, 77.7%, and 87.9% (p<0.01), respectively. ASA reduced secondary aggregation rate between 150 and 300s without effect on primary deposition rate on collagen from 60 to 150s. In contrast, 2MeSAMP and MRS 2179 acted earlier and reduced primary deposition to collagen between 60 and 105s and secondary aggregation between 105 and 300s. RCOX and RP2Y (defined as a ratio of secondary aggregation rate to primary deposition rate) demonstrated 9 of 10 subjects had RCOX<1 or RP2Y<1 following ASA or 2MeSAMP addition, while 6 of 10 subjects had RP2Y<1 following MRS 2179 addition. Combined MRS 2179 and 2MeSAMP inhibited primary platelet deposition rate and platelet secondary aggregation beyond that of each individual inhibitor. Receiver-Operator Characteristic area under the curve (AUC) indicated the robustness of RCOX and RP2Y to detect inhibition of secondary platelet aggregation by ASA, 2MeSAMP, and MRS 2179 (AUC of 0.874 0.966, and 0.889, respectively). Microfluidic devices can detect platelet sensitivity to antiplatelet agents. The R-value can serve as a self-normalized metric of platelet function for a single blood sample.
    Preview · Article · Nov 2013 · Thrombosis Research
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    • "Although several studies demonstrate a low prevalence of aspirin-resistance (0–2.8%),[18],[19] most studies report a relatively high rate (5.5%–33%) of aspirin resistance in patients with cardiovascular disease.[16],[17],[20]–[22] These different data could possibly be due to the lack of a standardized method for determining aspirin resistance. "
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    ABSTRACT: To assess the prevalence of and related risk factors for aspirin resistance in elderly patients with coronary artery disease (CAD). Two hundred and forty-six elderly patients (75.9 ± 7.4 years) with CAD who received daily aspirin therapy (≥ 75 mg) over one month were recruited. The effect of aspirin was assessed using light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). Aspirin resistance was defined as ≥ 20% arachidonic acid (AA)-induced aggregation and ≥ 70% adenosine diphosphate (ADP)-induced aggregation in the LTA assay. An aspirin semi-responder was defined as meeting one (but not both) of the criteria described above. Based on the results of TEG, aspirin resistance was defined as ≥ 50% aggregation induced by AA. As determined by LTA, 23 (9.3%) of the elderly CAD patients were resistant to aspirin therapy; 91 (37.0%) were semi-responders. As determined by TEG, 61 patients (24.8%) were aspirin resistant. Of the 61 patients who were aspirin resistant by TEG, 19 were aspirin resistant according to LTA results. Twenty-four of 91 semi-responders by LTA were aspirin resistant by TEG. Multivariate logistic regression analysis revealed that elevated fasting serum glucose level (Odds ratio: 1.517; 95% CI: 1.176-1.957; P = 0.001) was a significant risk factor for aspirin resistance as determined by TEG. A significant number of elderly patients with CAD are resistant to aspirin therapy. Fasting blood glucose level is closely associated with aspirin resistance in elderly CAD patients.
    Full-text · Article · Mar 2013 · Journal of Geriatric Cardiology
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