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Influence of Sex on Platelet Reactivity in Response to Aspirin.

ABSTRACT: Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378?208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217?112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet-rich plasma was used to measure platelet reactivity in response to epinephrine, collagen, and ADP at baseline, 3 hours after the first aspirin dose, and after 4 weeks of daily aspirin therapy. A subset of patients underwent pharmacokinetic and pharmacodynamic assessment with levels of salicylate and cyclooxygenase-1-derived prostaglandin metabolites and light transmittance aggregometry in response to arachidonic acid and after ex vivo exposure to aspirin. At baseline, women had increased platelet aggregation in response to ADP and collagen. Innate platelet response to aspirin, assessed with ex vivo aspirin exposure of baseline platelets, did not differ by sex. Three hours after the first oral aspirin dose, platelet aggregation was inhibited in women to a greater degree in response to epinephrine and to a lesser degree with collagen. After 4 weeks of daily therapy, despite higher salicylate concentrations and greater cyclooxygenase-1 inhibition, women exhibited an attenuation of platelet inhibition in response to epinephrine and ADP. Conclusions We observed agonist-dependent sex differences in platelet responses to aspirin. Despite higher cyclooxygenase-1 inhibition, daily aspirin exposure resulted in a paradoxical attenuation of platelet inhibition in response to epinephrine and ADP over time in women but not in men.

SUBMITTER: Friede KA

PROVIDER: S-EPMC7660714 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Influence of Sex on Platelet Reactivity in Response to Aspirin.

Friede Kevin A KA Infeld Margaret M MM Tan Ru San RS Knickerbocker Holly J HJ Myers Rachel A RA Dubois Laura G LG Thompson J Will JW Kaddurah-Daouk Rima R Ginsburg Geoffrey S GS Ortel Thomas L TL Voora Deepak D

Journal of the American Heart Association 20200711 14

Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378 208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217 112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet-rich plasma was ...[more]

PMID: 32654613

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Project description:BackgroundPlatelet aggregation during aspirin treatment displays considerable inter-individual variability. A genetic etiology likely exists, but it remains unclear to what extent genetic polymorphisms determine platelet aggregation in aspirin-treated individuals.AimTo identify platelet-related single nucleotide polymorphisms (SNPs) influencing platelet aggregation during aspirin treatment. Furthermore, we explored to what extent changes in cyclooxygenase-1 activity and platelet activation may explain such influence.MethodsWe included 985 Danish patients with stable coronary artery disease treated with aspirin 75 mg/day mono antiplatelet therapy. Patients were genotyped for 16 common SNPs in platelet-related genes using standard PCR-based methods (TaqMan). Platelet aggregation was evaluated by whole blood platelet aggregometry employing Multiplate Analyzer (agonists: arachidonic acid and collagen) and VerifyNow Aspirin. Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity. Soluble P-selectin was used as marker of platelet activation. Platelet aggregation, cyclooxygenase-1 activity, and platelet activation were compared across genotypes in adjusted analyses.ResultsThe A-allele of the rs12041331 SNP in the platelet endothelial aggregation receptor-1 (PEAR1) gene was associated with reduced platelet aggregation and increased platelet activation, but not with cyclooxygenase-1 activity. Platelet aggregation was unaffected by the other SNPs analyzed.ConclusionA common genetic variant in PEAR1 (rs12041331) reproducibly influenced platelet aggregation in aspirin-treated patients with coronary artery disease. The exact biological mechanism remains elusive, but the effect of this polymorphism may be related to changes in platelet activation. Furthermore, 14 SNPs previously suggested to influence aspirin efficacy were not associated with on-aspirin platelet aggregation.Clinical trial registrationClinicalTrials.gov NCT01383304.

Project description:Platelet gene polymorphisms are associated with variable on-treatment platelet reactivity and vary by race. Whether differences in platelet reactivity and aspirin or ticagrelor exist between African-American and European-Americans remains poorly understood. Biological samples from three prior prospective antiplatelet challenge studies at the Duke Clinical Research Unit were used to compare platelet reactivity between African-American and European-American subjects. Platelet reactivity at baseline, on-aspirin, on-ticagrelor, and the treatment effect of aspirin or ticagrelor were compared between groups using an adjusted mixed effects model. Compared with European-Americans (n = 282; 50% female; mean ± standard deviation age, 50 ± 16), African-Americans (n = 209; 67% female; age 48 ± 12) had lower baseline platelet reactivity with platelet function analyzer-100 (PFA-100) (p < 0.01) and with light transmission aggregometry (LTA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and epinephrine agonists (p < 0.05). African-Americans had lower platelet reactivity on aspirin in response to ADP, epinephrine, and collagen (p < 0.05) and on ticagrelor in response to AA, ADP, and collagen (p < 0.05). The treatment effect of aspirin was greater in European-Americans with an AA agonist (p = 0.002). Between-race differences with in vitro aspirin mirrored those seen in vivo. The treatment effect of ticagrelor was greater in European-Americans in response to ADP (p < 0.05) but with collagen, the treatment effect was greater for African-Americans (p < 0.05). Platelet reactivity was overall lower in African-Americans off-treatment, on aspirin, and on ticagrelor. European-Americans experienced greater platelet suppression on aspirin and on ticagrelor. The aspirin response difference in vivo and in vitro suggests a mechanism intrinsic to the platelet. Whether the absolute level of platelet reactivity or the degree of platelet suppression after treatment is more important for clinical outcomes is uncertain.

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Influence of Sex on Platelet Reactivity in Response to Aspirin.

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Influence of Sex on Platelet Reactivity in Response to Aspirin.

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