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. 2014 Aug;78(2):320-8.
doi: 10.1111/bcp.12335.

Increased Platelet Expression of Glycoprotein IIIa Following Aspirin Treatment in Aspirin-Resistant but Not Aspirin-Sensitive Subjects

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Free PMC article

Increased Platelet Expression of Glycoprotein IIIa Following Aspirin Treatment in Aspirin-Resistant but Not Aspirin-Sensitive Subjects

Christopher N Floyd et al. Br J Clin Pharmacol. .
Free PMC article

Abstract

Aims: Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects.

Methods: Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting.

Results: In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance.

Conclusions: In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.

Keywords: aspirin resistance; glycoprotein IIIa; platelets; proteomics.

Figures

Figure 1
Figure 1
Aspirin resistance in a cohort of 93 healthy subjects. Aggregation responses are shown to (A) arachidonic acid (AA, 1.6mmol l−1) and (B) ADP 30 μmol l−1 in platelet-rich plasma. Also shown are urinary 11-dehydrothromboxane B2 (11-dehydroTXB2) (C). Visits 1 and 2 represent values 1 week apart. Visit 3 represents values after subjects were treated with 300 mg aspirin daily for 28 days. ***P < 0.001 as compared with both visit 1 and visit 2
Figure 2
Figure 2
Concentration–response relationship of aspirin on arachidonic acid-mediated platelet aggregation in vitro. (A) Arachidonic acid (AA)-induced platelet aggregation at a concentration of 1.6 mmol l−1 was measured in the presence of either vehicle (ethanol) or increasing aspirin concentrations. *** P < 0.001 as compared with vehicle. (B) Percentage inhibition of AA (1.6 mmol l−1)-induced aggregation in the presence of different concentrations of aspirin, in aspirin-resistant vs. aspirin-sensitive subjects. formula image, sensitivity (n = 29); formula image, resistant (n = 2)
Figure 3
Figure 3
Inter-individual heterogeneity in platelet responses to aspirin at different concentrations in vitro. Frequency distribution graphs are shown demonstrating percentage inhibition by aspirin (50 μmol l−1: A, 100 μmol l−1: B, 200 μmol l−1: C, 500 μmol l−1: D and 1000 μmol l−1: E) on arachidonic acid 1.6 mmol l−1-induced aggregation
Figure 4
Figure 4
Platelet glycoprotein IIIa (GPIIIa) expression in aspirin-resistant vs. aspirin-sensitive subjects with coronary artery disease. (A) Typical Western blot of GPIIIa (125 kDa) and beta-actin (42 kDa), in platelets from an aspirin-resistant subject (ASP-R) compared to those from several aspirin-sensitive subjects. (B) Bar chart of expression of GPIIIa expressed relative to beta-actin, as assessed by Western blotting. ASP-R and ASP-S refer to aspirin-resistant and aspirin-sensitive subjects respectively. ** P < 0.01 vs. aspirin-sensitive subjects

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