Functional testing methods for the antiplatelet effects of aspirin

Abstract

At antiplatelet doses of 75–325 mg/day, aspirin irreversibly inhibits the platelet cyclooxygenase (COX)-1-dependent thromboxane A2 (TXA2) formation. This is the pharmacological mode of action of aspirin, and it can be predicted that if aspirin does not inhibit COX-1 sufficiently, patients will not benefit from its antiplatelet effects. A pharmacodynamic failure of aspirin occurs in 1–2% of patients. The vast majority of atherothrombotic events in patients treated with aspirin result from mechanisms that are dependent on residual (non-COX-1-dependent) platelet reactivity. Global tests of platelet activation in vitro may identify patients with high residual platelet reactivity but are not sufficiently specific to test the pharmacological effect of aspirin. A further problem is the absence of standardized normal ranges for many assays and the fact that different equipment measures different signals, which are also influenced by the agonist and the anticoagulant used. Similar considerations apply for the determination of platelet-derived biomarkers such as circulating P-selectin, soluble CD40 ligand and others. The direct measurement of inhibition of thromboxane-forming capacity is the most specific pharmacological assay for aspirin. However, there is no linear correlation between inhibition of TXA2 formation and inhibition of platelet function. Measurement of urinary levels of the TXB2 metabolite, 11-dehydro-thromboxane B2, represents an index of TXA2 biosynthesis in vivo, but is also sensitive to other cellular sources of TXA2. One general problem of all assays is the relationship with clinical outcome, which is still unclear. Monitoring aspirin treatment by testing platelet function or measuring biomarkers in clinical practice should not be recommended until a clear relationship for the predictive value of these assays for clinical outcome has been established.