A historical review of the biological, semantic and clinical aspects of aspirin resistance

Aspirin is one of the most widely used antithrombotic agents worldwide. Nevertheless, the concept of aspirin resistance has generated sustained controversy for more than two decades. Initially introduced in the mid-1990s, the term was inconsistently applied to describe either recurrent ischaemic events, despite aspirin therapy, or inadequate platelet inhibition, as measured using various laboratory assays. Reported prevalence estimates consequently varied widely, reflecting profound methodological and semantic heterogeneity rather than a uniform biological concept. This historical review retraces the evolution of knowledge about aspirin pharmacodynamics, from the earliest studies on bleeding time and platelet aggregation to the identification of platelet cyclo-oxygenase-1 as aspirin's molecular target and the recognition of serum thromboxane B 2 as a specific biomarker of target inhibition. We examine how reliance on integrative platelet function tests fostered the concept of apparent resistance, later recognised, in many cases, as pseudo-resistance related to assay choice or pharmacokinetic factors. We then review the clinical, genetic and disease-related determinants of variability in aspirin response, highlighting conditions characterised by accelerated platelet production and turnover, such as essential thrombocythaemia, as a notable exception in which target-guided dosing has influenced practice. Finally, we summarise the outcome studies and guideline statements that uniformly discourage routine testing and aspirin dose escalation. Taken together, the historical evidence supports abandoning the term aspirin resistance in favour of recognising the variability in platelet reactivity found among patients treated with aspirin.