“Aspirin Resistance”: Low Prevalence and Assay Discordance in a Pediatric Cohort.

“Aspirin resistance” (i.e., inadequate platelet inhibition as suggested by ex vivo assays in patients on aspirin) has been reported to occur commonly in adults and has been linked to an increased risk of adverse clinical events in this age group. However, its prevalence and clinical significance are largely unknown in children, with only limited pediatric data available. We have studied 22 children (ages 1 to 17 years) started on aspirin therapy for various indications (12 with a history of ischemic stroke, 6 after intervention via cardiac catheterization or surgery, 3 with a primary rheumatologic diagnosis, 1 with thrombocytosis) using a variety of measures of platelet inhibition, including optical aggregometry, PFA-100® and urinary thromboxane B₂ concentration. We considered previously published definitions of aspirin resistance in adults, including ≥ 70% aggregation to 10 μM adenosine diphosphate (ADP) and ≥ 20% aggregation to 0.5 mg/mL arachidonic acid (AA), normal PFA-100 closure time (collagen/epinephrine cartridge) and normal urinary thromboxane B₂ concentration (normal range defined by healthy pediatric controls). Subjects had received aspirin for a minimum of one week (range 1 to 249 weeks) prior to testing and mean aspirin dose was 3.4 mg/kg/d (range 1.3 to 7.9). Only 1 of 22 pediatric subjects (5%) met any of the pre-specified definitions for aspirin resistance; this single subject exhibited a normal PFA-100 closure time while receiving aspirin but was not aspirin resistant according to optical aggregometry or urinary thromboxane B₂ criteria. Two other subjects on aspirin exhibited inappropriately “normal” aggregation to either ADP or AA (but not both). Each subject on aspirin excreted low levels of urinary thromboxane B₂ compared with healthy non-medicated controls. To confirm an aspirin effect, five subjects were studied prior to initiation of aspirin therapy; each demonstrated pronounced changes in measured parameters after aspirin dosing (e.g. mean aggregation to AA decreased from 83 to 7%, p<.001). The small number of subjects who demonstrated any evidence of aspirin resistance did not differ from fully aspirin responsive subjects in terms of age, gender, race, platelet count, or aspirin dose, indication or therapy duration. Nor was there significant correlation between any of the measures of aspirin resistance we studied. In this initial prevalence study of a clinically diverse group of pediatric patients, laboratory evidence of aspirin resistance was not commonly encountered, despite our utilization of a broad panel of assays previously reported to identify aspirin resistance in adults. The prevalence of aspirin resistance in children thus appears low, and possibly less than that in adults. However, for the minority of pediatric patients who demonstrate laboratory evidence of aspirin resistance, this finding may hold clinical relevance; clinical follow-up of this cohort is ongoing. Finally, the lack of correlation we observed between assays previously linked to adverse clinical outcomes in patients taking aspirin supports that multiple molecular mechanisms contribute to the clinical phenotype of aspirin treatment failure.