Aspirin Resistance in Children after Interventional Cardiac Catheterisation.
Authors: Schmugge Markus , Speer Oliver , Kroiss Sabine , Schmid Marlies , Knirsch Walter , Kretschmar Oliver , Rand Margaret L. , Albisetti Manuela 
Published: April 2020

Abstract
Several large trials have demonstrated the benefit of aspirin for the prevention of arterial thrombotic events in adults. Aspirin has also been increasingly used as an anti-platelet agent in children. However, very few well-designed clinical trials assessing the clinical efficacy and dosing of aspirin in children have been performed. In children, aspirin is usually administrated at a dose between 1 and 10 mg/kg/day. The term “aspirin resistance” (AR) describes the inability of aspirin to protect individuals from arterial thrombotic events (clinical AR) or the failure of aspirin to produce an expected response on laboratory measures of platelet activation and aggregation (laboratory AR). In adults, a prevalence of 5%–51% of AR had been reported, depending on the laboratory method used. A recent study using the platelet function analyser PFA-100 and levels of urinary 11-dehydrothromboxane B2 (11-dTXB2) excretion to define AR in paediatric cardiology patients, found a prevalence of 26% of laboratory AR (Heistein et al 2007). Here we studied the frequency of AR in children given aspirin at 3–5 mg/kg/d after interventional cardiac catheterization for atrial or ventricular septal defects or patent ductus arteriosus. Blood samples were taken 1–3 months after the initiation of aspirin therapy. Definition of AR was based on results from platelet aggregometry (% arachidonate-induced aggregation (AAG) of ≥ 20%) and results were compared with collagen/epinephrine closure times using the platelet function analyser PFA-100 and the levels of 11-dTXB2 excretion. As cyclooxygenase 1 (COX-1) is the primary target of aspirin and mutations could lead to a loss of functional protein, the presence of COX-1 was analyzed by western blot. Further, all children were followed clinically and side effects were monitored.
Of 56 children included to date (median age: 10 y, range: 10 mo −20 y), 44 have completed the study. AR, was detected in 6 (14%) children. Of these 6 children, 3 had a normal response to aspirin (i.e. decreased AAG to &lt;20%) after doubling the dose to 6–10 mg/kg, 1 child did not respond to a dose increase, and 2 were unavailable for further studies. Children under the age of 7 had higher urinary 11-dTXB2 levels initially compared to older children (323 vs 178 ng/mmol creatinine; p&lt; 0.001). During aspirin therapy, 11-dTXB2 levels decreased to 38 ± 15 ng/mmol creatinine (mean ± SD). However, in 2 children, 11-dTXB2 decreased only minimally (81 and 84% of pre-aspirin level, respectively; results &gt; mean+2SD ): Of these 2 children, one child had AR by the AAG definition even after aspirin dose increase and the other revealed AR by the PFA-100, with normal closure time, but not by AAG. While PFA-100 closure times were prolonged in 48% of children already prior to administration of aspirin, all children with AR according to AAG had prolonged closure times during aspirin-therapy. All 6 AR patients and 10 patients with a normal response to aspirin by AAG demonstrated equal amounts of COX-1 by western blot. While 6 children (14%) showed easy bruising and epistaxis during aspirin therapy, no severe bleeding or thrombotic complications were recorded
In conclusion, AR was detected in 14% of children after interventional cardiac catheterization by AAG and could be overcome in some patients by increasing the dose of aspirin. These results are in keeping with findings from adults. By the use of the PFA-100 a previous study found a prevalence of 26% of AR in children (Heistein et al 2007). However, the authors did not correlate these results to AAG. In our cohort, the assessment of AR by the PFA100 was hampered by a high rate of abnormal PFA results previous to the initiation of therapy. Although reduction of 11-dTXB2 excretion indicates an inhibition of the COX-1 pathway by aspirin therapy, 11-dTXB2 and AAG results were not always congruent.