Incidence of Aspirin 'Resistance' as Determined Using the PFA-100 in Pediatric Patients with Arterial Ischemic Stroke.

Abstract

A significant benefit of aspirin (ASA) has been demonstrated in the prevention of arterial thrombotic events in high-risk adult patients. Despite ASA therapy, recurrence of thromboembolic events, or treatment failure, has been reported in 10–20% of patients, and this has been termed ASA 'resistance'. This term has also been applied to the failure of ASA to affect ASA-dependent laboratory tests. As there is little information on ASA 'resistance' in children, we examined the efficacy of ASA treatment on platelets from pediatric stroke patients using the PFA-100. Pediatric arterial ischemic stroke afflicts 2–3 children per 100,000 per year, and is associated with recurrent arterial ischemic stroke or transient ischemic attack in 20–40% of cases. Current treatment includes ASA prophylaxis (3 – 5 mg/kg/day) to inhibit platelet function and prevent recurrence, but it is not known whether this ASA dosing regimen is adequate to inhibit platelet function. Our study population consisted of 95 consecutive children with an index arterial ischemic stroke at mean age 5.9 ± 4.8 yrs (range: 0.1 – 17.0 yrs) on active ASA therapy (2.9 ± 1.2 mg/kg/day). Citrated blood samples were obtained at mean age 9.8 ± 4.8 yrs (range: 0.9 – 19 yrs), and were used to measure primary, platelet-related hemostasis in the high-shear PFA-100 system; closure times (CTs) were determined with the collagen/epinephrine cartridge that is sensitive to ASA's inhibition of thromboxane A2 formation via platelet cyclo-oxygenase 1. The mean CT for all 95 patients was 244 ± 68.1 sec, which is greater than 163 sec, the upper limit of the normal range that we have previously determined for healthy children. The majority of patients, 75/95 (79%), had prolonged CTs (172 sec to > 300 sec), indicating inhibition of platelet function by ASA, and they were thus responsive to ASA therapy. 45 of the 75 ASA responders (63%) had CTs > 300 sec, i.e. CTs greater than the maximum test time of 300 sec, demonstrating aperture non-closure. The remaining 20/95 patients (21%) were ASA 'resistant', as they did not respond to ASA therapy, having CTs (93 – 163 sec) within the normal range. Mean ASA dosage did not differ between ASA responders (2.8 ± 1.2 mg/kg/day) and ASA 'resistant' patients (3.0 ± 1.4 mg/kg/day). 6 of the ASA 'resistant' patients had their ASA dosage increased, and on repeat PFA-100 testing, 5/6 showed increased CTs > 163 sec. In conclusion, in children with arterial ischemic stroke, the majority, 79%, demonstrate inhibition of platelet function, as determined using the PFA-100, by ASA therapy at a mean dose of 2.9 mg/kg/day. The reason for the lack of inhibition of platelet function in 21% of pediatric patients, whether increased ASA dosage or alternative anti-platelet agents (e.g. clopidogrel) should be used in ASA 'resistant' patients, and the relationship between ASA 'resistance' and recurrence of arterial thrombotic events in children require further studies.