Platelet cyclooxygenase activity, as reflected by serum TXB(2) levels, is uniformly and persistently suppressed by low-dose aspirin in healthy subjects. However, the effect of aspirin is variably detected by functional assays, potentially leading to misclassification of "responder" as "resistant" phenotypes owing to poor reproducibility of functional measurements. The nonlinearity of the relationship between inhibition of TX production and inhibition of platelet function has important clinical implications.

See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX‐1 at bay. This issue, pp 1217–9. Summary  Background.  Interindividual variability in response to aspirin has been popularized as ‘resistance’. We hypothesized that faster recovery of platelet cyclooxygenase‐1 activity may explain incomplete thromboxane (TX) inhibition during the 24‐h dosing interval. Objective.  To characterize the kinetics and determinants of platelet cyclooxygenase‐1 recovery in aspirin‐treated diabetic and non‐diabetic patients. Patients/Methods.  One hundred type 2 diabetic and 73 non‐diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB2 was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase‐1 recovery. Patients with the fastest TXB2 recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB2 recovery was reassessed. Results and Conclusions.  Platelet TXB2 production was profoundly suppressed at 12 h in both groups. Serum TXB2 recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL−1 h−1) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non‐diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB2 recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low‐dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r ‫؍‬ 0.71, P < .001). The rate of TXA 2 biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB 2 (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB 2 , were higher in patients compared with aspirintreated healthy volunteers. Serum TXB 2 was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB 2 . Fourteen of the 41 patients were studied again 21 (؎ 7) months after the first visit. Serum TXB 2 was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50M aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA 2 biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET. (Blood. 2010;115:1054-1061) IntroductionEssential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by high platelet generation, whose incidence is estimated to be around 1 to 2.5 per 100 000 subjects, although this estimate is likely to increase in the near future due to the continuous rise of "occasional," asymptomatic diagnoses. [1][2][3][4] ET usually occurs in 50-to 60-year-old patients and has a longer life-expectancy compared with other myeloproliferative neoplasm. [4][5][6][7] However up to 60% of all ET patients experience a minor or major thrombotic event in their life, mainly arterial, such as myocardial infarction, stroke, or transient ischemic attack. 8,9 Thrombotic complications significantly increase morbidity and impair survival. 7,10,11 Annual thrombotic event rates range from 2% to 7% in ET patients treated with cytoreductive agents with or without antiplatelet drugs, [7][8][9][11][12][13] with estimates up to 13%, in the absence of cytoreduction. 12 In the Primary Thrombocythemia 1 randomized trial, the annual rate of a composite cardiovascular endpoint was 4% in patients randomized to anagrelide, and 2.7% in the hydroxyurea arm, on a background of aspirin (98% of enrolled patients were on 75 mg of aspirin daily). 13 The annual recurrence rate of thrombosis after a first event has been estimated to be approximately 6% to 8% on antiplatelet drugs. 14 Hemorrhagic complications are less frequent, approximately 0.33% per year, 9 possibly due to an acquired von Willebrand-like defect, associated with the highest platel...

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