Abstract 5011: The Contribution of COX-1 and COX-2 to Platelet Activation in Essential Thrombocythemia: A Clinical Paradigm of Aspirin-resistant Thromboxane Biosynthesis
Low dose aspirin-resistant thromboxane (TX) A2 biosynthesis has been reported in different clinical settings, including acute coronary syndromes, myeloproliferative disorders and diabetes mellitus. Cyclooxygenase (COX)-2 expression in newly formed platelets and/or unacetylated COX-1, because of accelerated platelet regeneration, might explain this phenomenon. We tested this hypothesis in patients with essential thrombocythemia (ET), an extreme pathophysiological paradigm of accelerated thrombopoiesis. The study was approved by local Ethical Committee. Forty-one ET patients (21M, 20F, mean age 52±14 yr) on chronic aspirin therapy (100 mg/day) were studied on repeated occasions. COX-2 expression was detectable by immunocytochemistry in a significantly (p<0.001) higher percentage of circulating platelets from ET patients than healthy subjects: 19 [16–19] % vs. 6 [4–7] % (median [IQR]), respectively. Furthermore, COX-2 expression in platelets was significantly and positively correlated with the fraction of the youngest, RNA-expressing circulating platelets in ET patients (r=0.62, p<0.01). Urinary 11-dehydro-TXB2 (TXM) excretion, a non-invasive marker of platelet activation, was significantly higher in ET patients than in 48 aspirin-treated controls: 349 [257–484] pg/mg creatinine vs. 137 [105–187] pg/mg creatinine (p<0.01) (median [IQR]). ET patients were randomized to continuing low-dose aspirin alone or adding etoricoxib (90 mg/day), a highly selective COX-2 inhibitor, for 7 days. Etoricoxib significantly reduced TXM excretion by 25% (p=0.04), while TXM excretion was unaffected in the aspirin-alone arm. Whole blood TXB2 was similarly and significantly reduced following etoricoxib ex vivo or in response to NS-398 (a selective, in vitro COX-2 inhibitor), added to whole blood samples in vitro (by 22 and 30%, respectively, p<0.001). The addition of aspirin (50 microM) to ET platelets in vitro completely suppressed whole blood TXB2 production. We conclude that a variable fraction of both unacetylated COX-1 and COX-2 contribute to TXA2 biosynthesis that is resistant to a conventional once daily regimen of low-dose aspirin, in a clinical setting characterized by accelerated thrombopoiesis and increased thrombotic risk.