Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target

Abstract

Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Oncedaily low-dose aspirin incompletely inhibits platelet thromboxane A 2 (TXA 2 ) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA 2 biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB 2 independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (␤ ‫؍‬ 3.53, P ‫؍‬ .001). Twenty-one aspirintreated patients with serum TXB 2 > 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric-coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB 2 reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB 2 excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB 2 only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorterlasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose. (Blood. 2012;119(15):3595-3603)

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

“…Histopathological studies in erythromelalgia have revealed platelet-rich arteriolar microthrombi with endothelial inflammation and intimal proliferation accompanied by increased platelet consumption that is coupled with abundant VW factor deposition [74][75][76]. In regards to aspirin therapy in PV or ET, a recent report suggested that twicedaily aspirin may work better than once daily dose in certain cases [77]. Accordingly, we sometimes consider such a therapeutic approach in patients who seem to be resistant to once daily dosing or considered to be at a higher risk of arterial thrombosis (Fig.…”

Coronary microvascular dysfunction due to essential thrombocythemia and policythemia vera: The missing piece in the puzzle of their increased cardiovascular risk?

“…This is not entirely unexpected as previous studies have reported only marginal benefit of aspirin in the risk of recurrence of cardiovascular events in patients with ET and PV with a previous acute coronary syndrome [24]. This may be explained by the inadequate suppression of platelet TXA 2 production in patients with ET on once-daily low-dose aspirin [25]. A better platelet inhibition could be achieved by prescribing low-dose aspirin twice daily although this approach needs to be validated in prospective studies [26].…”

Advances and challenges in the management of essential thrombocythemia

“…As patients on aspirin still get thrombosis, it has been challenged whether the thromboxane inhibition produced by low dose aspirin is sufficient, and data supporting this view have been reported [Dragani et al 2010;Pascale et al 2012]. Furthermore, adenosine diphosphate (ADP) receptor inhibition has been suggested as an additional therapeutic effort apart from thromboxane inhibition [Panova-Noeva et al 2013].…”