Association of Platelet Thromboxane Inhibition by Low‐Dose Aspirin With Platelet Count and Cytoreductive Therapy in Essential Thrombocythemia

Abstract

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once-daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once-vs. twice-or three-times daily low-dose aspirin in inhibiting platelet thromboxane (TX) A 2 production, as reflected by serum (s) TXB 2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once-daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB 2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB 2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P < 0.01, n = 84), but not in patients on cytoreduction. Patients in the lowest sTXB 2 quartile were older, more often on cytoreductive drugs, had lower platelet count and Janus-Associated Kinase2 (JAK2)-V617F allele frequency as compared with patients in the upper sTXB 2 quartiles. After 2 weeks of a twiceor 3-times daily aspirin regimen, the association between the platelet count and sTXB 2 became similar in cytoreduced and non-cytoreduced patients. In conclusion, the platelet count appears the strongest determinant of TXA 2 inhibition by once-daily low-dose aspirin in ET, with different patterns depending of cytoreductive treatment. More frequent aspirin dosing restores adequate platelet inhibition and reduces interindividual variability, independently of cytoreduction.

Physiologically based modelling of the antiplatelet effect of aspirin: A tool to characterize drug responsiveness and inform precision dosing

“…Indeed, the ARES phase II trial has recently showed a superior efficacy of multiple (both bid and tid) daily low-dose aspirin regimens in adequately suppressing sTXB 2 , as compared to the standard od regimen [ 31 ]. Moreover, the same trial showed that a tid regimen was similar to a bid regimen in the degree of platelet COX-1 inhibition [ 31 , 35 , 36 ] which is consistent with our in silico prediction ( Fig 7 ).…”

Late In-Stent Thrombosis After Carotid Artery Stenting for Symptomatic Internal Carotid Artery Stenosis in a Patient With JAK2 V617F-Positive Essential Thrombocythemia: An Illustrative Case Report

“…Kwon et al demonstrated a close relationship between inflammatory conditions and the progression of atherosclerosis in myeloproliferative disorder and that reducing inflammation may help to regress plaque [16]. Tosetto et al indicated that platelet count is the most important factor for determining how well oncedaily low-dosage ASA inhibits thromboxane A2 in ET, which may also improve the efficacy of antithrombotic therapy itself [17]. Therefore, it is necessary to suppress the disease state and normalize platelet counts, especially in progressive cases, similar to our own.…”

“…No studies have compared the therapeutic efficacy of CLZ and ASA in patients with ET and the JAK2 V617F mutation; however, as previous reports have documented thromboxane metabolite excretion due to platelet activation [19], the administration of aspirin, which inhibits thromboxane A2 (TXA2), is sensible. According to Tosetto et al, platelet count appears to be the most important factor for determining how well once-daily lowdosage aspirin inhibits TXA2 in ET [17].…”

Illustrated State‐of‐the‐Art Capsules of the ISTH 2022 Congress

“…For references, see Tosetto et al 45 ; Rocca et al 46 ; Petrucci et al The plasminogen/plasmin s ys tem beyond f ibrinolysis: Emerging player s in resolution of inflammation…”