title: 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. Once-daily 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 (β = 3.53, P = .001). Twenty-one aspirin-treated 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 shorter-lasting 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.
authors.affiliation: Department of Hematology, Spirito Santo Hospital, Pescara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pascale
authors.forename: Giovanna
authors.initials: G
authors.lastname: Petrucci
authors.forename: Alfredo
authors.initials: A
authors.lastname: Dragani
authors.forename: Aida
authors.initials: A
authors.lastname: Habib
authors.forename: Francesco
authors.initials: F
authors.lastname: Zaccardi
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagliaccia
authors.forename: Davide
authors.initials: D
authors.lastname: Pocaterra
authors.forename: Enzo
authors.initials: E
authors.lastname: Ragazzoni
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Rolandi
authors.forename: Bianca
authors.initials: B
authors.lastname: Rocca
authors.forename: Carlo
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000054:Acceleration; D000328:Adult; D000368:Aged; D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003430:Cross-Sectional Studies / Q000706:statistics & numerical data; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D014176:Protein Biosynthesis / Q000187:drug effects; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000378:metabolism*; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin