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

Giovanna Petrucci, Bianca Rocca, Davide Pocaterra, Carlo Patrono, Silvia Pascale, Alfredo Dragani, Aida Habib, Giancarlo Rolandi

Research output: Contribution to journalArticle

148 Citations (Scopus)

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 (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) TXB2 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. © 2012 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)3595-3603
Number of pages9
JournalBlood
Volume119
DOIs
Publication statusPublished - 2012

Keywords

  • Acceleration
  • Adult
  • Aged
  • Algorithms
  • Anti-Inflammatory Agents, Non-Steroidal
  • Aspirin
  • Biochemistry
  • Cell Biology
  • Cross-Over Studies
  • Cross-Sectional Studies
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Drug Resistance
  • Female
  • Half-Life
  • Hematology
  • Humans
  • Immunology
  • Male
  • Metabolic Networks and Pathways
  • Middle Aged
  • Molecular Targeted Therapy
  • Protein Biosynthesis
  • Thrombocythemia, Essential
  • Thromboxane A2

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