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

Blood. 2012 Apr 12;119(15):3595-603. doi: 10.1182/blood-2011-06-359224. Epub 2012 Jan 10.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acceleration
  • Adult
  • Aged
  • Algorithms
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Aspirin / administration & dosage
  • Aspirin / therapeutic use*
  • Cross-Over Studies
  • Cross-Sectional Studies / statistics & numerical data
  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Drug Resistance / drug effects
  • Female
  • Half-Life
  • Humans
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Protein Biosynthesis / drug effects
  • Thrombocythemia, Essential / drug therapy*
  • Thrombocythemia, Essential / metabolism*
  • Thromboxane A2 / biosynthesis*
  • Thromboxane A2 / pharmacokinetics


  • Anti-Inflammatory Agents, Non-Steroidal
  • Thromboxane A2
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Aspirin