Open AccessPlatelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation
Author(s) -
Petrucci Giovanna,
Giaretta Alberto,
Ranalli Paola,
Cavalca Viviana,
Dragani Alfredo,
Porro Benedetta,
Hatem Duaa,
Habib Aida,
Tremoli Elena,
Patrono Carlo,
Rocca Bianca
Publication year - 2022
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.13415
Subject(s) - aspirin , medicine , platelet , ex vivo , pharmacodynamics , thromboxane , pharmacology , platelet activation , thromboxane b2 , polycythemia vera , urinary system , pharmacokinetics , in vivo , gastroenterology , biology , microbiology and biotechnology
Low‐dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses. Based on aspirin pharmacodynamics in essential thrombocythemia, a twice‐daily regimen is recommended for patients with PV deemed at particularly high thrombotic risk. We investigated the effects of low‐dose aspirin on platelet cyclooxygenase activity and in vivo platelet activation in 49 patients with PV, as assessed by serum thromboxane (TX) B 2 and urinary TXA 2 /TXB 2 metabolite (TXM) measurements, respectively. A previously described pharmacokinetic‐pharmacodynamic in silico model was used to simulate the degree of platelet TXA 2 inhibition by once‐daily (q.d.) and twice‐daily (b.i.d.) aspirin, and to predict the effect of missing an aspirin dose during q.d. and b.i.d. regimens. Serum TXB 2 averaged 8.2 (1.6–54.7) ng/ml and significantly correlated with the platelet count ( γ = 0.39) and urinary TXM ( γ = 0.52) in multivariable analysis. One‐third of aspirin‐treated patients with PV displayed less‐than‐maximal platelet TXB 2 inhibition, and were characterized by significantly higher platelet counts and platelet‐count corrected serum TXB 2 than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB 2 and urinary TXM values. The in silico model predicted complete inhibition of platelet‐derived TXB 2 by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB 2 value while on aspirin q.d. and treated short‐term with a b.i.d. regimen. In conclusion, one in three patients with PV on low‐dose aspirin display less‐than‐maximal inhibition of platelet TXA 2 production. Serum TXB 2 measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.