Poor Responsiveness to Low-Dose Aspirin Contributes to Persistent In Vivo Platelet Activation in Polycythemia Vera

Introduction . Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by peripheral erythrocytosis, increased thrombotic risk affecting morbidity and mortality. Low-dose aspirin once-daily (od) is currently recommended for cardiovascular prevention in PV. However, it has been recently suggested that aspirin should be used at 100 mg twice-daily (bid) in PV patients at high cardiovascular risk (JAK2V617F allelic burden, age >60 years) on the assumption of a shorter lasting antiplatelet effect, similarly to essential thrombocythemia. However, pharmacological and clinical data supporting the need for a bid ASA regimen in PV are missing.

Methods . We studied the platelet responsiveness to standard aspirin (100 mg od) in PV patients, assessed at the end of the 24-h dosing interval. Patients were diagnosed according to the WHO 2008 criteria, were all on od low-dose aspirin and underwent a run-in phase (7-10 days) where aspirin tablets were always ingested at breakfast. Routine hematochemistry, genotype and allelic burden, clinical characteristics and history, medications were recorded. Serum thromboxane B₂ (sTXB₂) was measured as ex vivo biomarker of aspirin pharmacodynamics, urinary 11-deidro-TXB₂ (TXM) as in vivo index of platelet activation, the major urinary prostacyclin metabolite, 2,3 dinor 6-keto-PGF_1α (PGIM), the urinary isoprostane 8-iso-PGF_2α and plasma salicylic acid esterase activity.

Results . Forty-nine patients (67±10 years, 16 females) on aspirin for ≥1 month gave their informed consent; aspirin compliance and non-steroidal anti-inflammatory drug intake were checked by phone calls and patient's interview on the day of the visit. Nine patients were on phlebotomy only, while the remaining patients were on phlebotomy and hydroxyurea to keep the hematocrit <45%. Average hematologic values were: hematocrit 43.8±3%; erythrocytes 5.3±1.3x10⁶/µL; leukocytes 9.1±4.3x10³/µL, platelets 359±165x10³/µL, immature platelets 11.8±7.4x10³/µL. The median sTXB₂ value was 8.6 [2-50] ng/ml, urinary TXM 509 [205-3428] pg/mg creatinine, 8-iso-PGF_2α 768 [234-2104] pg/mg creatinine, PGIM 172 [120-275] pg/mg creatinine, plasma esterase activity 53 [47-60] µmol/L salycilic acid/min. Overall, sTXB₂ significantly (p<0.01) correlated with immature platelets (rho=0.46), erythrocyte count (rho=0.41), leukocytes (rho=0.39). Patients were then divided according to sTXB₂ tertiles, and patients in the lowest tertile showed sTXB₂ levels within the expected range (3.4 [2.4-4.2] ng/ml, Figure). The patients in the upper tertile of sTXB₂ levels (19.8 [15.3-40.9] ng/ml) were characterized by significantly (p<0.05) higher erythrocyte counts, total platelet counts, and immature platelets (p=0.05), while age, JAK2V617F allelic burden, leukocytes, hematocrit, hemoglobin, and sex distribution were comparable across tertiles. Urinary TXM significantly (p<0.05) correlated with sTXB₂ (rho=0.39 and Figure), disease duration (rho=0.33), and leukocytes (rho=0.33). By multivariable analysis, only sTXB₂ (p=0.009) positively predicted urinary TXM excretion. Urinary PGIM correlated with 8-iso-PGF_2α excretion but not with TXM. Plasma esterase activity correlated with hemoglobin levels (rho=0.33, p=0.04), but not with the hematocrit, erythrocyte count, urinary TXM or sTXB₂. JAK2V617F burden was significantly associated with polymorphonucleate count (rho=0.65), hemoglobin (rho=-0.49), and male sex (rho=0.41) while it was unrelated to previous thrombosis, sTXB₂, urinary TXM and PGIM. By multivariable analysis JAK2V617F allelic burden predicted leukocyte counts only.

Conclusions . A fraction of PV patients characterized by high erythrocyte, platelet and immature platelet count have a reduced response to a standard regimen of low-dose aspirin, which may contribute to persistently enhanced in vivo platelet activation. An improved antiplatelet regimen should be tested in these patients.

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