ABSTRACT
Title
Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia: effect of different aspirin doses, formulations and dosing regimens.
Authors
G. Petrucci
Doctorate School in Pathophysiology and Pharmacology of hemostasis and thrombosis
Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
Doctorate School in Pathophysiology and Pharmacology of hemostasis and thrombosis
Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
Abstract
Essential thrombocythemia (ET) is a myeloproliferative neoplasm showing high platelet generation, thrombocytosis and increased (up to 60%) incidence of arterial thromboses, which largely lowers survival. Low-dose aspirin (ASA), although not formally proven, is recommended in primary and secondary cardiovascular prevention. We have previously shown that in low-dose aspirin (100 mg once-daily) treated ET patients there is an aspirin-insensitive thromboxane (TX) A2 generation ex vivo from platelets that can be fully inhibited by adding more aspirin to patient blood in vitro. Considering the high platelet turnover in ET, we tested whether a twice-daily low-dose (100 mg) aspirin dosing might inhibit more effectively platelet-dependent TXA2 generation.
Twenty-two ET patients (9 males, age 52.5 [29-67] years, medians and IQR) all on 100 mg/day enteric-coated (EC) aspirin (Cardioaspirina®, Bayer), and with levels of serum TXB2 > 4 ng/ml (e.g. 2 standard deviations above the mean of aspirin-treated controls), participated in a crossover study. Patients were taking their aspirin at the same time of the day (morning) and were always studied 24 hours after the last aspirin intake. The study consisted in a run-in phase, where patients were studied twice at 7-day interval, followed by a randomized sequence of 3 different treatments with washouts in between. The three treatments were: EC aspirin 100 mg twice daily (h 8-20); EC aspirin 200 mg once daily (as dose control), and plain aspirin (Aspirinetta®, Bayer)100 mg o.d. Each treatment and washout lasted 7 days. Patients were studied every week and we measured: i) serum TXB2, an index of maximal cyclooxygenase-dependent biosynthetic capacity from platelets; ii) urinary 11-dehydro-TXB2, an index of in vivo platelet activation and iii) 8-iso-PGF2α an in vivo oxidative, non enzimatic product of arachidonic acid. During washouts patients were resuming their EC aspirin 100 mg o.d.
At baseline (run-in), serum TXB2 levels in patients averaged 16.3 [10.5-35] ng/ml (medians and IQR), 11-dehydro-TXB2 excretion averaged 262.2 [177-330] pg/mg creatinine and 8-iso-PGF2α averaged 467.1 [397-521] pg/mg creatinine. Determinants of residual serum TXB2 generation from platelets at baseline were the platelet mass (but not counts) (rho=0.5, p=0.02), and Janus kinase-2 (JAK2) positivity (rho=0.51, p=0.02).
Twice daily 100 mg regimen further suppressed both serum TXB2 generation by 88.2 [78.4-92.3] % (p<0.001) vs. EC aspirin 100 mg once-daily, as well as 11-dehydro TXB2 excretion by 23 [1-44.3] % (p = 0.019). Two-hundred mg EC aspirin gave an intermediate suppression (38.8 [29-54] %) vs. 100 mg EC aspirin.
We conclude that a low-dose aspirin twice-daily regimen might be a better option in diseases characterised by high platelet turnover.
Twenty-two ET patients (9 males, age 52.5 [29-67] years, medians and IQR) all on 100 mg/day enteric-coated (EC) aspirin (Cardioaspirina®, Bayer), and with levels of serum TXB2 > 4 ng/ml (e.g. 2 standard deviations above the mean of aspirin-treated controls), participated in a crossover study. Patients were taking their aspirin at the same time of the day (morning) and were always studied 24 hours after the last aspirin intake. The study consisted in a run-in phase, where patients were studied twice at 7-day interval, followed by a randomized sequence of 3 different treatments with washouts in between. The three treatments were: EC aspirin 100 mg twice daily (h 8-20); EC aspirin 200 mg once daily (as dose control), and plain aspirin (Aspirinetta®, Bayer)100 mg o.d. Each treatment and washout lasted 7 days. Patients were studied every week and we measured: i) serum TXB2, an index of maximal cyclooxygenase-dependent biosynthetic capacity from platelets; ii) urinary 11-dehydro-TXB2, an index of in vivo platelet activation and iii) 8-iso-PGF2α an in vivo oxidative, non enzimatic product of arachidonic acid. During washouts patients were resuming their EC aspirin 100 mg o.d.
At baseline (run-in), serum TXB2 levels in patients averaged 16.3 [10.5-35] ng/ml (medians and IQR), 11-dehydro-TXB2 excretion averaged 262.2 [177-330] pg/mg creatinine and 8-iso-PGF2α averaged 467.1 [397-521] pg/mg creatinine. Determinants of residual serum TXB2 generation from platelets at baseline were the platelet mass (but not counts) (rho=0.5, p=0.02), and Janus kinase-2 (JAK2) positivity (rho=0.51, p=0.02).
Twice daily 100 mg regimen further suppressed both serum TXB2 generation by 88.2 [78.4-92.3] % (p<0.001) vs. EC aspirin 100 mg once-daily, as well as 11-dehydro TXB2 excretion by 23 [1-44.3] % (p = 0.019). Two-hundred mg EC aspirin gave an intermediate suppression (38.8 [29-54] %) vs. 100 mg EC aspirin.
We conclude that a low-dose aspirin twice-daily regimen might be a better option in diseases characterised by high platelet turnover.