Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation
Abstract 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13415 |
| _version_ | 1811294669203570688 |
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| author | Giovanna Petrucci Alberto Giaretta Paola Ranalli Viviana Cavalca Alfredo Dragani Benedetta Porro Duaa Hatem Aida Habib Elena Tremoli Carlo Patrono Bianca Rocca |
| author_facet | Giovanna Petrucci Alberto Giaretta Paola Ranalli Viviana Cavalca Alfredo Dragani Benedetta Porro Duaa Hatem Aida Habib Elena Tremoli Carlo Patrono Bianca Rocca |
| author_sort | Giovanna Petrucci |
| collection | DOAJ |
| description | Abstract 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) B2 and urinary TXA2/TXB2 metabolite (TXM) measurements, respectively. A previously described pharmacokinetic‐pharmacodynamic in silico model was used to simulate the degree of platelet TXA2 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 TXB2 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 TXB2 inhibition, and were characterized by significantly higher platelet counts and platelet‐count corrected serum TXB2 than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB2 and urinary TXM values. The in silico model predicted complete inhibition of platelet‐derived TXB2 by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB2 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 TXA2 production. Serum TXB2 measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV. |
| first_indexed | 2024-04-13T05:21:50Z |
| format | Article |
| id | doaj.art-2a8bd4e335b94572881af6e277d88e56 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-13T05:21:50Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-2a8bd4e335b94572881af6e277d88e562022-12-22T03:00:44ZengWileyClinical and Translational Science1752-80541752-80622022-12-0115122958297010.1111/cts.13415Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulationGiovanna Petrucci0Alberto Giaretta1Paola Ranalli2Viviana Cavalca3Alfredo Dragani4Benedetta Porro5Duaa Hatem6Aida Habib7Elena Tremoli8Carlo Patrono9Bianca Rocca10Department of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine Rome ItalyDepartment of Pathology University of Cambridge Cambridge UKDepartment of Hematology S. Spirito Hospital Pescara ItalyCentro Cardiologico Monzino, IRCCS Milan ItalyDepartment of Hematology S. Spirito Hospital Pescara ItalyCentro Cardiologico Monzino, IRCCS Milan ItalyDepartment of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine Rome ItalyDepartment of Basic Medical Sciences, College of Medicine, QU Health Qatar University Doha QatarMaria Cecilia Hospital Cotignola ItalyDepartment of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine Rome ItalyDepartment of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine Rome ItalyAbstract 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) B2 and urinary TXA2/TXB2 metabolite (TXM) measurements, respectively. A previously described pharmacokinetic‐pharmacodynamic in silico model was used to simulate the degree of platelet TXA2 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 TXB2 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 TXB2 inhibition, and were characterized by significantly higher platelet counts and platelet‐count corrected serum TXB2 than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB2 and urinary TXM values. The in silico model predicted complete inhibition of platelet‐derived TXB2 by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB2 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 TXA2 production. Serum TXB2 measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.https://doi.org/10.1111/cts.13415 |
| spellingShingle | Giovanna Petrucci Alberto Giaretta Paola Ranalli Viviana Cavalca Alfredo Dragani Benedetta Porro Duaa Hatem Aida Habib Elena Tremoli Carlo Patrono Bianca Rocca Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation Clinical and Translational Science |
| title | Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation |
| title_full | Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation |
| title_fullStr | Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation |
| title_full_unstemmed | Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation |
| title_short | Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation |
| title_sort | platelet thromboxane inhibition by low dose aspirin in polycythemia vera ex vivo and in vivo measurements and in silico simulation |
| url | https://doi.org/10.1111/cts.13415 |
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