Dose-dependent effects of eltrombopag iron chelation on platelet formation
Abstract: Iron deficiency is associated with thrombocytosis in patients, although thrombocytopenia can occur in cases of severe iron deficiency anemia. Eltrombopag (EP), a thrombopoietic agent approved for immune thrombocytopenia, also acts as an iron chelator. Our study demonstrates that megakaryoc...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Blood Vessels, Thrombosis & Hemostasis |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950327225000178 |
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| author | Elisabetta Bassi Vittorio Abbonante Alicia Aguilar Hana Raslova James B. Bussel Christian Andrea Di Buduo Alessandro Malara Alessandra Balduini |
| author_facet | Elisabetta Bassi Vittorio Abbonante Alicia Aguilar Hana Raslova James B. Bussel Christian Andrea Di Buduo Alessandro Malara Alessandra Balduini |
| author_sort | Elisabetta Bassi |
| collection | DOAJ |
| description | Abstract: Iron deficiency is associated with thrombocytosis in patients, although thrombocytopenia can occur in cases of severe iron deficiency anemia. Eltrombopag (EP), a thrombopoietic agent approved for immune thrombocytopenia, also acts as an iron chelator. Our study demonstrates that megakaryocytes (MKs) exhibit an increased requirement for iron as they mature and acquire the ability to form proplatelets and release platelets. Although low EP concentrations maintain MK functions, high EP concentrations disrupt iron homeostasis, reducing proplatelet formation. Mechanistically, EP-dependent iron chelation impairs MK cytoskeletal dynamics, induces higher extracellular signal–regulated kinase 1/2 (ERK1/2) signaling, and reduces posttranslational glutathionylation of tubulin protein. Addition of exogenous iron or oxidized glutathione to high-dose EP-treated MKs counteracts the negative effect on iron status and ERK1/2 signaling, thereby rescuing proplatelet formation. Overall, these data reveal the complex role of iron status on MK cytoskeletal dynamics and platelet biogenesis and may explain the varied clinical manifestations of iron deficiency on platelet counts. |
| format | Article |
| id | doaj-art-d2a77efa11254a82a836ca2c7bcba054 |
| institution | OA Journals |
| issn | 2950-3272 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Vessels, Thrombosis & Hemostasis |
| spelling | doaj-art-d2a77efa11254a82a836ca2c7bcba0542025-08-20T02:28:00ZengElsevierBlood Vessels, Thrombosis & Hemostasis2950-32722025-05-012210006010.1016/j.bvth.2025.100060Dose-dependent effects of eltrombopag iron chelation on platelet formationElisabetta Bassi0Vittorio Abbonante1Alicia Aguilar2Hana Raslova3James B. Bussel4Christian Andrea Di Buduo5Alessandro Malara6Alessandra Balduini7Department of Molecular Medicine, University of Pavia, Pavia, ItalyDepartment of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, ItalyDepartment of Molecular Medicine, University of Pavia, Pavia, ItalyINSERM, Unité Mixte de Recherche 1287, Gustave Roussy, Université Paris Saclay, Villejuif, FranceDepartment of Pediatrics, Weill Cornell Medicine, New York, NYDepartment of Molecular Medicine, University of Pavia, Pavia, ItalyDepartment of Molecular Medicine, University of Pavia, Pavia, ItalyDepartment of Molecular Medicine, University of Pavia, Pavia, Italy; Correspondence: Alessandra Balduini, Department of Molecular Medicine, University of Pavia, Campus della Salute, Via Golgi 19, 27100 Pavia, Italy;Abstract: Iron deficiency is associated with thrombocytosis in patients, although thrombocytopenia can occur in cases of severe iron deficiency anemia. Eltrombopag (EP), a thrombopoietic agent approved for immune thrombocytopenia, also acts as an iron chelator. Our study demonstrates that megakaryocytes (MKs) exhibit an increased requirement for iron as they mature and acquire the ability to form proplatelets and release platelets. Although low EP concentrations maintain MK functions, high EP concentrations disrupt iron homeostasis, reducing proplatelet formation. Mechanistically, EP-dependent iron chelation impairs MK cytoskeletal dynamics, induces higher extracellular signal–regulated kinase 1/2 (ERK1/2) signaling, and reduces posttranslational glutathionylation of tubulin protein. Addition of exogenous iron or oxidized glutathione to high-dose EP-treated MKs counteracts the negative effect on iron status and ERK1/2 signaling, thereby rescuing proplatelet formation. Overall, these data reveal the complex role of iron status on MK cytoskeletal dynamics and platelet biogenesis and may explain the varied clinical manifestations of iron deficiency on platelet counts.http://www.sciencedirect.com/science/article/pii/S2950327225000178 |
| spellingShingle | Elisabetta Bassi Vittorio Abbonante Alicia Aguilar Hana Raslova James B. Bussel Christian Andrea Di Buduo Alessandro Malara Alessandra Balduini Dose-dependent effects of eltrombopag iron chelation on platelet formation Blood Vessels, Thrombosis & Hemostasis |
| title | Dose-dependent effects of eltrombopag iron chelation on platelet formation |
| title_full | Dose-dependent effects of eltrombopag iron chelation on platelet formation |
| title_fullStr | Dose-dependent effects of eltrombopag iron chelation on platelet formation |
| title_full_unstemmed | Dose-dependent effects of eltrombopag iron chelation on platelet formation |
| title_short | Dose-dependent effects of eltrombopag iron chelation on platelet formation |
| title_sort | dose dependent effects of eltrombopag iron chelation on platelet formation |
| url | http://www.sciencedirect.com/science/article/pii/S2950327225000178 |
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