Dose-dependent effects of eltrombopag iron chelation on platelet formation

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-02-06 DOI:10.1016/j.bvth.2025.100060

Elisabetta Bassi , Vittorio Abbonante , Alicia Aguilar , Hana Raslova , James B. Bussel , Christian Andrea Di Buduo , Alessandro Malara , Alessandra Balduini

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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.

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铁螯合对血小板形成的剂量依赖性影响

actiron缺乏症与患者血小板增多有关，尽管严重缺铁性贫血患者也可能出现血小板减少症。Eltrombopag （EP）是一种被批准用于免疫性血小板减少症的血小板生成药物，也可作为铁螯合剂。我们的研究表明，巨核细胞（mk）对铁的需求随着它们的成熟而增加，并获得形成血小板和释放血小板的能力。虽然低EP浓度维持MK功能，但高EP浓度破坏铁稳态，减少血小板形成。在机制上，ep依赖性铁螯合损害MK细胞骨架动力学，诱导更高的细胞外信号调节激酶1/2 （ERK1/2）信号传导，并减少微管蛋白翻译后谷胱甘肽化。在高剂量ep处理的mk中加入外源性铁或氧化谷胱甘肽可抵消对铁状态和ERK1/2信号的负面影响，从而挽救血小板形成。总的来说，这些数据揭示了铁状态在MK细胞骨架动力学和血小板生物发生中的复杂作用，并可能解释铁缺乏对血小板计数的不同临床表现。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Vessels, Thrombosis & Hemostasis

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