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MDS is characterized by a variable degree of clonal cytopenia. Compared to anemia, thrombocytopenia is less common but presents more significant challenges due to high risk of acute complications and dearth effective treatment options. Platelet transfusions are effective in increasing platelet counts but provide limited and transient benefits, along with associated risks of transfusions. Anti-fibrinolytic drugs have been attempted including in clinical trial settings but its efficacy remains unproven. Successful development of thrombopoietin agonists appeared promising especially in other conditions associated with thrombocytopenia but its utility in MDS has been controversial. Two of the novel thrombopoietin receptor agonists (TPO-RA), romiplostim and eltrombopag have established clinical activity in immune thrombocytopenic purpura (ITP) and have been explored for the treatment of thrombocytopenia in MDS. Due to early research data showing TPO-RA leading to a small increase in blast counts and possibly promoting leukemic transformation, subsequent clinical trials sought to establish its safety and efficacy in MDS. Despite considerable amount of evidence demonstrating favorable safety profiles in lower risk MDS, many hematologists are often hesitant to use TPO-RA to treat thrombocytopenia in MDS due to theoretical concern of stimulating blasts. In higher risk MDS the safety is not proven and certainly requires more investigation. In this review, we aim to highlight pathophysiology of thrombocytopenia in MDS and provide comprehensive management strategies supported by past and current clinical research data.<\/jats:p>","DOI":"10.1007\/s00277-025-06374-2","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T01:33:49Z","timestamp":1757640829000},"page":"4319-4332","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["An unconquered challenge in MDS: review of pathophysiology, clinical manifestations, and management options of MDS with thrombocytopenia"],"prefix":"10.1007","volume":"104","author":[{"given":"Xiaoyi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihir","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun H.","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"6374_CR1","doi-asserted-by":"publisher","unstructured":"Khoury JD, Solary E, Abla O et al (2022) The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms. 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