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The published literature we review appears to answer this question in the affirmative: basic science considerations, animal model experiments, and noncontrolled clinical observations all suggest a therapeutic potential of iron restriction in SCD. This is because SCD's clinical manifestations are ultimately attributable to the polymerization of hemoglobin S (HbS), a process strongly influenced by intracellular HbS concentration. Even small decrements in HbS concentration greatly reduce polymerization, and iron deficiency lowers erythrocyte hemoglobin concentration. Thus, iron deficiency could improve SCD by changing its clinical features to those of a more benign anemia (i.e., a condition with fewer or no vaso\u2010occlusive events). We propose that well\u2010designed clinical studies be implemented to definitively determine whether iron restriction is a safe and effective option in SCD. These investigations are particularly timely now that pharmacologic agents are being developed, which may directly reduce red cell hemoglobin concentrations without the need for phlebotomies to deplete total body iron.<\/jats:p>","DOI":"10.1002\/ajh.27267","type":"journal-article","created":{"date-parts":[[2024,2,24]],"date-time":"2024-02-24T07:25:04Z","timestamp":1708759504000},"page":"1349-1359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Iron restriction in sickle cell disease: When less is more"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3522-4568","authenticated-orcid":false,"given":"Oswaldo L.","family":"Castro","sequence":"first","affiliation":[{"name":"Center for Sickle Cell Disease Howard University  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7093-777X","authenticated-orcid":false,"given":"Lucia","family":"De Franceschi","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Verona and AOUI Verona  Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-5469","authenticated-orcid":false,"given":"Tomas","family":"Ganz","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7002-8891","authenticated-orcid":false,"given":"Julie","family":"Kanter","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology University of Alabama, Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-3217","authenticated-orcid":false,"given":"Gregory J.","family":"Kato","sequence":"additional","affiliation":[{"name":"Hematology Therapeutic Area, CSL Behring  King of Prussia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5502-0434","authenticated-orcid":false,"given":"Sant\u2010Rayn","family":"Pasricha","sequence":"additional","affiliation":[{"name":"Population Health and Immunity Division Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-6558","authenticated-orcid":false,"given":"Stefano","family":"Rivella","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; RNA Institute, University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"RNA Gene Therapeutics Group RNA Institute, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0996-3439","authenticated-orcid":false,"given":"John C.","family":"Wood","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics and Radiology Children's Hospital of Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.10"},{"key":"e_1_2_12_3_1","unstructured":"Institute for Health Metrics and Evaluation.Sickle cell disorders\u2014level 4 cause. 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