{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:48:18Z","timestamp":1789202898048,"version":"build-2803163510"},"reference-count":122,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Therapeutic phlebotomy remains a key intervention in the management of erythrocytosis and iron overload disorders, particularly polycythemia vera (PV) and hereditary hemochromatosis. Despite its historical origins as an ancient practice, venesection continues to be recommended in international guidelines for the reduction of hematocrit and iron burden, thereby mitigating thrombotic and organ-related complications. However, the evolving landscape of targeted pharmacologic therapies is reshaping the therapeutic paradigm. This review examines the current role of therapeutic phlebotomy, with a particular focus on PV, outlining its physiological rationale, clinical benefits, and well-documented limitations\u2014including iron deficiency, procedural burden, and incomplete hematocrit control between sessions. Comparative insights are provided between phlebotomy and red cell apheresis, highlighting differences in efficacy, tolerability, and accessibility. The emergence of disease-modifying agents\u2014such as interferons, JAK inhibitors, hepcidin mimetics, and epigenetic modulators like givinostat and bomedemstat\u2014promises more sustained hematologic control with the potential to reduce or eliminate the need for repeated phlebotomies. While phlebotomy remains indispensable in early-stage or low-risk PV, its future utility will likely shift toward complementary or bridge therapy in the context of individualized, pharmacologically driven strategies, redefining the role of phlebotomy in the era of precision medicine.<\/jats:p>","DOI":"10.3390\/ph18081212","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T07:53:12Z","timestamp":1755503592000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Old Therapy, New Questions: Rethinking Phlebotomy in a Pharmacologic Landscape"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-4755","authenticated-orcid":false,"given":"Andrea","family":"Duminuco","sequence":"first","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5704-466X","authenticated-orcid":false,"given":"Patrick","family":"Harrington","sequence":"additional","affiliation":[{"name":"Department of Haematology, Guy\u2019s and St Thomas\u2019 NHS Foundation Trust, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4405-2716","authenticated-orcid":false,"given":"Vittorio","family":"Del Fabro","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, \u201cKore\u201d University of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Scalisi","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Santuccio","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Santisi","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Sbriglione","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7540-805X","authenticated-orcid":false,"given":"Bruno","family":"Garibaldi","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0868-5676","authenticated-orcid":false,"given":"Uros","family":"Markovic","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Raimondo","sequence":"additional","affiliation":[{"name":"Hematology Unit with BMT, A.O.U. Policlinico \u201cG. Rodolico-San Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1859-6319","authenticated-orcid":false,"given":"Giuseppe Alberto","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2714-5109","authenticated-orcid":false,"given":"Novella","family":"Pugliese","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, Hematology Section, University of Naples \u201cFederico II\u201d, Via Sergio Pansini, 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1922-5157","authenticated-orcid":false,"given":"Calogero","family":"Vetro","sequence":"additional","affiliation":[{"name":"Hematology and Bone Marrow Transplantation Unit (BMTU), Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), 39100 Bolzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/NAN.0b013e3181d00010","article-title":"Therapeutic Phlebotomy: A Review of Diagnoses and Treatment Considerations","volume":"33","author":"Cook","year":"2010","journal-title":"J. Infus. Nurs."},{"key":"ref_2","first-page":"2683","article-title":"Clinical Advantages of Phlebotomy: An Umbrella Review of Meta-Analyses","volume":"53","author":"Khatami","year":"2024","journal-title":"Iran J. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2147\/JBM.S108479","article-title":"Clinical Applications of Therapeutic Phlebotomy","volume":"7","author":"Kim","year":"2016","journal-title":"J. Blood Med."},{"key":"ref_4","first-page":"1831","article-title":"Phlebotomy","volume":"143","author":"Srikanth","year":"2023","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s12185-024-03868-z","article-title":"Iron Deficiency and Phlebotomy in Patients with Polycythemia Vera","volume":"121","author":"Edahiro","year":"2025","journal-title":"Int. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.clml.2023.11.004","article-title":"SOHO State of the Art Update and Next Questions: Novel Therapies for Polycythemia Vera","volume":"24","author":"Masarova","year":"2024","journal-title":"Clin. Lymphoma Myeloma Leuk"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1177\/0267659113505637","article-title":"Cardiovascular Benefits of Phlebotomy: Relationship to Changes in Hemorheological Variables","volume":"29","author":"Holsworth","year":"2014","journal-title":"Perfusion"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"58359","DOI":"10.12775\/JEHS.2025.80.58359","article-title":"Hereditary Hemochromatosis: Pathogenesis, Symptoms, Diagnosis and Current Treatment\u2014Literature Review","volume":"80","author":"Rulewska","year":"2025","journal-title":"J. Educ. Health Sport"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/ajh.27002","article-title":"Polycythemia Vera: 2024 Update on Diagnosis, Risk-Stratification, and Management","volume":"98","author":"Tefferi","year":"2023","journal-title":"Am. J. Hematol."},{"key":"ref_10","first-page":"e3925","article-title":"Association between Blood Viscosity and Cardiovascular Risk Factors in Patients with Arterial Hypertension in a High Altitude Setting","volume":"11","author":"Barrera","year":"2019","journal-title":"Cureus"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Milone, G., Bellofiore, C., Leotta, S., Milone, G.A., Cupri, A., Duminuco, A., Garibaldi, B., and Palumbo, G. (2022). Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology. J. Clin. Med., 11.","DOI":"10.3390\/jcm11030623"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12933-023-02097-8","article-title":"Mechanisms of Endothelial Activation, Hypercoagulation and Thrombosis in COVID-19: A Link with Diabetes Mellitus","volume":"23","author":"Valencia","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1111\/imj.16188","article-title":"Diagnosis and Management of Endothelial Disorders Following Haematopoietic Stem Cell Transplantation","volume":"53","author":"McEwan","year":"2023","journal-title":"Intern. Med. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1056\/NEJMoa065202","article-title":"JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis","volume":"356","author":"Scott","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1056\/NEJMc051878","article-title":"JAK2 Mutations in Myeloproliferative Disorders","volume":"353","author":"Inokuchi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1182\/blood-2006-12-064287","article-title":"Clinical Profile of Homozygous JAK2 617V>F Mutation in Patients with Polycythemia Vera or Essential Thrombocythemia","volume":"110","author":"Vannucchi","year":"2007","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1056\/NEJMoa1208500","article-title":"Cardiovascular Events and Intensity of Treatment in Polycythemia Vera","volume":"368","author":"Marchioli","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rishi, G., and Subramaniam, V.N. (2017). The Relationship between Systemic Iron Homeostasis and Erythropoiesis. Biosci. Rep., 37.","DOI":"10.1042\/BSR20170195"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1179\/135100002125000596","article-title":"Iron and Carcinogenesis: From Fenton Reaction to Target Genes","volume":"7","author":"Toyokuni","year":"2002","journal-title":"Redox Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/CRD.0000000000000622","article-title":"Cardiovascular Manifestations of Hemochromatosis: A Review of Pathophysiology, Mechanisms, and Treatment Options","volume":"33","author":"Ahmed","year":"2025","journal-title":"Cardiol. Rev."},{"key":"ref_21","first-page":"2135","article-title":"Hemochromatosis","volume":"Volume 2","author":"Porter","year":"2024","journal-title":"Firestein & Kelley\u2019s Textbook of Rheumatology, 2-Volume Set"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41392-024-01969-z","article-title":"Iron Homeostasis and Ferroptosis in Human Diseases: Mechanisms and Therapeutic Prospects","volume":"9","author":"Ru","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/1096-8652(200011)65:3<223::AID-AJH8>3.0.CO;2-9","article-title":"Iron Deficiency Due to Excessive Therapeutic Phlebotomy Hemochromatosis","volume":"65","author":"Barton","year":"2000","journal-title":"Am. J. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1182\/blood.V20.2.173.173","article-title":"The Natural History of Iron Deficiency Induced by Phlebotomy","volume":"20","author":"Conrad","year":"1962","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1182\/asheducation-2011.1.538","article-title":"The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders","volume":"2011","author":"Ganz","year":"2011","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13045-021-01157-4","article-title":"Momelotinib: An Emerging Treatment for Myelofibrosis Patients with Anemia","volume":"15","author":"Chifotides","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1097\/MOH.0000000000000747","article-title":"Hepcidin Mimetics in Polycythemia Vera: Resolving the Irony of Iron Deficiency and Erythrocytosis","volume":"30","author":"Handa","year":"2023","journal-title":"Curr. Opin. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1111\/bjh.17252","article-title":"Physiological and Pathophysiological Mechanisms of Hepcidin Regulation: Clinical Implications for Iron Disorders","volume":"193","author":"Xu","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.tips.2021.05.001","article-title":"Iron Metabolism: Pathophysiology and Pharmacology","volume":"42","author":"Roemhild","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.3324\/haematol.2018.215582","article-title":"Masked Polycythemia Vera: Analysis of a Single Center Cohort of 2480 Red Cell Masses","volume":"105","author":"Maslah","year":"2020","journal-title":"Haematologica"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1056\/NEJMoa2308809","article-title":"Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera","volume":"390","author":"Kremyanskaya","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s11899-022-00670-8","article-title":"Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia","volume":"17","author":"Krecak","year":"2022","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.23736\/S1593-232X.18.00408-3","article-title":"Adverse Complications of Venipuncture: A Systematic Review","volume":"19","author":"Serra","year":"2018","journal-title":"ACTA Phlebol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Novello, G., Mauro, E., Scalisi, E., Del Fabro, V., Sambataro, D., Palumbo, G., Di Raimondo, F., and Romeo, D. (2025). Chemotherapy Extravasation: Diagnosis, Prevention and Management. J. Chemother., 1\u201313.","DOI":"10.1080\/1120009X.2025.2488599"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1111\/trf.17862","article-title":"Adverse Effects of Therapeutic Phlebotomies: Prospective Study of 587 Procedures","volume":"64","author":"Calzada","year":"2024","journal-title":"Transfusion"},{"key":"ref_36","first-page":"132","article-title":"Therapeutic Recommendations in Polycythemia Vera Based on Polycythemia Vera Study Group Protocols","volume":"23","author":"Berk","year":"1986","journal-title":"Semin. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3324\/haematol.2016.152769","article-title":"Risk of Thrombosis According to Need of Phlebotomies in Patients with Polycythemia Vera Treated with Hydroxyurea","volume":"102","author":"Magro","year":"2017","journal-title":"Haematologica"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.3324\/haematol.2017.165126","article-title":"No Correlation of Intensity of Phlebotomy Regimen with Risk of Thrombosis in Polycythemia Vera: Evidence from European Collaboration on Low-Dose Aspirin in Polycythemia Vera and Cytoreductive Therapy in Polycythemia Vera Clinical Trials","volume":"102","author":"Barbui","year":"2017","journal-title":"Haematologica"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1159\/000504144","article-title":"Red Blood Cells: Exchange, Transfuse, or Deplete","volume":"46","author":"Stussi","year":"2019","journal-title":"Transfus. Med. Hemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/voxs.12397","article-title":"Red Cell Apheresis: Pros and Cons","volume":"13","author":"Infanti","year":"2018","journal-title":"ISBT Sci. Ser."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.transci.2013.01.011","article-title":"A Clinical Analysis of Erythrocytapheresis for the Treatment of Polycythemia","volume":"48","author":"Liu","year":"2013","journal-title":"Transfusion. Apher. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.htct.2023.07.003","article-title":"Evaluation of Erythrocytapheresis Compared to Phlebotomy in Polycythaemia Vera Patients","volume":"46","author":"Cabibbo","year":"2024","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/jca.22043","article-title":"Guidelines on the Use of Therapeutic Apheresis in Clinical Practice\u2013Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue","volume":"38","author":"Alquist","year":"2023","journal-title":"J. Clin. Apher."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1001\/jama.2024.20377","article-title":"Diagnosis and Treatment of Polycythemia Vera: A Review","volume":"333","author":"Tremblay","year":"2025","journal-title":"JAMA"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Nardo, A., Giuffrida, G., Leotta, S., Markovic, U., Giallongo, C., Tibullo, D., Romano, A., Di Raimondo, F., and Palumbo, G.A. (2023). Myelofibrosis and Survival Prognostic Models: A Journey between Past and Future. J. Clin. Med., 12.","DOI":"10.3390\/jcm12062188"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1002\/cncr.35156","article-title":"Incidence of Blast Phase in Myelofibrosis Patients According to Anemia Severity at Ruxolitinib Start and during Therapy","volume":"130","author":"Palandri","year":"2024","journal-title":"Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.beha.2014.07.003","article-title":"Leukemic Transformation in Myeloproliferative Neoplasms: Therapy-Related or Unrelated?","volume":"27","author":"Hultcrantz","year":"2014","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41408-023-00878-8","article-title":"Blast Phase Myeloproliferative Neoplasm: Contemporary Review and 2024 Treatment Algorithm","volume":"13","author":"Tefferi","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100081","DOI":"10.1016\/j.tru.2021.100081","article-title":"Thrombosis in Myeloproliferative Neoplasms: A Clinical and Pathophysiological Perspective","volume":"5","author":"Kelliher","year":"2021","journal-title":"Thromb. Update"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e12657","DOI":"10.1002\/rth2.12657","article-title":"Thrombosis in Myeloproliferative Neoplasms during Cytoreductive and Antithrombotic Drug Treatment","volume":"6","author":"Barbui","year":"2022","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating Morphologic, Clinical, and Genomic Data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.1182\/blood-2011-02-339002","article-title":"Risk Factors for Arterial and Venous Thrombosis in WHO-Defined Essential Thrombocythemia: An International Study of 891 Patients","volume":"117","author":"Carobbio","year":"2011","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1200\/JCO.2005.07.062","article-title":"Vascular and Neoplastic Risk in a Large Cohort of Patients with Polycythemia Vera","volume":"23","author":"Marchioli","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5370","DOI":"10.1182\/blood-2019-121386","article-title":"REVEAL: Characteristics of Patients with Polycythemia Vera Who Were Diagnosed within 6 Months of Enrollment","volume":"134","author":"Gerds","year":"2019","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Masselli, E., Pozzi, G., Gobbi, G., Merighi, S., Gessi, S., Vitale, M., and Carubbi, C. (2020). Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants. Cells, 9.","DOI":"10.3390\/cells9092136"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jaccao.2022.04.002","article-title":"Cardiovascular Disease in Myeloproliferative Neoplasms: JACC: CardioOncology State-of-the-Art Review","volume":"4","author":"Leiva","year":"2022","journal-title":"JACC CardioOncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2018.02.006","article-title":"The Morphological and Molecular Mechanisms of Epithelial\/Endothelial-to-Mesenchymal Transition and Its Involvement in Atherosclerosis","volume":"106","author":"Wesseling","year":"2018","journal-title":"Vasc. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/ajh.23409","article-title":"The Expression of Lysyl-Oxidase Gene Family Members in Myeloproliferative Neoplasms","volume":"88","author":"Tadmor","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil Extracellular Traps Kill Bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/bjh.15647","article-title":"A Guideline for the Management of Specific Situations in Polycythaemia Vera and Secondary Erythrocytosis: A British Society for Haematology Guideline","volume":"184","author":"McMullin","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1002\/cam4.2886","article-title":"Thrombosis among 1537 Patients with JAK2V617F-Mutated Myeloproliferative Neoplasms: Risk Factors and Development of a Predictive Model","volume":"9","author":"Zhang","year":"2020","journal-title":"Cancer Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1002\/hem3.143","article-title":"Development of a Natural Language Processing Pipeline for Assessment of Cardiovascular Risk in Myeloproliferative Neoplasms","volume":"8","author":"Duminuco","year":"2024","journal-title":"Hemasphere"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/ajh.24293","article-title":"Validation of the Revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-Thrombosis) in 585 Mayo Clinic Patients","volume":"91","author":"Haider","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Vaghela, R., Virdee, S., Woodley, C., Asirvatham, S., Curto-Garcia, N., Sriskandarajah, P., O\u2019Sullivan, J., de Lavallade, H., and Radia, D. (2025). QRISK3 Score Is Predictive of Thrombotic Risk in Patients with Myeloproliferative Neoplasms. Leukemia.","DOI":"10.1038\/s41375-025-02681-9"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1038\/s41375-021-01401-3","article-title":"Polycythemia Vera: Historical Oversights, Diagnostic Details, and Therapeutic Views","volume":"35","author":"Tefferi","year":"2021","journal-title":"Leukemia"},{"key":"ref_67","first-page":"172","article-title":"Adverse Effects of Antiaggregating Platelet Therapy in the Treatment of Polycythemia Vera","volume":"23","author":"Tartaglia","year":"1986","journal-title":"Semin. Hematol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1056\/NEJMoa035572","article-title":"Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera","volume":"350","author":"Landolfi","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e017559","DOI":"10.1161\/JAHA.120.017559","article-title":"Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges","volume":"9","author":"Chen","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1056\/NEJMoa1711948","article-title":"Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism","volume":"378","author":"Raskob","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1038\/s41375-021-01279-1","article-title":"Direct Oral Anticoagulants for Myeloproliferative Neoplasms: Results from an International Study on 442 Patients","volume":"35","author":"Barbui","year":"2021","journal-title":"Leukemia"},{"key":"ref_72","first-page":"17","article-title":"From Efficacy to Safety: A Polycythemia Vera Study Group Report on Hydroxyurea in Patients with Polycythemia Vera: Polycythemia Vera","volume":"34","author":"Fruchtman","year":"1997","journal-title":"Semin. Hematol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/ajh.24851","article-title":"A Reappraisal of the Benefit-Risk Profile of Hydroxyurea in Polycythemia Vera: A Propensity-Matched Study","volume":"92","author":"Barbui","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3907","DOI":"10.1200\/JCO.2011.36.0792","article-title":"Treatment of Polycythemia Vera with Hydroxyurea and Pipobroman: Final Results of a Randomized Trial Initiated in 1980","volume":"29","author":"Kiladjian","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1182\/blood-2008-09-176818","article-title":"Response Criteria for Essential Thrombocythemia and Polycythemia Vera: Result of a European LeukemiaNet Consensus Conference","volume":"113","author":"Barosi","year":"2009","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/ajh.21699","article-title":"The Risks and Benefits of Long-Term Use of Hydroxyurea in Sickle Cell Anemia: A 17.5 Year Follow-Up","volume":"85","author":"Steinberg","year":"2010","journal-title":"Am. J. Hematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/leu.2015.326","article-title":"Interferon-Alpha for the Therapy of Myeloproliferative Neoplasms: Targeting the Malignant Clone","volume":"30","author":"Kiladjian","year":"2015","journal-title":"Leukemia"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1182\/blood.2021012743","article-title":"A Randomized Phase 3 Trial of Interferon-\u03b1 vs Hydroxyurea in Polycythemia Vera and Essential Thrombocythemia","volume":"139","author":"Mascarenhas","year":"2022","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e196","DOI":"10.1016\/S2352-3026(19)30236-4","article-title":"Ropeginterferon Alfa-2b versus Standard Therapy for Polycythaemia Vera (PROUD-PV and CONTINUATION-PV): A Randomised, Non-Inferiority, Phase 3 Trial and Its Extension Study","volume":"7","author":"Gisslinger","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s11899-023-00702-x","article-title":"A Journey Through JAK Inhibitors for the Treatment of Myeloproliferative Diseases","volume":"18","author":"Duminuco","year":"2023","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1056\/NEJMoa1409002","article-title":"Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera","volume":"372","author":"Vannucchi","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1470-2045(16)30558-7","article-title":"Ruxolitinib for the Treatment of Inadequately Controlled Polycythaemia Vera without Splenomegaly (RESPONSE-2): A Randomised, Open-Label, Phase 3b Study","volume":"18","author":"Passamonti","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1200\/JCO.22.01935","article-title":"Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial","volume":"41","author":"Harrison","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Scarso, S., Cupri, A., Parrinello, N.L., Villari, L., Scuderi, G., Giunta, G., Leotta, S., Milone, G.A., and Giuffrida, G. (2023). Leishmania Infection during Ruxolitinib Treatment: The Cytokines-Based Immune Response in the Setting of Immunocompromised Patients. J. Clin. Med., 12.","DOI":"10.3390\/jcm12020578"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Palumbo, G.A., Cambria, D., La Spina, E., Duminuco, A., Laneri, A., Longo, A., Vetro, C., Giallongo, S., Romano, A., and Di Raimondo, F. (2023). Ruxolitinib Treatment in Myelofibrosis and Polycythemia Vera Causes Suboptimal Humoral Immune Response Following Standard and Booster Vaccination with BNT162b2 MRNA COVID-19 Vaccine. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1117815"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/cncr.35005","article-title":"Efficacy and Safety of Tixagevimab-Cilgavimab versus SARS-CoV-2 Breakthrough Infection in the Hematological Conditions","volume":"130","author":"Duminuco","year":"2024","journal-title":"Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Elli, E.M., Barat\u00e8, C., Mendicino, F., Palandri, F., and Palumbo, G.A. (2019). Mechanisms Underlying the Anti-Inflammatory and Immunosuppressive Activity of Ruxolitinib. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01186"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jaad.2021.10.004","article-title":"A 10-Year Retrospective Cohort Study of Ruxolitinib and Association with Nonmelanoma Skin Cancer in Patients with Polycythemia Vera and Myelofibrosis","volume":"86","author":"Lin","year":"2022","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/ajh.24976","article-title":"Ruxolitinib-Associated Infections: A Systematic Review and Meta-Analysis","volume":"93","author":"Lussana","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1080\/23744235.2017.1390248","article-title":"Infectious Complications in Patients on Treatment with Ruxolitinib: Case Report and Review of the Literature","volume":"50","author":"Dioverti","year":"2018","journal-title":"Infect. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.clml.2014.12.008","article-title":"Effects of Ruxolitinib Treatment on Metabolic and Nutritional Parameters in Patients with Myelofibrosis from COMFORT-I","volume":"15","author":"Mesa","year":"2015","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"107719","DOI":"10.1016\/j.leukres.2025.107719","article-title":"Treatment Strategies and Survival after Ruxolitinib Discontinuation in Myelofibrosis Patients: The Italian RUX-MF Multicenter Study","volume":"154","author":"Palandri","year":"2025","journal-title":"Leuk. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.clml.2017.08.016","article-title":"Management of Post ET\/PV MF: Different from Primary MF","volume":"17","author":"Passamonti","year":"2017","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Chifotides, H.T., Giallongo, S., Giallongo, C., Tibullo, D., and Palumbo, G.A. (2023). ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. Cancers, 16.","DOI":"10.3390\/cancers16010154"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s11899-025-00751-4","article-title":"Emerging Therapeutic Approaches for Anemia in Myelofibrosis","volume":"20","author":"Chifotides","year":"2025","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1080\/14656566.2023.2228695","article-title":"The Pharmacotherapeutic Management of Patients with Myelofibrosis: Looking beyond JAK Inhibitors","volume":"24","author":"Duminuco","year":"2023","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Duminuco, A., Del Fabro, V., De Luca, P., Leotta, D., Limoli, M.C., Longo, E., Nardo, A., Santuccio, G., Petronaci, A., and Stanzione, G. (2024). Emergencies in Hematology: Why, When and How I Treat?. J. Clin. Med., 13.","DOI":"10.3390\/jcm13247572"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e3259","DOI":"10.1002\/hon.3259","article-title":"Occurrence of Lymphoproliferative Disorders during Ruxolitinib Treatment: May Fedratinib Be the Turning Point?","volume":"42","author":"Duminuco","year":"2024","journal-title":"Hematol. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.clml.2024.04.003","article-title":"Contemporary Challenges in Polycythemia Vera Management From the Perspective of Patients and Physicians","volume":"24","author":"Kuykendall","year":"2024","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev-nutr-071715-050731","article-title":"Regulation of Hepcidin by Erythropoiesis: The Story so Far","volume":"36","author":"Pasricha","year":"2016","journal-title":"Annu. Rev. Nutr."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1038\/s41375-018-0207-9","article-title":"Dysregulated Iron Metabolism in Polycythemia Vera: Etiology and Consequences","volume":"32","author":"Ginzburg","year":"2018","journal-title":"Leukemia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1182\/blood-2024-197985","article-title":"Final Results from the Phase 2 Revive Study Investigating the Hepcidin Mimetic Rusfertide in Patients with Polycythemia Vera (PV)","volume":"144","author":"Gerds","year":"2024","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"840","DOI":"10.3324\/haematol.2008.001867","article-title":"Matriptase-2 (TMPRSS6): A Proteolytic Regulator of Iron Homeostasis","volume":"94","author":"Ramsay","year":"2009","journal-title":"Haematologica"},{"key":"ref_104","unstructured":"Carden, M. (2025, July 20). Single- and Multiple-Ascending Doses of Disc-3405, A Recombinant Humanized Antibody Targeting Tmprss6, Increased Hepcidin and Reduced Iron and Hematocrit in Healthy Volunteers. EHA-1724. 14 June 2025. Available online: https:\/\/library.ehaweb.org\/eha\/2025\/eha2025-congress\/4161281\/marcus.carden.single-.and.multiple-ascending.doses.of.disc-3405.a.recombinant.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Atopic%3D1574%2Asearch%3Dconcept."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.cmet.2008.09.012","article-title":"The Serine Protease Matriptase-2 (TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin","volume":"8","author":"Silvestri","year":"2008","journal-title":"Cell Metab."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2582","DOI":"10.3324\/haematol.2023.283057","article-title":"Novel Potential Therapeutics to Modify Iron Metabolism and Red Cell Synthesis in Diseases Associated with Defective Erythropoiesis","volume":"108","author":"Guerra","year":"2023","journal-title":"Haematologica"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1080\/13543784.2023.2267980","article-title":"Bomedemstat as an Investigative Treatment for Myeloproliferative Neoplasms","volume":"32","author":"Rienhoff","year":"2023","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Gill, H. (2022). Lysine-Specific Demethylase 1 (LSD1\/KDM1A) Inhibition as a Target for Disease Modification in Myelofibrosis. Cells, 11.","DOI":"10.3390\/cells11132107"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1080\/13543784.2020.1761323","article-title":"Givinostat: An Emerging Treatment for Polycythemia Vera","volume":"29","author":"Chifotides","year":"2020","journal-title":"Expert Opin. Investig. Drugs."},{"key":"ref_110","unstructured":"Amaru Calzada, A. (2025). Mechanism of Action of Histone Deacetylase Inhibitor. Givinostat in Chronic Myeloproliferative Neoplasm. [Ph.D. Thesis, University of Milano-Bicocca]."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1182\/blood-2004-09-3426","article-title":"Acute Leukemia in Polycythemia Vera: An Analysis of 1638 Patients Enrolled in a Prospective Observational Study","volume":"105","author":"Finazzi","year":"2005","journal-title":"Blood"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Ahmed, A.U., Williams, B.R.G., and Hannigan, G.E. (2015). Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity. Biomolecules, 5.","DOI":"10.3390\/biom5043087"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/bjh.12332","article-title":"A Phase II Study of Givinostat in Combination with Hydroxycarbamide in Patients with Polycythaemia Vera Unresponsive to Hydroxycarbamide Monotherapy","volume":"161","author":"Finazzi","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_114","first-page":"s75","article-title":"Current Applications of Therapeutic Phlebotomy","volume":"12","author":"Assi","year":"2014","journal-title":"Blood Transfus."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.blre.2012.06.002","article-title":"Front-Line Therapy in Polycythemia Vera and Essential Thrombocythemia","volume":"26","author":"Barbui","year":"2012","journal-title":"Blood Rev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1001\/jama.1976.03270190036025","article-title":"Hazards of Phlebotomy in Polycythemic Patients With Cardiovascular Disease","volume":"236","author":"Kiraly","year":"1976","journal-title":"JAMA"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1136\/hrt.79.4.315","article-title":"Management of Polycythaemia in Adults with Cyanotic Congenital Heart Disease","volume":"79","author":"Thorne","year":"1998","journal-title":"Heart"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/ejh.12381","article-title":"Target Hematologic Values in the Management of Essential Thrombocythemia and Polycythemia Vera","volume":"94","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_119","unstructured":"Anastasi, J., and Vardiman, J.W. (2014). Myeloproliferative Neoplasms. Knowles\u2019 Neoplastic Hematopathology, Lippincott Williams & Wilkins. [3rd ed.]."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1200\/JCO.2015.62.9337","article-title":"Symptomatic Profiles of Patients with Polycythemia Vera: Implications of Inadequately Controlled Disease","volume":"34","author":"Geyer","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1038\/s41375-018-0199-5","article-title":"Evidence- and Consensus-Based Recommendations for Phlebotomy in Polycythemia Vera","volume":"32","author":"Barbui","year":"2018","journal-title":"Leukemia"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1182\/blood.2023022418","article-title":"How I Treat Patients with Low-Risk Polycythemia Vera Who Require Cytoreduction","volume":"145","author":"McMullin","year":"2025","journal-title":"Blood"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:29:12Z","timestamp":1760034552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,16]]},"references-count":122,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ph18081212"],"URL":"https:\/\/doi.org\/10.3390\/ph18081212","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,16]]}}}