Weatherall D. J. & Clegg J. B. The Thalassaemia Syndromes (Blackwell Science, 2001).Kato, G. J. et al. Sickle cell disease. Nat. Rev. Dis. Primers 4, 18010 (2018).Article PubMed Google Scholar Modell, B. & Darlison, M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull. World Health Organ. 86, 480–487 (2008).Article PubMed PubMed Central Google Scholar Weatherall, D. J. & Clegg, J. B. Inherited haemoglobin disorders: an increasing global health problem. Bull. World Health Organ. 79, 704–712 (2001).CAS PubMed PubMed Central Google Scholar Huisman T. H. J., Carver M. F. H. & Baysal E. A Syllabus of Thalassemia Mutations (The Sickle Cell Anemia Foundation, 1997).Schrier, S. L. et al. The unusual pathobiology of hemoglobin constant spring red blood cells. Blood 89, 1762–1769 (1997).Article CAS PubMed Google Scholar Fucharoen, S. & Viprakasit, V. Hb H disease: clinical course and disease modifiers. Hematology 2009, 26–34 (2009).Article Google Scholar Piel, F. B. & Weatherall, D. J. The α-thalassemias. N. Engl. J. Med. 371, 1908–1916 (2014).Article PubMed Google Scholar Leon, N. Y. & Harley, V. R. ATR-X syndrome: genetics, clinical spectrum, and management. Hum. Genet. 140, 1625–1634 (2021).Article PubMed Google Scholar Chui, D. H. K. & Waye, J. S. Hydrops fetalis caused by α-thalassemia: an emerging health care problem. Blood 91, 2213–2222 (1998).Article CAS PubMed Google Scholar Songdej, D., Babbs, C. & Higgs, D. R. An international registry of survivors with Hb Bart’s hydrops fetalis syndrome. Blood 129, 1251–1259 (2017).Article CAS PubMed PubMed Central Google Scholar Giardine, B. et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res. 42, D1063–D1069 (2014).Article CAS PubMed Google Scholar Taher, A. T., Musallam, K. M. & Cappellini, M. D. β-Thalassemias. N. Engl. J. Med. 384, 727–743 (2021).Article PubMed Google Scholar Thein, S. L. The molecular basis of β-thalassemia. Cold Spring Harb. Perspect. Med. 3, a011700 (2013).Article PubMed PubMed Central Google Scholar Harteveld, C. L. et al. The hemoglobinopathies, molecular disease mechanisms and diagnostics. Int. J. Lab. Hematol. 44, 28–36 (2022).Article PubMed PubMed Central Google Scholar Achour, A. et al. Moderate–severe beta-thalassemia intermedia phenotype caused by sextuplicated alpha-globin gene allele in two beta-thalassemia carriers. Am. J. Hematol. 99, 1655–1658 (2024).Article PubMed Google Scholar Modell, B. et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 10, 42 (2008).Article PubMed PubMed Central Google Scholar Farmakis, D. et al. 2021 Thalassaemia International Federation guidelines for the management of transfusion-dependent thalassemia. HemaSphere 6, e732 (2022).Article PubMed PubMed Central Google Scholar Musallam, K. M. et al. Revisiting the non-transfusion-dependent (NTDT) vs. transfusion-dependent (TDT) thalassemia classification 10 years later. Am. J. Hematol. 96, E54–E56 (2021).Article PubMed Google Scholar Musallam, K. M. et al. ‘Phenoconversion’ in adult patients with β-thalassemia. Am. J. Hematol. 99, 490–493 (2024).Article PubMed Google Scholar Flint, J. et al. High frequencies of α-thalassaemia are the result of natural selection by malaria. Nature 321, 744–750 (1986).Article CAS PubMed Google Scholar Williams, T. N. & Weatherall, D. J. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb. Perspect. Med. 2, a011692 (2012).Article PubMed PubMed Central Google Scholar Modiano, G. et al. Protection against malaria morbidity: near-fixation of the α-thalassemia gene in a Nepalese population. Am. J. Hum. Genet. 48, 390–397 (1991).CAS PubMed PubMed Central Google Scholar Kattamis, A., Forni, G. L., Aydinok, Y. & Viprakasit, V. Changing patterns in the epidemiology of β-thalassemia. Eur. J. Haematol. 105, 692–703 (2020).Article PubMed PubMed Central Google Scholar Gill, P. S. & Modell, B. Thalassaemia in Britain: a tale of two communities. Births are rising among British Asians falling in Cypriots. BMJ 317, 761–762 (1998).Article CAS PubMed PubMed Central Google Scholar Sayani, F. A. & Kwiatkowski, J. L. Increasing prevalence of thalassemia in America: implications for primary care. Ann. Med. 47, 592–604 (2015).Article PubMed Google Scholar Xu, J. Z. et al. Identification of optimal thalassemia screening strategies for migrant populations in Thailand using a qualitative approach. BMC Public Health 21, 1796 (2021).Article PubMed PubMed Central Google Scholar Martinez, P. A. et al. Haemoglobinopathies in Europe: health & migration policy perspectives. Orphanet J. Rare Dis. 9, 97 (2014).Article Google Scholar Paiboonsukwong, K., Yupin, J., Pranee, W. & Fucharoen, S. Thalassemia in Thailand. Hemoglobin 46, 53–57 (2022).Article CAS PubMed Google Scholar Rujito, L., Maritska, Z. & Sofro, A. S. β Thalassemia mutation flow in Indonesia: a migration perspective. Thalass. Rep. 13, 253–261 (2023).Article CAS Google Scholar Old, J. et al. New challenges in diagnosis of haemoglobinopathies: migration of populations. Thalass. Rep. 8, 7474 (2018).Article Google Scholar Tuo, Y. et al. Global, regional, and national burden of thalassemia, 1990–2021: a systematic analysis for the Global Burden of Disease study 2021. eClinicalMedicine 72, 102619 (2024).Article PubMed PubMed Central Google Scholar Gianesin, B. et al. Incorporating national disease burden in GBD estimates of haemoglobinopathies in Italy. Lancet Haematol. 12, e857–e859 (2025).Article CAS PubMed Google Scholar Musallam, K. M. et al. Epidemiology of clinically significant forms of alpha- and beta-thalassemia: a global map of evidence and gaps. Am. J. Hematol. 98, 1436–1451 (2023).Article PubMed Google Scholar Angastiniotis, M. A. & Hadjiminas, M. G. Prevention of thalassaemia in Cyprus. Lancet 317, 369–371 (1981).Article Google Scholar Samavat, A. & Modell, B. Iranian national thalassaemia screening programme. BMJ 329, 1134–1137 (2004).Article PubMed Central Google Scholar Thalassaemia International Federation. Global Thalassaemia Review 2025 https://thalassaemia.org.cy/what-we-do/global-thalassaemia-review/ (2026).Padilla, C. D. et al. Successful implementation of newborn screening for hemoglobin disorders in the Philippines. Int. J. Neonatal Screen. 7, 30 (2021).Article PubMed PubMed Central Google Scholar Colah, R., Gorakshakar, A. & Nadkarni, A. Global burden, distribution and prevention of β-thalassemias and hemoglobin E disorders. Expert Rev. Hematol. 3, 103–117 (2010).Article PubMed Google Scholar Gianesin, B. et al. Prevalence and mortality trends of hemoglobinopathies in Italy: a nationwide study. Haematologica 110, 1211–1216 (2025).Article PubMed PubMed Central Google Scholar Musallam, K. M. et al. Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia. Haematologica 106, 2489–2492 (2021).Article PubMed PubMed Central Google Scholar Pauling, L., Itano, H. A., Singer, S. J. & Wells, I. C. Sickle cell anemia, a molecular disease. Science 110, 543–548 (1949).Article CAS PubMed Google Scholar Weatherall, D. J. Thalassaemia: the long road from bedside to genome. Nat. Rev. Genet. 5, 625–631 (2004).Article CAS PubMed Google Scholar Nandakumar, S. K., Ulirsch, J. C. & Sankaran, V. G. Advances in understanding erythropoiesis: evolving perspectives. Br. J. Haematol. 173, 206–218 (2016).Article CAS PubMed PubMed Central Google Scholar Smith, E. & Shilatifard, A. Enhancer biology and enhanceropathies. Nat. Struct. Mol. Biol. 21, 210–219 (2014).Article CAS PubMed Google Scholar Gibbons, R. J., Picketts, D. J., Villard, L. & Higgs, D. R. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80, 837–845 (1995).Article CAS PubMed Google Scholar Harteveld, C. L. & Higgs, D. R. α-Thalassaemia. Orphanet J. Rare Dis. 5, 13 (2010).Article PubMed PubMed Central Google Scholar Mettananda, S., Gibbons, R. J. & Higgs, D. R. α-Globin as a molecular target in the treatment of β-thalassemia. Blood 125, 3694–3701 (2015).Article CAS PubMed PubMed Central Google Scholar Cheng, M.-l. et al. Antioxidant deficit and enhanced susceptibility to oxidative damage in individuals with different forms of α-thalassaemia. Br. J. Haematol. 128, 119–127 (2005).Article CAS PubMed Google Scholar Fibach, E. & Dana, M. Oxidative stress in β-thalassemia. Mol. Diagn. Ther. 23, 245–261 (2019).Article CAS PubMed Google Scholar Bou-Fakhredin, R., Cappellini, M. D., Taher, A. T. & De Franceschi, L. Hypercoagulability in hemoglobinopathies: decoding the thrombotic threat. Am. J. Hematol. 100, 103–115 (2025).Article CAS PubMed Google Scholar Castro-Mollo, M. et al. The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry. eLife 10, e68217 (2021).Article CAS PubMed PubMed Central Google Scholar Camaschella, C. & Nai, A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br. J. Haematol. 172, 512–523 (2016).Article CAS PubMed Google Scholar Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014).Article CAS PubMed PubMed Central Google Scholar Kautz, L. et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood 126, 2031–2037 (2015).Article CAS PubMed PubMed Central Google Scholar Olivera, J., Zhang, V., Nemeth, E. & Ganz, T. Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia. Blood Adv. 7, 3339–3349 (2023).Article CAS PubMed PubMed Central Google Scholar Arezes, J. et al. Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia. Blood 135, 547–557 (2020).Article PubMed PubMed Central Google Scholar Sardo, U. et al. The hepatokine FGL1 regulates hepcidin and iron metabolism during anemia in mice by antagonizing BMP signaling. Blood 143, 1282–1292 (2024).Article CAS PubMed PubMed Central Google Scholar Traeger-Synodinos, J. et al. EMQN best practice guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies. Eur. J. Hum. Genet. 23, 426–437 (2015).Article CAS PubMed Google Scholar Taher, A. T., Bou-Fakhredin, R., Kattamis, A., Viprakasit, V. & Cappellini, M. D. Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies. Expert Rev. Hematol. 14, 897–909 (2021).Article CAS PubMed Google Scholar Sharma, V., Kumar, B., Kumar, G. & Saxena, R. Alpha globin gene numbers: an important modifier of HbE/β thalassemia. Hematology 14, 297–300 (2009).Article CAS PubMed Google Scholar Hamid, M. et al. Alpha-globin gene triplication and its effect in beta-thalassemia carrier, sickle cell trait, and healthy individual. eJHaem 2, 366–374 (2021).Article CAS PubMed PubMed Central Google Scholar Fisher, C. A. et al. The molecular basis for the thalassaemias in Sri Lanka. Br. J. Haematol. 121, 662–671 (2003).Article CAS PubMed Google Scholar Thein, S. L. Genetic association studies in β-hemoglobinopathies. Hematology 2013, 354–361 (2013).Article PubMed Google Scholar Mandrile, G. et al. First and second level haemoglobinopathies diagnosis: best practices of the Italian society of thalassemia and haemoglobinopathies (SITE). J. Clin. Med. 11, 5426 (2022).Article CAS PubMed PubMed Central Google Scholar Munkongdee, T., Chen, P., Winichagoon, P., Fucharoen, S. & Paiboonsukwong, K. Update in laboratory diagnosis of thalassemia. Front. Mol. Biosci. 7, 74 (2020).Article CAS PubMed PubMed Central Google Scholar Tran, D. et al. Prevalence of thalassemia in the Vietnamese population and building a clinical decision support system for prenatal screening for thalassemia. Electron. J. Gen. Med. 20, em501 (2023).Article Google Scholar Ferih, K. et al. Applications of artificial intelligence in thalassemia: a comprehensive review. Diagnostics 13, 1551 (2023).Article CAS PubMed PubMed Central Google Scholar Therrell, B. L. Newborn screening for hemoglobin disorders. Clin. Perinatol. 52, 461–476 (2025).Article PubMed Google Scholar Quarmyne, M. O. et al. Newborn screening for sickle cell disease and thalassemia. JAMA Health Forum 6, e250064 (2025).Article PubMed Google Scholar Weil, L. G., Charlton, M. R., Coppinger, C., Daniel, Y. & Streetly, A. Sickle cell disease and thalassaemia antenatal screening programme in England over 10 years: a review from 2007/2008 to 2016/2017. J. Clin. Pathol. 73, 183–190 (2020).Article PubMed Google Scholar Angastiniotis, M. et al. The prevention of thalassemia revisited: a historical and ethical perspective by the Thalassemia International Federation. Hemoglobin 45, 5–12 (2021).Article CAS PubMed Google Scholar Petrou, M. Informed choice in a multicultural world. Thalass. Rep. 8, 7475 (2018).Article Google Scholar Noori, T. et al. International comparison of thalassemia registries: challenges and opportunities. Acta Inform. Med. 27, 58–63 (2019).Article PubMed PubMed Central Google Scholar Farmakis, D., Angastiniotis, M., El Ghoul, M. M., Cannon, L. & Eleftheriou, A. Thalassaemia registries: a call for action. a position statement from the Thalassaemia International Federation. Hemoglobin 46, 225–232 (2022).Article CAS PubMed Google Scholar Taher, A. T., Farmakis, D., Porter, J. B., Cappellini, M. D. & Musallam, K. M. (eds) Guidelines for the Management of Transfusion-Dependent β-Thalassaemia (TDT) 5th edn (Thalassaemia International Federation, 2025).Cazzola, M. et al. Relationship between transfusion regimen and suppression of erythropoiesis in β-thalassaemia major. Br. J. Haematol. 89, 473–478 (1995).Article CAS PubMed Google Scholar Musallam, K. M. et al. Pretransfusion hemoglobin level and mortality in adults with transfusion-dependent β-thalassemia. Blood 143, 930–932 (2024).Article CAS PubMed Google Scholar Viprakasit, V. et al. Geographical variations in current clinical practice on transfusions and iron chelation therapy across various transfusion-dependent anaemias. Blood Transfus. 11, 108–122 (2013).PubMed Google Scholar El-Beshlawy, A. et al. Management of transfusion-dependent β-thalassemia (TDT): expert insights and practical overview from the Middle East. Blood Rev. 63, 101138 (2024).Article CAS PubMed Google Scholar Tang, C. H. et al. Relationship between transfusion burden, healthcare resource utilization, and complications in patients with beta-thalassemia in Taiwan: a real-world analysis. Transfusion 61, 2906–2917 (2021).Article CAS PubMed PubMed Central Google Scholar Weiss, M., Parisi Jun, M. & Sheth, S. Clinical and economic burden of regularly transfused adult patients with β-thalassemia in the United States: a retrospective cohort study using payer claims. Am. J. Hematol. 94, E129–E132 (2019).Article PubMed Google Scholar Betts, M. et al. Systematic literature review of the burden of disease and treatment for transfusion-dependent β-thalassemia. Clin. Ther. 42, 322–337.e2 (2020).Article CAS PubMed Google Scholar Musallam, K. M. et al. Quantifying morbidity risk attributed to red-cell transfusion volume in optimally transfused patients with β-thalassemia. Am. J. Hematol. 101, 149–151 (2026).Article CAS PubMed Google Scholar Musallam, K. M., Rivella, S., Vichinsky, E. & Rachmilewitz, E. A. Non-transfusion-dependent thalassemias. Haematologica 98, 833–844 (2013).Article CAS PubMed PubMed Central Google Scholar Musallam, K. M. et al. Risk of mortality from anemia and iron overload in nontransfusion-dependent β-thalassemia. Am. J. Hematol. 97, E78–E80 (2022).Article PubMed Google Scholar Musallam, K. M., Cappellini, M. D., Daar, S. & Taher, A. T. Morbidity-free survival and hemoglobin level in non-transfusion-dependent β-thalassemia: a 10-year cohort study. Ann. Hematol. 101, 203–204 (2022).Article CAS PubMed Google Scholar Musallam, K. M., Cappellini, M. D. & Taher, A. T. Variations in hemoglobin level and morbidity burden in non-transfusion-dependent β-thalassemia. Ann. Hematol. 100, 1903–1905 (2021).Article CAS PubMed Google Scholar Taher, A. T. et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood 115, 1886–1892 (2010).Article CAS PubMed Google Scholar Taher, A., Musallam, K. & Cappellini, M. D. (eds) Guidelines for the Management of Non-Transfusion-Dependent β-Thalassaemia 3rd edn (Thalassaemia International Federation, 2023).Taher, A. T. et al. Splenectomy and thrombosis: the case of thalassemia intermedia. J. Thromb. Haemost. 8, 2152–2158 (2010).Article CAS PubMed Google Scholar Piga, A. et al. Changing patterns of splenectomy in transfusion-dependent thalassemia patients. Am. J. Hematol. 86, 808–810 (2011).Article PubMed Google Scholar Borgna-Pignatti, C. et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 89, 1187–1193 (2004).PubMed Google Scholar Angelucci, E. et al. Hepatic iron concentration and total body iron stores in thalassemia major. N. Engl. J. Med. 343, 327–331 (2000).Article CAS PubMed Google Scholar Viprakasit, V. et al. MRI for the diagnosis of cardiac and liver iron overload in patients with transfusion-dependent thalassemia: an algorithm to guide clinical use when availability is limited. Am. J. Hematol. 93, E135–E137 (2018).Article PubMed Google Scholar St Pierre, T. G. et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 105, 855–861 (2005).Article Google Scholar Carpenter, J. P. et al. On T2* magnetic resonance and cardiac iron. Circulation 123, 1519–1528 (2011).Article PubMed PubMed Central Google Scholar Wood, J. C. et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 106, 1460–1465 (2005).Article CAS PubMed PubMed Central Google Scholar Kirk, P. et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation 120, 1961–1968 (2009).Article CAS PubMed PubMed Central Google Scholar Musallam, K. M. et al. Anemia and iron overload as prognostic markers of outcomes in β-thalassemia. Expert Rev. Hematol. 17, 631–642 (2024).Article CAS PubMed Google Scholar Almuqbel, M. M. et al. Quantitative MRI iron load assessment in β-thalassemia patients beyond the liver and heart: a systematic review. Eur. J. Radiol. 194, 112537 (2026).Article PubMed Google Scholar Meloni, A., Positano, V., Ricchi, P., Pepe, A. & Cau, R. What is the importance of monitoring iron levels in different organs over time with magnetic resonance imaging in transfusion-dependent thalassemia patients? Expert Rev. Hematol. 18, 291–299 (2025).Article CAS PubMed Google Scholar Shah, R., Shah, A. & Badawy, S. M. An evaluation of deferiprone as twice-a-day tablets or in combination therapy for the treatment of transfusional iron overload in thalassemia syndromes. Expert Rev. Hematol. 16, 81–94 (2023).Article CAS PubMed PubMed Central Google Scholar Forni, G. L. et al. Iron chelation therapy for children with transfusion-dependent β-thalassemia: how young is too young? Pediatr. Blood Cancer 71, e31035 (2024).Article PubMed Google Scholar Elalfy, M. S. et al. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: a randomized controlled trial. Am. J. Hematol. 93, 262–268 (2018).Article CAS PubMed Google Scholar Pennell, D. J. et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA). Blood 123, 1447–1454 (2014).Article CAS PubMed PubMed Central Google Scholar Pennell, D. J. et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 107, 3738–3744 (2006).Article CAS PubMed Google Scholar Tanner, M. A. et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 115, 1876–1884 (2007).Article CAS PubMed Google Scholar Pennell, D. J. et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major. Haematologica 97, 842–848 (2012).Article CAS PubMed PubMed Central Google Scholar Cappellini, M. D. et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood 118, 884–893 (2011).Article CAS PubMed Google Scholar Maggio, A. et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cell Mol. Dis. 28, 196–208 (2002).Article Google Scholar Taher, A. T. et al. New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: results of the randomized, phase II ECLIPSE study. Am. J. Hematol. 92, 420–428 (2017).Article CAS PubMed PubMed Central Google Scholar Maggio, A. et al. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol. 7, e469–e478 (2020).Article PubMed Google Scholar Taher, A. T. et al. Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study. Haematologica 109, 1413–1425 (2024).CAS PubMed PubMed Central Google Scholar Rivella, S. Iron metabolism under conditions of ineffective erythropoiesis in β-thalassemia. Blood 133, 51–58 (2019).Article CAS PubMed Google Scholar Musallam, K. M. et al. Serum ferritin level and morbidity risk in transfusion-independent patients with β-thalassemia intermedia: the ORIENT study. Haematologica 99, e218–e221 (2014).Article CAS PubMed PubMed Central Google Scholar Musallam, K. M., Cappellini, M. D. & Taher, A. T. Evaluation of the 5mg/g liver iron concentration threshold and its association with morbidity in patients with β-thalassemia intermedia. Blood Cell Mol. Dis. 51, 35–38 (2013).Article CAS Google Scholar Musallam, K. M. et al. Alpha-thalassemia: a practical overview. Blood Rev. 64, 101165 (2024).Article CAS PubMed Google Scholar Musallam, K. M. et al. Systematic review and evidence gap assessment of the clinical, quality of life, and economic burden of alpha-thalassemia. eJHaem 5, 541–547 (2024).Article PubMed PubMed Central Google Scholar Forni, G. L. et al. Overall and complication-free survival in a large cohort of patients with β-thalassemia major followed over 50 years. Am. J. Hematol. 98, 381–387 (2023).Article PubMed Google Scholar Voskaridou, E. et al. National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality. Ann. Hematol. 98, 55–66 (2019).Article CAS PubMed Google Scholar Taher, A. T. & Cappellini, M. D. How I manage medical complications of β-thalassemia in adults. Blood 132, 1781–1791 (2018).Article CAS PubMed Google Scholar Forni, G. L., Puntoni, M., Boeri, E., Terenzani, L. & Balocco, M. The influence of treatment in specialized centers on survival of patients with thalassemia major. Am. J. Hematol. 84, 317–318 (2009).Article PubMed Google Scholar Amid, A., Lal, A., Coates, T. D. & Fucharoen, S. (eds) Guidelines for the Management of α-Thalassemia (Thalassaemia International Federation, 2023).Musallam, K. M., Bou-Fakhredin, R., Cappellini, M. D. & Taher, A. T. 2021 update on clinical trials in β-thalassemia. Am. J. Hematol. 96, 1518–1531 (2021).Article CAS PubMed Google Scholar Pinto, V. M., Mazzi, F. & De Franceschi, L. Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders. Blood 144, 853–866 (2024).Article CAS PubMed Google Scholar Musallam, K. M., Taher, A. T., Cappellini, M. D. & Sankaran, V. G. Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia. Blood 121, 2199–2212 (2013).Article CAS PubMed Google Scholar Olivieri, N. F. et al. A pilot study of subcutaneous decitabine in β-thalassemia intermedia. Blood 118, 2708–2711 (2011).Article CAS PubMed PubMed Central Google Scholar Zuccato, C. et al. Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin). Ther. Adv. Hematol. 13, 20406207221100648 (2022).Article CAS PubMed PubMed Central Google Scholar Algiraigri, A. H., Wright, N. A. M., Paolucci, E. O. & Kassam, A. Hydroxyurea for lifelong transfusion-dependent β-thalassemia: a meta-analysis. Pediatr. Hematol. Oncol. 34, 435–448 (2017).Article CAS PubMed Google Scholar Hatamleh, M. I. et al. Efficacy of hydroxyurea in transfusion-dependent major β-thalassemia patients: a meta-analysis. Cureus 15, e38135 (2023).PubMed PubMed Central Google Scholar Ali, Z. et al. Long-term clinical efficacy and safety of thalidomide in patients with transfusion-dependent β-thalassemia: results from Thal-Thalido study. Sci. Rep. 13, 13592 (2023).Article CAS PubMed PubMed Central Google Scholar Ansari, S. H. et al. Evaluation of the combination therapy of hydroxyurea and thalidomide in β-thalassemia. Blood Adv. 6, 6162–6168 (2022).Article CAS PubMed PubMed Central Google Scholar Lu, Y., Wei, Z., Yang, G., Lai, Y. & Liu, R. Investigating the efficacy and safety of thalidomide for treating patients with β-thalassemia: a meta-analysis. Front. Pharmacol. 12, 814302 (2021).Article CAS PubMed Google Scholar Chen, J. M. et al. Safety and efficacy of thalidomide in patients with transfusion-dependent β-thalassemia: a randomized clinical trial. Signal Transduct. Target. Ther. 6, 405 (2021).Article PubMed PubMed Central Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04432623 (2025).Pace, B. S. et al. Benserazide racemate and enantiomers induce fetal globin gene expression in vivo: studies to guide clinical development for beta thalassemia and sickle cell disease. Blood Cell Mol. Dis. 89, 102561 (2021).Article CAS Google Scholar Kuo, K. H. M. et al. Initial results in a phase 1b trial of PB-04 in sickle cell disease demonstrate fetal hemoglobin induction, additive activity with hydroxyurea, and improved red blood cell sickling parameters [abstract]. Blood 142, 1148 (2023).Article Google Scholar Fucharoen, S. et al. A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in β-thalassaemia intermedia and HbE/β-thalassaemia. Br. J. Haematol. 161, 587–593 (2013).Article CAS PubMed PubMed Central Google Scholar Inati, A. et al. A phase 2 study of HQK-1001, an oral fetal haemoglobin inducer, in β-thalassaemia intermedia. Br. J. Haematol. 164, 456–458 (2014).Article CAS PubMed Google Scholar Patthamalai, P. et al. A phase 2 trial of HQK-1001 in HbE-β thalassemia demonstrates HbF induction and reduced anemia. Blood 123, 1956–1957 (2014).Article PubMed PubMed Central Google Scholar Maciel, T. T. et al. PDE9 inhibition by IMR-687 improves markers of beta-thalassemia in the Hbbth1/th1 experimental mouse model [abstract]. Blood 138, 945 (2021).Article Google Scholar Imara. Imara announces results of interim analyses of tovinontrine (IMR-687) phase 2b clinical trials in sickle cell disease and beta-thalassemia. GlobeNewswire https://go.nature.com/44202Os (2026).Taher, A. T. et al. Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from a phase 2a study. Blood 131, 263–265 (2018).Article CAS PubMed Google Scholar Taher, A. T. et al. Haematological effects of oral administration of bitopertin, a glycine transport inhibitor, in patients with non-transfusion-dependent β-thalassaemia. Br. J. Haematol. 194, 474–477 (2021).Article CAS PubMed Google Scholar Casu, C. et al. Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult β-thalassemia major. Haematologica 105, 1835–1844 (2020).Article CAS PubMed Google Scholar Porter, J. et al. Effect of LJPC-401 (synthetic human hepcidin) on iron parameters in healthy adults [abstract]. Blood 132, 2336 (2018).Article Google Scholar US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03381833 (2021).Taranath, R. et al. Regulation of iron homeostasis By PTG-300 improves disease parameters in mouse models for beta-thalassemia and hereditary hemochromatosis [abstract]. Blood 134, 3540 (2019).Article Google Scholar Lal, A. et al. A hepcidin mimetic, PTG-300, demonstrates pharmacodynamic effects indicating reduced iron availability in transfusion-dependent beta-thalassemia subjects [abstract]. HemaSphere 4 (Suppl. 1), 110 (2020).Google Scholar Modi, N. B., Shames, R., Lickliter, J. D. & Gupta, S. Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: a double-blind first-in-human study. Eur. J. Haematol. 113, 340–350 (2024).Article CAS PubMed Google Scholar Guo, S. et al. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. J. Clin. Invest. 123, 1531–1541 (2013).Article CAS PubMed PubMed Central Google Scholar McCaleb, M. et al. Transmembrane protease, serine 6 (TMPRSS6) antisense oligonucleotide (IONIS-TMPRSS6-LRX) reduces plasma iron levels of healthy volunteers in a phase 1 clinical study [abstract]. Blood 132, 3634 (2018).Article Google Scholar Kalleda, N. et al. Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions. Haematologica 108, 2703–2714 (2023).Article CAS PubMed PubMed Central Google Scholar Richard, F. et al. Oral ferroportin inhibitor VIT-2763: first-in-human, phase 1 study in healthy volunteers. Am. J. Hematol. 95, 68–77 (2020).Article CAS PubMed Google Scholar Taher, A., Kourakli-Symeonidis, A., Tantiworawit, A., Wong, P. & Szecsödy, P. Safety and preliminary pharmacodynamic effects of the ferroportin inhibitor vamifeport (VIT-2763) in patients with non-transfusion-dependent beta thalassemia (NTDT): results from a phase 2a study [abstract]. HemaSphere 6, 173–174 (2022).Article Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04718844 (2024).Schmidt, P. J. et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe-/- mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood 121, 1200–1208 (2013).Article CAS PubMed Google Scholar Porter, J. B. et al. SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers. Am. J. Hematol. 98, 1425–1435 (2023).Article CAS PubMed Google Scholar Business Wire. Silence Therapeutics announces preliminary single dose results from SLN124 phase 1 study in patients with thalassemia. Business Wire https://www.businesswire.com/news/home/20220929005148/en/ (2026).Suragani, R. N. et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat. Med. 20, 408–414 (2014).Article CAS PubMed Google Scholar Suragani, R. N. et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood 123, 3864–3872 (2014).Article CAS PubMed PubMed Central Google Scholar Attie, K. M. et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am. J. Hematol. 89, 766–770 (2014).Article CAS PubMed PubMed Central Google Scholar Piga, A. et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood 133, 1279–1289 (2019).Article CAS PubMed PubMed Central Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02604433 (2023).Cappellini, M. D. et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 382, 1219–1231 (2020).Article CAS PubMed Google Scholar Cappellini, M. D. et al. Long-term efficacy and safety of luspatercept for the treatment of anaemia in patients with transfusion-dependent β-thalassaemia (BELIEVE): final results from a phase 3 randomised trial. Lancet Haematol. 12, e180–e189 (2025).Article CAS PubMed Google Scholar Origa R. et al. Luspatercept for transfusion-dependent beta-thalassemia: real-world experience in a large cohort of patients from Italy. Am. J. Hematol. 100, 1651–1655 (2025).Article PubMed PubMed Central Google Scholar Musallam, K. M. et al. Luspatercept for transfusion-dependent β-thalassemia: time to get real. Ther. Adv. Hematol. 14, 20406207231195594 (2023).Article PubMed PubMed Central Google Scholar Musallam K. M. Luspatercept in transfusion-dependent β-thalassemia: the benefit is real, and so are the risks. Am J Hematol. 100, 1480–1482 (2025).Article PubMed PubMed Central Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04064060 (2025).Porter, J. B. et al. Improvement of iron overload parameters in patients with transfusion-dependent β-thalassemia treated with luspatercept: data from the phase 3b long-term rollover study following the BELIEVE trial [abstract]. Blood 144, 2475 (2024).Article Google Scholar Garbowski, M. W. et al. Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia. Am. J. Hematol. 99, 182–192 (2024).Article CAS PubMed Google Scholar Hermine, O. et al. Effect of luspatercept on red blood cell (RBC) transfusion burden, iron chelation therapy (ICT), and iron overload in adults with transfusion-dependent β-thalassemia (TDT) from the believe trial: a long-term analysis [abstract]. Blood 140, 8215–8217 (2022).Article Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03342404 (2023).Sheth, S., Taher, A. T., Coates, T. D., Kattamis, A. & Cappellini, M. D. Management of luspatercept therapy in patients with transfusion-dependent β-thalassaemia. Br. J. Haematol. 201, 824–831 (2023).Article CAS PubMed Google Scholar Musallam, K. M. & Taher, A. T. Luspatercept: a treatment for ineffective erythropoiesis in thalassemia. Hematology 2024, 419–425 (2024).Article PubMed PubMed Central Google Scholar van Dijk, M. J. et al. Activation of pyruvate kinase as therapeutic option for rare hemolytic anemias: shedding new light on an old enzyme. Blood Rev. 61, 101103 (2023).Article PubMed Google Scholar Siciliano A. et al. Mitapivat metabolically reprograms human β-thalassemic erythroblasts, increasing their responsiveness to oxidation. Blood Adv. 9, 2818–2830 (2025).Article CAS PubMed PubMed Central Google Scholar Matte, A. et al. Mitapivat, a pyruvate kinase activator, improves transfusion burden and reduces iron overload in β-thalassemic mice. Haematologica 108, 2535–2541 (2023).CAS PubMed PubMed Central Google Scholar Matte, A. et al. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model. J. Clin. Invest. 131, e144206 (2021).Article CAS PubMed PubMed Central Google Scholar Kuo, K. H. M. et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label, multicentre, phase 2 study. Lancet 400, 493–501 (2022).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04770753 (2026).US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04770779 (2026).Taher A. T. et al. Mitapivat in adults with non-transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet 406, 33–42 (2025).Article CAS PubMed Google Scholar Cappellini, M. D. et al. ENERGIZE-T: a global, phase 3, double-blind, randomized, placebo-controlled study of mitapivat in adults with transfusion-dependent alpha- or beta-thalassemia. Blood 144, 409–411 (2024).Article Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04987489 (2025).Forsyth, S. et al. Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial. Clin. Pharmacol. Drug Dev. 11, 654–665 (2022).Article CAS PubMed PubMed Central Google Scholar Lal, A. et al. Trial in progress: a phase 2, open-label study evaluating the safety and efficacy of the erythrocyte pyruvate kinase activator etavopivat in patients with thalassemia or sickle cell disease [abstract]. HemaSphere 6, 2102–2103 (2022).Article PubMed Central Google Scholar Musallam, K. M. et al. Management of transfusion-dependent β-thalassaemia in the era of novel therapies: a prioritisation-based matrix for settings with limited resources. Lancet Haematol. 13, e49–e54 (2026).Article CAS PubMed Google Scholar Angelucci, E. Hematopoietic stem cell transplantation in thalassemia. Hematology 2010, 456–462 (2010).Article PubMed Google Scholar Emanuele, A. et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 99, 811–820 (2014).Article Google Scholar Baronciani, D. et al. Hemopoietic stem cell transplantation in thalassemia: a report from the European society for blood and bone marrow transplantation hemoglobinopathy registry, 2000–2010. Bone Marrow Transplant. 51, 536–541 (2016).Article CAS PubMed Google Scholar Baronciani, D. et al. Hematopoietic cell transplantation in thalassemia and sickle cell disease: report from the European society for blood and bone marrow transplantation hemoglobinopathy registry: 2000-2017 [abstract]. Blood 132 (Suppl. 1), 168 (2018).Article Google Scholar Angelucci, E., Pilo, F. & Coates, T. D. Transplantation in thalassemia: revisiting the Pesaro risk factors 25 years later. Am. J. Hematol. 92, 411–413 (2017).Article PubMed Google Scholar Fleischhauer, K. et al. Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction. Blood 107, 2984–2992 (2006).Article CAS PubMed Google Scholar Algeri, M., Lodi, M. & Locatelli, F. Hematopoietic stem cell transplantation in thalassemia. Hematol. Oncol. Clin. N. Am. 37, 413–432 (2023).Article Google Scholar Amid, A., Liu, S., Babbs, C. & Higgs, D. R. Hemoglobin Bart’s hydrops fetalis: charting the past and envisioning the future. Blood 144, 822–833 (2024).Article CAS PubMed Google Scholar Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02906202 (2023).Locatelli, F. et al. Betibeglogene autotemcel gene therapy for β0/β0 genotype β-thalassemia. N. Engl. J. Med. 386, 415–427 (2022).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03207009 (2024).Kwiatkowski, J. L. et al. Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial. Lancet 404, 2175–2186 (2024).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02633943 (2025).Magrin, E. et al. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial. Nat. Med. 28, 81–88 (2022).Article CAS PubMed Google Scholar Marktel, S. et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent β-thalassemia. Nat. Med. 25, 234–241 (2019).Article CAS PubMed Google Scholar Boulad, F. et al. Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial. Nat. Med. 28, 63–70 (2022).Article CAS PubMed PubMed Central Google Scholar Sankaran, V. G. et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322, 1839–1842 (2008).Article CAS PubMed Google Scholar Hoban, M. D., Orkin, S. H. & Bauer, D. E. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127, 839–848 (2016).Article CAS PubMed PubMed Central Google Scholar Bauer, D. E. et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342, 253–257 (2013).Article CAS PubMed PubMed Central Google Scholar Frangoul, H. et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 384, 252–260 (2021).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03655678 (2025).US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04208529 (2026).Locatelli, F. et al. Durable clinical benefits with exagamglogene autotemcel for transfusion-dependent β-thalassemia [abstract]. Blood 144, 512 (2024).Article Google Scholar Locatelli, F. et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N. Engl. J. Med. 390, 1663–1676 (2024).Article CAS PubMed Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03432364 (2023).Walters, M. C. et al. Updated results of a phase 1/2 clinical study of zinc finger nuclease-mediated editing of BCL11A in autologous hematopoietic stem cells for transfusion-dependent beta thalassemia [abstract]. Blood 138, 3974 (2021).Article Google Scholar US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05444894 (2025).Franghoul, H. et al. Reni-cel, the first AsCas12a gene-edited cell therapy, shows promising preliminary results in key clinical outcomes in transfusion-dependent beta-thalassemia patients treated in the EDITHAL trial [abstract]. HemaSphere 8, 2727–2728 (2024).Google Scholar Rees, H. A. & Liu, D. R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet. 19, 770–788 (2018).Article CAS PubMed PubMed Central Google Scholar Christakopoulos, G. E., Telange, R., Yen, J. & Weiss, M. J. Gene therapy and gene editing for beta-thalassemia. Hematol. Oncol. Clin. N. Am. 37, 433–447 (2023).Article Google Scholar Gupta, A. O. et al. Initial results from the BEACON clinical study: a phase 1/2 study evaluating the safety and efficacy of a single dose of autologous CD34+ base edited hematopoietic stem cells (BEAM-101) in patients with sickle cell disease with severe vaso-occlusive crises [abstract]. Blood 144, 513 (2024).Article Google Scholar Hardouin, G. et al. Adenine base editor-mediated correction of the common and severe IVS1-110 (G>A) beta-thalassemia mutation. Blood 141, 1169–1179 (2023).Article CAS PubMed PubMed Central Google Scholar Radke, T., Paulukonis, S., Hulihan, M. M. & Feuchtbaum, L. Providers’ perspectives on treating patients with thalassemia. J. Pediatr. Hematol. Oncol. 41, e421–e426 (2019).Article PubMed PubMed Central Google Scholar Shah, R. & Badawy, S. M. Health-related quality of life with standard and curative therapies in thalassemia: a narrative literature review. Ann. N. Y. Acad. Sci. 1532, 50–62 (2024).Article CAS PubMed PubMed Central Google Scholar Sobota, A. et al. Quality of life in thalassemia: a comparison of SF-36 results from the thalassemia longitudinal cohort to reported literature and the US norms. Am. J. Hematol. 86, 92–95 (2011).Article CAS PubMed PubMed Central Google Scholar Musallam, K. M. et al. Health-related quality of life in adults with transfusion-independent thalassaemia intermedia compared to regularly transfused thalassaemia major: new insights. Eur. J. Haematol. 87, 73–79 (2011).Article PubMed Google Scholar Cappellini, M. D. et al. Quality of life in patients with β-thalassemia: a prospective study of transfusion-dependent and non-transfusion-dependent patients in Greece, Italy, Lebanon, and Thailand. Am. J. Hematol. 94, E261–E264 (2019).Article PubMed Google Scholar Thavorncharoensap, M. et al. Factors affecting health-related quality of life in Thai children with thalassemia. BMC Blood Disord. 10, 1 (2010).PubMed PubMed Central Google Scholar Etemad, K. et al. Quality of life and related factors in β-thalassemia patients. Hemoglobin 45, 245–249 (2021).Article CAS PubMed Google Scholar Piga, A. Impact of bone disease and pain in thalassemia. Hematology 2017, 272–277 (2017).Article PubMed PubMed Central Google Scholar Bu, M. et al. Brain iron content and cognitive function in patients with β-thalassemia. Ther. Adv. Hematol. 14, 20406207231167050 (2023).Article CAS PubMed PubMed Central Google Scholar Bizri, M. et al. Quality of life, mood disorders, and cognitive impairment in adults with β-thalassemia. Blood Rev. 65, 101181 (2024).Article PubMed Google Scholar Wangi, K., Shaleha, R., Wijaya, E. & Birriel, B. Psychosocial problems in people living with thalassemia: a systematic review. SAGE Open Nurs. 11, 23779608251323811 (2025).Article PubMed PubMed Central Google Scholar Greco, F. & Marino, F. Social impact and quality of life of patients with β-thalassaemia: a systematic review. EMJ Hematol. https://doi.org/10.33590/emjhematol/22-00041 (2022).De Sanctis, V. et al. Marital status and paternity in patients with transfusion-dependent thalassemia (TDT) and non transfusion-dependent thalassemia (NTDT): an ICET - a survey in different countries. Acta Biomed. 90, 225–237 (2019).PubMed PubMed Central Google Scholar Economidou, E. C., Angastiniotis, M., Avraam, D., Soteriades, E. S. & Eleftheriou, A. Addressing thalassaemia management from patients’ perspectives: an international collaborative assessment. Medicina 60, 650 (2024).Article PubMed PubMed Central Google Scholar Boardman, F. K., Clark, C., Jungkurth, E. & Young, P. J. Social and cultural influences on genetic screening programme acceptability: a mixed-methods study of the views of adults, carriers, and family members living with thalassemia in the UK. J. Genet. Couns. 29, 1026–1040 (2020).Article PubMed PubMed Central Google Scholar Angastiniotis, M. Beta thalassemia: looking to the future, addressing unmet needs and challenges. Ann. N. Y. Acad. Sci. 1532, 63–72 (2024).Article PubMed Google Scholar Udeze, C. et al. Economic and clinical burden of managing transfusion-dependent β-thalassemia in the United States. J. Med. Econ. 26, 924–932 (2023).Article PubMed Google Scholar Eleftheriou, A. et al. Estimating the cost of thalassemia care across the world: a Thalassemia International Federation model. Hemoglobin 46, 308–311 (2022).Article CAS PubMed Google Scholar Weidlich, D., Kefalas, P. & Guest, J. F. Healthcare costs and outcomes of managing β-thalassemia major over 50 years in the United Kingdom. Transfusion 56, 1038–1045 (2016).Article PubMed Google Scholar Rodigari, F., Brugnera, G. & Colombatti, R. Health-related quality of life in hemoglobinopathies: a systematic review from a global perspective. Front. Pediatr. 10, 886674 (2022).Article PubMed PubMed Central Google Scholar Drahos, J. et al. Health-related quality of life and economic impacts in adults with transfusion-dependent β-thalassemia: findings from a prospective longitudinal real-world study. Qual. Life Res. 34, 2005–2017 (2025).Article PubMed PubMed Central Google Scholar Jacobs, J. W. et al. Ensuring a safe and sufficient global blood supply. N. Engl. J. Med. 391, 1079–1081 (2024).Article PubMed Google Scholar Raykar, N. P. et al. Innovative blood transfusion strategies to address global blood deserts: a consensus statement from the blood delivery via emerging strategies for emergency remote transfusion (blood DESERT) coalition. Lancet Glob. Health 12, e522–e529 (2024).Article CAS PubMed PubMed Central Google Scholar Custer, B. et al. Addressing gaps in international blood availability and transfusion safety in low- and middle-income countries: a NHLBI workshop. Transfusion 58, 1307–1317 (2018).Article PubMed PubMed Central Google Scholar Wang, L. E., Muttar, S. & Badawy, S. M. The challenges of iron chelation therapy in thalassemia: how do we overcome them? Expert Rev. Hematol. 18, 351–357 (2025).Article CAS PubMed PubMed Central Google Scholar Rund, D. & Rachmilewitz, E. β-Thalassemia. N. Engl. J. Med. 353, 1135–1146 (2005).Article CAS PubMed Google Scholar Hoffman, R. et al. (eds) Hematology: Basic Principles and Practice 5th edn (Elsevier, 2008).Tesio, N. & Bauer, D. Molecular basis and genetic modifiers of thalassemia. Hematol. Oncol. Clin. N. Am. 37, 273–299 (2023).Article Google Scholar United Nations Department of Social and Economic Affairs Population Division. World Population Prospects (UNDESA, accessed 14th June 2024); https://population.un.org/wpp/.van Vliet, M. E., Kerkhoffs, J. H., Harteveld, C. L. & Houwink, E. J. F. Hemoglobinopathy prevention in primary care: a reflection of underdetection and difficulties with accessibility of medical care, a quantitative study. Eur. J. Hum. Genet. 30, 790–794 (2022).Article PubMed PubMed Central Google Scholar Shchemeleva, E. et al. Active spread of β-thalassemia beyond the thalassemia belt: a study on a Russian population. Clin. Genet. 107, 23–33 (2025).Article CAS PubMed Google Scholar Longo, F. et al. Changing patterns of thalassaemia in Italy: a WebThal perspective. Blood Transfus. 19, 261–268 (2021).PubMed Google Scholar Hossain, M. S. et al. Lack of knowledge and misperceptions about thalassaemia among college students in Bangladesh: a cross-sectional baseline study. Orphanet J. Rare Dis. 15, 54 (2020).Article PubMed PubMed Central Google Scholar An, Y., Shen, Y., Ma, Y. & Wang, H. Research needs for birth defect prevention and control in China in the genomic screening era. BMJ 386, e078637 (2024).Article PubMed PubMed Central Google Scholar Zhou, J. et al. Thalassemia genetic screening of pregnant women with anemia in Northern China through comprehensive analysis of thalassemia alleles (CATSA). Clin. Chim. Acta 569, 120151 (2025).Article CAS PubMed Google Scholar Musallam, K. M. et al. TIF guidelines for the management of transfusion-dependent β-thalassemia. HemaSphere 9, e70095 (2025).Article PubMed PubMed Central Google Scholar Shah, F. T. et al. Guideline for the management of conception and pregnancy in thalassaemia syndromes: a British society for haematology guideline. Br. J. Haematol. 204, 2194–2209 (2024).Article PubMed Google Scholar Pinto, V. M. et al. Thalassemias and sickle cell diseases in pregnancy: site good practice. J. Clin. Med. 14, 948 (2025).Article CAS PubMed PubMed Central Google Scholar Committee of Thalassemia Prevention and Treatment, China Maternal and Child Health Association, Subspecialty Group of Hematology, Society of Pediatrics, Chinese Medical Association, China Thalassemia Prevention and Control Collaboration Network & Editorial Board of Chinese Journal of Contemporary Pediatrics. Guidelines for iron chelation therapy in thalassemia in China (2025). Chin. J. Contemp. Pediatr. 27, 377–388 (2025).Google Scholar Casale, M. et al. The management of endocrine complications in patients with haemoglobinopathies: good clinical practice of the Italian society of thalassemia and haemoglobinopathies (SITE). Recenti Prog. Med. 113, 495–554 (2022).PubMed Google Scholar National Health Mission. Prevention and Control of Haemoglobinopathies in India – Thalassemias, Sickle Cell Disease and Other Variant Hemoglobins (Ministry of Health & Family Welfare, Government of India, 2016).Musallam, K. M., Angastiniotis, M., Eleftheriou, A. & Porter, J. B. Cross-talk between available guidelines for the management of patients with beta-thalassemia major. Acta Haematol. 130, 64–73 (2013).Article CAS PubMed Google Scholar