International Journal of Hematology

, Volume 108, Issue 1, pp 5–21 | Cite as

β-Thalassemia intermedia: a comprehensive overview and novel approaches

  • Chingiz Asadov
  • Zohra Alimirzoeva
  • Tahira Mammadova
  • Gunay Aliyeva
  • Shahla Gafarova
  • Jeyhun Mammadov
Review Article
  • 323 Downloads

Abstract

β-Thalassemia intermedia is a clinical condition of intermediate gravity between β-thalassemia minor, the asymptomatic carrier, and β-thalassemia major, the transfusion-dependent severe anemia. It is characterized by a significant clinical polymorphism, which is attributable to its genetic heterogeneity. Ineffective erythropoiesis, chronic anemia, and iron overload contribute to the clinical complications of thalassemia intermedia through stepwise pathophysiological mechanisms. These complications, including splenomegaly, extramedullary erythropoiesis, iron accumulation, leg ulcers, thrombophilia, and bone abnormalities can be managed via fetal hemoglobin induction, occasional transfusions, chelation, and in some cases, stem cell transplantation. Given its clinical diversity, thalassemia intermedia patients require tailored approaches to therapy. Here we present an overview and novel approaches to the genetic basis, pathophysiological mechanisms, clinical complications, and optimal management of thalassemia intermedia.

Keywords

β-Thalassemia intermedia Non-transfusion-dependent thalassemia Transfusion Complications Novel treatment 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev. 2012;26(Suppl 1):S3–6.PubMedGoogle Scholar
  2. 2.
    Taher AT, Vinchinsky E, Musallam KM, Cappellini MD, Viprakasit V, editors. Guidelines for the management of non-transfusion dependent thalassaemia (NTDT). Nicosa: Thalassaemia International Federation; 2013.Google Scholar
  3. 3.
    Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias. Haematologica. 2013;98(6):833–44.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Bazarbachi AA, Chaya BF, Moukhadder HM, Taher AT. Non-transfuison-dependent thalassemia: a panoramic survey from pathophysiology to treatment. Eur Med J. 2016;1(4):53–61.Google Scholar
  5. 5.
    Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the Optimal Care study. Blood. 2010;115(10):1886–92.PubMedGoogle Scholar
  6. 6.
    Haddad A, Tyan P, Radwan A, Mallat N, Taher A. β-Thalassemia intermedia: a bird’s-eye view. Turk J Haematol. 2014;31(1):5–16.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Karimi M, Cohan N, De Sanctis V, Mallat NS, Taher A. Guidelines for diagnosis and management of beta-thalassemia intermedia. Pediatr Hematol Oncol. 2014;31(7):583–96.PubMedGoogle Scholar
  8. 8.
    Thein SL. Genetic insights into the clinical diversity of β-thalassaemia. Br J Haematol. 2004;124(3):264–74.PubMedGoogle Scholar
  9. 9.
    Patrinos GP, Giardine B, Riemer C, Miller W, Chui DH, Anagnou NP, et al. Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies. Nucleic Acids Res. 2004;32((Database issue)):D537–41.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Taher AT, Musallam KM, Cappellini MD. Thalassaemia intermedia: an update. Mediterr J Hematol Infect Dis. 2009;1(1):e2009004.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Asadov CD, Abdulalimov ER, Mammadova TA, Qafarova SN, Guliyeva YJ, Tuli A, et al. Identification of two rare β-globin gene mutations in a patient with β-thalassemia intermedia from Azerbaijan. Hemoglobin. 2013;37:291–6.PubMedGoogle Scholar
  12. 12.
    Viprakasit V, Gibbons RJ, Broughton BC, Tolmie JL, Brown D, Lunt P, et al. Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. Hum Mol Genet. 2001;10(24):2797–802.PubMedGoogle Scholar
  13. 13.
    Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood. 2002;100(6):2040–5.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Huisman THJ. Levels of HbA2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. Acta Haematol. 1997;98(4):187–94.PubMedGoogle Scholar
  15. 15.
    Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature. 2015;527(7577):192–7.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Liu D, Zhang X, Yu L, Cai R, Ma X, Zheng C, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of beta-thalassemia. Blood. 2014;124(5):803–11.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Traeger-Synodinos J, Harteveld CL, Old JM, et al. EMQN best practice guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies. Eur J Hum Genet. 2015;23:426–37.PubMedGoogle Scholar
  18. 18.
    Haidar R, Mhaidli H, Taher AT. Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. Eur Spine J. 2010;19(6):871–8.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Rev. 2012;26(Suppl 1):S16–9.PubMedGoogle Scholar
  20. 20.
    Taher AT, Viprakasit V, Musallam KM, Cappellini MD. Treating iron overload in patients with non-transfusion-dependent thalassemia. Am J Hematol. 2013;88(5):409–15.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Porter JB, Cappellini MD, Kattamis A, Viprakasit V, Musallam KM, Zhu Z, et al. Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions. Br J Haematol. 2017;176(2):288–99.PubMedGoogle Scholar
  22. 22.
    Rivella S. The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia. Blood Rev. 2012;26(Suppl1):S12–5.PubMedPubMedCentralGoogle Scholar
  23. 23.
    De Domenico I, Ward DM, Kaplan J. Hepcidin regulation: ironing out the details. J Clin Investig. 2007;117(7):1755–8.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Investig. 2007;117(7):1926–32.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096–101.PubMedGoogle Scholar
  26. 26.
    Asadov CD. Immunologic abnormalities in β-thalassemia. J Blood Disord Transf. 2014;5(7):1000224.Google Scholar
  27. 27.
    Galanello R, Piras S, Barella S, Leoni GB, Cipollina MD, Perseu L, et al. Cholelithiasis and Gilbert’s syndrome in homozygous beta-thalassemia. Br J Haematol. 2001;115(4):926–8.PubMedGoogle Scholar
  28. 28.
    Borgna-Pignatti C, Rigon F, Merlo L, Chakrok R, Micciolo R, Perseu L, et al. Thalassemia minor, the Gilbert mutation, and the risk of gallstones. Haematologica. 2003;88(10):1106–9.PubMedGoogle Scholar
  29. 29.
    Maakaron JE, Cappellini MD, Graziadei G, Ayache JB, Taher AT. Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis. Ann Hepatol. 2013;12(1):142–6.PubMedGoogle Scholar
  30. 30.
    Moukhadder HM, Halawi R, Cappellini MD, Taher AT. Hepatocellular carcinoma as an emerging morbidity in the thalassemia syndromes: a comprehensive review. Cancer. 2017;123(5):751–8.PubMedGoogle Scholar
  31. 31.
    Mallat NS, Mallat SG, Musallam KM, Taher AT. Potential mechanisms for renal damage in beta-thalassemia. J Nephrol. 2013;26(5):821–8.PubMedGoogle Scholar
  32. 32.
    Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010;24(6):239–44.PubMedGoogle Scholar
  33. 33.
    Gimmon Z, Wexler MR, Rachmilewitz EA. Juvenile leg ulceration in beta-thalassemia major and intermedia. Plast Reconstr Surg. 1982;69(2):320–5.PubMedGoogle Scholar
  34. 34.
    Levin C, Koren A. Healing of refractory leg ulcer in a patient with thalassemia intermedia and hypercoagulability after 14 years of unresponsive therapy. Isr Med Assoc J. 2011;13(5):316–8.PubMedGoogle Scholar
  35. 35.
    Al Momen AK. Recombinant human erythropoietin induced rapid healing of a chronic leg ulcer in a patient with sickle cell disease. Acta Haematol. 1991;86(1):46–8.PubMedGoogle Scholar
  36. 36.
    Afradi H, Saghaei Y, Kachoei ZA, Babaei V, Teimourian S. Treatment of 100 chronic thalassemic leg wounds by plasma-rich platelets. Int J Dermatol. 2017;56(2):171–5.PubMedGoogle Scholar
  37. 37.
    Taher A, Isma’eel H, Mehio G, Bignamini D, Kattamis A, Rachmilewitz EA, et al. Prevalence of thromboembolic events among 8860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488–91.PubMedGoogle Scholar
  38. 38.
    Cappellini MD, Musallam KM, Poggiali E, Taher AT. Hypercoagulability in non-transfusion-dependent thalassemia. Blood Rev. 2012;26(Suppl 1):S20–3.PubMedGoogle Scholar
  39. 39.
    Borenstain-Ben Yashar V, Barenholz Y, Hy-Am E, Rachmilewitz EA, Eldor A. Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes. Am J Hematol. 1993;44(1):63–5.PubMedGoogle Scholar
  40. 40.
    Helley D, Eldor A, Girot R, Ducrocq R, Guillin MC, Bezeaud A. Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia. Thromb Haemost. 1996;76(3):322–7.PubMedGoogle Scholar
  41. 41.
    Chen S, Eldor A, Barshtein G, Zhang S, Golfarb A, Rachmilewitz E, et al. Enhanced aggregability of red blood cells of beta-thalassemia major patients. Am J Physiol. 1996;270(6 Pt 2):H1951–6.PubMedGoogle Scholar
  42. 42.
    Ruf A, Pick M, Deutsch V, Patscheke H, Goldfarb A, Rachmilewitz EA, et al. In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major. Br J Haematol. 1997;98(1):51–6.PubMedGoogle Scholar
  43. 43.
    Winichagoon P, Fucharoen S, Wasi P. Increased circulating platelet aggregates in thalassaemia. Southeast Asian J Trop Med Public Health. 1981;12(4):556–60.PubMedGoogle Scholar
  44. 44.
    Del Principle D, Menichelli A, Di Giulio S, De Matteis W, Cianciulli P, Papa G. PADGEM/GMP-140 expression on platelet membranes from homozygous beta thalassaemic patients. Br J Haematol. 1993;84(1):111–7.Google Scholar
  45. 45.
    Pattanapanyasat K, Gonwong S, Chaichompoo P, Noulsri E, Lerdwana S, Sukapirom K, et al. Activated platelet-derived microparticles in thalassaemia. Br J Haematol. 2007;136(3):462–71.PubMedGoogle Scholar
  46. 46.
    Iolascon A, Giordano P, Storelli S, Li HH, Coppola B, Piga A, et al. Thrombophilia in thalassemia major patients: analysis of genetic predisposing factors. Haematologica. 2001;86(10):1112–3.PubMedGoogle Scholar
  47. 47.
    Sharma S, Raina V, Chandra J, Narayan S, Sharma S. Lupus anticoagulant and anticardiolipin antibodies in polytransfused beta thalassemia major. Hematology. 2006;11(4):287–90.PubMedGoogle Scholar
  48. 48.
    Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. 2002;99(1):36–43.PubMedGoogle Scholar
  49. 49.
    Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Manucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol. 2000;111(2):467–73.PubMedGoogle Scholar
  50. 50.
    Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi A, Hatziliami A, et al. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood. 2001;97(11):3411–6.PubMedGoogle Scholar
  51. 51.
    Derchi G, Galanello R, Bina P, Cappellini MD, Piga A, Lai ME, et al. Prevalence and risk factors for pulmonary arterial hypertension in a large group of β-thalassemia patients using right heart catheterization: a Webthal study. Circulation. 2014;129(3):338–45.PubMedGoogle Scholar
  52. 52.
    Atichartakarn V, Likittanasombat K, Chuncharunee S, Chandanamattha P, Worapongpaiboon S, Angchaisuksi P, et al. Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders. Int J Hematol. 2003;78(2):139–45.PubMedGoogle Scholar
  53. 53.
    Atichartakarn V, Chuncharunee S, Chandanamattha P, Likittanasombat K, Aryurachai K. Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders. Blood. 2004;103(7):2844–6.PubMedGoogle Scholar
  54. 54.
    Kurtoglu AU, Kurtoglu E, Temizkan AK. Effect of iron overload on endocrinopathies in patients with beta-thalassemia major and intermedia. Endokrynol Polska. 2012;63(4):260–3.Google Scholar
  55. 55.
    Savona-Ventura C, Bonello F. Beta-thalassemia syndromes and pregnancy. Obstetr Gynecol Surv. 1994;49(2):129–37.Google Scholar
  56. 56.
    Roumi JE, Moukhadder HM, Graziadei G, Pennisi M, Cappellini MD, Taher AT. Pregnancy in β-thalassemia intermedia at two tertiary care centers in Lebanon and Italy: a follow-up report on fetal and maternal outcomes. Am J Hematol. 2017.  https://doi.org/10.1002/ajh.2469 (Epub ahead of print).PubMedCrossRefGoogle Scholar
  57. 57.
    Nassar AH, Usta IM, Rechda JB, Koussa S, Inati A, Taher AT. Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns. Am J Hematol. 2006;81(7):499–502.PubMedGoogle Scholar
  58. 58.
    Origa R, Piga A, Quarta G, Forni GL, Longo F, Melpignano A, et al. Pregnancy and beta-thalassemia: an Italian multicenter experience. Haematologica. 2010;95(3):376–81.PubMedGoogle Scholar
  59. 59.
    Petrakos G, Andriopoulos P, Tsironi M. Pregnancy in women with thalassemia: challenges and solutions. Int J Womens Health. 2016;8(8):441–51.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Perrotta S, Cappellini MD, Bertoldo F, Servedio V, Iolascon G, D’Agruma L, et al. Osteoporosis in beta-thalassaemia major patients: analysis of the genetic background. Br J Haematol. 2000;111(2):461–6.PubMedGoogle Scholar
  61. 61.
    Haidar R, Musallam KM, Taher AT. Bone disease and skeletal complications in patients with β-thalassemia major. Bone. 2011;48(3):425–32.PubMedGoogle Scholar
  62. 62.
    Sien Y, Yusoff A, Shahar S, Rajikan R. Bone health status among thalassemia children. Int J Public Health Res. 2014;4(1):399–404.Google Scholar
  63. 63.
    Wonke B, Jensen C, Hanslip JJ, Prescott E, Lalloz M, Layton M, et al. Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major. J Pediatr Endocrinol Metab. 1998;11(Suppl 3):795–801.PubMedGoogle Scholar
  64. 64.
    Vogiatzi MG, Macklin EA, Fung EB, Vichinsky E, Olivieri N, Kwiatkowski J, et al. Prevalence of fractures among the thalassemia syndromes in North America. Bone. 2006;38(4):571–5.PubMedGoogle Scholar
  65. 65.
    Karimi M, Ghiam AF, Hashemi A, Alinejad S, Soweid M, Kashef S. Bone mineral density in beta-thalassemia major and intermedia. Indian Pediatr. 2007;44(1):29–32.PubMedGoogle Scholar
  66. 66.
    Napoli N, Carmina E, Bucchieri S, Sferrazza C, Rini GB, Di Fede G. Low serum levels of 25-hydroxy vitamin D in adults affected by thalassemia major or intermedia. Bone. 2006;38(6):888–92.PubMedGoogle Scholar
  67. 67.
    Vogiatzi MG, Autio KA, Mait JE, Schneider R, Lesser M, Giardina PJ. Low bone mineral density in adolescents with beta-thalassemia. Ann N Y Acad Sci. 2005;1054:462–6.PubMedGoogle Scholar
  68. 68.
    Pollak RD, Rachmilewitz E, Blumenfeld A, Idelson M, Goldfarb AW. Bone mineral metabolism in adults with beta-thalassaemia major and intermedia. Br J Haematol. 2000;111(2):902–7.Google Scholar
  69. 69.
    Morabito N, Gaudio A, Lasco A, Atteritano M, Pizzoleo MA, Cincotta M, et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Miner Res. 2004;19(5):722–7.PubMedGoogle Scholar
  70. 70.
    Hashemieh M, Azarkeivan A, Radfar M, Saneifard H, Hosseini-Zijoud SM, Noghabaei G, et al. Prevalence of osteoporosis among thalassemia patients from Zafar adult thalassemia clinic. Iran J Blood Cancer. 2014;6(3):143–8.Google Scholar
  71. 71.
    Voskaridou E, Kyrtsonis MC, Terpos E, Skordili M, Theodoropoulos I, Bergele A, et al. Bone resorption is increased in young adults with thalassaemia major. Br J Haematol. 2001;112(1):36–41.PubMedGoogle Scholar
  72. 72.
    Inati A, Noureldine MA, Mansour A, Abbas HA. Endocrine and bone complications in β-thalassemia intermedia: current understanding and treatment. Biomed Res Int. 2015;2015:813098.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol. 2007;138(3):291–304.PubMedGoogle Scholar
  74. 74.
    Giusti A, Pinto V, Forni GL, Pilotto A. Management of beta-thalassemia-associated osteoporosis. Ann N Y Acad Sci. 2016;1368(1):73–81.PubMedGoogle Scholar
  75. 75.
    Forni GL, Perrotta S, Giusti A, Quarta G, Pitrolo L, Cappellini MD, et al. Neridronate improves bone mineral density and reduces back pain in 𝛽-thalassaemia patients with osteoporosis: results from a phase 2, randomized, parallel-arm, open-label study. Br J Haematol. 2012;158(2):274–82.PubMedGoogle Scholar
  76. 76.
    Musallam KM, Khoury B, Abi-Habib R, Bazzi L, Succar J, Halawi R, 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. 2011;87(1):73–9.PubMedGoogle Scholar
  77. 77.
    Vichinsky E. Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management. Curr Med Res Opin. 2016;32(1):191–204.PubMedGoogle Scholar
  78. 78.
    Taher AT, Musallam KM, Nasreddine W, Hourani R, Inati A, Beydoun A. Asymptomatic brain magnetic resonance imaging abnormalities in splenectomized adults with thalassemia intermedia. J Thromb Haemost. 2010;8(1):54–9.PubMedGoogle Scholar
  79. 79.
    Shelley EC, Buchanan GR. Vascular complications after splenectomy for hematologic disorders. Blood. 2009;114(14):2861–8.Google Scholar
  80. 80.
    Musallam KM, Taher AT, Karimi M, Rachmilewitz EA. Cerebral infarction in β-thalassemia intermedia: breaking the silence. Thromb Res. 2012;130(5):695–702.PubMedGoogle Scholar
  81. 81.
    Tavazzi D, Duca L, Graziadei G, et al. Membrane-bound iron contributes to oxidative damage of β-thalassaemia intermedia erythrocytes. Br J Haematol. 2001;112:48–50.PubMedGoogle Scholar
  82. 82.
    Taher AT, Musallam KM, Cappellini MD, Weatherall DJ. Optimal management of beta-thalassaemia intermedia. Br J Haematol. 2011;152(5):512–23.PubMedGoogle Scholar
  83. 83.
    Easow Mathew M, Sharma A, Aravindakshan R. Splenectomy for people with thalassaemia major or intermedia. Cochrane Database Syst Rev. 2016.  https://doi.org/10.1002/14651858.CD010517.pub2.CrossRefPubMedGoogle Scholar
  84. 84.
    Aessopos A, Kati M, Meletis J. Thalassemia intermedia today: should patients regularly receive transfusions? Transfusion. 2007;47:792–800.PubMedGoogle Scholar
  85. 85.
    Spanos T, Karageorga M, Ladis V, Peristeri J, Hatziliami A, Kattamis C. Red cell alloantibodies in patients with thalassemia. Vox Sang. 1990;58(1):50–5.PubMedGoogle Scholar
  86. 86.
    Seferi I, Xhetani M, Face M, Burazeri G, Nastas E, Vyshka G. Frequency and specificity of red cell antibodies in thalassemia patients in Albania. Int J Lab Hematol. 2015;37(4):569–74.PubMedGoogle Scholar
  87. 87.
    Taher AT, Radwan A, Viprakasit V. When to consider transfusion therapy for patients with non-transfusion-dependent thalassaemia. Vox Sang. 2015;108(1):1–10.PubMedGoogle Scholar
  88. 88.
    Taher AT, Musallam KM, Viprakasit V, Porter JB, Cappellini MD. Iron chelation therapy for non-transfusion-dependent thalassemia (NTDT): a status quo. Blood Cells Mol Dis. 2014;52(2–3):88–90.PubMedGoogle Scholar
  89. 89.
    Taher A, Hershko C, Cappellini MD. Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies. Br J Haematol. 2009;147(5):634–40.PubMedGoogle Scholar
  90. 90.
    Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamim H, et al. Elevated liver iron concentration is a marker of increased morbidity in patients with beta thalassemia intermedia. Haematologica. 2011;96(11):1605–12.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Roghi A, Cappellini MD, Wood JC, Musallam KM, Patrizia P, Fasulo MR, et al. Absence of cardiac siderosis despite hepatic iron overload in Italian patients with thalassemia intermedia: an MRI T2* study. Ann Hematol. 2010;89(6):585–9.PubMedGoogle Scholar
  92. 92.
    Halawi R, Motta I, Taher A, Cappellini MD. Deferasirox: an orphan drug for chronic iron overload in non-transfusion dependent thalassemia syndromes. Expert Opin Orphan Drugs. 2016;4(6):677–86.Google Scholar
  93. 93.
    Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes. Drug Des Dev Ther. 2016;10:465–81.Google Scholar
  94. 94.
    Saliba AN, El Rassi F, Taher AT. Clinical monitoring and management of complications related to chelation therapy in patients with β-thalassemia. Expert Rev Hematol. 2016;9(2):151–68.PubMedGoogle Scholar
  95. 95.
    Musallam KM, Taher AT, Cappellini MD, Sankaran VG. Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia. Blood. 2013;121(12):2199–212.PubMedGoogle Scholar
  96. 96.
    Foong WC, Ho JJ, Loh CK, Viprakasit V. Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias. Cochrane Database Syst Rev. 2016;10:CD011579.PubMedGoogle Scholar
  97. 97.
    Ehsani MA, Hedayati-Asl AA, Bagheri A, Zeinali S, Rashidi A. Hydroxyurea-induced hematological response in transfusion-independent beta-thalassemia intermedia: case series and review of literature. Pediatr Hematol Oncol. 2009;26(8):560–5.PubMedGoogle Scholar
  98. 98.
    Asadov C, Alimirzoeva Z, Hasanova M, Mammadova T, Shirinova A. Clinical application of recombinant erythropoietin in beta-thalassemia intermedia. Georgian Med News. 2016;255(6):86–92.Google Scholar
  99. 99.
    Alimirzoeva Z, Hasanova M, Asadov C. Modern principles of management of thalassemia intermedia. Leuk Res. 2014;38(Supl1):526–7.Google Scholar
  100. 100.
    Asadov C, Hasanova M, Alimirzoeva Z, Mammadova T. Serum erythropoietin in intermediate β-thalassemias. Klin Lab Diagn. 2012;1:16–8.Google Scholar
  101. 101.
    Hasanova M, Asadov C, Alimirzoeva Z, Mammadova T, Shirinova A. Efficiency of recombinant erythropoietin administration in hemoglobinopathy H. Georgian Med News. 2014;226:46–9.Google Scholar
  102. 102.
    Elafy MS, Adly AA, Ismail EA, Elhenawy YI, Elghamry IR. Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β-thalassemia intermedia patients. Eur J Haematol. 2013;91(6):522–33.Google Scholar
  103. 103.
    Srivastava A, Shaji RV. Cure for thalassemia major—from allogeneic hematopoietic stem cell transplantation to gene therapy. Haematologica. 2017;102(2):214–23.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Canver MC, Orkin SH. Customizing the genome as therapy for the β-hemoglobinopathies. Blood. 2016;127(21):2536–45.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Rivella S. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015;100(4):418–30.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Libani IV, Guy EC, Melchiori L, Schiro R, Ramos P, Breda L, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. Blood. 2008;112(3):875–85.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Melchiori L, Gardenghi S, Rivella S. β-Thalassemia: HiJAKing ineffective erythropoiesis and iron overload. Adv Hematol. 2010;2010:938640.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Melchiori L, Gardenghi S, Guy EG, Rachmilewitz E, Giardina PJ, Grady RW, et al. Use of JAK2 inhibitors to limit ineffective erythropoiesis and iron absorption in mice affected by β-thalassemia and other disorders of red cell production. Blood. 2009;114(22):2020.Google Scholar
  109. 109.
    Aydinok Y, Karakas Z, Cassinerio E, Siritanaratkul N, Kattamis A, Maggio A, et al. Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from single-arm, multicenter, phase 2a truth study. Blood. 2016;128(22):852.Google Scholar
  110. 110.
    Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Investig. 2010;120(12):4466–77.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Parrow NL, Gardenghi S, Rivella S. Prospects for a hepcidin mimic to treat beta-thalassemia and hemochromatosis. Expert Rev Hematol. 2011;4(3):233–5.PubMedGoogle Scholar
  112. 112.
    Preza GC, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta MA, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Investig. 2011;121(12):4880–8.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088–92.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010;115(18):3817–26.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021–9.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Guo S, Casu C, Gardenghi S, Booten S, Aghajan M, Peralta R, et al. Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice. J Clin Investig. 2013;123(4):1531–41.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Schmidt PJ, Toudjarska I, Sendamarai A, Racie T, Milstein S, Bettencourt BR, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(−/−) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood. 2013;121(7):1200–8.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Li H, Rybicki AC, Suzuka SM, von Bonsdorff L, Breuer W, Hall CB, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16(2):177–82.PubMedGoogle Scholar
  119. 119.
    Suragani RN, Cawley SM, Li R, Wallner S, Alexander MJ, Mulivor AW, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia. Blood. 2014;123(25):3864–72.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med. 2014;20(4):398–407.PubMedGoogle Scholar
  121. 121.
    Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408–14.PubMedGoogle Scholar
  122. 122.
    Cappellini MD, Porter J, Origa R, Forni GR, Laadem A, Galacteros F, et al. A phase 2a, open-label, dose-finding study to determine the safety and tolerability of sotatercept (ACE-011) in adults with beta (β)-thalassemia: interim results. Blood. 2013;122(21):3448.Google Scholar
  123. 123.
    Piga AG, Perrotta S, Melpignano A, Borgna-Pignatti C, Voskaridou E, Caruso V, et al. ACE-536 increases hemoglobin and decreases transfusion burden and serum ferritin in adults with beta-thalassemia: preliminary results from a phase 2 study. Blood. 2014;124(21):53.Google Scholar
  124. 124.
    Piga AG, Perrotta S, Melpignano A, Borgna-Pignatti C, Gamberini MR, Voskaridou E, et al. Luspatercept increases haemoglobin and improves quality of life in non-transfusion dependent adults with β-thalassemia. Haematologica. 2017;102(s1):90.Google Scholar
  125. 125.
    Anderson ER, Taylor M, Xue X, Ramakrishan SK, Martin A, Xie L, et al. Intestinal HIF2alpha promotes tissue-iron accumulation in disorders of iron overload with anemi. Proc Natl Acad Sci. 2013;110(50):E4922–30.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Breda L, Casu C, Gardenghi S, Bianchi N, Cartegni L, Narla M, et al. Therapeutic hemoglobin levels after gene transfer in beta-thalassemia mice and in hematopoietic cells of beta-thalassemia and sickle cells disease patients. PLoS One. 2012;7(3):e32345.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318–22.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Boulad F, Wang X, Qu J, Taylor C, Ferro L, Karponi G, et al. Safe mobilization of CD34+ cells in adults with beta-thalassemia and validation of effective globin gene transfer for clinical investigation. Blood. 2014;123(10):1483–6.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Hoban MD, Cost GJ, Mendel MC, Romero Z, Kaufman ML, Joglekar AV, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597–604.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Hoban MD, Orkin SH, Bauer DE. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood. 2016;127(7):839–48.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Wienert B, Funnell AP, Norton LJ, Pearson RC, Wilkinson-White LE, Lester K, et al. Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin. Nat Commun. 2015;6:7085.PubMedGoogle Scholar
  132. 132.
    Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell AP, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science. 2016;351(6270):285–9.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Renneville A, Van Galen P, Canver MC, McConkey M, Krill-Burger JM, Dorfman DM, et al. EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood. 2015;126(16):1930–9.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S, et al. Gene therapy of the β-hemoglobinopathies by lentiviral transfer of the βA(T87Q)-Globin gene. Hum Gene Ther. 2016;27(2):148–65.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Ribeil JA, Cavazzana M, Touzot F, Payen E, Neven B, Lefrere F, et al. Clinical outcomes of gene therapy with BB305 lentiviral vector for sickle cell disease and β-thalassaemia. Haematologica. 2017;102(s1):59.Google Scholar
  136. 136.
    Pakbaz Z, Treadwell M, Yamashita R, Quirolo K, Foote D, Quill L, et al. Quality of life in patients with thalassemia intermedia compared to thalassemia major. Ann N Y Acad Sci. 2005;1054:457–61.PubMedGoogle Scholar
  137. 137.
    Safizadeh H, Farahmandinia Z, Nejad SS, Pourdamghan N, Araste M. Quality of life in patients with thalassemia major and intermedia in kerman-iran (I.R.). Mediterr J Hematol Infect Dis. 2012;4(1):e2012058.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Vitrano A, Calvaruso G, Lai E, Colletta G, Quota A, Gerardi C, et al. The era of comparable life expectancy between thalassaemia major and intermedia: is it time to revisit the major-intermedia dichotomy? Br J Haematol. 2017;176(1):124–30.PubMedGoogle Scholar
  139. 139.
    Khoury B, Musallam KM, Abi-Habib R, Bazzi L, Ward ZA, Succar J, et al. Prevalence of depression and anxiety in adult patients with β-thalassemia major and intermedia. Int J Psychiatry Med. 2012;44(4):291–303.PubMedGoogle Scholar
  140. 140.
    Karimi M, Haghpanah S, Farhadi A, Yanvarian M. Genotype-phenotype relationship of patients with β-thalassemia taking hydroxyurea: a 13-year experience in Iran. Int J Hematol. 2012;95(1):51–6.PubMedGoogle Scholar
  141. 141.
    Amoozgar H, Farhani N, Khodadadi N, Karimi M, Cheriki S. Comparative study of pulmonary circulation and myocardial function in patients with β-thalassemia intermedia with and without hydroxyurea, a case-control study. Eur J Haematol. 2011;87(1):61–7.PubMedGoogle Scholar
  142. 142.
    Ansari SH, Shamsi TS, Ashraf M, Perveen K, Farzana T, Bohray M, et al. Efficacy of hydroxyurea in providing transfusion independence in β-thalassemia. J Pediatr Hematol Oncol. 2011;33(5):339–43.PubMedGoogle Scholar
  143. 143.
    Karimi M, Cohan N, Mousavizadeh K, Falahi MJ, Haghpanah S. Adverse effects of hydroxyurea in beta-thalassemia intermedia patients: 10 years’ experience. Pediatr Hematol Oncol. 2010;27(3):205–11.PubMedGoogle Scholar
  144. 144.
    Rigano P, Pecoraro A, Calzolari R, Troia A, Acusto S, Renada S, et al. Desensitization to hydroxycarbamide following long-term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients. Br J Haematol. 2010;151(5):509–15.PubMedGoogle Scholar
  145. 145.
    Italia KY, Jijina FF, Merchant R, Panjwani S, Nadkarni AH, Sawant PM, et al. ffect of hydroxyurea on the transfusion requirements in patients with severe HbE-beta-thalassaemia: a genotypic and phenotypic study. J Clin Pathol. 2010;63(2):147–50.PubMedGoogle Scholar
  146. 146.
    Koren A, Levin C, Dgany O, Kransnov T, Elhasid R, Zalman L, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008;83(5):366–70.PubMedGoogle Scholar
  147. 147.
    Bradai M, Pissard S, Abad MT, Dechartes A, Ribeil JA, Landais P, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007;47(10):1830–6.PubMedGoogle Scholar
  148. 148.
    Manusco A, Maggio A, Renda D, Di Marzo R, Rigano P. Treatment with hydroxycarbamide for intermedia thalassaemia: decrease of efficacy in some patients during long-term follow up. Br J Haematol. 2006;133(1):105–6.Google Scholar
  149. 149.
    Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. 2005;27(7):380–5.PubMedGoogle Scholar
  150. 150.
    Dixit A, Chatterjee TC, Mishra P, Choudhry DR, Mahapatra M, Tyagi S, et al. Hydroxyurea in thalassemia intermedia—a promising therapy. Ann Hematol. 2005;84(7):441–6.PubMedGoogle Scholar
  151. 151.
    Bradai M, Abad MT, Pissard S, Lamraoui F, Skopinski L, de Maontalembert M. Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia. Blood. 2003;102(4):1529–30.PubMedGoogle Scholar
  152. 152.
    Gamberini MR, Fortini M, De Sanctis V. Paraplegia due to spinal cord compression by extramedullary erythropoietic tissue in a thalassaemia intermedia patient with gynecomastia secondary to cirrhosis: successful treatment with hydroxyurea. Pediatr Endocrinol Rev. 2004;2(Suppl 2):316–8.PubMedGoogle Scholar
  153. 153.
    De Paula EV, Lima CSP, Arruda VR, Alberto FL, Saad ST, Costa FF. Long-term hydroxyurea therapy in beta-thalassaemia patients. Eur J Haematol. 2003;70(3):151–5.PubMedGoogle Scholar
  154. 154.
    Cianciulli P, di Toritto TC, Sorrentino F, Sergiacomi L, Massa A, Amadori S. Hydroxyurea therapy in paraparesis and cauda equina syndrome due to extramedullary haematopoiesis in thalassaemia: improvement of clinical and haematological parameters. Eur J Haematol. 2000;64(6):426–9.PubMedGoogle Scholar
  155. 155.
    Hoppe C, Vichinsky E, Lewis B, Foote D, Styles L. Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia. Am J Hematol. 1999;62(4):221–7.PubMedGoogle Scholar
  156. 156.
    Chaidos A, Makis A, Hatzimichael E, Tsiara S, Gouva M, Tzouvara E, et al. Treatment of β-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4):189–95.PubMedGoogle Scholar
  157. 157.
    Olivieri NF, Freedman MH, Perrine SP, Dover GJ, Sheridan B, Essentine DL, et al. Trial of recombinant human erythropoietin: three patients with thalassemia intermedia. Blood. 1992;80(12):3258–60.PubMedGoogle Scholar
  158. 158.
    Bourantas K, Economou G, Georgiou J. Administration of high doses of recombinant human erythropoietin to patients with β-thalassemia intermedia: a preliminary trial. Eur J Haematol. 1997;58(1):22–5.PubMedGoogle Scholar
  159. 159.
    Nisli G, Kavakli K, Vergin C, Oztop S, Cetingül N. Recombinant human erythropoietin trial in thalassemia intermedia. J Trop Pediatr. 1996;42(6):330–4.PubMedGoogle Scholar
  160. 160.
    Dore F, Bonfigli S, Gaviano E, Pardini S, Longinotti M. Serum transferrin receptor levels in patients with thalassemia intermedia during RHuEPO administration. Haematologica. 1996;81(1):37–9.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Chingiz Asadov
    • 1
  • Zohra Alimirzoeva
    • 1
  • Tahira Mammadova
    • 1
  • Gunay Aliyeva
    • 1
  • Shahla Gafarova
    • 1
  • Jeyhun Mammadov
    • 2
  1. 1.Institute of Hematology and TransfusiologyBakuAzerbaijan
  2. 2.Thalassemia CentreBakuAzerbaijan

Personalised recommendations