Thalassemia an update: molecular basis, clinical features and treatment

Document Type : Review article

Authors

1 Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran

2 Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran

3 Department of Hematology, Faculty of medical science, Tarbiat Modares University, Tehran, Iran.

4 Stem Cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

5 Department of Hematology and Blood Transfusion, School of Allied Medical Science, Iran University of Medical Sciences, Tehran

Abstract

Thalassemia are a group of inherited blood disorders caused by the decrease or absence of beta-globin chain synthesis will be determined with decrease in erythrocyte hemoglobin, decreased production of erythrocytes and anemia. More thalassemia is inherited as recessive autosomal. According to this fact that which one of the chains are involved, they invide into two type including alpha and beta thalassemia, which each of them including several types. Thalassemia major is more extensive and patient needs to blood transfusion, but thalassemia minor is slight. The most important problem in this patient include iron overload, cardiac arrhythmia, hepatitis, osteoporosis and endocrine disorder however there are typical signs and symptoms of anemia. Treatment including Change of expression and production of HbF, Hematopoietic stem cell transplantation and Maintenance Treatment such as chelators therapy, Induction of fetal hemoglobin production by using Hydroxia urea, use of immunomodulator agents and Molecular Therapy by targeting of genes involving in HbF expression.in this article we review the thalassemia disorder and discuss on molecular basis, clinical features and treatment.

Keywords


 
1.   Birgens H, Ljung R. The thalassaemia syndromes. Scandinavian journal of clinical and laboratory investigation. 2007;67(1):11-26.
2.   Ingram V, Stretton A. Genetic basis of the thalassaemia diseases. Nature. 1959;184:1903-9.
3.   Flint J, Harding RM, Boyce AJ, Clegg JB. 1 The population genetics of the haemoglobinopathies. Baillière's clinical haematology. 1998;11(1):1-51.
4.   Vichinsky EP. Changing patterns of thalassemia worldwide. Annals of the New York Academy of Sciences. 2005;1054(1):18-24.
5.   Taher A, Vichinsky E, Musallam K, Cappellini M, Viprakasit V. Thalassemia International Federation. Guidelines for the management of non-transfusion dependent thalassaemia (NTDT). Thalassaemia International Federation, Nicosia, Cyprus Available at: http://www thalassaemia org cy/wp-content/uploads/pdf/educational-programmes/Publications/Non-Transfusion% 20Dependent% 20Thalassaemias. 2013;20(282013):29.
6.   Rahim F, Abromand M. Spectrum of ß-Thalassemia mutations in various Ethnic Regions of Iran. PAKISTAN Journal of Medical Sciences. 2008;24(3):410.
7.   Giardine B, van Baal S, Kaimakis P, Riemer C, Miller W, Samara M, et al. HbVar database of human hemoglobin variants and thalassemia mutations: 2007 update. Human Mutation. 2007;28(2):206-.
8.   Hardison RC, Chui DH, Giardine B, Riemer C, Patrinos GP, Anagnou N, et al. HbVar: a relational database of human hemoglobin variants and thalassemia mutations at the globin gene server. Human mutation. 2002;19(3):225-33.
9.   Galanello R, Cao A. Relationship between Genotype and Phenotype: Thalassemia Intermediaa. Annals of the New York Academy of Sciences. 1998;850(1):325-33.
10. Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, et al. Beta-Thalassemia. 2013.
11. Maakaron JE, Cappellini MD, Taher AT. An update on thalassemia intermedia. Le Journal medical libanais The Lebanese medical journal. 2012;61(3):175-82.
12. Origa R. Beta-Thalassemia. Genetics in Medicine, 2017, 19.6: 609.
13. Origa R, Moi P, Galanello R, Cao A. Alpha-thalassemia. 2013.
14. Mahdavi M, Kowsarian M, Karami H, Mohseni A, Vahidshahi K, Roshan P, et al. Prevalence of hemoglobin alpha-chain gene deletion in neonates in North of Iran. Eur Rev Med Pharmacol Sci. 2010;14(10):871-5.
15. Reyes-Núñez V, Garcés-Eisele J, Jorge S, Kimura E, Ferreira-Costa F, de Fátima Sonati M, et al. Molecular characterization of alpha-thalassemia in the Mexican population. Revista de investigación clínica. 2006;58(3):234.
16. Zimmer E, Martin S, Beverley S, Kan Y, Wilson AC. Rapid duplication and loss of genes coding for the alpha chains of hemoglobin. Proceedings of the National Academy of Sciences. 1980;77(4):2158-62.
17. Muncie Jr HL, Campbell J. Alpha and beta thalassemia. American family physician. 2009;80(4):339-44.
18. Tang DC, Fucharoen S, Ding I, Rodgers GP. Rapid differentiation of five common α-thalassemia genotypes by polymerase chain reaction. Journal of Laboratory and Clinical Medicine. 2001;137(4):290-5.
19. Galanello R, Origa R. Beta-thalassemia. Orphanet journal of rare diseases. 2010;5(1):1.
20. Papakonstantinou O, Drakonaki EE, Maris T, Vasiliadou A, Papadakis A, Gourtsoyiannis N. MR imaging of spleen in beta-thalassemia major. Abdominal imaging. 2015;40(7):2777-82.
21. Taher A, Vichinsky E, Musallam K, Cappellini M, Viprakasit V. Guidelines for the Clinical Management of Non-Transfusion Dependent Thalassaemia (NTDT). ed. D. Weatherall; 2013.
22. Trivedi DJ, Sagare A. Assessment of Iron Overload in Homozygous and Heterozygous Beta Thalassemic Children below 5 Years of Age. Journal of Krishna Institute of Medical Sciences (JKIMSU). 2014;3(2).
23. Salama KM, Ibrahim OM, Kaddah AM, Boseila S, Ismail LA, Hamid MMA. Liver enzymes in children with beta-thalassemia major: Correlation with iron overload and viral hepatitis. Open Access Macedonian Journal of Medical Sciences. 2015;3(2):287.
24. Elalfy MS, Esmat G, Matter RM, Abdel Aziz H, Massoud WA. Liver fibrosis in young Egyptian beta-thalassemia major patients: relation to hepatitis C virus and compliance with chelation. Ann Hepatol. 2013;12(10):54.
25. Galanello R, Origa R. Beta-thalassemia: Orphanet J Rare Dis. Journal of Continuing Education Topics & Issues. 2012;14(1):33-4.
26. Keikhaei B, Zandian K, Rahim F. Existence of cord compression in extramedullary hematopoiesis due to beta thalassemia intermedia. Hematology. 2013.
27. Chalevelakis G, Clegg J, Weatherall D. Imbalanced globin chain synthesis in heterozygous beta-thalassemic bone marrow. Proceedings of the National Academy of Sciences. 1975;72(10):3853-7.
28. Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxidants & redox signaling. 2008;10(11):1923-40.
29. Fang J, Menon M, Kapelle W, Bogacheva O, Bogachev O, Houde E, et al. EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts. Blood. 2007;110(7):2361-70.
30. Gregory T, Yu C, Ma A, Orkin SH, Blobel GA, Weiss MJ. GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood. 1999;94(1):87-96.
31. Yatim NFM, Rahim MA, Menon K, Al-Hassan FM, Ahmad R, Manocha AB, et al. Molecular Characterization of α-and β-Thalassaemia among Malay Patients. International journal of molecular sciences. 2014;15(5):8835-45.
32. Yin A, Li B, Luo M, Xu L, Wu L, Zhang L, et al. The prevalence and molecular spectrum of α-and β-globin gene mutations in 14,332 families of Guangdong Province, China. PLoS One. 2014;9(2):e89855.
33. Kazazian Jr H, Orkin S, Antonarakis S, Sexton J, Boehm CD, Goff S, et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. The EMBO journal. 1984;3(3):593.
34. Arab A, Karimipoor M, Rajabi A, Hamid M, Arjmandi S, Zeinali S. Molecular characterization of β-thalassemia intermedia: a report from Iran. Molecular biology reports. 2011;38(7):4321-6.
35. Najmabadi H, Karimi-Nejad R, Sahebjam S, Pourfarzad F, Teimourian S, Sahebjam F, et al. The β-thalassemia mutation spectrum in the Iranian population. Hemoglobin. 2001;25(3):285-96.
36. Hosseinpour Feizi MA, Hosseinpour Feizi AA, Pouladi N, Haghi M, Azarfam P. Molecular spectrum of β-thalassemia mutations in Northwestern Iran. Hemoglobin. 2008;32(3):255-61.
37. Socolovsky M, Murrell M, Liu Y, Pop R, Porpiglia E, Levchenko A. Negative autoregulation by FAS mediates robust fetal erythropoiesis. PLoS Biol. 2007;5(10):e252.
38. Palis J. Ontogeny of erythropoiesis. Current opinion in hematology. 2008;15(3):155-61.
39. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770-6.
40. Heemels M-T, Dhand R, Allen L. The biochemistry of apoptosis. Nature. 2000;407(6805):770-6.
41. Yuan J, Angelucci E, Lucarelli G, Aljurf M, Snyder L, Kiefer C, et al. Accelerated programmed cell death (apoptosis) in erythroid precursors of patients with severe beta-thalassemia (Cooley's anemia)[see comments]. Blood. 1993;82(2):374-7.
42. Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, et al. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in Thai patients with thalassemia. Blood. 2000;96(7):2606-12.
43. Ribeil J-A, Arlet J-B, Dussiot M, Cruz Moura I, Courtois G, Hermine O. Ineffective erythropoiesis in β-thalassemia. The Scientific World Journal. 2013;2013.
44. Rund D, Rachmilewitz E. β-Thalassemia. New England Journal of Medicine. 2005;353(11):1135-46.
45. Schrier SL, Centis F, Verneris M, Ma L, Angelucci E. The role of oxidant injury in the pathophysiology of human thalassemias. Redox report. 2013.
46. Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood reviews. 2012;26:S16-S9.
47. Hershko C, Link G, Cabantchik I. Pathophysiology of Iron Overloada. Annals of the New York Academy of Sciences. 1998;850(1):191-201.
48. Malik S, Syed S, Ahmed N. Complications in transfusion–dependent patients of ß-thalassemia major. Pak J Med Sci. 2009;25(4):678-82.
49. Aessopos A, Farmakis D. Pulmonary Hypertension in β‐Thalassemia. Annals of the New York Academy of Sciences. 2005;1054(1):342-9.
50. Anthi A, Orfanos SE, Armaganidis A. Pulmonary hypertension in β thalassaemia. The Lancet Respiratory Medicine. 2013;1(6):488-96.
51. Aessopos A, Berdoukas V, Tsironi M. The heart in transfusion dependent homozygous thalassaemia today–prediction, prevention and management. European journal of haematology. 2008;80(2):93-106.
52. Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complications in patients with Thalassaemia Major. Pediatric endocrinology reviews. 2007;5(2):642.
53. De Sanctis V, Eleftheriou A, Malaventura C. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Pediatric endocrinology reviews: PER. 2004;2:249-55.
54. Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pourzahedgilani N, Bouzari N, Habibzadeh M, et al. Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran. BMC Endocrine Disorders. 2003;3(1):1.
55. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR, Network TCR. Complications of β-thalassemia major in North America. Blood. 2004;104(1):34-9.
56. Cappellini MD, Musallam KM, Marcon A, Taher AT. Coagulopathy in beta-thalassemia: current understanding and future perspectives. Mediterranean journal of hematology and infectious diseases. 2009;1(1).
57. Eldor A, Durst R, Hy‐Am E, Goldfarb A, Gillis S, Rachmilewitz E, et al. A chronic hypercoagulable state in patients with β‐thalassaemia major is already present in childhood. British journal of haematology. 1999;107(4):739-46.
58. Okada S, Taketa K, Ishikawa T, Koji T, Swe T, Win N, et al. High prevalence of hepatitis C in patients with thalassemia and patients with liver diseases in Myanmar (Burma). Acta Medica Okayama. 2000;54(3):137-8.
59. Bielinski B, Darbyshire P, Mathers L, Boivin C, Shaw N. Bone density in the Asian thalassaemic population: a cross‐sectional review. Acta Paediatrica. 2001;90(11):1262-6.
60. Saffari F, Abolfazl M. Bone mineral density in patients with Beta-Thalassemia Major in Qazvin. Journal of Isfahan Medical School. 2008;26(89):175~ 82.
61. Thein SL. The emerging role of fetal hemoglobin induction in non-transfusion-dependent thalassemia. Blood reviews. 2012;26:S35-S9.
62. 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.
63. Ansari SH, Lassi ZS, Ali SM, Adil SO, Shamsi TS. Hydroxyurea for ß‐thalassaemia major. The Cochrane Library. 2016.
64. Fard AD, Hosseini SA, Shahjahani M, Salari F, Jaseb K. Evaluation of novel fetal hemoglobin inducer drugs in treatment of β-hemoglobinopathy disorders. International journal of hematology-oncology and stem cell research. 2013;7(3):47-54.
65. Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014;99(5):811-20.
66. Bernardo ME, Piras E, Vacca A, Giorgiani G, Zecca M, Bertaina A, et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. 2012;120(2):473-6.
67. Mathews V, George B, Viswabandya A, Abraham A, Ahmed R, Ganapule A, et al. Improved clinical outcomes of high risk β thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts. PloS one. 2013;8(4):e61637.
68. King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood. 2014;123(20):3089-94.
69. Kwiatkowski JL. Real-world use of iron chelators. ASH Education Program Book. 2011;2011(1):451-8.
70. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117(15):3945-53.
71. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115(12):2354-63.
72. El-Beshlawy A, Hamdy M, El Ghamrawy M. Fetal globin induction in β-thalassemia. Hemoglobin. 2009;33(sup1):S197-S203.
73. Krakoff IH, Brown NC, Reichard P. Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Research. 1968;28(8):1559-65.
74. McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert opinion on drug safety. 2015;14(11):1749-58.
75. Zargari O, Kimyai-Asadi A, Jafroodi M, Chaine B, Neonato M, Girot R, et al. Hydroxyurea for Sickle Cell Anemia. N Engl J Med. 2008;2008(359):98-9.
76. Platt O, Orkin S, Dover G, Beardsley G, Miller B, Nathan D. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. Journal of Clinical Investigation. 1984;74(2):652.
77. Ramamurthi A, Devaraj J, Ramkrishna D. Monitoring Hydroxyurea Treatment Of Sickle Cell Anemia. 2014.
78. Tang DC, Zhu J, Liu W, Chin K, Sun J, Chen L, et al. The hydroxyurea-induced small GTP-binding protein SAR modulates γ-globin gene expression in human erythroid cells. Blood. 2005;106(9):3256-63.
79. King SB. Nitric oxide production from hydroxyurea. Free Radical Biology and Medicine. 2004;37(6):737-44.
80. McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain? Current Opinion in Hematology. 2011;18(3):158.
81. Ley TJ, DeSimone J, Anagnou NP, Keller GH, Humphries RK, Turner PH, et al. 5-Azacytidine selectively increases γ-globin synthesis in a patient with β+ thalassemia. New England Journal of Medicine. 1982;307(24):1469-75.
82. Lowrey CH, Nienhuis AW. Treatment with azacitidine of patients with end-stage β-thalassemia. New England Journal of Medicine. 1993;329(12):845-8.
83. Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine: a new anticancer drug with effectiveness in acute myelogenous leukemia. Annals of Internal Medicine. 1976;85(2):237-45.
84. LuÈbbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C, et al. Cytogenetic responses in high‐risk myelodysplastic syndrome following low‐dose treatment with the DNA methylation inhibitor 5‐aza‐2′‐deoxycytidine. British Journal of Haematology. 2001;114(2):349-57.
85. Lavelle D, Saunthararajah Y, Vaitkus K, Singh M, Banzon V, Phiasivongsva P, et al. S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis). Journal of Translational Medicine. 2010;8(1):1.
86. Fibach E, Kollia P, Schechter A, Noguchi C, Rodgers G. Hemin-induced acceleration of hemoglobin production in immature cultured erythroid cells: preferential enhancement of fetal hemoglobin. Blood. 1995;85(10):2967-74.
87. Scott MD, Eaton JW. Thalassaemic erythrocytes: cellular suicide arising from iron and glutathione‐dependent oxidation reactions? British Journal of Haematology. 1995;91(4):811-9.
88. Moutouh-de Parseval LA, Verhelle D, Glezer E, Jensen-Pergakes K, Ferguson GD, Corral LG, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. The Journal of clinical investigation. 2008;118(1):248-58.
89. Masera N, Tavecchia L, Capra M, Cazzaniga G, Vimercati C, Pozzi L, et al. Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy. Blood Transfus. 2010;8(1):63-5.
90. Meiler SE, Wade M, Kutlar F, Yerigenahally SD, Xue Y, Moutouh-de Parseval LA, et al. Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood. 2011;118(4):1109-12.
91. Dehghani-Fard A, Kaviani S, Saki N, Mortaz E. The emerging role of immunomodulatory agents in fetal hemoglobin induction. International Journal of Hematology-Oncology and Stem Cell Research. 2015;6(4):35-6.
92. Quek L, Thein SL. Molecular therapies in β‐thalassaemia. British Journal of Haematology. 2007;136(3):353-65.
93. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839-42.
94. Zhou D, Liu K, Sun C-W, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and [gamma]-to [beta]-globin gene switching. Nature Genetics. 2010;42(9):742-4.
95. Bradner JE, Mak R, Tanguturi SK, Mazitschek R, Haggarty SJ, Ross K, et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proceedings of the National Academy of Sciences. 2010;107(28):12617-22.
96. Satta S, Perseu L, Moi P, Asunis I, Cabriolu A, Maccioni L, et al. Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. Haematologica. 2011;96(5):767-70.
97. Sankaran VG, Xu J, Byron R, Greisman HA, Fisher C, Weatherall DJ, et al. A functional element necessary for fetal hemoglobin silencing. New England Journal of Medicine. 2011;365(9):807-14.
98. Jiang J, Best S, Menzel S, Silver N, Lai MI, Surdulescu GL, et al. cMYB is involved in the regulation of fetal hemoglobin production in adults. Blood. 2006;108(3):1077-83.
99. Lopez RA, Schoetz S, DeAngelis K, O'Neill D, Bank A. Multiple hematopoietic defects and delayed globin switching in Ikaros null mice. Proceedings of the National Academy of Sciences. 2002;99(2):602-7.
100. Tanabe O, Katsuoka F, Campbell AD, Song W, Yamamoto M, Tanimoto K, et al. An embryonic/fetal β‐type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. The EMBO journal. 2002;21(13):3434-42.
101. Jane SM, Nienhuis AW, Cunningham JM. Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein. The EMBO Journal. 1995;14(1):97-105.