UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Fetal hemoglobin (hemoglobin F) in health and disease

Authors
Martin H Steinberg, MD
Swee Lay Thein, MD, FRCP, FRCPath, DSc
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Fetal hemoglobin (hemoglobin F, HbF) is the major hemoglobin present during gestation; it constitutes approximately 60 to 80 percent of total hemoglobin in the full-term newborn. It is almost completely replaced by adult hemoglobin (hemoglobin A, HbA) by approximately 6 to 12 months of age, and it amounts to less than 1 percent of total hemoglobin in the adult.

As a minor hemoglobin in the normal child and adult, HbF has little in the way of clinical relevance in normal physiology. However, it is assuming ever greater importance in certain of the hemoglobinopathies, in which congenital, acquired, and drug-induced increases in HbF have been shown to improve the clinical performance of affected individuals with sickle cell disease and beta thalassemia. This important subject is discussed in depth separately. (See "Hydroxyurea and other disease-modifying therapies in sickle cell disease" and "Treatment of beta thalassemia", section on 'Manipulation of fetal hemoglobin switching'.)

The biology of HbF in health and disease will be discussed here. Reviews of the other normal hemoglobins (eg, hemoglobin A, hemoglobin A2) and the most common hemoglobin mutations are presented separately. (See "Structure and function of normal hemoglobins" and "Introduction to hemoglobin mutations".)

BIOLOGY OF FETAL HEMOGLOBIN

Evolution — Hemoglobin evolved from ancient hemoproteins by gene duplication, gene conversion (non-reciprocal exchange of genetic material between two linked homologous genes), translocation to different chromosomes, and mutations that caused changes in the primary structure and properties of globin and their various genetic regulatory regions [1].

Human alpha- (HBA1 and HBA2) and beta- (HBB) globin gene clusters diverged from their predecessors approximately 450 million years ago, with modern adult hemoglobin becoming a heterotetramer of the products of these two genes (alpha2beta2).

                                          

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Mar 28 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Hardison RC. Evolution of hemoglobin and its genes. Cold Spring Harb Perspect Med 2012; 2:a011627.
  2. Adachi K, Kim J, Asakura T, Schwartz E. Characterization of two types of fetal hemoglobin: alpha 2G gamma 2 and alpha 2A gamma 2. Blood 1990; 75:2070.
  3. Slightom JL, Blechl AE, Smithies O. Human fetal G gamma- and A gamma-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell 1980; 21:627.
  4. Ricco G, Mazza U, Turi RM, et al. Significance of a new type of human fetal hemoglobin carrying a replacement isoleucine replaced by threonine at position 75 )E 19) of the gamma chain. Hum Genet 1976; 32:305.
  5. Yagami T, Ballard BT, Padovan JC, et al. N-terminal contributions of the gamma-subunit of fetal hemoglobin to its tetramer strength: remote effects at subunit contacts. Protein Sci 2002; 11:27.
  6. Shear HL, Grinberg L, Gilman J, et al. Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism. Blood 1998; 92:2520.
  7. Amaratunga C, Lopera-Mesa TM, Brittain NJ, et al. A role for fetal hemoglobin and maternal immune IgG in infant resistance to Plasmodium falciparum malaria. PLoS One 2011; 6:e14798.
  8. Frier JA, Perutz MF. Structure of human foetal deoxyhaemoglobin. J Mol Biol 1977; 112:97.
  9. McDonald MJ, Turci SM, Mrabet NT, et al. The kinetics of assembly of normal and variant human oxyhemoglobins. J Biol Chem 1987; 262:5951.
  10. SCHROEDER WA, CUA JT, MATSUDA G, FENNINGER WD. Hemoglobin F1, an acetyl-containing hemoglobin. Biochim Biophys Acta 1962; 63:532.
  11. Barbosa CG, Goncalves-Santos NJ, Souza-Ribeiro SB, et al. Promoter region sequence differences in the A and G gamma globin genes of Brazilian sickle cell anemia patients. Braz J Med Biol Res 2010; 43:705.
  12. Bard H, Peri KG, Gagnon C. Changes in the G gamma- and A gamma-globin mRNA components of fetal hemoglobin during human development. Biol Neonate 2001; 80:26.
  13. Galarneau G, Palmer CD, Sankaran VG, et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 2010; 42:1049.
  14. BETKE K, MARTI HR, SCHLICHT I. Estimation of small percentages of foetal haemoglobin. Nature 1959; 184(Suppl 24):1877.
  15. Kazanetz EG, Smetanina NS, Adekile AD, et al. Variability in the fetal hemoglobin level of the normal adult. Am J Hematol 1996; 53:59.
  16. Mundee Y, Bigelow NC, Davis BH, Porter JB. Flow cytometric method for simultaneous assay of foetal haemoglobin containing red cells, reticulocytes and foetal haemoglobin containing reticulocytes. Clin Lab Haematol 2001; 23:149.
  17. Steinberg MH, Lu ZH, Barton FB, et al. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood 1997; 89:1078.
  18. Dover GJ, Boyer SH. Hemoglobin determinations in single cells: Comparison of different techniques. Prog Clin Biol Res 1981; 60:115.
  19. Boyer SH, Belding TK, Margolet L, Noyes AN. Fetal hemoglobin restriction to a few erythrocytes (F cells) in normal human adults. Science 1975; 188:361.
  20. Dover GJ, Boyer SH. Quantitation of hemoglobins within individual red cells: asynchronous biosynthesis of fetal and adult hemoglobin during erythroid maturation in normal subjects. Blood 1980; 56:1082.
  21. HOSOI T. STUDIES ON HEMOGLOBIN F WITHIN SINGLE ERYTHROCYTE BY FLUORESCENT ANTIBODY TECHNIQUE. Exp Cell Res 1965; 37:680.
  22. Dover GJ, Boyer SH, Charache S, Heintzelman K. Individual variation in the production and survival of F cells in sickle-cell disease. N Engl J Med 1978; 299:1428.
  23. Franco RS, Lohmann J, Silberstein EB, et al. Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. J Clin Invest 1998; 101:2730.
  24. Dover GJ, Boyer SH, Bell WR. Microscopic method for assaying F cell production: illustrative changes during infancy and in aplastic anemia. Blood 1978; 52:664.
  25. Thein SL, Craig JE. Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. Hemoglobin 1998; 22:401.
  26. Creary LE, McKenzie CA, Menzel S, et al. Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic loci controlling fetal haemoglobin. Br J Haematol 2009; 144:954.
  27. Zago MA, Wood WG, Clegg JB, et al. Genetic control of F cells in human adults. Blood 1979; 53:977.
  28. Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders. Blood 2012; 120:2945.
  29. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3:a011643.
  30. Ginder GD. Epigenetic regulation of fetal globin gene expression in adult erythroid cells. Transl Res 2015; 165:115.
  31. Deng W, Lee J, Wang H, et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 2012; 149:1233.
  32. Deng W, Rupon JW, Krivega I, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 2014; 158:849.
  33. Perrine SP. Hemoglobin F: new targets, new path. Blood 2006; 108:783.
  34. Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol 2009; 145:455.
  35. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet 2009; 18:R216.
  36. Dulmovits BM, Appiah-Kubi AO, Papoin J, et al. Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors. Blood 2016; 127:1481.
  37. Labie D, Pagnier J, Lapoumeroulie C, et al. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci U S A 1985; 82:2111.
  38. Thein SL, Weatherall DJ. A non-deletion hereditary persistance of fetal hemoglobin (HPFH) determinant not linked to the beta-globin gene complex. In: Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms, Stamatoyannopoulos G, Nienhuis AW (Eds), Alan R Liss, Inc, New York 1989. p.97.
  39. Thein SL, Sampietro M, Rohde K, et al. Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers. Am J Hum Genet 1994; 54:214.
  40. Menzel S, Garner C, Gut I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet 2007; 39:1197.
  41. Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A 2008; 105:1620.
  42. Yu Y, Wang J, Khaled W, et al. Bcl11a is essential for lymphoid development and negatively regulates p53. J Exp Med 2012; 209:2467.
  43. Liu P, Keller JR, Ortiz M, et al. Bcl11a is essential for normal lymphoid development. Nat Immunol 2003; 4:525.
  44. Yin B, Delwel R, Valk PJ, et al. A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene. Blood 2009; 113:1075.
  45. Thein SL, Menzel S, Peng X, et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A 2007; 104:11346.
  46. Sedgewick AE, Timofeev N, Sebastiani P, et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis 2008; 41:255.
  47. Bhatnagar P, Purvis S, Barron-Casella E, et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet 2011; 56:316.
  48. Bae HT, Baldwin CT, Sebastiani P, et al. Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood 2012; 120:1961.
  49. Lettre G, Sankaran VG, Bezerra MA, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 2008; 105:11869.
  50. Makani J, Menzel S, Nkya S, et al. Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia. Blood 2011; 117:1390.
  51. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009; 461:747.
  52. Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet 2010; 42:801.
  53. Borg J, Patrinos GP, Felice AE, Philipsen S. Erythroid phenotypes associated with KLF1 mutations. Haematologica 2011; 96:635.
  54. Helias V, Saison C, Peyrard T, et al. Molecular analysis of the rare in(Lu) blood type: toward decoding the phenotypic outcome of haploinsufficiency for the transcription factor KLF1. Hum Mutat 2013; 34:221.
  55. Arnaud L, Saison C, Helias V, et al. A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. Am J Hum Genet 2010; 87:721.
  56. Jaffray JA, Mitchell WB, Gnanapragasam MN, et al. Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood Cells Mol Dis 2013; 51:71.
  57. Viprakasit V, Ekwattanakit S, Riolueang S, et al. Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Blood 2014; 123:1586.
  58. Magor GW, Tallack MR, Gillinder KR, et al. KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. Blood 2015; 125:2405.
  59. Liu D, Zhang X, Yu L, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of β-thalassemia. Blood 2014; 124:803.
  60. Satta S, Perseu L, Moi P, et al. Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. Haematologica 2011; 96:767.
  61. Gallienne AE, Dréau HM, Schuh A, et al. Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults. Haematologica 2012; 97:340.
  62. Ngo D, Bae H, Steinberg MH, et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol Dis 2013; 51:22.
  63. Mtatiro SN, Singh T, Rooks H, et al. Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania. PLoS One 2014; 9:e111464.
  64. Esteghamat F, Gillemans N, Bilic I, et al. Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. Blood 2013; 121:2553.
  65. Zhou D, Liu K, Sun CW, et al. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 2010; 42:742.
  66. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood 2011; 118:2044.
  67. Yien YY, Bieker JJ. EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Mol Cell Biol 2013; 33:4.
  68. Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008; 322:1839.
  69. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013; 342:253.
  70. Xu J, Bauer DE, Kerenyi MA, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci U S A 2013; 110:6518.
  71. Xu J, Sankaran VG, Ni M, et al. Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev 2010; 24:783.
  72. Canver MC, Smith EC, Sher F, et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 2015; 527:192.
  73. Basak A, Hancarova M, Ulirsch JC, et al. BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. J Clin Invest 2015; 125:2363.
  74. Funnell AP, Prontera P, Ottaviani V, et al. 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 2015; 126:89.
  75. Stadhouders R, Aktuna S, Thongjuea S, et al. Common intergenic polymorphisms affect long-range transcriptional regulation of MYB modulating fetal hemoglobin and other erythroid traits. J Clin Invest 2014.
  76. Stadhouders R, Thongjuea S, Andrieu-Soler C, et al. Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development. EMBO J 2012; 31:986.
  77. Suzuki M, Yamazaki H, Mukai HY, et al. Disruption of the Hbs1l-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model. Mol Cell Biol 2013; 33:1687.
  78. Farrell JJ, Sherva RM, Chen ZY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood 2011; 117:4935.
  79. Vegiopoulos A, García P, Emambokus N, Frampton J. Coordination of erythropoiesis by the transcription factor c-Myb. Blood 2006; 107:4703.
  80. Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer 2008; 8:523.
  81. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol 2005; 33:259.
  82. Bianchi E, Zini R, Salati S, et al. c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression. Blood 2010; 116:e99.
  83. Tallack MR, Perkins AC. Three fingers on the switch: Krüppel-like factor 1 regulation of γ-globin to β-globin gene switching. Curr Opin Hematol 2013; 20:193.
  84. Menzel S, Garner C, Rooks H, et al. HbA2 levels in normal adults are influenced by two distinct genetic mechanisms. Br J Haematol 2013; 160:101.
  85. Ganesh SK, Zakai NA, van Rooij FJ, et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 2009; 41:1191.
  86. Soranzo N, Spector TD, Mangino M, et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 2009; 41:1182.
  87. van der Harst P, Zhang W, Mateo Leach I, et al. Seventy-five genetic loci influencing the human red blood cell. Nature 2012; 492:369.
  88. Kamatani Y, Matsuda K, Okada Y, et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 2010; 42:210.
  89. Menzel S, Jiang J, Silver N, et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood 2007; 110:3624.
  90. Welch JJ, Watts JA, Vakoc CR, et al. Global regulation of erythroid gene expression by transcription factor GATA-1. Blood 2004; 104:3136.
  91. Sankaran VG, Menne TF, Šćepanović D, et al. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci U S A 2011; 108:1519.
  92. Sankaran VG, Joshi M, Agrawal A, et al. Rare complete loss of function provides insight into a pleiotropic genome-wide association study locus. Blood 2013; 122:3845.
  93. Masuda T, Wang X, Maeda M, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 2016; 351:285.
  94. Wood WG. Hereditary persistence of fetal hemoglobin and δβ thalassemia. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Steinberg MH, Forget BG, Higgs DR, Nagel RL (Eds), Cambridge University Press, Cambridge 2001. Vol 1, p.356.
  95. Neishabury M, Azarkeivan A, Oberkanins C, et al. Analyzing 5'HS3 and 5'HS4 LCR core regions and NF-E2 in Iranian thalassemia intermedia patients with normal or carrier status for beta-globin mutations. Blood Cells Mol Dis 2011; 46:201.
  96. Solovieff N, Milton JN, Hartley SW, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. Blood 2010; 115:1815.
  97. Suzuki M, Yamamoto M, Engel JD. Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies. Mol Cell Biol 2014; 34:3560.
  98. Shi L, Cui S, Engel JD, Tanabe O. Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med 2013; 19:291.
  99. van Dijk TB, Gillemans N, Stein C, et al. Friend of Prmt1, a novel chromatin target of protein arginine methyltransferases. Mol Cell Biol 2010; 30:260.
  100. Bradner JE, Mak R, Tanguturi SK, et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci U S A 2010; 107:12617.
  101. Hahn CK, Lowrey CH. Induction of fetal hemoglobin through enhanced translation efficiency of γ-globin mRNA. Blood 2014; 124:2730.
  102. Bard H. Postnatal fetal and adult hemoglobin synthesis in early preterm newborn infants. J Clin Invest 1973; 52:1789.
  103. Bard H, Prosmanne J. Relative rates of fetal hemoglobin and adult hemoglobin synthesis in cord blood of infants of insulin-dependent diabetic mothers. Pediatrics 1985; 75:1143.
  104. Perrine SP, Greene MF, Faller DV. Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med 1985; 312:334.
  105. Perrine SP, Rudolph A, Faller DV, et al. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci U S A 1988; 85:8540.
  106. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328:81.
  107. Kutlar A, Ataga K, Reid M, et al. A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. Am J Hematol 2012; 87:1017.
  108. Fucharoen S, Inati A, Siritanaratku N, 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 2013; 161:587.
  109. Popat N, Wood WG, Weatherall DJ, Turnbull AC. Pattern of maternal F-cell production during pregnancy. Lancet 1977; 2:377.
  110. HUEHNS ER, HECHT F, KEIL JV, MOTULSKY AG. DEVELOPMENTAL HEMOGLOBIN ANOMALIES IN A CHROMOSOMAL TRIPLICATION: D1 TRISOMY SYNDROME. Proc Natl Acad Sci U S A 1964; 51:89.
  111. Sankaran VG, Sapp MV. Persistence of fetal hemoglobin expression in an older child with trisomy 13. J Pediatr 2012; 160:352.
  112. Xiang J, Wu DC, Chen Y, Paulson RF. In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood 2015; 125:1803.
  113. Sheridan BL, Weatherall DJ, Clegg JB, et al. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol 1976; 32:487.
  114. Alter BP, Rappeport JM, Huisman TH, et al. Fetal erythropoiesis following bone marrow transplantation. Blood 1976; 48:843.
  115. Dover GJ, Boyer SH, Zinkham WH. Production of erythrocytes that contain fetal hemoglobin in anemia. Transient in vivo changes. J Clin Invest 1979; 63:173.
  116. Papayannopoulou T, Vichinsky E, Stamatoyannopoulos G. Fetal Hb production during acute erythroid expansion. I. Observations in patients with transient erythroblastopenia and post-phlebotomy. Br J Haematol 1980; 44:535.
  117. Hahn CK, Lowrey CH. Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism. Blood 2013; 122:477.
  118. Weinberg RS, Ji X, Sutton M, et al. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood 2005; 105:1807.
  119. Alter BP. Fetal erythropoiesis in stress hematopoiesis. Exp Hematol 1979; 7 Suppl 5:200.
  120. Alter BP, Rosenberg PS, Day T, et al. Genetic regulation of fetal haemoglobin in inherited bone marrow failure syndromes. Br J Haematol 2013; 162:542.
  121. Weatherall DJ, Clegg JB, Wood WG, et al. Foetal erythropoiesis in human leukaemia. Nature 1975; 257:710.
  122. Weatherall DJ, Edwards JA, Donohoe WT. Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia. Br Med J 1968; 1:679.
  123. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 1997; 89:3534.
  124. Dover GJ, Boyer SH, Zinkham WH, et al. Changing erythrocyte populations in juvenile chronic myelocytic leukemia: evidence for disordered regulation. Blood 1977; 49:355.
  125. Papayannopoulou T, Nakamoto B, Anagnou NP, et al. Expression of embryonic globins by erythroid cells in juvenile chronic myelocytic leukemia. Blood 1991; 77:2569.
  126. Passmore SJ, Hann IM, Stiller CA, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 1995; 85:1742.
  127. Craig JE, Sampietro M, Oscier DG, et al. Myelodysplastic syndrome with karyotype abnormality is associated with elevated F-cell production. Br J Haematol 1996; 93:601.
  128. Krauss JS, Rodriguez AR, Milner PF. Erythroleukemia with high fetal hemoglobin after therapy for ovarian carcinoma. Am J Clin Pathol 1981; 76:721.
  129. Chudwin DS, Rucknagel DL, Scholnik AP, et al. Fetal hemoglobin and alpha-fetoprotein in various malignancies. Acta Haematol 1977; 58:288.
  130. Stewart C. The occurrence of foetal haemoglobin in a patient with hepatoma. Med J Aust 1971; 2:664.
  131. Nyman M, Skölling R, Steiner H. Acquired macrocytic anemia and hemoglobinopathy--a paraneoplastic manifestation? Am J Med 1970; 48:792.
  132. Wood WG. Increased HbF in adult life. In: Baillière's Clinical Haematology: International Practice and Research, Higgs DR, Weatherall DJ (Eds), Baillière Tindall, W.B. Saunders, London 1993. Vol 1, p.177.
  133. Thein SL. Pathophysiology of beta thalassemia--a guide to molecular therapies. Hematology Am Soc Hematol Educ Program 2005; :31.
  134. Thein SL, Rees D. Haemoglobin and the inherited disorders of globin synthesis. In: Postgraduate Haematology, 6th ed, Hoffbrand AV, Catovsky D, Tuddenham EG, Green AR (Eds), Wiley-Blackwell, 2011. p.83.
  135. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes, 4th ed, Blackwell Science, Oxford 2001.
  136. Thein SL. The molecular basis of β-thalassemia. Cold Spring Harb Perspect Med 2013; 3:a011700.
  137. Craig JE, Kelly SJ, Barnetson R, Thein SL. Molecular characterization of a novel 10.3 kb deletion causing beta-thalassaemia with unusually high Hb A2. Br J Haematol 1992; 82:735.
  138. Ho PJ, Hall GW, Luo LY, et al. Beta-thalassaemia intermedia: is it possible consistently to predict phenotype from genotype? Br J Haematol 1998; 100:70.
  139. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010; 5:11.
  140. Garner C, Tatu T, Reittie JE, et al. Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood 2000; 95:342.
  141. Garner C, Tatu T, Game L, et al. A candidate gene study of F cell levels in sibling pairs using a joint linkage and association analysis. GeneScreen 2000; 1:9.
  142. Badens C, Joly P, Agouti I, et al. Variants in genetic modifiers of β-thalassemia can help to predict the major or intermedia type of the disease. Haematologica 2011; 96:1712.
  143. Nuinoon M, Makarasara W, Mushiroda T, et al. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet 2010; 127:303.
  144. So CC, Song YQ, Tsang ST, et al. The HBS1L-MYB intergenic region on chromosome 6q23 is a quantitative trait locus controlling fetal haemoglobin level in carriers of beta-thalassaemia. J Med Genet 2008; 45:745.
  145. Galanello R, Sanna S, Perseu L, et al. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood 2009; 114:3935.
  146. Danjou F, Anni F, Perseu L, et al. Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion. Haematologica 2012; 97:989.
  147. Danjou F, Francavilla M, Anni F, et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica 2015; 100:452.
  148. Chakalova L, Osborne CS, Dai YF, et al. The Corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression. Blood 2005; 105:2154.
  149. Galanello R, Melis MA, Podda A, et al. Deletion delta-thalassemia: the 7.2 kb deletion of Corfu delta beta-thalassemia in a non-beta-thalassemia chromosome. Blood 1990; 75:1747.
  150. Kulozik AE, Yarwood N, Jones RW. The Corfu delta beta zero thalassemia: a small deletion acts at a distance to selectively abolish beta globin gene expression. Blood 1988; 71:457.
  151. Sankaran VG, Xu J, Byron R, et al. A functional element necessary for fetal hemoglobin silencing. N Engl J Med 2011; 365:807.
  152. Feingold EA, Forget BG. The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster. Blood 1989; 74:2178.
  153. Tuan D, Feingold E, Newman M, et al. Different 3' end points of deletions causing delta beta-thalassemia and hereditary persistence of fetal hemoglobin: implications for the control of gamma-globin gene expression in man. Proc Natl Acad Sci U S A 1983; 80:6937.
  154. http://globin.cse.psu.edu (Accessed on February 11, 2014).
  155. Giardine B, Borg J, Higgs DR, et al. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nat Genet 2011; 43:295.
  156. Toma S, Tenorio M, Oakley M, et al. Two novel mutations (HBG1: c.-250C > T and HBG2: c.-250C > T) associated with hereditary persistence of fetal hemoglobin. Hemoglobin 2014; 38:67.
  157. Shimasaki S, Iuchi I. Diversity of human gamma-globin gene loci including a quadruplicated arrangement. Blood 1986; 67:784.
  158. Thein SL, Hill FG, Weatherall DJ. Haematological phenotype of the triplicated gamma-globin gene arrangement. Br J Haematol 1984; 57:349.
  159. Rodgers GP, Steinberg MH. Pharmacologic treatment of sickle cell disease and thalassemia: The augmentation of fetal hemoglobin. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Steinberg MH, Forget BG, Higgs DR, Nagel RL (Eds), Cambridge University Press, Cambridge 2001. Vol 1, p.1028.
  160. Adekile AD. Historical and anthropological correlates of beta S haplotypes and alpha- and beta-thalassemia alleles in the Arabian Peninsula. Hemoglobin 1997; 21:281.
  161. Lapouméroulie C, Dunda O, Ducrocq R, et al. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet 1992; 89:333.
  162. Nagel RL. Origins and dispersion of the sickle g. In: Cell Disease: Basic Principles and Clinical Practice, mbury SH, Hebbel RP, Mohandas N, Steinberg MH (Eds), Raven Press, New York 1994. Vol 1, p.353.
  163. Green NS, Fabry ME, Kaptue-Noche L, Nagel RL. Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia. Am J Hematol 1993; 44:145.
  164. Nagel RL, Rao SK, Dunda-Belkhodja O, et al. The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between G gamma and HbF level. Blood 1987; 69:1026.
  165. Nagel RL, Fabry ME, Pagnier J, et al. Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type. N Engl J Med 1985; 312:880.
  166. Pembrey ME, Wood WG, Weatherall DJ, Perrine RP. Fetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia. Br J Haematol 1978; 40:415.
  167. Bhanushali AA, Patra PK, Nair D, et al. Genetic variant in the BCL11A (rs1427407), but not HBS1-MYB (rs6934903) loci associate with fetal hemoglobin levels in Indian sickle cell disease patients. Blood Cells Mol Dis 2015; 54:4.
  168. Pule GD, Ngo Bitoungui VJ, Chetcha Chemegni B, et al. Association between Variants at BCL11A Erythroid-Specific Enhancer and Fetal Hemoglobin Levels among Sickle Cell Disease Patients in Cameroon: Implications for Future Therapeutic Interventions. OMICS 2015; 19:627.
  169. Bitoungui VJ, Ngogang J, Wonkam A. Polymorphism at BCL11A compared to HBS1L-MYB loci explains less of the variance in HbF in patients with sickle cell disease in Cameroon. Blood Cells Mol Dis 2015; 54:268.
  170. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330:1639.
  171. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984; 63:921.
  172. Steinberg MH, Forget BJ, Higgs DH, Weatherall DJ. Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, 2nd ed, Cambridge University Press, Cambridge 2009.
  173. Milton JN, Gordeuk VR, Taylor JG 6th, et al. Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction models. Circ Cardiovasc Genet 2014; 7:110.
  174. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21:37.
  175. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers in patients with sickle cell disease. Blood 1989; 74:1403.
  176. Nolan VG, Adewoye A, Baldwin C, et al. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol 2006; 133:570.
  177. Taylor JG 6th, Nolan VG, Mendelsohn L, et al. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One 2008; 3:e2095.
  178. Ngo DA, Aygun B, Akinsheye I, et al. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br J Haematol 2012; 156:259.
  179. Horiuchi K, Osterhout ML, Kamma H, et al. Estimation of fetal hemoglobin levels in individual red cells via fluorescence image cytometry. Cytometry 1995; 20:261.
  180. Maier-Redelsperger M, Noguchi CT, de Montalembert M, et al. Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease. Blood 1994; 84:3182.
  181. Fertrin KY, van Beers EJ, Samsel L, et al. Imaging flow cytometry documents incomplete resistance of human sickle F-cells to ex vivo hypoxia-induced sickling. Blood 2014; 124:658.
  182. Buchanan GR. "Packaging" of fetal hemoglobin in sickle cell anemia. Blood 2014; 123:464.
  183. Steinberg MH, Chui DH, Dover GJ, et al. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014; 123:481.
  184. Jeffers A, Gladwin MT, Kim-Shapiro DB. Computation of plasma hemoglobin nitric oxide scavenging in hemolytic anemias. Free Radic Biol Med 2006; 41:1557.
  185. Deonikar P, Kavdia M. Low micromolar intravascular cell-free hemoglobin concentration affects vascular NO bioavailability in sickle cell disease: a computational analysis. J Appl Physiol (1985) 2012; 112:1383.
  186. Akinsheye I, Solovieff N, Ngo D, et al. Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans. Am J Hematol 2012; 87:217.
  187. Acquaye JK, Omer A, Ganeshaguru K, et al. Non-benign sickle cell anaemia in western Saudi Arabia. Br J Haematol 1985; 60:99.
  188. Al-Jam'a AH, Al-Dabbous IA, Chirala SK, et al. Splenic function in sickle cell anemia patients in Qatif, Saudi Arabia. Am J Hematol 2000; 63:68.
  189. Annobil SH, Omojola MF, Adzaku FK, et al. Cerebrovascular accidents (strokes) in children with sickle cell disease residing at high and low altitudes of Saudi Arabia. Ann Trop Paediatr 1990; 10:191.
  190. Padmos MA, Roberts GT, Sackey K, et al. Two different forms of homozygous sickle cell disease occur in Saudi Arabia. Br J Haematol 1991; 79:93.
  191. Alsultan A, Solovieff N, Aleem A, et al. Fetal hemoglobin in sickle cell anemia: Saudi patients from the Southwestern province have similar HBB haplotypes but higher HbF levels than African Americans. Am J Hematol 2011; 86:612.
  192. el-Hazmi MA. Heterogeneity and variation of clinical and haematological expression of haemoglobin S in Saudi Arabs. Acta Haematol 1992; 88:67.
  193. Kulozik AE, Bail S, Kar BC, et al. Sickle cell-beta+ thalassaemia in Orissa State, India. Br J Haematol 1991; 77:215.
  194. Kulozik AE, Kar BC, Satapathy RK, et al. Fetal hemoglobin levels and beta (s) globin haplotypes in an Indian populations with sickle cell disease. Blood 1987; 69:1742.
  195. Kulozik AE, Wainscoat JS, Serjeant GR, et al. Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am J Hum Genet 1986; 39:239.
  196. Perrine RP, Brown MJ, Clegg JB, et al. Benign sickle-cell anaemia. Lancet 1972; 2:1163.
  197. Pembrey ME, Perrine RP, Wood WG, Weatherall DJ. Sickle beta 0 thalassemia in Eastern Saudi Arabia. Am J Hum Genet 1980; 32:26.
  198. Perrine RP, Pembrey ME, John P, et al. Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann Intern Med 1978; 88:1.
  199. Adekile AD. Limitations of Hb F as a phenotypic modifier in sickle cell disease: study of Kuwaiti Arab patients. Hemoglobin 2011; 35:607.
  200. Marouf R, Gupta R, Haider MZ, Adekile AD. Silent brain infarcts in adult Kuwaiti sickle cell disease patients. Am J Hematol 2003; 73:240.
  201. Marouf R, Gupta R, Haider MZ, et al. Avascular necrosis of the femoral head in adult Kuwaiti sickle cell disease patients. Acta Haematol 2003; 110:11.
  202. Alsultan A, Ngo D, Bae H, et al. Genetic studies of fetal hemoglobin in the Arab-Indian haplotype sickle cell-β(0) thalassemia. Am J Hematol 2013; 88:531.
Topic Outline

GRAPHICS