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Fetal hemoglobin (Hb F) in health and disease

Fetal hemoglobin (Hb F) in health and disease
Literature review current through: Sep 2023.
This topic last updated: Jun 13, 2023.

INTRODUCTION — Fetal hemoglobin (Hb F; alpha2gamma2) is the major hemoglobin in fetal red blood cells (RBCs) during gestation and constitutes 60 to 80 percent of total hemoglobin in the full-term newborn. By approximately 6 to 12 months of age, Hb F is almost completely replaced by adult hemoglobin (Hb A; alpha2beta2).

Regulation of Hb F and clinical implications of increased Hb F are discussed here. Other normal hemoglobins and RBC production are reviewed separately. (See "Structure and function of normal hemoglobins" and "Regulation of erythropoiesis".)

BIOLOGY OF Hb F

Globin evolution and genomic organization — Human Hb F arose from millennia of evolution of ancient hemoproteins by gene duplication, deletions, conversions, inactivations, mutations, and translocations to different chromosomes that resulted in altered regulatory control and globin function [1,2]. Functional hemoglobins are tetramers of two alpha and two non-alpha globin chains. (See "Structure and function of normal hemoglobins".)

Hb F evolved to potentiate the transfer of oxygen (O2) from maternal blood to fetal tissues, a goal achieved by the higher O2 affinity of Hb F compared with adult Hb A. This is largely due to the insensitivity of Hb F to 2,3 BPG (sometimes called 2,3 DPG), the major modulator of hemoglobin-O2 affinity. Modern human globin genes reside in two separate gene clusters (figure 1).

Alpha globin locus – The alpha globin locus, near the telomere of the short arm of chromosome 16 (16p13.3), has three globin coding genes:

Two alpha globin genes (HBA2 and HBA1)

The embryonic alpha-like zeta globin gene (HBZ)

Beta globin locus – The beta globin locus, on the short arm of chromosome 11 (11p15.5), has five globin coding genes:

An embryonic epsilon globin gene (HBE1)

Two gamma globin genes (HBG2, also called Gγ [G-gamma] and HBG1, also called Aγ [A-gamma]; together referred to herein as HBG), expressed predominantly in the fetal liver and bone marrow and forming Hb F (alpha2gamma2)

A delta globin gene (HBD), coding for the minor adult hemoglobin Hb A2 (alpha2delta2)

The beta globin gene (HBB), coding for the major adult hemoglobin Hb A (alpha2beta2)

HBD and HBB are expressed in adults.

Gamma globin genes (HBG2 and HBG1) — HBG2 (Gy [G-gamma]) and HBG1 (Ay [A-gamma]) are 5' (upstream) of HBB (figure 1). (See 'Globin evolution and genomic organization' above.)

SequenceHBG2 and HBG1 share same the intron-exon structure of all human globins, with identical exons except at position 136, where HBG2 codes for glycine (G-gamma), while HBG1 codes for alanine (A-gamma) [3]. Whether position 136 is alanine or glycine does not affect Hb F function.

Expression HBG2 is expressed at higher values than HBG1 during fetal development. After the switch from production of Hb F to Hb A, G-gamma globin falls from approximately 70 percent at birth to approximately 40 percent six months postnatally. The HBG2 to HBG1 switch does not occur in individuals with the Xmn1 G-gamma site in the HBG2 promoter [4]. (See 'HBG2 Xmn1 polymorphism' below.)

HBG variants – The Globin Gene Server reports >140 variants affecting the structure or expression of the gamma globin genes (another resource is ithanet.eu). A common polymorphism found in HBG1, where threonine replaces isoleucine at codon gamma 75, is known as Hb F Sardinia [5]. It has no clinical significance. Hb F variants that affect hemoglobin stability can result in anemia (due to hemolysis) or cyanosis (due to methemoglobin formation), but these effects are only seen in neonates, as they "disappear" when Hb F values decline and Hb F is replaced by Hb A. (See "Unstable hemoglobin variants" and "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Methemoglobinemia", section on 'Hemoglobin M disease and cytochrome b5 deficiency'.)

Structural and functional properties of Hb F

Structural properties – Crystallographic studies of Hb F at 2.5 angstrom resolution show almost complete isomorphism between Hb A and Hb F, with the sole difference being located at the N-terminus [6].

Hb F has a strong globin-heme interaction and a lower rate of dimerization compared with Hb A [7]. Approximately 20 percent of Hb F in the developing fetus has an acetylated gamma globin N terminus [8]. An effect on Hb F function is likely minimal.

Amino acid sequence – Hb F and Hb A differ by 39 out of 146 amino acids. At position 87 the gamma (and delta) chain has a glutamine (Q) residue while the beta chain contains threonine (T). This single difference accounts in large part for the inhibitory effect of Hb F (and Hb A2) on Hb S polymerization [9]. Another residue contributing to the anti-polymerization effect of Hb F is aspartic acid at position 80. Glutamine (Q) 87 has been introduced into the Hb A gene (Hb AT87Q) as a gene addition therapy to successfully treat sickle cell disease and beta thalassemia. (See 'Cell-based therapeutics' below.)

Increased oxygen affinity – A major functional difference between Hb F and Hb A is their oxygen (O2) affinity. The higher O2 affinity of Hb F allows preferential transfer of O2 from the maternal to the fetal circulation during gestation. The P50 (partial pressure at which the hemoglobin molecule is half saturated with O2) is approximately 19 torr in cells with primarily Hb F compared with approximately 27 torr for Hb A-containing cells (figure 2). High O2 affinity is a feature of mammalian fetal hemoglobins, although a hemoglobin expressed predominantly in the fetal stage of development is not present in all mammals.

The difference in O2 affinity between Hb F and Hb A is primarily a result of the failure of Hb F to interact with the organic phosphate 2,3 BPG due to a serine at amino acid 143 in gamma globin, rather than the 143 histidine in beta globin. Solutions of Hb F in which organic phosphates have been removed have a P50 identical to that of Hb A. (See "Structure and function of normal hemoglobins", section on 'Oxygen affinity'.)

This single amino acid difference also alters the Bohr effect, through which an increase in blood acidity (decrease in pH) causes a shift in the P50 with increased release of O2 from hemoglobin. The Bohr effect of Hb F is 20 percent higher than that of Hb A, which maximizes O2 transport to the fetus, contributing to approximately half of the O2 transport between mother and fetus. (See "Structure and function of normal hemoglobins", section on 'pH'.)

Alkaline resistance – Hb F is more resistant to alkali compared with Hb A. Alkaline resistance may be due to two differences in the alpha1/gamma1 interface (gamma 112 threonine, which is a cysteine residue in beta globin, and gamma 130 tryptophan, which is a tyrosine in beta globin). This difference between Hb F and Hb A provided the basis for measuring Hb F by the historical but still used method of alkali denaturation [10]. The Kleihauer-Betke acid elution stain of blood smears is one method to detect maternal-fetal hemorrhage, although newer Hb F fluorescence activated cell sorting (FACS)-based methods are available [11]. (See "Spontaneous massive fetomaternal hemorrhage", section on 'Kleihauer-Betke assay'.)

Protection against malaria – A protective effect of Hb F against malaria is in part due to a stronger hemoglobin tetramer that less readily dissociates into digestible dimers [12]. Structural differences at amino acid positions 1, 5, and 7 in the amino-terminal alpha helix of gamma globin compared with beta globin account for the greater strength of the Hb F tetramer compared with Hb A [13,14]. Other mechanisms of malaria resistance conferred by Hb F might also occur [15]. However, some data have questioned the protective effects of Hb F on malaria [16]. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Fetal hemoglobin'.)

Hemoglobin switching and downregulation of Hb F expression — After the eighth week of gestation, Hb F replaces embryonic hemoglobins to become the predominant hemoglobin in the fetus, with values increasing until midway through gestation. The concentration of Hb F then decreases with increasing gestational age. If an infant is born prematurely at 28 weeks gestation, the concentration of Hb F is approximately 90 percent, decreasing to approximately 60 percent by 10 weeks after birth (38 weeks since conception) and equivalent to that of a full-term infant born at 38 weeks. (See "Anemia of prematurity (AOP)", section on 'Physiologic consequences'.)

After birth, Hb F is gradually but never totally replaced by Hb A, such that after approximately six months of age, Hb F comprises <1 percent of total hemoglobin. Hb F values are largely genetically controlled, with some contribution by the dynamics of erythropoiesis, which might be influenced by environmental factors [17]. Complex genetic regulation explains the lack of clear Mendelian inheritance patterns in some patients with increased Hb F [18,19]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Causes of non-Mendelian inheritance'.)

Switching from Hb F to Hb A involves repression of HBG (HBG2 and HBG1) and upregulation of HBB expression. Some of the key regulators are illustrated in the figure (figure 3).

Hemoglobin switching is the result of developmentally timed inactivation and activation of genes within the HBB cluster [20-26]. Switching also occurs in the alpha globin gene cluster with many of the same transcription factors involved. However, it is expression of HBG that allows the formation of Hb F [27]. Transcription factors involved in nuclear chromatin remodeling (NuRD) complexes, along with epigenetic modulation via chromatin "writers," "readers," and "erasers," which effect histone methylation and acetylation (such as DNA methyltransferases and demethylases) and interact with the locus control region (LCR), a super-enhancer approximately 60 kb upstream of the HBB cluster.

The DNA of the LCR loops back around to the region of the globin gene promoters, recruiting transcription factors such as GATA1, TAL1, E2A, LMO2, and LDB1, leading to silencing of the embryonic and fetal genes and activation of the adult globin genes. During development, repressors of HBG are active, allowing expression of the adult genes. Other developmental factors modulating hemoglobin switching include:

Long-noncoding (lnc) RNAs [28,29]

LIN28

IGF2BP

RNA-binding factors

Let-7 family microRNAs

Let-7 microRNAs are dramatically elevated in adult reticulocytes. Reduction of let-7, or over-expression of its regulator LIN28B, leads to increased HBG expression [30].

BCL11A (B cell lymphoma/leukemia 11A) and ZBTB7A (zinc finger and BTB domain-containing protein 7A; also called LRF [leukemia/lymphoma-related factor]) are the major repressors of HBG expression. When Hb F values are high, BCL11A values are very low or absent; as Hb F values fall, BCL11A values rise. LIN28B might also act independently of let-7 by directly binding BCL11A mRNA and preventing its effective translation. The absence of LIN28B expression in adult erythroid cells allows effective BCL11A protein synthesis, suppressing HBG expression [31].

ZBTB7A encodes a zinc finger transcription factor with an effect on Hb F gene silencing similar to BCL11A. Its inactivation in the HUDEP-2 cell line that expresses predominantly Hb A led to an increase in Hb F to approximately 50 percent. And knockout of both BCL11A and ZBTB7A was associated with >90 percent Hb F [32]. ZBTB7A is not polymorphic and does not appear to account for Hb F variation in individuals with sickle cell disease [33].

Quantitative trait loci associated with HBG expression — Quantitative trait loci (QTL) are genes or genetic regions that affect quantitative phenotypes along a continuum. Traits such as height and weight and the common Hb F variation do not follow a mendelian pattern of inheritance. They are referred to as complex traits, and a combination of QTLs account for their variation.

Three QTL have large effects on Hb F values and are highly polymorphic (showing a high degree of variation). (See "Genetics: Glossary of terms", section on 'Quantitative traits and quantitative trait loci (QTL)'.)

Polymorphisms within three QTL affect HBG expression:

BCL11A – Polymorphisms rs654815 and rs1427407. (See 'BCL11A' below.)

HBS1L and MYB intergenic region (HMIP)Polymorphisms rs66650371 and rs9399137. (See 'HBSIL-MYB intergenic region (HMIP)' below.)

HBG2 promotor (a locus in the promotor of HBG2 marked by a recognition site for the restriction endonuclease Xmn1) – Polymorphism rs7482144. (See 'HBG2 Xmn1 polymorphism' below.)

In one study of 581 individuals homozygous for the Hb S gene or with Hb S-beta0 thalassemia, these four polymorphisms accounted for 22 percent of Hb F variability in cohorts of individuals with sickle cell anemia, Hb S-β0 thalassemia, and Hb SC disease [34].

BCL11A — BCL11A (chromosome 2p16) codes for a zinc finger transcription factor that was first identified as a major QTL for Hb F by genome-wide association studies (GWAS).

Despite the complexity of hemoglobin switching and the dozens of transcription factors and other elements involved, knockdown of BCL11A activity, either by disrupting its erythroid enhancer or altering its major HBG binding sites, increases Hb F sufficiently so that its clinical effects are profound. (See 'Sickle cell disease' below.)

The functional variants of BCL11A are marked by single nucleotide polymorphisms (SNPs; also called single nucleotide variants) localized to an erythroid-specific enhancer in the second intron of the gene [35]. The erythroid-specific enhancer of BCL11A consists of three DNase hypersensitive sites located +62, +58, and +55 kb from the transcription initiation site. The sentinel SNP marking this QTL is rs1427407 at the +62 locus.

The features of the enhancer elements that have the greatest effect on HBG expression have been defined at near nucleotide resolution [36]. Naturally occurring variants and CRISPR-Cas9 mediated disruption of the BCL11A -115 binding site increased HBG expression. A point mutation at position -113 that causes hereditary persistence of fetal hemoglobin (HPFH) does not disrupt BCL11A binding but rather creates a de novo binding site for the transcriptional activator GATA1, thereby increasing Hb F [37]. (See 'Hereditary persistence of fetal hemoglobin (HPFH)' below.)

BCL11A enhancer variants associated with increased Hb F are present in approximately 20 percent of patients with sickle cell disease. The frequency of Hb F boosting variants differs among populations. BCL11A binds TGACCA motifs found at 35 sites in the HBB gene cluster, preferentially binding around position -115 bp relative to the transcription initiation site and overlapping CCAAT boxes in the HBG promoters. Turning HBG expression on or off is in large part a result of competition of BCL11A with NF-Y, the ubiquitous activator, for occupancy of the proximal CCAAT box of the HBG promoters; loss of either factor increases chromatin accessibility, thereby allowing NF-Y to gain partial competitive advantage [38]. Reducing the expression of the BCL11A ortholog in transgenic sickle cell mice resulted in derepression of HBG [39].

HBSIL-MYB intergenic region (HMIP) — MYB (chromosome 6q23) codes for a member of a large family of transcription factors that regulate cell cycle progression and differentiation; MYB regulates proliferation and maturation of erythroid cells and modulates gene expression within the HBB gene cluster.

The importance of MYB in regulating Hb F was first identified in a family from India and ultimately localized to variants in the intergenic region between HBS1L and MYB (also called HMIP, for HBSIL-MYB intergenic polymorphism, or HBFQTL2); this region contains an MYB enhancer [40]. Polymorphisms of this locus also impact platelet and monocyte counts, hematocrit, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) [41,42].

The functional/causative variant in HMIP associated with high Hb F is a 3 bp deletion in an enhancer 84 kb upstream of MYB that is in complete linkage disequilibrium with the two sentinel polymorphisms noted above (rs9399137 and rs66650371). The region of the 3 bp deletion binds TAL1, E47 GATA, RUNX1, LDB1 and KLF1. A DNA fragment including the region of this deletion had enhancer-like activity that was augmented by the introduction of the 3 bp deletion. Downregulation of a lncRNA transcribed from this region increased HBG expression [28,42-45].

HBG2 Xmn1 polymorphism — A polymorphism in the HBG2 promotor (chromosome 16) was the first Hb F QTL identified. (See 'Gamma globin genes (HBG2 and HBG1)' above.)

The HBG2 Xmn1 polymorphism first came to attention when it was noted that patients with sickle cell disease who had the Senegal and Arab Indian haplotypes of sickle cell disease had relatively higher Hb F compared to patients with the other haplotypes.

The two haplotypes had in common a single nucleotide C-T polymorphism 158 bp upstream of HBG2. CRISPR-Cas9 disruption of this site in CD34+ cells from patients with sickle cell disease caused an increase in gamma globin to approximately 25 percent, and 55±5 percent F cells, compared with 30 to 40 percent gamma globin and 75 to 80 percent F cells when BCL11A and ZBTB7A binding sites, respectively, were disrupted.

While BCL11A enhancer polymorphisms are associated with increased expression of both gamma globin genes only the HBG2 allele is affected by the -158 polymorphism. The transcription factor(s) binding to the -158 HBG2 motif are uncharacterized.

Other regulators of Hb F switching

KLF1 – Kruppel-like factor 1 (KLF1) is a major erythroid transcription factor that activates BCL11A and ZBTB7A and promotes HBB expression, as illustrated in the figure (figure 3) [46-50]. (See 'Hemoglobin switching and downregulation of Hb F expression' above and "Regulation of erythropoiesis", section on 'Krϋppel-like factor 1'.)

The role of the KLF1 gene in Hb F expression was originally identified in a family with beta thalassemia and HPFH; affected individuals had a nonsense mutation (K288X) that disrupted the ability of KLF1 to bind DNA [51]. Subsequent reports described KLF1 variants in individuals with other RBC disorders [52-60].

The T to C polymorphism at position -198 of the HBG1 gene promoter (responsible for British type HPFH) creates a binding site for KLF1 [61]. When this mutation was introduced into an erythroid cell line expressing Hb A, Hb F values rose substantially.

KLF1 binds to the promoter of ZBTB7A, increasing its expression, and also increases expression of BCL11A repressing HBG. Reduced KLF1 expression or activity is associated with Hb F derepression [62,63]. In CD34+ human progenitor cells, base editing at -123 and -124 bp in the HBG promoters increased Hb F to putatively therapeutic values, perhaps by creating a de novo KLF1 binding site.

KLF1 may also play a role in the silencing of HBE and HBZ expression [57]. Pathogenic variants in KLF1 have also been reported to cause pyruvate kinase deficiency. (See "Pyruvate kinase deficiency", section on 'Genetics'.)

A microRNA, miR-326, suppresses KLF1 expression directly by targeting its 3' untranslated region [50].

The pseudogene HHBBP1 appears to have a roles in hemoglobin switching that may be related to effects on chromatin structure [38,64-66].

Other factors that regulate Hb F switching

LSD1/CoREST (lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor), a histone demethylase complex [67]

SOX6, an HMG-box-containing transcription factor [68]

IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1), a possible posttranscriptional regulator of BCL11A abundance [69]

LIN28B, a BCL11A mRNA binding protein that prevents translation [31]

PRMTs (protein arginine methyltransferases) that suppress translation [70-72]

Other polymorphisms in the HBB cluster [64,73-75]

X-linked elements [76,77]

MicroRNAs-15a and 16-1, which contribute to MYB expression, and let-7 [30,78]

Orphan nuclear receptors TR2/TR4 (part of the DRED complex) [79-81]

Protein arginine methyltransferase PRMT5 [82]

Ubiquitin ligase substrate speckle-type POZ protein (SPOP)

Protein deacetylase SIRT1 [83,84]

Zinc-finger protein POGZ [85]

FOXO3 [86]

Translation initiation factor eIF2alpha [87]

Sp1 transcription factor [88]

ZNF410, a DNA-binding protein that activates NuRD component CHD4 [89-91]

ANTXR1, an anthrax toxin receptor [92,93]

Heme-regulated inhibitor (HRI) and downstream transcription factor ATF4 [94,95]

Epigenetic regulators [65,66,96,97]

BGLT3 linc (long intergenic noncoding) RNA [29]

The emerging understanding of Hb F regulation has provided new insights and opportunities for therapeutic Hb F reactivation [20,98,99]. Therapeutic targeting of BCL11A expression or BCL11A binding and other strategies to turn off or reverse hemoglobin switching therapeutically are under clinical development to treat sickle cell disease and beta thalassemia. (See 'Therapeutic approaches to Hb F modulation' below and "Hydroxyurea use in sickle cell disease", section on 'Increased Hb F production' and "Investigational therapies for sickle cell disease", section on 'Increasing Hb F'.)

F cells and F reticulocytes — Erythrocytes containing enough Hb F to be detected by fluorescence activated cell sorting (FACS) are called F cells. F cell numbers correlate closely with Hb F values [100]. FACS can detect approximately 4 to 6 picograms (pg) of Hb F per cell [101]. More sensitive methods can detect approximately 2 pg of Hb F per cell and might be able to measure the distribution of Hb F concentrations among F cells [102]. The amount of Hb F per F cell remains stable as nucleated red cells become reticulocytes that mature to RBCs [103].

F reticulocytes estimate the expression of HBG better than F cells, because in sickle cell disease and beta thalassemia, F cells have a survival advantage in the circulation [104]. In biotin-labeled sickle cells, F cells survived six to eight weeks, compared with approximately two weeks for non-F cells [105].

After the first year of life, F cells account for <4 percent of RBCs and F reticulocytes account for approximately 1 percent of circulating RBCs [106]. As with the percentage of Hb F, F cells in sickle cell trait (approximately 2 percent) are similar to those in AA, but increased in sickle cell disease (approximately 11 percent).

CONDITIONS CAUSING INCREASED Hb F

Overview of conditions with high Hb F — The reference range for Hb F in adults is <1 percent. (See "Laboratory test reference ranges in adults", section on 'Hemoglobin fractionation'.)

Hb F values can be increased by heritable (genetic) and acquired conditions (table 1); their effects on Hb F values are summarized in the table (table 2) and illustrated in the schematic (figure 4).

Genetic causes

Beta thalassemia – (See 'Beta thalassemia' below.)

Delta-beta thalassemia – (See 'Delta-beta thalassemia' below.)

Hereditary persistence of fetal hemoglobin (HPFH) – (See 'Hereditary persistence of fetal hemoglobin (HPFH)' below.)

Sickle cell disease – (See 'Sickle cell disease' below.)

Minor alleles of Hb F quantitative trait loci (QTL) – (See 'Quantitative trait loci associated with HBG expression' above.)

Acquired causes

Hydroxyurea therapy – (See "Hydroxyurea use in sickle cell disease", section on 'Increased Hb F production'.)

Erythropoietic stress such as pregnancy – (See "Regulation of erythropoiesis", section on 'Stress and erythropoiesis'.)

Miscellaneous other causes are summarized in the table (table 1) and discussed below – (See 'Secondary increases in Hb F' below.)

When found serendipitously on high performance liquid chromatography (HPLC) analysis during diagnostic studies for anemias other than sickle cell disease or beta thalassemia and related conditions, increased Hb F usually has no clinical significance.

Population surveys show that the values of Hb F are usually <1 percent, but nevertheless are highly variable within this range. F cells vary over 20-fold in adults without hemoglobinopathies; the distribution is continuous and positively skewed [107-109].

For both Hb F and F cells, which are highly correlated, the variation is likely due to the influence of common Hb F boosting polymorphisms in the major Hb F QTLs along with many rare variants in these QTLs and elsewhere in the genome. (See 'Quantitative trait loci associated with HBG expression' above.)

The table (table 2) lists typical Hb F values in different conditions. The highest values of Hb F are seen with severe, transfusion-dependent beta thalassemia or gene deletion HPFH, in which Hb F can range from 30 percent in heterozygous individuals to 100 percent in homozygous individuals.

Depending on patient age, hydroxyurea can increase Hb F to up to 40 percent. Delta-beta thalassemia and non-deletional HPFH can raise Hb F >10 percent in individuals with sickle cell disease or Hb S-beta thalassemia. In adults with sickle cell disease in the absence of any treatment, Hb F can reach 25 percent, although in most patients of African descent it measures 5 to 8 percent. (See 'Sickle cell disease' below.)

Other findings on the complete blood count that can be helpful in distinguishing among these conditions include the presence of microcytosis, which suggests (but is not specific for) beta thalassemia. (See 'Interpretation of high Hb F values' below.)

Beta thalassemia — Hb F values are highest (from 10 to 100 percent) in transfusion dependent beta thalassemia and are normal or only slightly elevated (>1 to 2 percent) in beta thalassemia trait [110-112]. In beta thalassemia trait, Hb F >3 percent suggests co-inheritance of Hb F boosting variants of the major Hb F QTLs [28,95].

Small deletions or point mutations of the promoter region of the HBB gene cause beta thalassemia with much higher values of Hb F than other thalassemia mutations. Perhaps these mutations favor locus control region (LCR) interactions with gamma globin gene promoters [113,114]. (See "Diagnosis of thalassemia (adults and children)", section on 'Overview of subtypes and disease severity' and "Molecular genetics of the thalassemia syndromes".)

Hereditary persistence of fetal hemoglobin (HPFH) — HPFH refers to a group of genetic variants within the HBB cluster that cause increased HBG expression and Hb F values. Individuals who are heterozygous and even homozygous for HPFH variants are asymptomatic. They are not anemic or are minimally anemic but often have microcytosis.

HPFH has gene deletion and non-gene deletion forms. Deletional HPFH is due to deletion of the genes encoding delta globin and beta globin, preserving one or both gamma globin genes. Non-deletional HPFH is due to point mutations or other small changes in the HBG promotors. In both forms, Hb F is usually pancellularly distributed (present in all red blood cells [RBCs]) when high Hb F values near 30 percent. Heterocellular distribution (Hb F present in a subset of RBCs) is typical with more modest elevations in Hb F.

High values of Hb F can be present without HPFH mutations. (See 'Overview of conditions with high Hb F' above.)

Deletional HPFH

Deletional HPFH (also called gene deletion HPFH) is caused by deletions in the HBB gene cluster from 13 to 106 kb that remove part or all of HBD and HBB and are associated with nearly complete compensatory increase in HBG expression and Hb F values (figure 5). These deletions are characteristically associated with a pancellular or homogenous distribution of Hb F among RBCs. It seems likely that each RBC does not have identical concentrations of Hb F; nevertheless, all cells have Hb F.

HPFH 1 and HPFH 2 are the most common types of deletional HPFH in people of African descent. They are characterized by >80 kb deletions that include HBD and HBB and are staggered by approximately 5 kb at the 5' and 3' ends. Heterozygous individuals have Hb F values of 20 to 30 percent and mild microcytosis. The ratio of G-gamma to A-gamma chains is approximately 50:50 in HPFH 1 and 30:70 in HPFH 2. Other HPFH deletions have similar hematologic findings with minor differences in the ratios of G-gamma to A-gamma chains. Homozygous individuals have 100 percent Hb F and no Hb A2.

There is overlap between deletional HPFH and delta-beta thalassemia. Both are caused by deletions in the HBB gene cluster affecting HBD and HBB. In delta-beta thalassemia, the increase in gamma globin chain synthesis does not fully compensate for the loss of beta globin. (See 'Delta-beta thalassemia' below.)

Non-deletion HPFH — Non-deletion HPFH is caused by point mutations in either HBG2 or HBG1 promoters that alter transcription factor binding. Heterozygotes have Hb F values from 5 to 40 percent. These variants include single base substitutions and minor deletions clustered in two regions in the HBG promoters [73,115]:

Positions -114 to -117

Positions -195 to -202

Position -175 (associated with the highest Hb F increases)

Transcription factors involved include [116]:

BCL11A (position -115)

ZBTB7A (position -200)

TSp-1 elements (positions -195 to -202)

GATA1, NFE-3, and NF-gamma (duplicated CCAAT boxes around position -117)

Some small deletions of critical regions of the HBG promoters, for example a 13 nucleotide deletion of the HBG1 promoter that included the CCAAT box, were associated with Hb F of approximately 30 percent that was distributed pancellularly [117,118].

Increased Hb F due to variants in QTLs modulating expression — Minor heterocellular increases in Hb F in adults, often familial, and not always inherited in a Mendelian fashion or linked to the HBB cluster, were frequently combined together as if they were the same disorder and historically called heterocellular HPFH. Single nucleotide variants in the BCL11A, HBS1L–MYB intergenic region (HMIP) and HBG2-Xmn1 QTLs and gene rearrangements such as Atlanta HPFH and triplicated and quadruplicated gamma globin genes explain many of these instances [119,120]. (See 'Cell-based therapeutics' below.)

Delta-beta thalassemia — Deletions in the HBB gene cluster that remove the beta globin and delta globin genes (HBB and HBD) but spare one or both gamma globin genes (figure 5) can also cause a delta-beta thalassemia phenotype.

These deletions overlap in size with HPFH deletions but are generally smaller, with different 5' and 3' breakpoints. Hb F ranges from 5 to 15 percent in heterozygous individuals, and because of this it appears heterocellularly distributed. Lower Hb F does not completely compensate for the lack of beta globin, and a thalassemic phenotype results. Homozygous individuals have 100 percent Hb F, yet some individuals still have moderate anemia. (See "Molecular genetics of the thalassemia syndromes", section on 'Delta-beta thalassemia'.)

The mechanism of increased Hb F in delta-beta thalassemia is unclear; several hypotheses have been proposed [73,121]:

Removal of regulatory regions between HBG1 and HBD that silence gamma globin expression, especially the Corfu deletion [122-125]. (See 'Globin evolution and genomic organization' above.)

Removal of competition between promotors for transcription factors, allowing greater transcription of gamma globin genes. (See 'Hemoglobin switching and downregulation of Hb F expression' above.)

Translocation of 3’ distal enhancers into the proximity of gamma globin genes [126,127].

Reports have described compound heterozygous individuals with the sickle cell variant on one HBB allele and delta-beta thalassemia on the other HBB allele [128,129]. While Hb F is between 30 and 50 percent and F cells can exceed 90 percent, the phenotype is variable, and complications of sickle cell disease have been described. This could be a result of the distributions of Hb F concentrations amongst F cells, where some cells might have less than fully protective Hb F values [101].

Sickle cell disease

Impact of Hb F on sickle cell disease severity — Hb F is the major modulator of the phenotypic severity of sickle cell disease (figure 6). Hb F prevents the polymerization of deoxy-sickle hemoglobin (Hb S) because its hybrid tetramer, alpha2betaS;gamma, cannot enter the polymer phase. Presence of Hb F also dilutes the intracellular Hb S concentration, a key factor in Hb S polymerization [130-132].

The incidence of acute sickle vaso-occlusive events such as painful episodes and acute chest syndrome are inversely correlated with Hb F concentration; events linked to hemolysis such as priapism, chronic kidney disease, cerebrovascular disease, and pulmonary hypertension are affected by Hb F, but the effect is less pronounced than with vaso-occlusive events [133-135]. This is likely because even with increased Hb F values, the heterocellular distribution of Hb F and differences in its concentration from cell to cell allow some F cells with lower Hb F (and non-F cells) to lyse within the circulation and release sufficient free heme to reduce nitric oxide bioavailability, a key determinant of the pathophysiology associated with intravascular hemolysis. (See "Pathophysiology of sickle cell disease", section on 'Vaso-occlusion' and "Pathophysiology of sickle cell disease", section on 'Hemolysis'.)

In large population-based studies, any increment in Hb F had a beneficial effect on morbidity and mortality [136-138]. When Hb F values are approximately 40 percent after gene therapy, nearly every cell has sufficient Hb F to prevent Hb S polymer-induced injury, and the phenotype of sickle cell disease is reversed [139,140]. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Modeling studies suggest that 9 to 12 pg of Hb F per F cell can nearly totally protect the cell from Hb S polymer-induced damage [141]. The higher the Hb F value, the more likely there are to be more cells with protective Hb F concentrations. (See "Hydroxyurea use in sickle cell disease".)

Genetic regulation of Hb F in sickle cell disease — Three main contributing factors are the background haplotype, QTL polymorphisms, and HPFH.

Haplotypes – The sickle cell point mutation is associated with five common haplotypes (variants that cosegregate with the sickle cell mutation, generally associated with a geographic region or racial/ethnic group).

Arab-Indian

Senegal

Benin

Bantu

Cameroon

These haplotypes are associated with different Hb F values in homozygous individuals. Untreated adults who are homozygous for the Arab-Indian haplotype have a mean Hb F of 17 percent; Senegal haplotype patients have Hb F of approximately 10 percent [142,143].

In patients with the Benin, Bantu and Cameroon haplotype, the Hb F value of individuals of African and Arab descent appear to differ. Benin haplotype patients of African descent have Hb F of 6 percent; Saudi-Arab patients with the Benin haplotype have Hb F of 11 percent [144]. A similar increment in Hb F is found in patients of Saudi origin with the Bantu and Cameroon haplotypes [145].

As children, untreated patients with the Arab-Indian haplotype have Hb F of approximately 30 percent [145-147]. As Hb F values decline, the phenotype of adults with the haplotype begins to resemble that of African patients.

Ascertainment of Hb S gene haplotype in individual patients has little prognostic value. Besides the -158 Xmn1 C-T polymorphism seen in Senegal and Arab-Indian haplotypes, the genetic and mechanistic basis of the variance of Hb F values in other Hb S gene haplotypes is undefined.

QTL polymorphisms – Some of the baseline Hb F increase in sickle cell disease is related to polymorphisms in the three QTL modulating HBG expression [64,75,144,146,148-170]. (See 'Quantitative trait loci associated with HBG expression' above.)

HPFH – Individuals who are compound heterozygous for Hb S and deletion HPFH can have Hb F values of approximately 30 percent, with approximately 10 pg of Hb F in all RBCs. (See 'Hereditary persistence of fetal hemoglobin (HPFH)' above and "Overview of compound sickle cell syndromes", section on 'Sickle-hereditary persistence of fetal hemoglobin'.)

This value of Hb F protects all cells from Hb S polymer-induced damage. In a series of 30 individuals with Hb S-HPFH in which the HPFH variant was molecularly defined, Hb F values were 50 to 90 percent during infancy and stabilized between ages 3 and 5 years at approximately 30 percent [171]. Patients were healthy without complications.

Acute vaso-occlusive events have occasionally been reported in Hb S-HPFH, but the molecular basis of the high Hb F was not always characterized [128].

Secondary increases in Hb F — Increased Hb F values in the postneonatal period have been found in various acquired and genetic disorders (table 1). In most cases, the increases appear to be secondary to perturbation of erythropoiesis.

Prematurity – The switch from fetal to adult hemoglobin production proceeds on a set developmental clock and is not affected by the gestational age of the infant [172]. Hb F remains the major hemoglobin synthesized up to 37 weeks gestation. In early preterm newborns, timing of the transition from Hb F to Hb A synthesis postnatally resembles that in utero. (See 'Hemoglobin switching and downregulation of Hb F expression' above.)

Infants of diabetic mothers – Full-term infants of diabetic mothers have a delayed Hb F to Hb A switch and higher Hb F than expected for gestational age; this occurs via an unclear mechanism [173,174]. Elevated alpha-amino-butyric acid was proposed as a mechanism, but trials of butyrate analogues to raise Hb F in sickle cell disease were inconclusive [175-178]. (See "Investigational therapies for sickle cell disease", section on 'Increasing Hb F'.)

Trisomy 13 – Individuals with trisomy 13 have a delayed Hb F to Hb A switch and persistently elevated Hb F values [179,180]. One study suggested this was due to increased expression of microRNAs 15a and 16-1 produced from the triplicated chromosome 13 [181]. These microRNAs downregulate MYB. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome'.)

Increased erythropoiesis – A number of conditions associated with stress erythropoiesis have been associated with increases in Hb F [182]:

Bone marrow recovery Bone marrow regeneration and acute expansion in erythropoietic activity have been proposed to underlie increases in F cells and Hb F in many leukemia patients following chemotherapy [183], after hematopoietic stem cell transplantation [184], following acute blood loss, and after treatment with iron in severe untreated iron deficiency [185].

Transient erythroblastopenia of childhood – Transient erythroblastopenia of childhood (TEC) is characterized by a transient arrest in erythropoiesis during which Hb F is not elevated. Spontaneous recovery is characterized by a brisk reticulocytosis and is typically associated with increased numbers of F cells and Hb F concentration [185,186]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

Hemolysis Acute hemolysis also results in increased F cell production, likely due to the acute compensatory expansion in erythropoietic activity. In some studies, F cell numbers were increased [184,185]. Hb F values also rose with an increase in reticulocyte count. Co-inheritance of some HPFH variants or Hb F-boosting alleles in QTLs might explain this variability [186]. (See 'Hereditary persistence of fetal hemoglobin (HPFH)' above and 'Quantitative trait loci associated with HBG expression' above.)

Pregnancy – Increases in Hb F during pregnancy reach a peak in the second trimester. In one study, Hb F value during pregnancy was 0.71±0.51 percent, while in the nonpregnant control group it was 0.28±0.35 percent [187]. Increased production of F cells is the physiologic result of erythroid expansion during this period [188].

Inherited bone marrow failure syndromes – Patients with inherited bone marrow failure syndromes (Diamond-Blackfan anemia, dyskeratosis congenita, Fanconi anemia, Shwachman-Diamond syndrome) frequently have increased Hb F as a component of stress hematopoiesis [189]. A wide range of Hb F increases has been observed. One study found an association of increased Hb F with young age, male sex, anemia, high erythropoietin values, and the minor allele (T) of the Xmn1-HBG2 QTL [190]. (See "Diamond-Blackfan anemia", section on 'Laboratory findings' and 'HBG2 Xmn1 polymorphism' above.)

Malignancies

JMML – Increased Hb F values have been observed in juvenile myelomonocytic leukemia (JMML; also called juvenile chronic myeloid leukemia) and other hematologic malignancies [191,192]. In a retrospective review of 100 children <16 years with JMML, Hb F comprised up to 90 percent of total hemoglobin in those with normal karyotype and chromosomal abnormalities other than monosomy 7 [193]. It was initially proposed that this was due to emergence of a clone of hematopoietic cells that had reverted to fetal erythropoiesis, but the uncoordinated expression of the various "fetal" characteristics suggested grossly distorted regulation of gene expression [194]. Hb F values appeared to be an independent risk factor of survival in the patients who did not undergo hematopoietic stem cell transplant [193].

Other hematologic malignancies – Some karyotypic abnormalities associated with myelodysplastic syndrome (MDS) have been associated with increased Hb F; Hb F >10 percent was correlated with worse prognosis in one study [195,196]. Increased Hb F has also been reported in acute myeloid leukemia (AML), erythroleukemia, lymphoblastic leukemia, and chronic myeloid leukemia [191].

A 2017 study suggested that Hb F could be a predictor of outcome in MDS and AML but genetic variants associated with Hb F were not evaluated [197].

A 2022 study showed that the common genetic Hb F QTL variants influence Hb F and other hematological traits in patients with myeloproliferative neoplasms, multiple myeloma, and myelodysplasia, both at baseline and in response to Hb F-inducing cytotoxic therapy [198].

Solid tumors – Rarely, increased Hb F values have been observed in solid tumors including choriocarcinoma, adenocarcinoma of the lung, and hepatoma [199-201]. The increased Hb F could be related to paraneoplastic phenomenon that involves inappropriate overproduction of erythropoietin [202].

Increased Hb F values have also been recorded in sporadic reports of thyrotoxicosis and pernicious anemia [203]. Review of a larger number of patients showed that increased Hb F is not a consistent feature.

EVALUATING Hb F VALUES AND INCREASED Hb F

When to assay Hb F — Measuring the Hb F value is most commonly used in monitoring hydroxyurea therapy in individuals sickle cell disease and in diagnosis of hemoglobinopathies, where the value of Hb F and other hemoglobins helps confirm or eliminate specific diagnoses.

The values of Hb F and Hb A2 (along with red blood cell [RBC] indices) help to distinguish beta thalassemia, delta-beta thalassemia, and hereditary persistence of fetal hemoglobin (HPFH). (See 'Overview of conditions with high Hb F' above and 'Interpretation of high Hb F values' below.)

Most clinicians will see the results for the Hb F value when hemoglobin fractionation is performed by high performance liquid chromatography (HPLC) or capillary electrophoresis, as Hb F is reported, similar to Hb A2. These analyses are usually ordered for the diagnosis of hemoglobinopathies and thalassemia. Slight Hb F increases in the absence of hemoglobin disorders rarely has clinical significance.

It is important not to overinterpret increased Hb F in an individual who does not have a hemoglobinopathy. Older forms of hemoglobin electrophoresis do not provide accurate measurement of Hb F.

Which test to order — Hb F can be assessed in several ways:

Protein chemistry methods – These are often used for beta hemoglobinopathies.

High performance liquid chromatography (HPLC) (figure 7)

Capillary electrophoresis (figure 8)

Alkaline denaturation [10]

HPLC and capillary electrophoresis are the most commonly used methods. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)

When Hb S is also present, capillary electrophoresis gives a small but statistically significant higher Hb F value than HPLC [204].

Alkaline and acid hemoglobin electrophoresis (figure 9) and isoelectric focusing (figure 10) are useful for separation of major hemoglobin fractions but do not provide quantitative information on Hb F values.

DNA-based methods – DNA testing cannot determine the percentage of Hb F, but it can be used to identify variants in beta globin genes that cause hemoglobinopathies and in genes that control HBG expression. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Molecular genetic (DNA-based) methods'.)

Counting F cells by flow cytometry is available in some research laboratories but is not commercially available. (See 'Resources for testing' below.)

Interpretation of high Hb F values — The reference range for Hb F is stated to be <1 percent. A study using HPLC in adults without a hemoglobinopathy found Hb F concentrations were between 0.1 and 0.4 percent [205]. (See "Laboratory test reference ranges in adults", section on 'Hemoglobin fractionation'.)

The table lists typical Hb F values in different conditions (table 2).

Increased Hb F should be evaluated using the following criteria:

Percentage of Hb F, Hb A2, and RBC indices

Hb F of 20 to 100 percent is typically due to transfusion-dependent beta thalassemia or some type of HPFH.

Hb F of 10 to 20 percent, when accompanied by hypochromic microcytic RBCs and normal Hb A2, may indicate delta-beta thalassemia or nontransfusion-dependent beta thalassemia. In individuals without a hemoglobinopathy, Hb F of 2 to 10 percent with minimally affected RBC indices suggests co-inheritance of Hb F boosting polymorphism(s) in the quantitative trait loci (QTL) modulating HBG expression.

Slightly increased Hb F (2 to 3 percent) with hypochromic microcytic RBCs and elevated Hb A2 suggests heterozygous beta thalassemia. (See 'Quantitative trait loci associated with HBG expression' above.)

Patient age – Hb F represents approximately 60 to 80 percent of total hemoglobin in the full-term newborn. By approximately 6 to 12 months of age, Hb F is almost completely replaced by Hb A.

Blood smear – Findings on the blood smear, especially sickled cells (indicative of sickle cell disease) or target cells (indicative of thalassemia) are critical for interpretation. (See "Diagnosis of sickle cell disorders", section on 'Findings in sickle cell anemia' and "Diagnosis of sickle cell disorders", section on 'Diagnostic patterns in other sickle cell disorders' and "Diagnosis of thalassemia (adults and children)", section on 'CBC and hemolysis testing'.)

Additional information on interpretation is presented separately. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Clues from the CBC' and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Common clinical scenarios'.)

Resources for testing — Making a specific diagnosis can be accomplished in most clinical laboratories. However, some conditions such as HPFH and delta-beta thalassemia may require DNA-based (molecular) methods. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Referral to a specialized laboratory'.)

The decision concerning which reference laboratory to send the sample to depends upon several factors. Many hospitals and medical centers have contractual agreements with one of the national reference laboratories and send the samples to these laboratories for further analysis. Some institutions prefer to send samples to one of the few laboratories that specialize in globin abnormalities (table 3). This choice may depend upon the familiarity of the referring clinician.

A few academic laboratories in the United States specialize in evaluating globin abnormalities.

Titus HJ Huisman Hemoglobinopathy Laboratory at Augusta University, Augusta, GA (https://www.augusta.edu/centers/blood-disorders/hemoglobinopathy/index.php)

Hemoglobin Diagnostic Reference Laboratory at Boston University, Boston, MA (https://www.bu.edu/sicklecell/diagnostics/)

Hemoglobinopathy Laboratory at UCSF Benioff Children's Hospital, Oakland, CA (https://www.childrenshospitaloakland.org/main/departments-services/hemoglobinopathy-laboratory-123.aspx)

Erythrocyte Diagnostic Lab, Cancer and Blood Diseases Institute, Cincinnati Children's, Cincinnati, OH (https://www.cincinnatichildrens.org/service/c/cancer-blood/hcp/clinical-laboratories/erythrocyte-diagnostic-lab)

THERAPEUTIC APPROACHES TO Hb F MODULATION

Drug therapies — Drugs that increase Hb F production are of interest because they have the potential to ameliorate disease manifestations of the beta hemoglobinopathies. Hydroxyurea is the only US Food and Drug Administration (FDA)-approved agent that can increase Hb F values, although others are in clinical trials [87,142,206-210]. (See "Investigational therapies for sickle cell disease", section on 'Increasing Hb F' and "Management of thalassemia", section on 'Investigational approaches'.)

Cell-based therapeutics — Genetic manipulations that increase Hb F production or produce a "Hb F-like" Hb A (gene therapies) have the potential to provide curative therapy, although many aspects of these therapies require further study.

Lentiviral-mediated gene addition of a fetal-like Hb A (Hb AT87Q)

Lentiviral-mediated short hairpin RNA (shRNA) knockdown of BCL11A

Targeting Hb F repressors using gene editing, base editing, and prime editing

Trials in sickle cell disease and beta thalassemia using mobilized autologous CD34+ cells where the therapeutic construct is introduced in vitro and the altered cells reinfused following myeloablative conditioning have produced dramatic initial clinical successes, leading to almost 100 percent F cells and eliminating disease complications [139,211].

These gene therapies either disrupt the BCL11A erythroid-specific enhancer using CRISPR-Cas9, interfere with enhancer function by its targeting with an shRNA, or add the Hb F-like Hb A, gene Hb AT87Q. The FDA has approved gene therapy with Hb AT87Q for severe beta thalassemia, and gene therapies for sickle cell disease are under investigation [212]. (See "Hematopoietic stem cell transplantation in sickle cell disease" and "Management of thalassemia" and "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

SUMMARY

Hb F structure – Fetal hemoglobin (Hb F) is a tetramer of alpha and gamma globin (alpha2gamma2) that predominates during fetal development. Gamma globin is produced from two gamma globin genes (arranged in the beta globin locus with HBG2 upstream of HBG1) (figure 1). Compared with adult hemoglobin (Hb A; alpha2beta2), Hb F has slightly increased oxygen (O2) affinity, which facilitates O2 delivery to the fetus during gestation. (See 'Globin evolution and genomic organization' above and 'Gamma globin genes (HBG2 and HBG1)' above and 'Structural and functional properties of Hb F' above.)

Regulation – The switch from Hb F to Hb A occurs shortly after birth; the figure illustrates major regulatory factors (figure 3). The degree of Hb F expression is a quantitative trait with multiple influences; the main quantitative trait loci (QTL) are the genes BCL11A and the HBS1L-MYB intergenic region (HMIP), which encode transcription factors, and the Xmn1 polymorphism in the HBG2 promoter. (See 'Hemoglobin switching and downregulation of Hb F expression' above.)

Causes of high Hb F – The table summarizes conditions with increased Hb F and typical Hb F values in these conditions (table 2). Common examples of genetic causes include beta thalassemia, hereditary persistence of fetal hemoglobin (HPFH; deletional and non-deletional), delta-beta thalassemia, and sickle cell disease. Secondary causes include stress erythropoiesis and others (table 1). HPFH is a benign condition that generally does not cause anemia or other findings. (See 'Conditions causing increased Hb F' above.)

Evaluating Hb F – Hb F value is most commonly measured using protein chemistry methods to monitor hydroxyurea therapy or transfusions in individuals with sickle cell disease and in diagnosis of hemoglobinopathies, where the value of Hb F and other hemoglobins helps confirm or eliminate specific diagnoses. The reference range in the absence of hemoglobinopathy is <1 percent. Resources for testing are listed in the table (table 3) and discussed above. When found serendipitously, increased Hb F rarely has clinical significance; it is important not to overinterpret this finding. (See 'Evaluating Hb F values and increased Hb F' above and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Initial evaluation'.)

Hb F manipulation – Therapeutic targeting of Hb F using medications such as hydroxyurea or genetic manipulations of gamma globin regulators, especially BCL11A, is being used or tested in sickle cell disease and beta thalassemia. (See 'Therapeutic approaches to Hb F modulation' above and "Hydroxyurea use in sickle cell disease" and "Investigational therapies for sickle cell disease".)

Other hemoglobins – Other normal hemoglobins and other aspects of red blood cell (RBC) production are discussed separately. (See "Structure and function of normal hemoglobins" and "Regulation of erythropoiesis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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Topic 90749 Version 37.0

References

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