FOETAL HEMOGLOBIN

The evolutionary development of oxygen-carrying proteins, the hemoglobins, increased the ability of blood to transport oxygen. The combination of oxygen with hemoglobin and its dissociation from it are accomplished without expenditure of metabolic energy.

Hemoglobin is a complex protein consisting of iron-containing heme groups and the protein moiety globin. A dynamic interaction between heme and globin gives hemoglobin its unique properties in the reversible transport of oxygen. The hemoglobin molecule is a tetramer made up of 2 pairs of polypeptide chains, with each chain having a heme group attached. The polypeptide chains of various hemoglobins are of chemically different types. The major hemoglobin of a normal adult (HbA) is made up of 1 pair of alpha (α) and 1 pair of beta (β) polypeptide chains, represented as α₂β₂. The major hemoglobin in the fetus (HbF), which is made up of 2 alpha and 2 gamma globin chains, is represented by α₂γ₂.

The various globin chains differ in both the number and sequence of amino acids, and the synthesis of these chains is directed by separate genes). Two sets of genes for the α chains are located on human chromosome 16. Two pairs of alleles provide the genetic information for the structure of the α chain. The β, γ, and δ genes are closely linked on chromosome 11

Within the red blood cell (RBC) mass of an embryo, fetus, child, and adult, 6 different hemoglobins may normally be detected (): the embryonic hemoglobins, Gower-1, Gower-2, and Portland; the fetal hemoglobin, HbF; and the adult hemoglobins, HbA and HbA₂. The electrophoretic mobilities of hemoglobins vary with their chemical structures. The time of appearance and quantitative relationships among the hemoglobins are determined by complex developmental processes

Embryonic Hemoglobins

The blood of early human embryos contains 2 slowly migrating hemoglobins, Gower-1 and Gower-2, and Hb Portland, which has HbF-like mobility. The zeta (ζ) chains of Hb Portland and Hb Gower-1 are structurally quite similar to α chains. Both Gower hemoglobins contain a unique type of polypeptide chain, the epsilon (ϵ) chain. Hb Gower-1 has the structure ζ₂ϵ₂, and Hb Gower-2 has the structure α₂ϵ₂. Hb Portland has the structure ζ₂γ₂. In embryos of 4-8 wk of gestation, the Gower hemoglobins predominate, but by the 3rd mo they have disappeared.

Fetal Hemoglobin

HbF contains γ polypeptide chains in place of the β chains of HbA. Its resistance to denaturation by strong alkali is the basis for determining the presence of fetal RBCs in the maternal circulation (the Kleihauer-Betke test). After the 8th wk, HbF is the predominant hemoglobin; at 24 wk of gestation it constitutes 90% of the total hemoglobin. During the 3rd trimester, a gradual decline occurs, so that at birth HbF averages 70% of the total hemoglobin. Synthesis of HbF decreases rapidly postnatally), and by 6-12 mo of age only a trace is present

Adult Hemoglobins

By the 24th wk of gestation, HbA constitutes 5-10% of total hemoglobin. A steady increase in HbA continues throughout gestation, reaching a level of 30% of total hemoglobin at term. By 6-12 mo of age, the normal HbA pattern appears. The minor HbA component HbA₂ contains delta (δ) chains and has the structure α₂δ₂. HbA₂ is seen only when significant amounts of HbA are also present. At birth, <1% of HbA₂ is seen, but by 12 mo of age the normal level of 2.0-3.4% is attained. Throughout life, the normal ratio of HbA to HbA₂ is about 30 : 1.

Normal Relationships Among the Hemoglobins

During fetal life and early childhood, the rates of synthesis of γ and β chains and the amounts of HbA and HbF are inversely related. This relationship has been attributed to a “switch mechanism” similar to genetic regulatory mechanisms in bacteria, but the genetic, biologic, and developmental processes that direct a switchover from predominantly γ-chain synthesis in utero to predominantly β-chain synthesis after birth are unclear. It is not certain whether the mechanisms involve selective genetic inhibition or facilitation. The increase in the α₁/α₂ globin ratio occurring after 36 wk of gestation corresponds with a rapid decline in γ-globin synthesis, suggesting that these changes could be regulated by a coordinated molecular mechanism. Differential selection and amplified production of RBC precursors derived from BFU-E cells result in considerable HbF production. This may be the basis for the increased levels of HbF that occur in many hypoproliferative or hemolytic anemias. Alternative explanations involve more basic epigenetic regulation through processes such as methylation and deacetylation in the DNA sequences that flank the hemoglobin gene complexes