What Is Fetal hemoglobin/Hb F: Health and Disease

• From a structural point of view, fetal hemoglobin (α₂γ₂) differs from the adult one (α₂Β₂) due to the presence of two gamma chains instead of the two alpha chains
  • • In particular, fetal hemoglobin is made up of two α chains and two γ chains, consisting of 141 and 146 amino acids respectively. The two alpha chains are identical to those present in adult hemoglobin, while the gamma ones differ from the beta ones by 39 amino acids

   

• This structural modification gives fetal hemoglobin a higher oxygen affinity; in other words, it binds to oxygen more tenaciously than adult hemoglobin

From a functional point of view, fetal hemoglobin (HbF or hemoglobin F) allows the fetus to extract oxygen more effectively from the maternal blood.

• at the low PO value₂ of fetal blood, fetal hemoglobin can carry up to 20-30% more oxygen than maternal hemoglobin, as demonstrated by the graph below; this is due to the lower affinity for 2,3-biphosphoglycerate compared to adult hemoglobin

The leftward shift of the dissociation curve of fetal hemoglobin compared to adult hemoglobin is observed

The transfer of oxygen to the fetal blood across the placental barrier is also favored by the higher concentration of hemoglobin, approximately 50% higher than that of maternal blood.

Normal Values

The synthesis of fetal hemoglobin begins around the sixth week of gestation, and slowly replaces the embryonic Gower hemoglobins (ζ₂ε₂), Gower II (α₂ε₂), and Portland (ζ₂γ₂), produced in the first weeks after conception.

Expression over time and in different tissues of the different types of human globin chains.

Human globin chains are expressed as a percentage of total hemoglobin

The synthesis of Beta globins characterizing adult hemoglobin, barely perceptible during fetal life, reaches normal levels only towards the end of the third month of extrauterine life.

• at birth, fetal hemoglobin constitutes approximately 70-90% of the total hemoglobin present in the newborn’s red blood cells
• the synthesis of fetal hemoglobin continues even after birth, but gradually decreases, constituting less than 8% of all hemoglobin at the end of six months of life
• within the first year of life fetal hemoglobin concentrations drop to levels generally less than 1%
• Normal adults have fetal hemoglobin values ​​between 0.3% and 1.2%, less than 3.5% of hemoglobin A2 (α2, δ2), and the remaining percentage (generally > 96%) covered by type A hemoglobin.

The different expression over time, from conception to adult life, of the different globin chains in humans depends on the activation and deactivation of specific genes.

High fetal hemoglobin

Pathological significance

• In the uterus, the normal fetus produces a small amount of adult hemoglobin (2.5-5%). The fetus with thalassemia major produces even less (less than 2%). To detect during pregnancy whether a fetus is affected by thalassemia major, it is possible to determine the amount of adult hemoglobin present in a blood sample taken by cordocentesis.
• A small percentage of fetal hemoglobin is also expressed during adult life and its levels can vary greatly under the influence of factors such as age, sex or genomic peculiarities. Some subjects are affected by the so-called hereditary persistence of fetal hemoglobin, a benign condition in which significant concentrations of fetal hemoglobin (> 10%) persist even into adulthood. It has been noted that this peculiarity, generally asymptomatic, can alleviate the severity of certain hemoglobinopathies and thalassemias.
• A drug therapy capable of increasing the concentration of fetal hemoglobin brings significant benefits to some categories of patients, such as those suffering from sickle cell anemia or Beta thalassemia. The prototype of these drugs was hydroxyurea, an antineoplastic drug with myelosuppressive action, which proved effective in increasing fetal hemoglobin levels and reducing the incidence of painful crises in patients suffering from sickle cell anemia.