Fetal hemoglobin, or foetal haemoglobin, (also hemoglobin F or HbF) is the main oxygen transport protein in the fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old. Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream.
In newborns, fetal hemoglobin is nearly completely replaced by adult hemoglobin by approximately 6 months postnatally. In adults, fetal hemoglobin production can be reactivated pharmacologically, which is useful in the treatment of diseases such as sickle-cell disease.
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Oxygenated blood is delivered to the fetus via the umbilical vein from the placenta, which is anchored to the wall of the mother's uterus. The chorion acts as a barrier between the maternal and fetal circulation so that there is no admixture of maternal and fetal blood. Blood in the maternal circulation is delivered via open ended arterioles to the intervillous space of the chorionic plate, where it bathes the chorionic villi that carry umbilical capillary beds, thereby allowing gas exchange to occur between the maternal and fetal circulation. Deoxygenated maternal blood drains into open ended intervillous venules to return to maternal circulation. Due to the admixture of oxygenated and deoxygenated blood, maternal blood in the intervillous space is lower in oxygen than arterial blood. As such, fetal hemoglobin must be able to bind oxygen with greater affinity than adult hemoglobin in order to compensate for the relatively lower oxygen tension of the maternal blood supplying the chorion.
Fetal hemoglobin's affinity for oxygen is substantially greater than that of adult hemoglobin. Notably, the P50 value for fetal hemoglobin (i.e., the partial pressure of oxygen at which the protein is 50% saturated; lower values indicate greater affinity) is roughly 19 mmHg, whereas adult hemoglobin has a value of approximately 26.8 mmHg. As a result, the so-called "oxygen saturation curve", which plots percent saturation vs. pO2, is left-shifted for fetal hemoglobin in comparison to the same curve in adult hemoglobin.
This greater affinity for oxygen is explained by the lack of fetal hemoglobin's interaction with 2,3-bisphosphoglycerate (2,3-BPG or 2,3-DPG). In adult red blood cells, this substance decreases the affinity of hemoglobin for oxygen. It is also present in fetal red blood cells, but does not interact with fetal hemoglobin, leaving its affinity for oxygen unchanged. Adult hemoglobin alone actually has a higher affinity for oxygen than its fetal equivalent, but the levels of 2,3-BPG reduce it.
For mothers to deliver oxygen to a fetus, it is necessary for the fetal hemoglobin to extract oxygen from the maternal oxygenated hemoglobin across the placenta. This requires the fetal hemoglobin to have a higher oxygen affinity than that of the maternal carrier. This is achieved by a fetal hemoglobin subunit γ (gamma), instead of the b (beta) subunit. The γ subunit has fewer positive charges than the adult hemoglobin b subunit. This means that 2,3-BPG is less electrostatically bound to fetal hemoglobin as compared to adult hemoglobin. This means that 2,3-BPG is less effective in lowering the oxygen affinity of the fetal hemoglobin. This lowered affinity allows for adult hemoglobin (the maternal hemoglobin) to readily transfer its oxygen to the fetal hemoglobin.
After the first 10 to 12 weeks of development, the fetus' primary form of hemoglobin switches from embryonic hemoglobin to fetal hemoglobin. At birth, fetal hemoglobin comprises 50-95% of the infant's hemoglobin. These levels decline after six months as adult hemoglobin synthesis is activated while fetal hemoglobin synthesis is deactivated. Soon after, adult hemoglobin (hemoglobin A in particular) takes over as the predominant form of hemoglobin in normal children. Certain genetic abnormalities can cause the switch to adult hemoglobin synthesis to fail, resulting in a condition known as hereditary persistence of fetal hemoglobin (HPFH).
Most types of normal hemoglobin, including hemoglobin A, hemoglobin A2, and hemoglobin F, are tetramers composed of four protein subunits and four heme prosthetic groups. Whereas adult hemoglobin is composed of two alpha and two beta subunits, fetal hemoglobin is composed of two alpha and two gamma subunits, commonly denoted as α2γ2. Because of its presence in fetal hemoglobin, the gamma subunit is commonly called the "fetal" hemoglobin subunit.
In humans, each chromosome 11 contains two similar copies of the gene that encodes the gamma subunit, γG (glycine as residue 136) and γA (alanine as residue 136). (The beta subunit is also on Chromosome 11) The gene that codes for the alpha subunit is located on chromosome 16 and is also present in duplicate.
When fetal hemoglobin production is switched off after birth, normal children begin producing adult hemoglobin (HbA). Children with sickle-cell disease instead begin producing a defective form of hemoglobin called hemoglobin S. This variety of hemoglobin aggregates, forming filaments that cause red blood cells to change their shape from round to sickle-shaped, which have a greater tendency to stack on top of one another and block blood vessels. These invariably lead to so-called painful vaso-occlusive episodes, which are a hallmark of the disease.
If fetal hemoglobin remains the predominant form of hemoglobin after birth, the number of painful episodes decreases in patients with sickle-cell disease. Hydroxyurea promotes the production of fetal hemoglobin and can be used to treat individuals with sickle-cell disease.[1][2] Combination therapy with hydroxyurea and recombinant erythropoietin—rather than treatment with hydroxyurea alone—has been shown to further elevate hemoglobin F levels and to promote the development of HbF-containing F-cells.[3]
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