Fetal hemoglobin

Fetal hemoglobin, or foetal haemoglobin (also hemoglobin F, HbF, or α₂γ₂) is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind (or attach to) oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.

In the newborn, levels of hemoglobin F gradually decrease and reach adult levels (less than 1% of total hemoglobin) usually within the first year, as adult forms of hemoglobin begin to be produced. Diseases such as beta thalassemias, which affect components of the adult hemoglobin, can delay this process, and cause hemoglobin F levels to be higher than normal. In sickle cell anemia, increasing the production of hemoglobin F has been used as a treatment to relieve some of the symptoms.

Hemoglobin F, like adult hemoglobin (hemoglobin A and hemoglobin A2), has four subunits or chains. Each subunit contains a heme group with an iron element which is key in allowing the binding and unbinding of oxygen. As such, hemoglobin F can adopt two states: oxyhemoglobin (bound to oxygen) and deoxyhemoglobin (without oxygen). As hemoglobin F has 4 heme groups, it can bind to up to four oxygen molecules. It is composed of two α (alpha) subunits and two γ (gamma) subunits, whereas hemoglobin A (97% of total hemoglobin in adults) is composed of two α and two β (beta) subunits.

In humans, the α subunit is encoded on chromosome 16 and the γ subunit is encoded on chromosome 11. There are two very similar genes that code for the α subunit, HBA1 and HBA2. The protein that they produce is identical, but they differ in gene regulatory regions that determine when or how much of the protein is produced. This leads to HBA1 and HBA2 contributing 40% and 60%, respectively, of the total α subunits produced. As a consequence, mutations on the HBA2 gene are expected to have a stronger effect than mutations on the HBA1 gene. There are also two similar copies of the gene coding for the γ subunit, HBG1 and HBG2, but the protein produced is slightly different, just in one protein unit: HBG1 codes for the protein form with an alanine at position 136, whereas HBG2 codes for a glycine BCL11A and ZBTB7A are major repressor proteins of hemoglobin F production, by binding to the gene coding for the γ subunit at their promoter region. This happens naturally as the newborn baby starts to switch from producing hemoglobin F to producing hemoglobin A. Some genetic diseases can take place due to mutations to genes coding for components of hemoglobin F. Mutations to HBA1 and HBA2 genes can cause alpha-thalassemia and mutations to the promoter regions of HBG1 and HBG2 can cause hemoglobin F to still be produced after the switch to hemoglobin A should have occurred, which is called hereditary persistence of fetal hemoglobin.

During the first 3 months of pregnancy, the main form of hemoglobin in the embryo/fetus is embryonic hemoglobin, which has 3 variants depending on the types of subunits it contains. The production of hemoglobin F starts from week 6, but it's only from 3 months onwards that it becomes the main type found in fetal red blood cells. The switch to produce adult forms of hemoglobin (essentially hemoglobin A) starts at around 40 weeks of gestation, which is close to the expected time of birth. At birth, hemoglobin F accounts for 50-95% of the infant's hemoglobin and at around 6 months after birth, hemoglobin A becomes the predominant type. By the time the baby is one year old, the proportions of different types of hemoglobin are expected to approximate the adult levels, with hemoglobin F reduced to very low levels. The small proportion of red blood cells containing hemoglobin F are called F-cells, which also contain other types of hemoglobin.

In healthy adults, the composition of hemoglobin is hemoglobin A (~97%), hemoglobin A2 (2.2 - 3.5%) and hemoglobin F (<1%).

Certain genetic abnormalities can cause the switch to adult hemoglobin synthesis to fail, resulting in a condition known as hereditary persistence of fetal hemoglobin.

The four hemes, which are the oxygen-binding parts of hemoglobin, are similar between hemoglobin F and other types of hemoglobin, including hemoglobin A. Thus, the key feature that allows hemoglobin F to bind more strongly to oxygen is by having γ subunits (instead of β, for example). In fact, some naturally existing molecules in our body can bind to hemoglobin and change its binding affinity for oxygen. One of the molecules is 2,3-bisphosphoglycerate (2,3-BPG) and it enhances hemoglobin's ability to release oxygen. 2,3-BPG interacts much more with hemoglobin A than hemoglobin F. This is because the adult β subunit has more positive charges than the fetal γ subunit, which attract the negative charges from 2,3-BPG. Due to the preference of 2,3-BPG for hemoglobin A, hemoglobin F binds to oxygen with more affinity, in average.