Hemoglobin F (fetal hemoglobin) is a “normal” form of hemoglobin produced almost exclusively in fetuses and newborns. The purpose of this alternate form of hemoglobin is for the fetus to obtain enough oxygen from the mother’s interstitial fluid during development (Dulbecco 1997); hemoglobin F’s higher affinity for oxygen helps take away oxygen from the mother’s cells for the fetus to use. This higher affinity for oxygen is a result of a lower affinity for DPG, whose presence decreases oxygen binding to the hemoglobin molecule (Dulbecco 1997).
Once a child is born, the increased oxygen affinity of hemoglobin is no longer needed and hemoglobin F is over time replaced by hemoglobin A. This replacement usually takes about 6 months, which explains the delay in sickle cell symptoms in newborns (SCDAA 2005). Some people have “hereditary persistence” of hemoglobin F, in which their HbF levels are higher than other adults; people with this persistence have much less severe cases of sickle cell anemia (Bridges 2002).
To achieve its higher oxygen affinity, hemoglobin F is made up of different hemoglobin chains than hemoglobin A. Hemoglobin F contains two alpha hemoglobin chains as in the A form, but instead of two beta chains completing the four chain molecule, hemoglobin F contains two gamma chains. These gamma chains help hemoglobin F attract and bind oxygen better than hemoglobin A. Deoxygenated hemoglobin F does not polymerize like hemoglobin S does.
The relative oxygen affinities of different hemoglobin forms. Hemoglobin F has the highest oxygen affinity of the three hemoglobin forms shown (Hb A, S, and F). Note that all three forms have two alpha chains per hemoglobin molecule in common. Only the beta chain in HbA, the mutated beta chain in HbS, and the gamma chain in HbF vary between the forms and result in different oxygen affinities.
As a result of its high oxygen affinity and aversion to forming chains, fetal hemoglobin has become the answer to many sickle cell anemia treatments. One of the most common of these is the drug hydroxyurea. Hydroxyurea and other cytotoxins can help induce the production of hemoglobin F, increasing the concentration of non-sickled cells in the blood and reducing the occurrence of pain crises (Platt et al. 1984). For more information about hydroxyurea, go to Treatments.
Probably the most important effect of hemoglobin F levels in sickle cell patients is decreased hemoglobin S concentrations in comparison to increased hemoglobin F concentrations (Eaton and Hofrichter 1995). Polymerization of hemoglobin S is much less likely to occur if it takes slightly longer for deoxygenated sickle cells to travel to the lungs to be oxygenated (Eaton and Hofrichter 1995). Even slightly smaller concentrations of HbS can cause significant delays in its polymerization, allowing more time for the cell to travel toward the lungs, decreasing its likelihood of polymerizing (Eaton and Hofrichter 1995).