Physiology, Fetal Hemoglobin

Fetal hemoglobin is useful in evaluating various conditions in pregnancy and the neonate. The hemoglobin alkaline denaturation test (Apt test) can help to differentiate maternal and fetal blood. In this test, a blood sample of 0.1 mL is added to a glass tube with alkali reagent containing potassium hydroxide, and the solution is shaken gently for 2 minutes. HbA will bind hydroxide to form hematin, turning the sample a dark-green brown, which indicates the presence of maternal blood in the sample. If only fetal blood is present, the solution will remain pink. The Kleihauer-Betke test assesses the extent of maternal-fetal hemorrhage and the required dose of RhoD immunoglobulin for Rh-negative mothers, for the prevention of maternal Rh antibody formation leading to Rhesus disease in the fetus/neonate. The test utilizes HbF's property of acid resistance. A blood smear taken from the mother is exposed to an acidic pH solution; maternal red blood cells become "ghost cells," as HbA is unstable at a low pH, and the cell membrane is denatured. Since fetal blood cells contain HbF, they remain pink, as HbF is stable at this pH range. The appropriate dose of RhoD immunoglobulin is calculated based on the percentage of fetal blood cells in the maternal blood.[8][9][10]

Fetal hemoglobin is of great significance in the pathophysiology of hemoglobinopathies. In alpha thalassemia, one or more of the four alpha-chain genes are deleted on chromosome 16, leading to decreased HbA production and/or abnormal hemoglobin production from beta or gamma chains. The severity is dependent upon the number (1 to 4) of deleted genes. Deletion of a single gene is largely asymptomatic, while the deletion of three genes presents with chronic microcytic anemia and hemolysis that may present with symptoms of fatigue, hepatosplenomegaly, and pigmented gallstones. When all four genes are deleted, there is the production of abnormal hemoglobin composed of four gamma chains; the term for this is Hb Barts. Hb Barts is incompatible with life because the gamma chains have too great an affinity for oxygen, and therefore oxygen delivery is significantly impacted. Affected fetuses suffer from a condition known as hydrops fetalis, marked by accumulations of fluid throughout the body, causing ascites, pleural effusions, pericardial effusions, and scalp edema. This condition results in spontaneous abortion in nearly all cases.[11][12][13]

One medical application of the properties of HbF is in the management of sickle cell anemia. At baseline, HbF accounts for 2% to 20% of hemoglobin in sickle cell disease, depending on various patient-dependent factors, and this elevation appears to be due to the greater oxygen affinity of HbF; therefore, HbF is less likely to deoxygenate, sickle, and cause pain crises in these patients. Indeed, sickle cell disease patients do not manifest symptoms in infancy due to elevated HbF, but as HbF decreases, patients may become symptomatic. HbA shows a decreased half-life in sickle cell disease because vaso-occlusive crises that occur during sickling and deoxygenation induce hemolysis. Through an unknown mechanism, the pharmacologic drug hydroxyurea increases the fraction of HbF found in adults. Treatment with hydroxyurea is indicated in patients that have frequent pain crises, acute chest syndrome, or severe anemia. By increasing HbF, hydroxyurea reduces the requirement for transfusions in patients with sickle cell anemia.[14][15]