Clinical Information

More than 75% of the hemoglobin in a newborn infant is fetal hemoglobin (HbF); it diminishes over a period of several months to adult levels, reducing to less than 2% by 1 year of age and less than 1% by 2 years of age.

Hemoglobin F may constitute 90% of the total Hb in patients with beta-thalassemia major or other combinations of beta thalassemia and fetal Hb (hereditary persistence of fetal hemoglobin: HPFH) variants.

Hemoglobin F is often mildly to moderately elevated in sickle cell disease, aplastic anemia, acute leukemia, and myeloproliferative disorders, such as juvenile myelomonocytic leukemia, hereditary spherocytosis, and alpha-thalassemia minor. It is commonly increased in hemoglobinopathies associated with hemolysis. HbF increases to as high as 10% during normal pregnancy. HbF is also increased due to medications such as hydroxyurea, decitabine, and lenalidomide. Elevation in HbF has a been cited as a discriminator between Diamond-Blackfan congenital pure red cell aplasia (elevated) and transient erythroblastopenia of childhood (normal), but whether this simply reflects the chronicity of anemia inherent to the former condition rather than a specific finding is unclear.

In the common (large deletional) form of the genetic trait HPFH, all erythrocytes contain HbF. When tested by flow cytometry using specificity for HbF, these HPFH cases display a homocellular distribution pattern of HbF within the red blood cell population. Other causes of increased HbF, including delta beta thalassemia, hydroxyurea, and some nondeletional HPFH variants, typically display a heterocellular distribution of HbF within the erythrocytes, reflecting disparate populations of F cells and cells lacking HbF. Quantification of HbF percentage should be determined prior to flow cytometry of HbF red blood cell distribution to establish the appropriateness of this test. The flow cytometry analysis of elevated HbF levels is useful when HbF percentage is 15% to 35% and the clinical differential diagnosis includes large deletional HPFH. HbF percentages below 15% are likely not due to large deletional HPFH, and the causes of HbF percentages above 35% are better confirmed by molecular and family studies.