Clinical Information

More than 75% of the hemoglobin of the newborn is hemoglobin (Hb) F; 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.

Hb 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.

Hb 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. Hb F increases to as high as 10% during normal pregnancy. Hb F is also increased due to medications such as hydroxyurea, decitabine, and lenalidomide. Elevation in Hb F 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 of the erythrocytes contain Hb F. When tested by flow cytometry using specificity for Hb F, these HPFH cases display a homocellular distribution pattern of Hb F within the red blood cell population. Other causes of increased Hb F, including delta beta thalassemia, hydroxyurea, and some nondeletional HPFH variants, typically display a heterocellular distribution of Hb F within the erythrocytes, reflecting disparate populations of F cells and cells lacking Hb F. Quantification of Hb F percentage should be determined prior to flow cytometry of Hb F red blood cell distribution to establish the appropriateness of this test. The flow cytometry analysis of elevated Hb F levels is useful when Hb F percentage is 15% to 35% and the clinical differential diagnosis includes large deletional HPFH. Hb F percentages below 15% are likely not due to large deletional HPFH, and the causes of Hb F percentages above 35% are better confirmed by molecular and family studies.