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Hemoglobin F Distribution

Hemoglobin F (Hb F) comprises more than 75% of the hemoglobin in newborns. Hb F concentration gradually decreases over a period of several months to less than 2% by age 1 and less than 1% by age 2.

Hb F concentration may be mildly to moderately elevated in patients with sickle cell disease, aplastic anemia, acute leukemia, myeloproliferative disorders, 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. It can also be increased following treatment with hydroxyurea, decitabine, and lenalidomide.

Hb F may constitute 90% of the total hemoglobin in patients with beta-thalassemia major or other combinations of beta thalassemia and fetal hemoglobin mutations. In the common form of hereditary persistence of fetal hemoglobin (HPFH) due to a large deletion of the beta globin gene all erythrocytes contain Hb F. In this case a Kleihauer Betke stain or flow cytometry using a monoclonal antibody to Hb F reveals a homocellular Hb F distribution within all red cells. Other causes of increased Hb F including delta beta thalassemia, some nondeletional HPFH mutations and hydroxyurea therapy demonstrate a heterocellular distribution of Hb F within red cells.

Specimens are analyzed by single-color flow cytometry using a fluorescein labeled anti-Hb F monoclonal antibody. In normal adults, a minimally fluorescent peak of Hb A is present. Neonates have a brightly fluorescent peak of Hb F. Patients with hereditary persistence of fetal hemoglobin demonstrate a single peak of intermediate fluorescence. This pattern corresponds to a homocellular (pancellular) pattern of staining of all RBCs using a Kleihauer-Betke method. Cases of beta thalassemia or delta/beta-thalassemia have both Hb A and Hb F peaks, corresponding to a heterocellular pattern of staining on the Kleihauer Betke method. Patients who are doubly heterozygous for Hb S and HPFH demonstrate a single peak.

Flow cytometry analysis is useful when Hb F percentage falls between 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 causes of Hb F percentages above 35% are better confirmed by molecular and family studies.

Specimen requirement is a tube of whole blood collected in EDTA. Results are reported as heterocellular or homocellular.


Hoyer JD, Penz CS, Fairbanks VF, et al: Flow cytometric measurement of hemoglobin F in RBCs: diagnostic usefulness in the distinction of hereditary persistence of fetal hemoglobin (HPFH) and hemoglobin S-hPFH from other conditions with elevated levels of hemoglobin F. Am J Clin Pathol 2002 Jun;117(6):857-863

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