The cellular distribution of fetal hemoglobin: Normal adults and hemoglobinopathies

Single cell analysis of the distribution of HbF in normal individuals and in subjects with various hemoglobinopathies have illustrated several important facts concerning the production of HbF in vivo. First, a distinct nonclonal subpopulation of erythrocytes exists which accounts for essentially all of the HbF produced in normal individuals. Second, HbF production is completed by the nucleated red blood cell stage in normal individuals while HbA production persists throughout erythroid maturation. Third, HbF levels in normal adults and in hemoglobinopathies are determined by three independently regulated mechanisms: increased production of cells containing HbF, alteration in the amount of HbF/F cell, and, in some instances, preferential survival of cells containing HbF. Fourth, F cell production is turned on first during acute erythropoietic expansion, and turned off first with suppression of erythropoiesis. Fifth, among 'normal' adults some individuals inherit high F cell levels, i.e., greater than 8%. These individuals are indistinguishable from individuals with a genetic disorder termed heterocellular HPFH whose F cell levels range between 10 and 50% in the heterozygous state. Sixth, increased F cell production in HbSS is not associated with comparable increases in parental F cell production. This suggests that the mechanism of increased F cell production in HbSS may be somewhat different than that of either normal individuals with greater than 8% F cells or individuals with heterocellular HPFH. Finally, using more sensitive immunologic techniques, a pancellular distribution of HbF can be seen in a variety of disorders, including homozygotes for heterocellular HPFH and heterozygotes or homozygotes with either pancellular HPFH or delta-beta thalassemia.