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Ontogeny of Hemoglobin

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P459

2026-02-26

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The Hb composition of the erythrocyte depends on when in gestation or postnatal development it is measured. This is a result of sequential activation and inactivation (i.e., switching) among genes within the α-globin and non-α-globin gene clusters (see Fig. 1). What controls these switches in globin gene transcription is not understood. The two early embryonic Hbs consist of ζ- and ε-globin chains (Hb Gower-1) and α- and ε-globin chains (Hb Gower-2). The ζ-globin gene is akin to the α-globin genes but is expressed only during early embryogenesis. The ε-embryonic globin chain is a β-like element. The combination of ζ- and γ-globin chains forms Hb Portland. These early Hbs are made primarily in yolk-sac erythroblasts and are detectable only during the very earliest stages of embryogenesis except in certain pathologic states, in which they may persist until gestation is complete. The major Hb of intrauterine life is HbF, which con sists of two α- and two γ-globin chains. Expression of the γ-globin gene begins early in embryogenesis, peaks during mid-gestation, and begins a rapid decline just before birth. By 6 months of age in normal infants, only a remnant of prior γ-globin gene expression remains. The level of HbF in the blood declines rapidly thereafter to less than 1% of the total. Expression of the α-globin gene starts early in the first trimester, peaks quickly, and is sustained for life. Expression of the β-globin gene also commences early in gestation and reaches its zenith within a few months after birth. The combination of α-globin with β-globin chains forms HbA, the predominant Hb of postnatal life. Adult cells also contain HbA2 . The δ-globin gene, which directs the synthesis of the non-α-globin chain of HbA2 , is very inefficiently expressed. Only low levels of HbA2 are present; defects in the δ-globin gene are of no clinical consequence. In adult blood, HbF is not evenly distributed among erythrocytes and is present in only a very small number of RBCs, called F cells. HbA2 is present in all RBCs, albeit at levels less than 3.5% of the total Hb in adult life.

Fig3. HEMOGLOBIN (HB) SWITCHING DURING EMBRYONIC, FETAL, AND ADULT DEVELOPMENT. The ζ and ε genes are transcribed during embryonic development and are soon replaced by the fetal γ-globin and adult α-globin gene. At birth, fetal Hb (HbF) forms approximately 75%, and HbA forms 25% of the total. Transcription of the γ gene begins to decrease before birth, and by 6 months of age, this gene is expressed only at very low levels. Expression of the δ-globin gene begins near birth. In adults, HbA makes up approximately 97%, HbA2 approximately 2.5%, and HbF less than 1% of the total. (Reproduced with permission from Steinberg MH. Hemoglobinopathies and thalassemias. In: Stein JH, ed. Internal Medicine. 4th ed. St. Louis: Mosby-Year Book; 1994:852.)