Definitive Estimate of Rate of Hemoglobin Switching: Measurement of Percent Hemoglobin F in Neonatal Reticulocytes

Abstract

HbF, optimal for oxygen transport in utero, is progressively replaced by HbA from about 32-36 wk of gestation (1). This maturational phenomenon is clinically important and shows marked individual variation. Prolonged postnatal dependence on HbF impairs oxygen transport and has been associated with clinicallv significant anaemia and with the sudden infant death on acid elution (5), and on indirect mathematical analysis of circulating fetal and adult Hb (6, 7). Studies of Hb actively synthesized by reticulocytes in vitroimply a gradual decline of HbF synthesis after a sigmoid curve, the "steep" part starting at about 32 wk gestation and proceding such that the "half-time" for 50% reduction in HbF synthesis is >6 wk. There is a corresponding increase in HbA production. This technique, which assesses HbF/A synthetic balance at the end of erythroid maturation in vitro, may not accurately reflect events in vivo.Studies using the acid elution method of Betke and Kleihauer for detecting HbF in erythrocytes point to the sudden appearance of a distinct subpopulation of cells containing predominantly HbA at about the time of resumption of erythropoiesis after the postnatal erythropoietic shut-down. This suggests a fairly rapid process followed by the appearance of a new population of erythroid cells containing HbA (1, 5).A similiar pattern can be inferred from mathematical analyses of the changing proportion of HbF and HbA in the circulation of individual infants studied postnatally. Mathematical analyses could be taken to imply that, on resumption of erythropoiesis after the postnatal shut-down, HbF synthesis has completely ceased (6, 7). The histo-chemical and mathematical findings could be reconciled with the in vitro observations by assuming that the switchover occurs gradually during a period of relatively inactive erythropoiesis and that, when erythropoiesis resumes, any residual HbF synthesis is insufficient to be detected by these techniques. However, this hypothesis has not been proven and the controversy between rapid and slower rates of switching has not yet been satisfactorily resolved.The discrepancies relating to the time course of the switching process prompted us to develop a direct means of assessing HbF to HbA switching patterns in infants by measurement of the %HbF in reticulocytes harvested from the peripheral blood at different postconceptual stages. We consider that the %HbF of reticulocytes accurately reflects the balance of HbF/A synthesis in the bone marrow in the 2-3 days immediately preceding sampling. This direct approach overcomes the shortcomings associated with the indirect nature of the previous studies. syndroie T2, 3). Despite its biological importance the time course of switching has remained controversial (1). There are PATIENTS theoretical reservations about the validity of methods previously used to study Hb switching. These depend respectively on in Thirty preterm infants of gestation at birth 26-33 wk (mean vitro globin chain synthesis (4), on histochemical studies based 29.5 + 1.74 ...

Effects of Recombinant Human Erythropoietin on Fetal and Adult Hemoglobin in Preterm Infants

“…Previous studies in preterm infants indicate that the switch from HbF to HbA synthesis is related to postconceptional age rather than to time of birth (5,6), although the mechanisms controlling this switch are not fully understood (2,7). Although some studies report a gradual fall in HbF levels in premature infants with increasing gestational age (5,6,16,17), the present results suggest a stable level of HbF% until close to the expected date of delivery (wk 38 -40 postconceptionally). In these nontransfused infants born at a mean postconceptional age of 30.5 wk, HbF remained high at about 90% of total Hb until wk 38-40.…”

“…birth, seem to be accompanied by a gradual decrease in the synthesis of HbF (2)(3)(4). Studies in preterm infants (5,6) and experimental animal studies (7) indicate that the switch is related to the postconceptional age, and that a "developmental clock" rather than environmental factors controls the Hb switching. The time of the switching has, however, not been clarified.…”

Racial discrepancy in pulse oximeter accuracy in preterm infants

“…Even at low gestational ages, infants have mixed hemoglobin subtypes. While the predominant subtype is fetal hemoglobin (HbF), adult hemoglobin (HbA) is also present with estimates ranging between 10 and 20% [ 24 , 25 ]. In some investigations, the absorption spectra of fetal and adult hemoglobin were found to be identical [ 26 , 27 ], however, there is some evidence that an admixture of HbF and HbA results in impaired pulse oximetry accuracy (underestimation) by 3–4% [ 28 , 29 ], although this effect occurs primarily at lower oxygen saturation [ 30 ].…”

Increased prevalence of fetal haemoglobin in Type 1 (insulin-dependent) diabetes mellitus

“…The transition from fetal haemoglobin (alpha 2/gamma 2) to adult haemoglobin (alpha 2/beta 2) begins at 32 to 36 weeks postconception [5]. The transition is gradual with a half-life of 16 to 18 weeks and there is considerable individual variation [5]. Betke pointed out that the adult distribution of Hb F is not reached until puberty, or at least until 6 years of age [6].…”