Читать книгу Neonatal Haematology - Barbara J. Bain, Irene Roberts - Страница 18

The rates of haemoglobin synthesis and red blood cell production fall dramatically immediately after birth and remain low for the first 2 weeks of life, probably in response to the sudden increase in tissue oxygenation at birth.³⁵ In healthy neonates the physiological rise in red cell production starts several weeks later, so that by 3 months of age a healthy infant, whatever the period of gestation at birth, should be able to produce up to 2 ml of packed red blood cells every day.³⁵ Studies in preterm neonates have estimated that over the first 2 months of life the maximal rate of red blood cell production may be closer to 1 ml/day. This is based on the observation that preterm babies receiving therapeutic EPO are unable to maintain their haemoglobin if more than 1 ml of blood per day is venesected for diagnostic purposes but can do so where sampling losses are less than this.³⁶

The gestation‐related changes in globin chain synthesis in the human embryo, fetus and neonate have been studied in detail and are summarised in Fig. 1.4.³⁷ The first haemoglobins, known as embryonic haemoglobins, are synthesised from approximately 2 or 3 weeks post‐conception, predominantly in the blood islands of the yolk sac, by the erythroblasts and red blood cells generated there. There are three embryonic haemoglobins (see Table 1.1). ζ or α globin, encoded by adjacent genes in the α globin locus on chromosome 16, combine with ε or γ globin, encoded by genes in the β globin locus on chromosome 11, to produce haemoglobin Gower 1 (ζ₂ε₂), haemoglobin Gower 2 (α₂ε₂) and haemoglobin Portland (ζ₂γ₂).

During normal human development, synthesis of embryonic haemoglobins is transient and largely restricted to yolk sac‐derived erythroblasts which are larger than those generated once definitive haemopoiesis starts in the AGM and fetal liver (Figs 1.5 and 1.6) and express different transcription factor and epigenetic programmes. From 4 or 5 weeks post‐conception, erythroblasts and red blood cells contain mainly haemoglobin F (α₂γ₂), which remains the principal haemoglobin throughout fetal life. The factors that control the switch from primitive to definitive erythropoiesis are not yet clear due to the difficulties in studying this process at such an early stage of development. Understanding more about the mechanisms which normally silence expression of ζ globin would potentially open up new ways of treating α thalassaemia major,³⁸ an important cause of fetal and early neonatal death (see Chapter 2).

Fig. 1.4 Diagrammatic representation of the sites and rates of synthesis of different haemoglobins in the embryonic and fetal periods and during infancy.

From Bain (2020)³⁷.

Fig. 1.5 First trimester (8 weeks) fetal blood film showing the large size of the erythroblasts (compare with Fig. 1.6) typical of those derived from the yolk sac. These erythroblasts contain mainly embryonic globins. Note the high proportion of red cells that are nucleated and the absence of white blood cells. May–Grünwald–Giemsa (MGG), ×40 objective.

Fig. 1.6 Second trimester (14 weeks) fetal blood film showing typical erythroblasts derived from definitive haematopoiesis. These erythroblasts contain mainly fetal haemoglobin. Note the smaller size of the erythroblasts and the higher proportion of enucleated red cells compared with the first trimester (Fig. 1.5). MGG, ×40.

The production of adult haemoglobin (haemoglobin A; α₂β₂) begins during the second trimester and remains at low levels until 30–32 weeks post‐conception, when haemoglobin A production starts to increase concomitantly with a fall in haemoglobin F production. The net result is an average haemoglobin F in term babies of 70–80% and haemoglobin A of 25–30%.^39,40 After birth, haemoglobin F falls, to approximately 2% by the age of 12 months, with a corresponding increase in haemoglobin A. The molecular control of this change from haemoglobin F to haemoglobin A is termed globin switching. In recent years, there has been considerable research into the genes involved in globin switching (e.g. BCL11A) in order to identify strategies to delay or reverse this physiological switch after birth and so maintain haemoglobin F production for children affected by severe β globin disorders such as sickle cell disease or thalassaemia major.^41,42

The timing of globin switching depends on post‐conceptional age rather than postnatal age. In fact, in term babies there is little change in haemoglobin F in the first 15 days after birth, but in preterm babies who are not transfused, haemoglobin F may remain at the same level for the first 6 weeks of life before haemoglobin A production starts to increase. This delay in haemoglobin A production (i.e. the switch from γ globin production to β globin production) can make the diagnosis of β globin disorders in the neonatal period difficult, particularly in preterm infants. This is in contrast to α globin disorders, which are almost invariably evident at birth since α globin chains are essential for the production of all but the very earliest embryonic haemoglobins (see Fig. 1.4 and Table 1.1).