Haematological disorders

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Haematological disorders

Haemopoiesis is the process which maintains lifelong production of haemopoietic (blood) cells. The main site of haemopoiesis in fetal life is the liver, whereas throughout postnatal life, it is the bone marrow. All haemopoietic cells are derived from pluripotent haemopoietic stem cells, which are crucial for normal blood production; deficiency causes bone marrow failure because stem cells are required for the ongoing replacement of dying cells. Haemopoietic stem cells can also be used for treatment, e.g. cells from healthy donors can be transplanted into children with bone marrow failure (stem cell transplantation).

Haemoglobin production in the fetus and newborn

The most important difference between haemopoiesis in the fetus compared with postnatal life is the changing pattern of haemoglobin (Hb) production at each stage of development. The composition and names of these haemoglobins are shown in Table 22.1. Understanding the developmental changes in haemoglobin helps to explain the patterns of abnormal haemoglobin production in some inherited childhood anaemias. Embryonic haemoglobins (Hb Gower 1, Hb Gower 2 and Hb Portland) are produced between 4 and 8 weeks’ gestation, after which haemoglobin production switches to fetal haemoglobin (HbF). HbF is made up of 2 α chains and 2 γ chains (α2γ2) and is the main Hb during fetal life. HbF has a higher affinity for oxygen than adult Hb (HbA), and is therefore better able to hold on to oxygen, an advantage in the relatively hypoxic environment of the fetus (Fig. 22.1). At birth, the types of Hb are: HbF, HbA and HbA2. HbF is gradually replaced by HbA and HbA2 during the first year of life. By 1 year of age, the percentage of HbF is very low in healthy children and increased proportions of HbF are a sensitive indicator of some inherited disorders of haemoglobin production (haemoglobinopathies) .

Table 22.1

Embryonic, fetal and adult haemoglobins

Haemoglobin type Globin chains
α-gene cluster β-gene cluster
Embryonic    
 Hb Gower 1 ξ2 ε2
 Hb Gower 2 α2 ε2
 Hb Portland ξ2 γ2
Fetal    
 HbF α2 γ2
Adult    
 HbA α2 β2
 HbA2 α2 δ2
Haemoglobin types in newborns and adults
 Newborn HbF 74%, HbA 25%, HbA2 1%
 Children >1 year old and adults HbA 97%, HbA2 2%

image

Haematological values at birth and the first few weeks of life

Features are:

• At birth, the Hb in term infants is high, 14–21.5 g/dl, to compensate for the low oxygen concentration in the fetus. The Hb falls over the first few weeks, mainly due to reduced red cell production, reaching a nadir of around 10 g/dl at 2 months of age (Fig. 22.2). Normal haematological values at birth and during childhood are shown in the Appendix.

• Preterm babies have a steeper fall in Hb to a mean of 6.5–9 g/dl at 4–8 weeks chronological age.

• Normal blood volume at birth varies with gestational age. In healthy term infants the average blood volume is 80 ml/kg; in preterm infants the average blood volume is 100 ml/kg.

• Stores of iron, folic acid and vitamin B12 in term and preterm babies are adequate at birth. However, in preterm infants, stores of iron and folic acid are lower and are depleted more quickly, leading to deficiency after 2–4 months if the recommended daily intakes are not maintained by supplements.

• White blood cell counts in neonates are higher than in older children (10–25 × 109/L).

• Platelet counts at birth are within the normal adult range (150–400 × 109/L).

Anaemia

Anaemia is defined as an Hb level below the normal range. The normal range varies with age, so anaemia can be defined as:

Anaemia results from one or more of the following mechanisms:

There may be a combination of these three mechanisms, e.g. anaemia of prematurity.

Using this approach, the principal causes of anaemia are shown in Figure 22.3 and a diagnostic approach to identifying their causes is shown in Figure 22.4.

Causes of anaemia in infants and children

Diagnostic clues to ineffective erythropoiesis are:

Iron deficiency

The main causes of iron deficiency are:

Inadequate intake of iron is common in infants because additional iron is required for the increase in blood volume accompanying growth and to build up the child’s iron stores (Fig. 22.5). A 1-year-old infant requires an intake of iron of about 8 mg/day, which is about the same as his father (9 mg/day) but only half that of his mother (15 mg/day).

Iron may come from:

Iron deficiency may develop because of a delay in the introduction of mixed feeding beyond 6 months of age or to a diet with insufficient iron-rich foods, especially if it contains a large amount of cow’s milk (Box 22.1). Iron absorption is markedly increased when eaten with food rich in vitamin C (fresh fruit and vegetables) and is inhibited by tannin in tea.

Iron requirements during childhood

Management

For most children, management involves dietary advice and supplementation with oral iron. The best tolerated preparations are Sytron (sodium iron edetate) or Niferex (polysaccharide iron complex) – unlike some other preparations these do not stain the teeth. Iron supplementation should be continued until the Hb is normal and then for a minimum of a further 3 months to replenish the iron stores. With good compliance, the Hb will rise by about 1 g/dl per week. Failure to respond to oral iron usually means the child is not getting the treatment. However, investigation for other causes, in particular malabsorption (e.g. due to coeliac disease) or chronic blood loss (e.g. due to Meckel diverticulum) is advisable if the history or examination suggests a non-dietary cause or if there is failure to respond to therapy in compliant patients. Blood transfusion should never be necessary for dietary iron deficiency. Even children with an Hb as low as 2–3 g/dl due to iron deficiency have arrived at this low level over a prolonged period and can tolerate it.

Treatment of iron deficiency with normal Hb

Some children have biochemical evidence of iron deficiency (e.g. low serum ferritin) but have not yet developed anaemia. Whether these children should be treated with oral iron is controversial. In favour of treatment is the knowledge that iron is required for normal brain development and there is evidence that iron deficiency anaemia is associated with behavioural and intellectual deficiencies, which may be reversible with iron therapy. However, it is not yet clear whether treatment of subclinical iron deficiency confers significant benefit. Treatment also carries a risk of accidental poisoning with oral iron, which is very toxic. A simple strategy is to provide dietary advice to increase oral iron and its absorption in all children with subclinical deficiency and to offer parents the option of additional treatment with oral iron supplements.

Red cell aplasia

There are three main causes of red cell aplasia in children:

The diagnostic clues to red cell aplasia are:

Diamond–Blackfan anaemia (DBA) is a rare disease (5–7 cases/million live births). There is a family history in 20% of cases; the remaining 80% are sporadic. Specific gene mutations in ribosomal protein (RPS) genes are implicated in some cases. Most cases present at 2–3 months of age, but 25% present at birth. Affected infants have symptoms of anaemia; some have other congenital anomalies, such as short stature or abnormal thumbs. Treatment is by oral steroids; monthly red blood cell transfusions are given to children who are steroid unresponsive and some may also be offered stem cell transplantation.

Transient erythroblastopenia of childhood (TEC) is usually triggered by viral infections and has the same haematological features as Diamond–Blackfan anaemia. The main differences between them is that, unlike Diamond–Blackfan anaemia, transient erythroblastopenia of childhood always recovers, usually within several weeks, there is no family history or RPS gene mutations and there are no congenital anomalies.

Increased red cell destruction (haemolytic anaemia)

Haemolytic anaemia is characterised by reduced red cell lifespan due to increased red cell destruction in the circulation (intravascular haemolysis) or liver or spleen (extravascular haemolysis). The lifespan of a normal red cell is 120 days and the bone marrow produces 173 000 million red cells per day. In haemolysis, red cell survival may be reduced to a few days but bone marrow production can increase about eight-fold, so haemolysis only leads to anaemia when the bone marrow is no longer able to compensate for the premature destruction of red cells.

In children, unlike neonates, immune haemolytic anaemias are uncommon. The main cause of haemolysis in children is intrinsic abnormalities of the red blood cells:

Haemolysis from increased red cell breakdown leads to:

The diagnostic clues to haemolysis are:

Hereditary spherocytosis

HS occurs in 1 in 5000 births in Caucasians. It usually has an autosomal dominant inheritance, but in 25% there is no family history and it is caused by new mutations. The disease is caused by mutations in genes for proteins of the red cell membrane (mainly spectrin, ankyrin or band 3). This results in the red cell losing part of its membrane when it passes through the spleen. This reduction in its surface-to-volume ratio causes the cells to become spheroidal, making them less deformable than normal red blood cells and leads to their destruction in the microvasculature of the spleen.

Management

Most children have mild chronic haemolytic anaemia and the only treatment they require is oral folic acid as they have a raised folic acid requirement secondary to their increased red blood cell production. Splenectomy is beneficial but is only indicated for poor growth or troublesome symptoms of anaemia (e.g. severe tiredness, loss of vigour) and is usually deferred until after 7 years of age because of the risks of post-splenectomy sepsis. Prior to splenectomy all patients should be checked that they have been vaccinated against Haemophilus influenzae (Hib), meningitis C and Streptococcus pneumoniae and lifelong daily oral penicillin prophylaxis is advised. Aplastic crisis from parvovirus B19 infection usually requires one or two blood transfusions over 3–4 weeks when no red blood cells are produced. If gallstones are symptomatic, cholecystectomy may be necessary.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

G6PD deficiency is the commonest red cell enzymopathy affecting over 100 million people worldwide. It has a high prevalence (10–20%) in individuals originating from central Africa, the Mediterranean, the Middle East and the Far East. Many different mutations of the gene have been described, leading to different clinical features in different populations.

G6PD is the rate-limiting enzyme in the pentose phosphate pathway and is essential for preventing oxidative damage to red cells. Red cells lacking G6PD are susceptible to oxidant-induced haemolysis. G6PD deficiency is X-linked and therefore predominantly affects males. Females who are heterozygotes are usually clinically normal as they have about half the normal G6PD activity. Females may be affected either if they are homozygous or, more commonly, when by chance more of the normal than the abnormal X chromosomes have been inactivated (extreme Lyonisation – the Lyon hypothesis is that, in every XX cell, one of the X chromosomes is inactivated and that this is random). In Mediterranean, Middle Eastern and Oriental populations, affected males have very low or absent enzyme activity in their red cells. Affected Afro-Caribbeans have 10–15% normal enzyme activity.

Clinical manifestations

Children usually present clinically with:

• Neonatal jaundice – onset is usually in the first 3 days of life. Worldwide it is the most common cause of severe neonatal jaundice requiring exchange transfusion

• Acute haemolysis – precipitated by:

Haemolysis due to G6PD deficiency is predominantly intravascular. This is associated with fever, malaise and the passage of dark urine, as it contains haemoglobin as well as urobilinogen. The haemoglobin level falls rapidly and may drop below 5 g/dl over 24–48 h.