After reading this chapter you should be able to:
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assess, diagnose and manage children with anaemia including bone marrow failure
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understand the risks, benefits and precautions involved in blood transfusion
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assess, diagnose and manage coagulation disorders, hypercoagulable states, purpura and bruising
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assess, diagnose and manage neutropenia
A general principle in all paediatric haematology is the need to refer to age-specific normal ranges. Children with haematological problems can present with a variety of symptoms:
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pallor
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bruising or bleeding
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recurrent infections
Anaemia
Anaemia is defined as a reduction in the haemoglobin concentration below the normal reference ranges for their age and in healthy children, haemoglobin concentrations reach adult levels by approximately 5 years of age. A normal response to anaemia is to increase bone marrow activity that leads to an increase in circulating reticulocytes. These red cells have retained their ribonucleic acid and can be counted separately on standard automated counters and can be recognised on blood films as polychromatic cells.
An understanding of the possible aetiology of anaemia helps during the evaluation of the anaemic patient and the causes can be broadly divided into impaired red cell production, ineffective erythropoiesis and increased red cell destruction ( Table 21.1 ).
| Physiological dysfunction | Associated condition |
|---|---|
| Impaired red cell production | bone marrow failure syndromes (Fanconi anaemia, Diamond Blackfan anaemia) acquired aplastic anaemia transient aplasia due to parvovirus infection bone marrow infiltration with malignancy renal failure leading to reduced erythropoietin haematinic deficiency hypothyroidism chronic inflammation |
| Ineffective erythropoiesis | thalassaemia sideroblastic anaemia vitamin B 12 and folic acid deficiency |
| Increased red cell destruction or loss | congenital haemolytic anaemias haemoglobinopathy autoimmune or alloimmune haemolytic anaemia paroxysmal nocturnal haemoglobinuria (PNH) chronic or acute blood loss |
Anaemia presents with clinical features such as pallor, fatigue and, in extreme situations, cardiac failure and death. Formal examination would confirm pallor, may detect jaundice suggesting increased red cell haemolysis and identify dysmorphic features indicative of bone marrow failure syndromes.
Investigations
A full blood count, blood film assessment and reticulocyte count will all provide important diagnostic clues in the initial assessment of anaemia. The mean cell volume (MCV) and mean cell haemoglobin (MCH) can help define various aetiological subtypes of anaemia. Other important tests include liver function tests to detect bilirubin levels which may indicate haemolysis, direct antiglobulin test that detects attached antibodies on red cells and haemoglobin electrophoresis to identify abnormal haemoglobin ( Figure 21.1 )
The reticulocyte count will offer information on the ability of the marrow to respond to a pathological insult ( Figure 21.2 ).
| Fe deficiency anaemia | Bone marrow failure | Beta thalassaemia | Normal range | |
|---|---|---|---|---|
| Hb | 68 | 68 | 68 | 110–140 g/l |
| MCV | 66 | 87 | 64 | 70–86 fl |
| MCH | 22 | 23 | 15 | 23–31 pg |
| RBC | 2.95 | 3.9 | 6.8 | 4.2–6.5 x 10 12 /l |
| WCC | 4.3 | 3 | 6 | 5.0–12.0 x 10 9 /l |
| Platelets | 504 | 99 | 354 | 150–450 x 109 /l |
| Reticulocytes (absolute) | Low/raised or normal | Low | low | 50–150 x 10 9 /l |
| Ferritin | low | Normal | high | 12–200 μg/l |
Impaired red cell production
Iron deficiency anaemia
Iron deficiency anaemia is the most frequent cause of anaemia in childhood and is the result of lack of iron in the diet. It may also reflect chronic blood loss, and appropriate investigations to exclude inflammatory bowel disease should be considered. The effects of anaemia are well recognised and include weakness, fatigue, palpitations and collapse. Less common effects of iron deficiency are the epithelial changes seen in the mouth and an attendant drive to eat nonnutritional substances such as soil and clay—pica. Chronic iron deficiency can also impair growth and intellectual development.
Investigations
An initial full blood count and serum ferritin would likely identify an iron deficiency. It is important to remember, however, that ferritin is also an acute phase reactant and can rise to within the normal range during intercurrent infection. Iron deficiency may be associated with either raised or reduced platelet counts. Poikilocytosis describes the variation in shape of red cells and includes ‘target cells’ and ‘pencil cells’ (hypochromic elliptocytes found in iron deficiency).
Treatment and management
Oral iron supplementation and improving the diet are often sufficient. In rare situations where the child is intolerant of oral iron, they may benefit from intravenous iron infusion ( Table 21.2 ).
Relevant pharmacological agents used
All oral ferrous preparations are similar in their efficacy and the choice is usually dictated by palatability and cost. Standard daily doses as listed in the BNFc should lead to an expected rise of the haemoglobin concentration of about 20 g/litre over a 3 to 4 week period, and dosing should continue for a further 3 months to replace iron stores. Term babies are born with adequate iron stores but need to maintain an adequate dietary intake. Iron in breast milk is well absorbed but the iron in artificial or cows’ milk is less so, although artificial milks have supplementation. Infants with a poor diet may become anaemic in the second year of life and those with unusual diets may present with anaemia when 3 or 4 years old. Gastrointestinal side effects of oral iron are well recognised and include constipation and production of dark brown or black stools whilst on medication.
Bone marrow failure
Children who present with bone marrow failure may have an underlying congenital cause or may develop the failure due to an inflammatory response, infection or to some environmental insult such as a reaction to medication or chemical exposure. The patient will present with the consequences of the pancytopenia—pallor, exhaustion, severe infection, bruising and petechiae. The causes of the bone marrow failure may be inherited or acquired. Those with inherited bone marrow failure may have dysmorphic features such as skeletal abnormalities, short stature and predisposition to malignancies. A full history will seek information on relevant family history, recent infections and exposure to drugs or potential environmental toxins such as benzene.
Investigations
The full blood count will identify the pancytopenia and a low reticulocyte count will be indicative of the reduced red cell production. Bone marrow aspirate and trephine examination may show a reduced cellularity whilst cytogenetic and molecular testing will look for chromosomal fragility and known genetic mutations which are associated with congenital bone marrow failure syndromes. Tissue typing of siblings is a mandatory consideration at the outset ( Table 21.2 ).
Inherited bone marrow failure syndromes
Fanconi anaemia
Fanconi anaemia is rare but more common in populations with higher rates of consanguinity. It is characterised by increased chromosomal fragility and is caused by mutations in at least 22 genes involved in DNA repair. Clinical severity in Fanconi anaemia is variable, and the age at presentation may vary from infancy to adulthood. Congenital malformations are common presenting features:
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short stature
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absent or hypoplastic thumbs
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absent or hypoplastic radii
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café-au-lait spots
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structural heart defects
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structural kidney defects
Only a small number of children with Fanconi anaemia are identified at an early age and many may first present with bone marrow failure due to myelodysplasia or acute myeloid leukaemia. Children with the condition require lifelong screening for epithelial tumours, especially in the head and neck, gut and genital areas. Bone marrow transplant improves the aplasia and reduces the risk of myeloid malignancy but not of epithelial malignancies ( Table 21.3 ).
Diamond Blackfan anaemia
This is a congenital erythroid aplasia that is usually identified in infancy. Affected children present with a macrocytic, normochromic anaemia with a low reticulocyte count. Bone marrow aspirate shows an absence of erythroid precursors but normal white cell and platelet precursors. They have congenital malformations of the craniofacial, eye, cardiac and thumb structures and have an increased risk of developing malignancies such as acute myeloid leukaemia, myelodysplastic disease and solid tumours.
Schwachman-Diamond syndrome
This is inherited as an autosomal recessive disorder and is associated with bone marrow failure, exocrine pancreatic insufficiency and skeletal abnormalities that generally present in infancy. The condition often presents in infancy or early childhood with a pancytopenia, short stature and steatorrhea due to exocrine pancreatic dysfunction. Loose, foul-smelling stools and an anaemia should always raise the possibility of this condition.
Acquired bone marrow failure
Aplastic anaemia
Aplastic anaemia is rare and the patient presents with the consequences of a pancytopenia. A bone marrow aspirate and trephine will confirm the absence of the haemopoietic precursor cells and exclude marrow infiltrative conditions. Most presentations of acquired aplastic anaemia are driven by autoimmune aetiologies and therefore many children will not have an identified cause for their disease. However, some drugs (including chloramphenicol, phenylbutazone, sulphonamides, antithyroid drugs and anticancer drugs), chemicals (benzene), viruses (parvovirus, human herpesvirus 6) or antigens have all been implicated.
Treatment and management
Unless treated, children generally succumb to complications associated with bone marrow failure, such as sepsis, bleeding or malignancy, and treatment is aimed at mitigating these complications. Exposure to blood products should be kept to a minimum to prevent development of red cell alloantibodies or HLA-related antibodies that reduce the effectiveness of future transfusions. Bone marrow transplant is recommended in those with available donors at the earliest opportunity. The transplant procedure requires the harvesting of cells from a donor and infusion into the recipient. The donor is usually a full sibling (matched donor) or an individual from a donor panel (matched unrelated donor—MUD). Severe acquired aplastic anaemia can be cured by bone marrow transplant, and outcomes of unrelated donor transplants are currently almost comparable to those with sibling donors. In the absence of available donors, long-term immunosuppression helps sustain remission.
Haemoglobin disorders
Thalassaemia
Thalassemia occurs as a result of mutations in genes encoding α and β globin proteins ( HBA and HBB, respectively) that make up the tetrameric haemoglobin A molecule. This results in reduced or absent production of the respective proteins required in the haemoglobin chain. Consequently, there is an imbalance between the numbers of α and β globin proteins available and these then combine to produce unstable combinations ( Table 21.3 ).
| Status | Haemoglobin |
|---|---|
| normal adult Hb | HbA (90%); HbA 2 (less than 3.5%) |
| foetal Hb | HbF |
| alpha-thalassaemia major | HbBarts; HbH |
| beta-thalassaemia trait | HbA 2 (greater than 3.5%) and HbA (90%) |
| transfusion dependent beta-thalassaemia | variable proportions of transfused HbA; some HbA2; variable proportion of HbF |
| sickle cell trait | HbS (25%–40%); HbA (50%–60%) |
| sickle cell disease | HbS (80%–95%); HbF (5%–10%) |
| HbC disease | HbC (90%–95%); HbF (5%–10%) |
| HbSC disease | HbS (40%–50%); HbC (40%–50%) |
α-thalassaemia
This condition develops when deletions or mutations occur in the alpha globin genes (four genes in total, two from each parental allele) which then result in reduced production of the alpha globin protein. As there are four genes contributing to the total alpha globin content of an individual, deletion of one or two genes (heterozygous state) result in no clinical consequence, as the other two remaining genes upregulate their alpha globin protein production. Deletion of three alpha globin genes causes the clinical syndrome of Haemoglobin (Hb) H disease. Deletion of all four alpha genes is known as α-thalassaemia major or Haemoglobin Barts hydrops fetalis and is incompatible with life as it does not produce any normal haemoglobin to sustain foetal and postnatal life. This type of thalassaemia mainly affects individuals who are of Southeast Asian descent.
Many children with alpha-thalassaemia trait may be asymptomatic or identified by the incidental finding of a microcytic anaemia. Hepatosplenomegaly is not usually present although the spleen may be enlarged on ultrasound assessment. Those with Hb Barts often present in utero with hydrops fetalis and rarely survive beyond the first few weeks of life.
Treatment and management
Treatment depends on the number of deleted alpha globin genes. One or two gene deletion alpha thalassaemia trait does not need any treatment. Three gene deletion state (HbH) can need occasional transfusions during intercurrent illness, pregnancy, puberty or surgery.
HbH
HbH is the haemoglobin formed when three out of four alpha globin genes are deleted, leading to the production of significantly lower amounts of alpha globin, leaving the excess beta globin chains to form beta tetramers (also known as Haemoglobin H). HbH is unstable and leads to ineffective erythropoiesis in marrow. However, due to the production of alpha globin from the single unmutated alpha globin gene, small amounts of HbA (α 2 β 2 ) are produced and so patients may not be transfusion dependent.
Hb Barts Hydrops fetalis
If all four alpha globin genes are mutated and no alpha globin is produced at all. This leads to the production of beta globin chains, or other beta-like globin proteins such as gamma globin. These excess gamma globin chains tend to form gamma tetramers (Hb Barts) which are very unstable, leading to ineffective foetal erythropoiesis and severe in utero anaemia and placental disease.
β-thalassaemia
The homozygous beta globin mutation results in underproduction of the beta globin protein that results in the excess alpha globin to form unstable alpha globin tetramers. These structures will denature and precipitate within early red cell precursors in the bone marrow and so lead to ineffective erythropoiesis, severe anaemia and transfusion dependence. There are more than 200 pathological mutations in the beta globin gene which results in β-thalassaemia of variable severity. It is now classified into three subgroups:
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transfusion dependent—homozygous for significant mutation
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transfusion independent
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beta thalassaemia trait—one mutated and one normal beta globin gene
Some individuals have a non-transfusion-independent thalassaemia (previously known as beta thalassaemia intermedia) and are homozygous for mild mutations. They may only require intermittent transfusions during puberty, pregnancy or intercurrent illness. Those with the transfusion-dependent condition may need transfusions as early as 3 months of age and remain transfusion dependent for life, or until they receive curative treatments. The condition is more common in individuals who are of Mediterranean (Greek, Italian and Middle Eastern), Asian or African descent.
Pregnant women who are identified as being at high risk of being a carrier of thalassaemia are offered screening during pregnancy as part of their routine blood tests. The direct assessment of at-risk newborn babies is not undertaken just after birth, as the test is unreliable due to the presence of high amounts of fetal haemoglobin, particularly in preterm infants. Infants must be over 6 months old before the absence or presence of beta-chains can be assessed.
Children with transfusion-dependent β-thalassaemia will be identified from an early age due to a pallor and likely breathlessness on feeding. Anaemia and jaundice are common problems and in the absence of adequate transfusions, the children will develop classical skeletal abnormalities as multiple marrow sites become involved in extramedullary hemopoiesis. Facial deformity is well recognised in under-transfused children as they develop frontal bossing, malar prominence, maxillary overgrowth and dental problems. Other bony sites will also be recruited including spine, skull and pelvis, and many children suffer from bone pain. The changes in the skull give a ‘hair on end’ appearance on a plain x-ray ( Figure 21.3 ). Bone expansion may lead to some degree of thinning, and the affected individuals are prone to fractures with even slight trauma. Many of these bony changes can be minimised by transfusion regimes particularly if started early in life. Extra-medullary haematopoiesis is common in liver and spleen and affected children will often have hepato- and splenomegaly.
Investigations
A hypochromic, microcytic anaemia is common to both thalassaemia and iron deficiency and consequently most laboratories require ferritin to be assessed in the first instance to exclude iron deficiency. Haemoglobin electrophoresis and genetic testing can then be undertaken to confirm the diagnosis. In children with β thalassaemia, the production of HbF and HbA 2 is increased, leading to higher circulating levels of these haemoglobins and can be measured by haemoglobin electrophoresis.
Treatment and management
Treatment of β-thalassaemia major, or transfusion-dependent thalassaemia, includes two to four weekly red cell transfusions to suppress the endogenous ineffective erythropoiesis, allowing children to achieve their full growth and developmental potential. Treatment programmes providing regular transfusions will lead to iron overload in the patient and so all such programmes will also include the administration of iron chelating therapy which may be sufficient to normalise tissue levels of iron. Regular ferritin assessment is an important part of the monitoring process. Bone marrow transplantation from a sibling donor is a curative treatment option. Gene therapy can allow a transfusion-dependent patient to become transfusion independent. This procedure is currently undergoing clinical trials.
Potential complications
Iron has a toxic effect and is deposited in liver, heart, brain and endocrine organs, leading to organ failure. Cardiac iron overload and death from cardiac failure is the commonest outcome in transfusion-dependent patients without chelation. Growth and pubertal failure, endocrinopathy and bone and joint damage are also common in children who are not adequately transfused or chelated. Some children may develop type 1 diabetes mellitus if iron is deposited in pancreatic cells.
Relevant pharmacological agents used
Deferoxamine is a chelating agent which binds to iron and facilitates excretion. It is given as a subcutaneous infusion over 8–12 hours between 3–7 times per week. Oral iron chelators deferasirox and deferiprone are also licensed for use in children and are often the preferred chelators due to their ease of administration.
Increased red cell destruction or loss
Haemolytic anaemia
