Anaemia

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11.2 Anaemia

Jane Cocks

Essentials

1 The normal haemoglobin concentration and type is age and sex dependent.
2 Clinical effects of anaemia depend on the timing of its development, the magnitude of the anaemia and the underlying cause.
3 Iron-deficiency anaemia is the commonest cause of microcytic and hypochromic anaemia.
4 Autoimmune haemolytic anaemia (AIHA) is commonly caused by a variety of infective agents, although it can be triggered by a number of medications and systemic illnesses.
5 Non-immune haemolytic anaemia can be due to infective agents, medications and chemical exposures.
6 Haemolytic uraemic syndrome (HUS) is the commonest cause of acute renal failure in children, most frequently secondary to infection with E. coli.
7 Thrombotic thrombocytopenic purpura affects children over the age of 10 years. The clinical features are similar to HUS with the addition of neurological deficit.
8 G6PD deficiency is an X-linked enzymatic inborn error in which haemolysis is triggered by exposure to an oxidant.
9 Thalassaemia is a relatively common inherited defect in the synthesis of the globin chain.
10 Sickle cell disease is an autosomal recessive inherited condition with a globin chain that is unstable in the deoxygenated state leading to haemolysis.

Introduction

Anaemia is defined as a reduction in the red blood cell (RBC) volume or haemoglobin concentration below normal values. The normal haemoglobin level is age and sex dependent, and racial differences exist. At birth, the haemoglobin level is 159–191 g L–1 and this falls to a trough level of 90–114 g L–1 between 8 and 12 weeks of age before rising again toward normal adult range.

Red blood cell production is regulated by erythropoietin, a hormone produced initially in the foetal liver and, after birth, in the renal peritubular cells. In normal erythropoiesis, erythropoietin stimulates differentiation of marrow stem cells into red blood cells. During this process there is a condensation of the cell’s nuclear material with continual production of the haemoglobin until it comprises 90% of the mass of the RBC. The nucleus is then extruded, leaving the RBC with no synthetic or replication ability, leading to a limited RBC lifespan of 120 days.

Haemoglobin is the major functional constituent of the RBC responsible for the task of carrying oxygen to the tissues, with the RBC acting as the carrier through the cardiovascular system. Haemoglobin is a complex protein consisting of iron-containing haem groups and polypeptide chains, known as globin. The haemoglobin molecule is made up of two pairs of polypeptide chains each coupled with a haem group. Chemical variations in the polypeptide chains lead to different types of haemoglobin being produced. At various stages of life, from the embryo to the adult, there are six different types of haemoglobin normally detectable. The normal adult haemoglobin, HbA, is comprised of two α-polypeptide chains and two β-chains, (α2β2). Haemoglobin F, or fetal Hb (HbF), is comprised of two α-chains and two γ-chains, (α2γ2) and constitutes 70% of the haemoglobin present at birth, reducing to trace levels by 6–12 months of age. Minor amounts of HbA2 (α2δ2) are present at all ages. Pathological variations in the polypeptide chains can produce disease states, known as haemoglobinopathies (see below).

Anaemia is not a single disease, but may occur as a result of a variety of pathological processes. The anaemias of childhood can be usefully divided into two groups: (1) those caused by inadequate production of RBC or haemoglobin; and (2) those due to increased destruction or loss of RBC. Tables 11.2.1 and 11.2.2 outline the major causes of childhood and neonatal anaemias.

Table 11.2.1 Causes of childhood anaemia

Production defect

1. Primary bone marrow failure

• Aplastic anaemia (congenital or acquired)
• Diamond-Blackfan syndrome
• Transient erythroblastopenia of childhood (TEC)

2. Erythropoietin production problem

• Chronic renal disease
• Hypothyroidism

3. Abnormal cytoplasmic maturation (microcytic anaemias)

• Iron deficiency
• Sideroblastic anaemia (congenital or acquired)
• Lead toxicity
• Thalassaemia syndrome

4. Megaloblastic anaemia

• Vitamin B12 deficiency
• Folate deficiency
• Thiamine-responsive megaloblastic anaemia
• Orotic aciduria (rare, associated with megaloblastic anaemia)

5. Others

• Primary dyserythropoietic anaemias
• Erythropoietic protoporphyria
• Marrow infiltration, e.g. malignancy or myelofibrosis

Decreased RBC survival

1. Hereditary haemolytic anaemias

a. Haemoglobin variants

• Thalassaemias
• Sickle cell disease

b. Abnormal RBC membranes

• Hereditary spherocytosis
• Hereditary elliptocytosis
• Hereditary stomatocytosis

c. Abnormal enzymes

• Glucose-6-phosphatase dehydrogenase deficiency (G6PD)
• Pyruvate kinase deficiency

2. Acquired haemolytic anaemias

a. Autoimmune haemolytic anaemia (AIHA)
b. Non-immune haemolytic anaemia
c. Fragmentation haemolysis

• Haemolytic uraemic syndrome (HUS)

3. Haemorrhage
• Traumatic
• Non-traumatic – acute or chronic
Table 11.2.2 Causes of anaemia in the neonate
1. Physiological anaemia
2. Abnormal RBC production

a. Nutritional deficiency
b. Secondary to infection

3. Decreased RBC survival – blood loss

a. Overt blood loss

• Iatrogenic during delivery
• Obstetric accidents

b. Occult blood loss

• Twin-to-twin transfusion
• Fetoplacental haemorrhage
• Fetomaternal haemorrhage

4. Decreased RBC survival – haemolysis

a. Immune-related: isoimmunisation
b. Infection-related
c. Hereditary haemoglobin variants, enzyme abnormalities, membrane abnormalities

Overview

The principles of management of anaemia in the emergency department (ED) are:

Resuscitate the patient with circulatory collapse.
Remove or treat the precipitant if known.
Treat the cause if treatment can be initiated in the ED.

Causes of life-threatening anaemia include uncontrolled haemorrhage, acute intravascular haemolysis in glucose-6-phosphatase deficiency (G6PD) or autoimmune haemolytic anaemia (AIHA), sequestration crisis in sickle cell disease (SCD) and acute decompensation in chronic anaemia.

Initial assessment is directed at respiration and circulation. The anaemic patient may be tachypnoeic with tissue hypoxia. The adequacy of ventilation should be ascertained and supplemental oxygen provided. Circulatory compromise in acute haemorrhage and acute haemolysis requires cardiorespiratory monitoring and intravenous access for fluid resuscitation (see Chapter 2.5 on shock). Packed red blood cells are used if haemorrhage or haemolysis is life threatening. If tissue oxygenation is not critically affected, the circulatory volume should be sustained with colloid or crystalloid until group-specific or cross-matched RBCs are available. If the bleeding is controlled, with further bleeding unlikely, the signs mentioned above are stable and the haemoglobin concentration is greater than 70 g L–1, a cross-match should be performed and the packed RBCs should be held in reserve for 24 hours. Early consultation with a haematologist is important in acute haemolytic anaemia especially if the underlying cause has not been diagnosed.

Anaemia is a clinical finding rather than a disease in its own right and symptoms depend on the timing of its development, the severity and the underlying cause. The presentation is frequently not specific to anaemia. Common presenting features consistent with insidious onset anaemia include:

• lethargy, irritability, sleep or settling difficulty;
• pallor or yellow skin hue;
• loss of appetite ± weight loss ± pica;
• bruising, bleeding or infection.

Patient factors to note are age, ethnicity and the presence of other significant disease. Iron-deficiency anaemia is uncommon in the first 6 months in term infants and sickle cell disease (SCD) is unlikely to present as anaemia under the age of 4 months. Haemolytic uraemic syndrome (HUS) mainly affects those under 4 years of age, whereas thrombotic thrombocytopenic purpura (TTP) affects children from 10 years of age. Iron deficiency is common in adolescent females, whereas G6PD deficiency occurs mainly in males. The association between ethnicity and various types of hereditary anaemia is shown in Table 11.2.3. Family history of anaemia may also suggest hereditary anaemia.

Table 11.2.3 Ethnicity and anaemia

1. Thalassaemia syndromes

• α-Thalassaemia – descendants from China, Malaysia, Indonesia and Africa
• β-Thalassaemia – descendants from Africa, Middle East, Mediterranean, India, Pakistan, China

2. Sickle cell disease

• Descendants from Africa, southern Arabia, Turkey, Greece, central India

3. Hereditary spherocytosis

• Descendants from northern Europe

4. G6PD deficiency

• Descendants from Africa, China, south-east Asia and the Mediterranean

Dietary history can provide important clues. Iron-deficiency anaemia is likely in prolonged breast-feeding beyond 6 months of age in term infants and sooner in preterm infants if no iron supplementation is provided, if there is excessive dependence on cows’ milk as a food source or if food sources are restricted, e.g. food fads. Ingestion of clay and dirt may cause lead toxicity and iron deficiency. Ingestion of fresh uncooked broad beans is a potent precipitant of haemolysis in G6PD deficiency, along with medications.

Recent infections may precipitate AIHA, non-immune haemolytic anaemia, HUS and TTP. Hyperbilirubinaemia caused by haemolysis leads to jaundice, cholelithiasis, cholecystitis and dark urine. Mechanical destruction of RBCs is caused by vascular malformations, shunts, abnormal native or prosthetic cardiac valves. Septic shock, bleeding disorders, chronic renal disease, severe burns and hypothyroidism may all cause anaemia.

The salient physical findings in the context of anaemia relate to general appearance, cardiovascular status and abdominal examination. Frontal bone expansion and frontal bossing is due to expansion of the medullary spaces and may be seen in severe thalassaemias. Some hereditary anaemias may also have associated physical abnormalities (e.g. Diamond–Blackfan anaemia). Hepatosplenomegaly is a feature of some of the hereditary haemolytic anaemias. Purpuric or petechial rashes are due to coagulation disorders or vasculitis. Dark urine from bilirubinuria is consistent with haemolysis. Haematuria must be confirmed by microscopy to distinguish haemoglobinuria from haematuria.

Anaemia is confirmed by the lowered haemoglobin concentration and decreased RBC count. An age-related reference range must be used. Abnormalities in the other cell lines should be noted. The mean cell volume (MCV) may suggest an underlying cause. The upper limit of normal in adults is 96 fL but MCV in children is less than in adults and average values may be estimated by adding 0.6 fL per year of age to 84 fl. The reticulocyte count is expressed as a percentage of the circulating RBC mass with a normal range of 0.5–1.5%. A low reticulocyte count is found in abnormalities of RBC production and a high reticulocyte count is found in increased destruction or from RBC loss, provided there is no concurrent bone-marrow pathology. Morphological features of RBC may be diagnostic of the underlying cause as shown in Table 11.2.4.

Table 11.2.4 Morphological features of RBCs to assist the diagnosis of anaemia
Schistocytes Erythrocyte fragmentation syndromes
Sickle cells Sickle cell disease
Spherocytes Immune-meditated haemolytic anaemia Hereditary spherocytosis
Blister or bite cells with poikilocytosis G6P deficiency

There are many additional investigations apart from full blood count to assist in identification of the underlying cause. Some that are undertaken in the ED include:

• bilirubin – elevated unconjugated bilirubin suggests haemolysis;
• urea and creatinine to detect renal failure in HUS and TTP;
• iron studies (serum iron, total iron binding capacity, transferrin saturation);
• Coombs’ tests to identify immune-related haemolysis;
• haemoglobin electrophoresis.

Identification and treatment of the underlying precipitant, where appropriate and possible, is a crucial part of the management of anaemia in the ED. Packed RBCs are indicated in the treatment of severe anaemia with cardiovascular compromise. A dose of 4 mL kg–1 of packed RBCs raises haemoglobin concentration by 10 g L–1. This dose can be given hourly or more slowly in the presence of cardiac failure. Furosemide 1 mg kg–1 may be given if there is evidence of volume overload. Involvement of a paediatric haematologist is recommended for all but the simple nutritional anaemias.

Neonatal anaemia

In the term neonate, the haemoglobin at birth is in the range of 159–191 g L–1 and rises in the first 24 hours. Subsequently it falls to a trough level of 90–114 g L–1 between 8 and 12 weeks of age. This decline is generally referred to as physiological anaemia of infancy, although it is an expected normal occurrence. The falling haemoglobin is due to a combination of rapid weight gain and blood volume expansion leading to relative haemodilution in the first 3 months of life, combined with a comparatively shorter life span of the fetal RBC and a sharp decline in erythropoiesis a few days after birth due to increased arterial oxygenation and a reduction in the production of erythropoietin. Following the nadir in Hb, erythropoiesis recommences and the Hb rises again.

Immune-related

Immune-related haemolysis is the commonest cause of anaemia in the neonate. Maternal antibodies pass through the placenta leading to fetal cell lysis. Haemolysis occurs when the target cells are the fetal RBCs. The commonest antigen responsible is the Rhesus antigen on the RBC surface, followed by ABO incompatibility. Sensitisation of the mother occurs when Rhesus incompatible fetal cells gain access to the maternal circulation. Fetal RBCs can be found from 8 weeks’ gestation onwards. As little as 0.05–0.10 mL is enough to cause primary sensitisation but the volume and risk increases with obstetric procedures, miscarriages and toxaemia. Fetal harm occurs during subsequent pregnancies with a Rhesus positive fetus in a Rhesus negative mother. The resultant intravascular haemolysis in the fetus can be devastating. The clinical significance is due both to the severity of the anaemia and kernicterus from the hyperbilirubinaemia. ABO incompatibility produces less severe jaundice and anaemia during the second week of life.

Prevention relies on identification of the Rhesus status of all pregnant women. This is an essential task for any doctor involved in antenatal care. Prophylaxis therapy using anti-D immunoglobulin (Ig) is given to all Rhesus negative women with per vaginal bleeding or requiring any obstetric procedures that may lead to fetomaternal haemorrhage. The recommended dose is 250 IU if the sensitising event occurs in the first trimester and 625 IU beyond this gestation period. This passive immunisation is given intramuscularly. If required in the postpartum period the immunoglobulin is administered intravenously.

Neonatal infection

Infections cause anaemia by producing bone-marrow suppression of erythropoiesis or by haemolysis. The infections of relevance in the neonate are cytomegalovirus (CMV), rubella, toxoplasmosis and congenital syphilis. The human parvovirus may lead to spontaneous miscarriage in early pregnancy and, in late pregnancy, can selectively depress erythropoiesis, producing severe fetal anaemia. In the older child, parvovirus is the cause of Erythema Infectiosum (Fifth Disease), which can be complicated by aplastic crisis or chronic haemolysis. Vertical transmission of malaria to the fetus is a major cause of anaemia in the neonate in endemic regions. Human immunodeficiency virus (HIV) infection in the neonate is predominantly acquired via perinatal transmission from the mother. The transmission rate is in the range of 20–40%. The mechanism for subsequent anaemia is bone-marrow suppression and associated pancytopenia as well as chronic multisystem disease.

Haemoglobinopathies and enzymopathies

G6PD deficiency is an important global cause of neonatal jaundice. Haemolysis from other enzymopathies and haemoglobin variants, such as thalassaemias and SCD, is usually unmasked beyond the neonatal period when the proportion of fetal haemoglobin falls. It is important to consider congenital causes of anaemia in children with a family history of hereditary anaemia or persisting neonatal jaundice.

Blood loss

Blood loss may arise from twin-to-twin transfusion, or obstetric procedures, or as part of the delivery of the neonate in the perinatal period. Haemorrhage from an underlying haematological disorder must be considered. Vitamin K deficiency is normally present at birth but only a minority of neonates develop generalised bleeding. Breast milk has a small amount of vitamin K and, in the breast-fed baby, maternal medications such as warfarin, phenytoin, rifampicin and isoniazid, may compound the deficiency. Nutritional vitamin K deficiency has been associated with prolonged breast-feeding without supplementation, malabsorption, chronic diarrhoea, and prolonged use of oral antibiotics. Vitamin K prophylaxis is normally given at birth. Haemophilia can rarely lead to spontaneous haemorrhage in the newborn.

Anaemias of childhood

Iron-deficiency

Iron deficiency is uncommon in the first 6 months in the term infant due to the efficient recycling of the iron from the haem component of haemoglobin when it is metabolised. In the preterm and low-birth-weight neonate, iron deficiency occurs earlier, often at the time of doubling of the birth weight. In the second 6 months of life, iron deficiency is found in 20% of Australian children, with associated anaemia in 3%. The respective figures in the second year are 35% and 9%. It is even more common in indigenous children and children from non-English-speaking backgrounds. In school-age children, iron deficiency is present in 1–2% but is found in up to 9% of adolescent girls.

Stages

The first stage of iron deficiency is a low serum ferritin level. Iron-dependent body functions, including erythropoiesis, are affected in stage two. Microcytes and an elevated erythrocyte protoporphyrin level are detectable and the serum iron falls. The third stage is the presence of a microcytic hypochromic anaemia.

Causes

The commonest cause globally is insufficient intake of dietary iron. In developing countries, the two most significant factors are the failure to obtain iron-rich nutrients and malabsorption from intestinal pathology. The aetiology is different in developed countries, such as Australia, where prolonged breastfeeding beyond 6 months of age without supplementation with iron-rich foods is a common finding. Breast milk has easily absorbable iron in modest amounts. The quantity is inadequate for the rapid growth in the second 6 months. Cows’ milk has minimal iron content, which exists in a poorly absorbable form and is not recommended under the age of 12 months. Cows’ milk can cause gastrointestinal bleeding in the immature gut and children who have an excess intake of cows’ milk have a lower appetite for other foods. More than two servings of milk per day is not advisable. Iron-fortified cereals should be introduced from 5 months of age.

Adverse effects

Iron deficiency before 24 months can lead to impaired development of cognitive and psychomotor skills, which may be only partially reversible when the deficiency, and the associated anaemia, is corrected. Many parents report loss of appetite, irritability and inability to concentrate in affected children. Pica may be present. Iron deficiency affects neutrophil and lymphocyte function in vitro and is indicated as one of the investigations of recurrent infections.

Diagnosis

Iron deficiency is the commonest cause of microcytic hypochromic anaemia and is characterised by a low serum iron, a high total iron binding capacity and a low transferrin saturation. The reticulocyte count is less than 2% unless iron had been reintroduced into the diet. The diagnosis is not confirmed until iron supplementation is followed by a reticulocytosis within 1–2 weeks and a rise in the haemoglobin over 2–4 weeks. Other conditions producing microcytic anaemia must be considered if there is poor response to iron supplementation.

Treatment

Dietary advice and education are the basis of prevention and treatment in developed countries. If iron supplementation is required, the ferrous form is more effectively absorbed either as syrup or tablets at 2–3 mg kg–1 day–1. The treatment dose for severe anaemia is up to 6 mg kg–1 day–1, but side effects of nausea, vomiting, and constipation are dose-related. Transfusion is only ever required if there is cardiovascular compromise. Parents should be informed regarding the toxicity of iron in overdose so that they store the medication safely.

Haemolytic anaemias

RBC exist in the circulation for 100–120 days with up to 1% of the RBC population being removed by haemolysis and replaced per day. Pathological haemolysis is that which occurs outside of this normal process leading to reduced RBC survival. In response, bone marrow activity increases, leading to an increased reticulocyte count of >2%. In the older age group, the bone marrow’s capacity to increase erythropoiesis can compensate for mild pathological haemolysis. In the infant and young child, the bone marrow is maximally active with minimal ability to increase erythropoiesis and anaemia accompanies pathological haemolysis.

The haemolytic anaemias of childhood may be classified as hereditary or acquired (Table 11.2.1). The hereditary haemolytic anaemias are caused by inherited traits that lead to abnormal haemoglobin chains (haemoglobinopathies), abnormal RBC membranes or abnormal RBC enzymes (enzymopathies). The acquired haemolytic anaemias may be immune or non-immune or as a result of fragmentation syndromes.

Acquired haemolytic anaemias

Autoimmune haemolytic anaemia (AIHA)

A variety of infectious agents (Epstein–Barr virus, CMV, mumps, mycoplasma and tuberculosis) can cause severe anaemia in the younger child. The antibody involved is mainly IgM, but may be IgG. Other diseases that trigger autoantibodies include systemic lupus erythematosus, rheumatoid arthritis, thyrotoxicosis, ulcerative colitis, malignancy and immunodeficiency syndromes. Idiopathic autoimmune anaemia can be rapidly progressive over days in the young infant and chronic and relapsing in the older child.

Haemolysis in these conditions occurs within the intravascular space. The Coombs’ test in these conditions is positive. This test detects a coating of immunoglobulins or components of complement on the RBC surface. During haemolysis, free haemoglobin is liberated in plasma and combines with haptoglobin resulting in decreased serum haptoglobin. RBC fragmentation, spherocytes and sometimes tear-shaped cells are found on the peripheral blood film. Spherocytosis and other characteristic red-cell changes are due to membrane loss as splenic macrophages attack antibody-coated red blood cells. Lactose dehydrogenase, a RBC enzyme, is raised and free haemoglobin and haem-albumin may be found in the plasma.

In children the clinical pattern is most frequently an acute episode of severe anaemia with resolution within 3 months. Haemoglobin drops to less than 60 g L–1 in over 50%. A slower onset is more likely to follow a chronic and relapsing course with guarded prognosis.

A reticulocytosis may not be present initially due to rapid onset. Associated immune thrombocytopenia is present in a third. Direct Coombs’ antiglobulin test is positive. Free antibodies may be detectable within serum. Antibodies that are maximally active at 37°C belong to the IgG class and are known as warm antibodies. Antibodies that are maximally active between 0 and 30°C belong to the IgM class and are known as cold antibodies. Serology may be useful in identifying the infective agent. Hyperbilirubinaemia is present.

IgG-induced AIHA responds to steroid therapy and variable regimes have been effective. This is not effective in cold agglutinin disease (IgM induced), which may require plasmapheresis. Both may respond to immunoglobulin, 1 g kg–1 IV, and require exchange transfusion if disease is severe. Splenectomy is a last resort in IgG-induced AIHA. A haematologist should be consulted regarding specific treatment.

Non-immune haemolytic anaemia

Non-immune haemolytic anaemia can also be caused by a variety of infectious agents (malaria, Gram-positive and Gram-negative organisms), medications (salicylates, sulfasalazine, nitrofurantoin) and chemicals (naphthalene). Clinical features are similar to AIHA but Coombs’ test is negative. Treatment is supportive, focusing on the identification and treatment of the underlying cause.

Erythrocyte fragmentation syndromes

These are haemolytic anaemias due to direct physical or mechanical damage to the erythrocytes. They are characterised by red cell fragmentation with schistocytes and spherocytes in the peripheral blood film and features of intravascular haemolysis. There are two groups.

Macroangiopathic haemolytic anaemia

Macroangiopathic haemolytic anaemia results from RBC damage upon passage through large vessels and the heart and is associated with structural cardiac abnormality or large vessel disease (coarctation of the aorta). It can follow cardiac surgery but infection or failure of the prostheses must be considered if it occurs distinct from the surgical period. It is less likely with xenografts and also when prostheses are covered by endothelium. The damage is from a combination of shearing forces from turbulent flow and interaction between the cells and the abnormal surfaces. The anaemia is usually mild and severe haemolysis is uncommon. Treatment of the underlying cause is important.

Microangiopathic haemolytic anaemia

Microangiopathic haemolytic anaemia is due to RBC damage as they pass through diseased or partially occluded arterioles and capillaries and is often acute and severe, with associated thrombocytopenia. The commonest causes are HUS under 4 years of age and TTP in the child 10 years and older but connective tissue disease, haemangiomas and severe burns can all be causes.

Haemolytic uraemic syndrome

HUS is the commonest cause of acute renal failure in children. It is classically characterised by the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and uraemia. In warmer climates it may be endemic but in cooler climates it occurs sporadically. More than 90% of affected children are under the age of 4 years, with peak incidence in children between the ages of 4 months and 2 years. Numerous infections can trigger HUS including Shigella, Salmonella, Yersinia, Campylobacter, Streptococcus pneumoniae, echovirus, Coxsackie virus A and B, and varicella. The commonest organism is Escherichia coli and verocytotoxin is the toxic agent. HUS may also develop in association with certain drugs, including oral contraceptives, mitomycin, or cyclosporin, and in diseases with significant endothelial cell injury such as systemic lupus erythematosus. A familial inherited version has been reported, although these occurrences are usually not associated with diarrhoea.

HUS is usually (80%) preceded by an infection with vomiting and bloody diarrhoea. Fever is present and oliguria occurs within days. Hypertension may be present. The thrombocytopenia is mild and severe bleeding is uncommon. Rarely, cardiomyopathy, cerebral infarcts or haemorrhage, bowel perforations and diabetes may complicate HUS.

The peripheral blood film shows the typical schistocytes. A leucocytosis with left shift often accompanies the anaemia and thrombocytopenia. Stool samples should be tested for verocytotoxin. Raised urea and creatinine indicate renal failure.

Treatment is directed at the acute renal failure with early dialysis indicated in some cases. Transfusion of packed RBCs may be required. Platelet transfusion is not indicated unless there is active bleeding. Careful monitoring is essential.

The long-term outcome for the acute renal failure is good, with 90% survival rate in the acute phase. Long-term monitoring is essential as chronic complications may not be apparent for several decades. Atypical HUS following an upper respiratory tract infection may manifest severe hypertension and renal failure. The prognosis for the latter is poor. The disease may recur.

Thrombotic thrombocytopenic purpura

This clinical syndrome is similar to that seen in HUS, with the addition of neurological deficit. The latter may take the form of an altered level of consciousness ranging from confusion, to seizure or coma. Cranial nerve palsies may also be present. The renal failure is not as severe compared to HUS but the thrombocytopenia is more severe. TTP usually affects children older than 10 years. Possible triggers include mycoplasma and viral infections, HIV and subacute bacterial endocarditis but none is evident in the majority of patients. Underlying immunological disease may be relevant, as is pregnancy, and genetic predisposition. Treatment is supportive, mainly via exchange transfusion using FFP. If there is no improvement in 24 hours then plasmapheresis is considered. Transfusion of packed RBCs is rarely needed for severe anaemia. Involvement of a paediatric haematologist is mandatory.

Hereditary haemolytic anaemia

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency

G6PD deficiency renders the RBC vulnerable to haemolysis when exposed to an oxidant. G6PD is the enzyme in the pathway leading to generation of reduced nicotinamide adenine dinucleotide phosphate, which maintains glutathione in its reduced form. Reduced glutathione is an essential factor in the degradation of cellular peroxides that may otherwise damage cellular proteins including haemoglobin. The enzyme activity is higher in the younger RBCs but deteriorates as the cell ages so older RBCs are more prone to haemolysis.

G6PD is an X-linked recessive condition with wide variability of expression depending on the biochemical type, the oxidant stress and the sex of the patient. Homozygous females are rare and the disease is predominantly found in males. The severity of the disease varies and levels of enzyme at or above 40% of normal will rarely result in clinically significant haemolysis. A number of different variants are found in patients of African, Chinese and Mediterranean descent.

Viral and bacterial infections can both cause acute haemolysis especially in children less than 2 to 3 years of age. Oxidant drugs and chemicals that commonly cause haemolysis include naphthalene, sulphonamides, antimalarials, nitrofurantoin, diazoxide and dapsone. Favism refers to the acute haemolysis resulting from the ingestion of broad bean (Vicia faba) or inhalation of the pollen in those with the Mediterranean variant but not those with the African variant. The haemolytic agent in the broad bean can be passed to the infant by breast milk. The anaemia is present within 3–36 hours and usually lasts for 2–6 days. Death can occur within 24 hours of the haemolysis. Definitive diagnosis of G6PD deficiency is via a quantitative assay of the enzyme. Treatment is non-specific. Prevention is crucial, with avoidance of oxidising medications and prompt treatment of infections.

Thalassaemias

Thalassaemia is one of the commonest inherited haemoglobin variants. Defective synthesis of globin chains leads to abnormal pairing of the globin chains in the haemoglobin molecule. Excess chains tend to aggregate, precipitate and cause damage to the RBCs. The nomenclature depicts the missing chain, e.g. β–thalassaemia refers to a deficiency of the β-chain. Haemoglobin electrophoresis defines the haemoglobin variants.

β-Thalassaemia major

Each carrier parent must donate one abnormal gene to the offspring and there is a 25% chance of a homozygote progeny with β-thalassaemia major. No β-chains are produced so presentation is in the first month of life when the fetal haemoglobin, HbF (α2γ2), is falling, with an increasing reliance on adult haemoglobin, HbA (α2β2). Excess unpaired α-chains aggregate to form an unstable tetramer, which is functionally useless. Haemolysis is increased and severe anaemia will occur. Extramedullary haemopoiesis leads to massive hepatosplenomegaly which may result in functional hypersplenism. Bone marrow expansion may result in skeletal changes (e.g. bossing of the frontal bone). The peripheral blood film shows a microcytic hypochromic anaemia with marked poikilocytosis, target cells and reticulocytosis. Basophilic stippling may be seen in the RBCs. Iron and folate deficiency may be demonstrated, although iron overload will eventually develop due to increased gastrointestinal tract absorption.

Treatment mainstay is regular (usually monthly) lifelong blood transfusions. Iron overload complicates this therapy and is managed with regular iron chelation therapy, but transfusion haemosiderosis is common, with its associated end-organ damage. HLA matched bone marrow transplantation has been curative.

β-Thalassaemia minor

Individuals with β-thalassaemia minor receive one abnormal gene only, thus demonstrating the heterozygote state. There is enough β-chain production and normal haemoglobin to avoid symptomatic anaemia. The life span of the RBCs is only slightly decreased. The anaemia is microcytic and hypochromic with target cells and elliptocytes. HbA2 level in the range of 3.5–7.0% is almost diagnostic of the β-thalassaemia trait. The bone marrow is hyperplastic. Attention to potential iron and folate deficiency is important. The absence of an age-related rise in the MCV and major histocompatibility complex in a patient of the relevant ethnicity should prompt further investigations.

α-Thalassaemia

Two genes on chromosome 16 code for the α-chain, producing four possible phenotypes. Deletion of one α-gene is asymptomatic, with a minority having a microcytic hypochromic anaemia. Deletion of two α-genes produces mild anaemia. Deletion of three α-genes results in HbH disease due to aggregation of β-chains, which leads to an unstable haemoglobin. There is chronic haemolysis with anaemia in the range of 70–110 g L–1, jaundice, cholelithiasis, hepatomegaly and leg ulcers. Deletion of four α-genes results in intrauterine death and stillbirths, usually after 25 weeks’ gestation. Live births have severe anaemia, which may lead to congestive cardiac failure. The fetus is grossly oedematous. The haemoglobins present are HbH, Hb Barat (four γ-chains) and small amounts of Hb Portland (two ζ and two γ). None of these are functional.

Sickle cell disease

Sickle cell disease (SCD) is an autosomal recessive inherited condition in which glutamine in the sixth position of the globin chain is replaced by valine. In the homozygote with HbSS the haemoglobin is unstable in the de-oxygenated state. It precipitates in the RBC and leads to a change in the biconcave shape to a configuration resembling a sickle. This change is initially reversible. The consequences are multiple. It is detrimental to the RBC and the end-organs. Sickle cells have a reduced life-span of 10–20 days and occlude the microvasculature, leading to end-organ ischaemia. The precipitants for the sickling are:

• tissue hypoxia;
• tissue acidosis;
• dehydration;
• vascular stasis;
• increased 2,3-diphosphoglycerate (2,3-DPG) levels in the RBC.

Diagnosis

Diagnosis is made on the family history and presentation. It is confirmed by haemoglobin electrophoresis and the ‘sickle prep’ test outside the neonatal age group. The ‘sickle prep’ uses sodium metabisulphite, which extracts oxygen from the RBC and causes sickling. Parents can be tested for further confirmation.

Clinical features

The baseline haemoglobin in SCD is in the range of 60–90 g L–1 with a reticulocytosis of 5–15%. Children with SCD have abnormal immune function. They have functional asplenism by age 5 years, although sometimes earlier, as well as abnormal complement components. Consequently, fever should be managed as a medical emergency with prompt medical evaluation and delivery of antibiotics because of the high risk of bacterial infection and mortality.

Dactylitis is frequently the first manifestation of pain in children with SCD, occurring in 50% of children by 2 years of age. Children present with symmetric painful swelling of the hands and/or feet and require careful management with pain medication. Differential diagnosis of osteomyelitis should be considered carefully if the presentation is unilateral.

Vaso-occlusive crises are acute episodes of severe pain from tissue infarction resulting from vessel occlusion by the sickled cells. The major organs involved are bones, lungs, liver, spleen, brain and the penis. Painful bone crisis is the commonest, with minimal signs on examination. Treatment is directed at effective pain relief. Intravenous fluids should be utilised only if clinical evidence of dehydration exists. Frequently recurrent episodes may be reduced by using hydroxyurea, but close monitoring is required.

In aplastic crisis, the reticulocytosis falls to less than 1%. The haematocrit may fall as rapidly as 10–15% per day. The precipitant is usually an infection. Spontaneous recovery is usual. Supportive therapy may involve transfusion of RBCs.

Acute splenic sequestration

Acute splenic sequestration (ASS) is a life-threatening complication of SCD occurring in 7–30% of patients under the age of 2 years with homozygous SCD. It has also been reported in heterozygous cases. ASS can occur suddenly with acute pallor, weakness, abdominal pain and distension with features of hypovolaemic shock. The precipitant is usually an intercurrent infection. The key finding is circulatory shock in a child with atraumatic abdominal pain and distension. A massive tender spleen is unmistakable.

The haematocrit is usually less than 50% of baseline. Reticulocytosis and moderately severe thrombocytopenia are present. Splenic sequestration of RBCs affects those SCD sufferers who are young enough to still have a spleen, as autosplenectomy from infarction commonly occurs. Hepatic sequestration may also occur but the volume of trapped RBCs is unlikely to lead to devastating hypovolaemia due to the tight hepatic capsule.

Treatment is resuscitation of the intravascular volume. Prevention of sickling of those RBCs remaining in the circulation is important as is the prompt treatment of the infective precipitant. ASS is recurrent in 50% of cases, with the interval between episodes being less each time. Splenectomy is the only method of preventing recurrent ASS.

Sickle cell trait

Sickle cell trait denotes the heterozygous or carrier state. The complete blood count is within the normal range. Haemoglobin analysis is diagnostic, revealing a ratio of HbS to HbA of 40:60. The RBCs have a normal lifespan. Serious complications in sickle cell trait are very rare, but may include sudden death during rigorous exercise, splenic infarcts at high altitude, haematuria, and bacteriuria. The life span of people with sickle cell trait is normal and children with sickle cell trait should not have any restrictions placed on activities.

Acknowledgement

The contribution of Marian Lee as author in the first edition is hereby acknowledged.

Further reading

Chang T.T. Transfusion therapy in critically ill children. Pediatr Neonatol. 2008;49(2):5-12.

Gera T., Sachdev H.P., Nestel P., Sachdev S.S. Effect of iron supplementation on haemoglobin response in children: systematic review of randomised controlled trials. J Pediatr Gastroenterol Nutr. 2007;44(4):468-486.

Kleigman R., Behrman R., Jenson H., Stanton B. Nelson’s Textbook of Pediatrics, 18th ed, Philadelphia: Saunders Elsevier, 2007.

Richardson M. Microcytic anemia. Pediatr Rev. 2007;28(4):151.

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