Blood and cancer

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7 Blood and cancer

Jo Ponnampalam, Nandu Thalange

Chapter contents

Introduction

Key concepts

Anaemia

Iron deficiency anaemia 
Haemolytic anaemia
General principles of treatment of haemolytic anaemias
Thalassaemia
Sickle-cell disease

Bruising and bleeding

Idiopathic thrombocytopenic purpura 
Haemophilia
von Willebrand disease

Bone marrow failure

Aplastic anaemia 

Malignant disease

Risk factors 
Symptoms and signs
Surveillance
Diagnosis and staging
Treatment
Presentations of principal childhood malignancies

Supportive and palliative care

Late sequelae of cancer and their treatment

Introduction

Abnormalities of the blood are found in a wide range of paediatric diseases, so examination of the cellular components and chemistry will often give helpful diagnostic information. Primary diseases of the blood, with the exception of iron deficiency anaemia, are individually quite uncommon. Their significance lies in their high morbidity (e.g. haemophilia) or severity (e.g. acute leukaemia).

Key concepts

Blood diseases generally present with evidence of failure either of the cellular components leading to anaemia, leucopenia or thrombocytopenia, or the clotting cascade with resultant easy bruising, and mucosal and soft-tissue bleeding, or bleeding into joints – haemarthrosis.

Anaemia

Iron deficiency anaemia

As shown in Case 7.1, tiredness, lethargy and listlessness are suggestive of anaemia. Pallor may be harder to detect in darker skin but may be apparent to parents, and will be clearly evident from inspection of mucous membranes. A pale blue tinge to the sclera is characteristic of iron deficiency. The findings of tachycardia with a flow murmur reflect the compensatory increase in cardiac output.

Iron deficiency is suggested by microcytic, hypochromic anaemia, but thalassaemia (see below) may also cause this picture. Iron deficiency is confirmed by the low ferritin level. Ferritin is an acute phase reactant and rises with infection or inflammation, so may be misleadingly normal in the unwell child.

Case 7.1

A boy with iron deficiency anaemia

Rajesh, a 3-year-old boy of Indian origin, presented to his GP with an acute viral infection. He was sleeping for 14 hours at night, had two naps in the daytime and had little energy for play. He ate poorly, much preferring to drink milk. His GP found that his conjunctivae were pale blue with pallor of the buccal mucosa. His heart rate was 110 beats per minute at rest, and he had a short ejection murmur at the upper left sternal edge. His GP requested a full blood count, which showed Hb 6.5 g/dL, WBC 10.5 × 106/L and platelets 680 × 106/L. The MCV (mean cell volume) and MCH (mean cell haemoglobin) were low and the blood film confirmed microcytosis and anisocytosis. The ferritin level was also very low, confirming iron deficiency anaemia.

Iron deficiency causes a range of effects:

• Symptoms of anaemia (see above)

• Impaired or abnormal appetite

• Mucosal abnormalities, e.g. angular cheilitis and atrophic glossitis, pruritis vulvae

• Impaired cognitive and motor development in toddlers; impaired short-term memory in older children

• Impaired neutrophil and lymphocyte function.

Iron deficiency is extremely common, affecting 15–20% of children in the UK. The commonest explanation for iron deficiency anaemia in young children is inadequate dietary intake but other causes should be considered, such as:

• Malabsorption, e.g. coeliac disease (see Chapter 12, p. 172)

• Chronic blood loss from gastroesophageal reflux (see Chapter 13, p. 164) or Meckel’s diverticulum, when ectopic gastric mucosa secretes acid, leading to ulceration and bleeding in the small bowel.

• Menstrual losses in older girls.

Iron deficiency may be prevented with adequate dietary intake in otherwise healthy children. Standard infant formulas and many weaning foods are iron-fortified. Premature infants are at higher risk and require supplementation with iron in the first months. Treatment of established iron deficiency usually requires a few weeks of oral supplementation with elemental iron.

Haemolytic anaemia

Haemolytic disease of the newborn

Case 7.2

A boy with jaundice

Oliver was noted to have early-onset jaundice within 12 hours of birth. He was promptly treated with phototherapy. Oliver’s mother was known to have blood group O, rhesus positive, excluding rhesus incompatibility, but a direct Coombs (antiglobulin) test was positive. Oliver was found to have blood group A, rhesus positive, confirming the diagnosis of ABO incompatibility.

Haemolytic disease of the newborn is a condition of rapid red cell destruction in the fetus or newborn infant caused by maternal antibodies raised against the infant’s red cells (see also Chapter 17, p. 252). Where a pregnant mother is blood group rhesus negative and the fetus rhesus positive, the leak of even a few fetal cells into the maternal circulation may be sufficient to trigger the production of IgG antibodies. These cross the placenta in the same, or more commonly in a subsequent, pregnancy to cause immune-mediated destruction of antibody-coated red cells. The same process occurs with ABO incompatibility (as shown in Case 7.2), although this usually causes milder haemolysis.

Clinical effects range from mild jaundice in the newborn period, sometimes associated with a greater drop in the physiological nadir of haemoglobin at around 10–12 weeks of age, to a severe fetal anaemia, with hydrops fetalis and fetal death.

Detection of potential rhesus haemolytic disease in ‘at-risk’ fetuses requires monitoring of maternal antibody status and fetal well-being. Treatment options include in-utero transfusion, and, if necessary, early delivery. First-line therapy in the affected newborn infant is phototherapy. If this is ineffective, exchange blood transfusion is performed in which blood is drawn from the infant and replaced with an equal volume of packed cells. Infants with haemolytic disease of the newborn require folate supplementation, and occasionally require late transfusion for correction of anaemia, typically at 6–8 weeks of age. Administration of anti-D immunoglobulin to rhesus negative women after pregnancy (including miscarriage and termination of pregnancy) reduces the risk of recurrence in subsequent pregnancies.

Haemolytic disorders of childhood

Haemolytic anaemias are characterized by shortened red cell lifespan, with a compensatory increase in erythropoiesis, increased synthesis of bilirubin, and anaemia. Presentation may occur at birth with early-onset or severe neonatal jaundice, with inter-current infection provoking haemolysis or aplastic crisis, with symptoms of anaemia, with specific complications such as dactylitis in sickle-cell anaemia (see below), or by chance, following routine investigations (see Case 7.3).

Haemolytic anaemias may arise from:

• Structural membrane abnormalities of the red cell, e.g. hereditary spherocytosis

• Abnormalities of haemoglobin, e.g. thalassaemia, sickle-cell anaemia

• Metabolic abnormalities of the red cell, e.g. glucose-6-phosphate dehydrogenase (G6PD) deficiency or pyruvate kinase deficiency

• Hypersplenism and immune-mediated haemolysis.

General principles of treatment of haemolytic anaemias

• Folic acid requirements are increased due to high red cell turnover, and supplementation is usually required to optimize erythropoiesis

• Chronic anaemia is usually well-tolerated and transfusion is done as infrequently as symptoms allow

• Transfusion may be required for acute haemolytic crises. These occur secondary to inter-current infection, notably with parvovirus which causes a temporary depression of erythropoiesis – aplastic crisis. In G6PD deficiency (an X-linked condition, therefore very rare in girls) a variety of oxidant drugs will provoke acute haemolysis

• Blood transfusions ultimately may lead to iron overload, particularly in thalassaemia, requiring use of iron chelation therapy with desferrioxamine administered by overnight subcutaneous infusion 5–6 days per week. Newer oral agents, deferiprone (DFP) and deferasirox (DFX), approved for use in 2006, are available. DFP is less effective than DFO in treating liver disease, and so is usually used in combination with DFO. DFX is as effective as DFO, but long-term efficacy and safety is not yet established, and use is not recommended in patients with cardiac involvement. All chelation agents have significant side-effects, notably agranulocytosis with DFP.

• Symptomatic pigment gallstones require cholecystectomy

• Bone marrow transplantation may be appropriate for thalassaemia and severe sickle-cell disease

Hyposplenism secondary to progressive splenic infarction in sickle-cell disease, or following splenectomy, is treated with prophylactic phenoxymethylpenicillin (‘penicillin V’) and pneumococcal immunization due to the risk of overwhelming pneumococcal infection.

Case 7.3

A boy with severe haemolysis

Craig was admitted to hospital at the age of 4 years with severe gastroenteritis. He was noted to have pallor, splenomegaly and mild jaundice. A urine dipstick was positive for urobilinogen and haemoglobin, but negative for bilirubin, suggesting haemolysis. His blood count showed anaemia (Hb 4.7 g/dL), with spherocytes and red cell fragments on his blood film. A Coombs test was negative, excluding autoimmune haemolysis. Examination of parental blood specimens showed that his father also had mild anaemia with spherocytes, suggesting the diagnosis of hereditary spherocytosis.

Hereditary spherocytosis

Thalassaemia

Thalassaemia is the commonest single-gene disorder worldwide. A gene deletion results in reduced synthesis of either alpha- or beta-globin chains, producing alpha- or beta-thalassaemia, respectively.

Normal individuals have four alpha-globin and two beta-globin genes. Alpha- and beta-globin chains combine to form α2β2 tetramers. Loss of a single alpha gene is asymptomatic, but loss of impairment of two or three alpha-globin genes results in alpha-thalassaemia trait and haemoglobin H disease respectively, characterized by hypochromic microcytic anaemia. Haemoglobin H is a β4 tetramer which results from inadequate alpha-globin synthesis. If all four alpha chains are affected, no normal haemoglobin is made, resulting in fetal death from hydrops fetalis.

Similarly, partial or complete loss of a single beta-globin gene produces beta-thalassaemia trait, whereas if both genes are affected, beta-thalassaemia major results. Beta-thalassaemia major may be partly ameliorated by persistence of fetal haemoglobin.

There is considerable variation in ethnic distribution of the different abnormal genes, with the Mediterranean, Middle East, Indian subcontinent and South-East Asia most affected.

Clinical features result from increased erythropoiesis occurring in the bone marrow and in extramedullary sites such as the liver. This process is driven by erythropoietin produced in response to relative tissue hypoxia.

The hallmark of thalassaemia major is hypochromic, microcytic anaemia, which may be severe, with associated hypersplenism due to increased red cell destruction (see Figure 7.1). Beta-thalassaemia also produces skeletal abnormalities, most notably frontal bossing, due to hyperplasic marrow, and growth failure.

image

Figure 7.1 Blood film of patient with thalassaemia showing characteristic findings of hypochromic, microcytic anaemia with target cells and faint basophilic stippling.

Sickle-cell disease

Sickle-cell anaemia results from a glutamate to valine substitution in position 6 of the beta-globin gene. When present in the homozygous form this renders the red cell prone to sickling. Common triggers are hypoxia, dehydration and fever, and the result is less compliant sickle-shaped red cells which occlude small vessels causing tissue ischaemia and end-organ damage. The sickle cells are rapidly removed from the circulation causing anaemia and hypersplenism (as shown in Case 7.4). Ultimately, hyposplenism results from recurrent splenic infarction. Hydroxycarbamide (see below) may help preserve splenic function, thereby reducing infection risk.

Case 7.4

A boy with sickle-cell crisis

John, aged 4 years, and his family were refugees from Sierra Leone. He was admitted to hospital with severe abdominal pain. On examination he was jaundiced with pallor and tachycardia, and he had severe upper abdominal tenderness, despite morphine analgesia, with what appeared to be a massively enlarged spleen. An urgent blood count and film showed sickle cells with severe anaemia (Hb 3.8 g/dL) and thrombocytopenia. A diagnosis of splenic sequestration crisis, secondary to sickle-cell anaemia, was made. He was treated with oxygen, analgesia, intravenous fluids, broad-spectrum antibiotics and repeated transfusions, and eventually made a full recovery. Homozygous sickle-cell anaemia was later confirmed. He was treated with regular folic acid and penicillin and periodic blood transfusion for symptomatic anaemia.

There are a number of clinical problems particular to sickle-cell disease:

• Vaso-occlusive crises leading to:

• Severe bone pain, including foot and hand involvement in young children (dactylitis)
• Avascular necrosis of bone
• Renal injury leading to haematuria and progressive loss of renal concentrating ability
• Stroke-like episodes
• Priapism
• Retinopathy

• Sequestration crises where large amounts of blood are sequestered to the spleen or liver, leading to anaemia, shock and severe abdominal pain

• Sickle chest in which widespread pulmonary infiltrates occur, leading to respiratory failure

• Infection with encapsulated organisms notably Pneumococcus, Haemophilus and Salmonella, due to progressive infarction of the spleen, leading to hyposplenism

• Impaired growth with delayed puberty (special growth charts are available in the UK for children with sickle-cell anaemia).

Hydroxycarbamide is now established as an effective treatment for sickle-cell disease. It is a ribonucleoside reductase inhibitor which inhibits cell division, and is widely used for the adult conditions chronic myeloid leukaemia and polycythaemia rubra vera. Randomized trials have shown that it is effective in reducing painful crises, dactylitis, episodes of sickle chest, and transfusion requirements, with an overall survival benefit. It has several actions:

• Increasing fetal haemoglobin

• Reducing rate of sickling

• Decreasing leucocytes, thereby reducing marginating neutrophils, which adhere to vascular endothelium and are implicated in painful crises and sickle chest.

Use of hydroxycarbamide in trials was associated with a 60% reduction in hospital admissions. Its use is indicated in patients with more than three admissions per year with painful crises, over the last 2 years, two or more episodes of sickle chest, or severe impairment in normal life due to pain. However, in May 2011 the outcome of a randomized control trial of hydroxycarbamide in children aged 9–18 months, treated for 2 years, showed very significantly improved outcomes compared with placebo, suggesting that it may have a wider role in the treatment of children.

Hydroxyurea is potentially leukaemogenic, and has significant toxicity. The most significant side-effect is myelosuppression. Skin rashes, nail discoloration, nausea/vomiting and diarrhoea may also occur. Frequent blood tests for monitoring purposes are required whilst on treatment.

Bruising and bleeding

Idiopathic thrombocytopenic purpura

Case 7.5

A girl with easy bruising

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