A PALE CHILD
History
Sarah is a 4-year-old girl who is referred to the paediatric day unit by her GP with a 2-day history of widespread bruising. She has also had two nosebleeds in the preceding 24 hours. There are no known injuries, although her mother says she is quite ‘hectic’, especially when playing with her younger brother. They both had a cold and a sore throat 2 weeks previously. She is otherwise very well. There is no significant past medical or family history and she is on no medication.
Examination
Sarah is drawing pictures and is cheerful and cooperative. She has no dysmorphic features. Her height and weight are on the 25th centiles. There is no jaundice and she is afebrile. She is pale and clinically anaemic with a few 1.0 cm lymph nodes in the cervical and inguinal regions. There is widespread bruising mainly on her limbs but no evidence of active bleeding. There is no hepatosplenomegaly. Her pulse is 96 beats/min and both heart sounds are normal. She has a grade 2/6 ejection systolic murmur. Examination of the respiratory system is normal.
INVESTIGATIONS
Normal
Haemoglobin 6.2 g/dL 11.5–15.5 g/dL
White cell count 1.2 109/L 6.0–17.5 109/L
Neutrophils 0.2 109/L 3.0–5.8 109/L
Lymphocytes 0.8 109/L 1.5–3.0 109/L
Platelets 6 109/L 150–400 109/L
Blood film No blasts
Prothrombin time 12 s 11–15 s
Partial thromboplastin time 32 s 25–35 s
Urea and electrolytes Normal
Liver function tests Normal
C-reactive protein 6 mg/L 6 mg/L
Questions
• What is the differential diagnosis?
• What investigations are indicated?
• What are her major current risks?
Medicine
Sarah has pancytopenia, loss of all bone marrow (BM) elements. This is not a diagnosis and needs further investigation.
Differential diagnosis of pancytopenia
Bone marrow failure
• Inherited – all rare. Commonest is Fanconi’s anaemia. Excess chromosome breaks. Defective DNA repair, decreased cell survival and susceptible to oxidant stress. Associated physical abnormalities, e.g. skeletal (absent thumbs), short stature. Only cure is a BM transplant.
• Acquired – viral, e.g. hepatitis, herpes, Epstein–Barr – drugs – idiosyncratic, e.g. chloramphenicol, anticonvulsants, or predictable, e.g. chemotherapy; 80 per cent are ‘idiopathic aplastic anaemia’.
Bone marrow infiltration
• Malignancy, e.g. leukaemia or neuroblastoma. Rarely myelofibrosis and myelodysplasia.
Bone marrow infiltration causes marrow expansion and pain unless it is slowly progressive as in myelofibrosis. There are also likely to be other symptoms and signs, e.g. lymphadenopathy or hepatosplenomegaly in leukaemia. Significantly enlarged lymph nodes are usually 1 cm in diameter. Despite her pallor, this child is playing happily, making BM failure more likely. About 20 per cent of patients with inherited pancytopenias have none of the associated features so an inherited cause cannot be excluded clinically, but these conditions are rare. This girl probably has an acquired pancytopenia – probably idiopathic aplastic anaemia (AA). Most cases appear to be caused by activated T-lymphocytes, producing cytokines that suppress haematopoiesis. Her mild tachycardia and murmur are most likely due to a hyperdynamic circulation secondary to anaemia. An echocardiogram may be indicated if it does not disappear or diminish following transfusion.
Investigation of pancytopenia
• Blood film – detailed morphology of all cell lines
• Red cell indices – the anaemia in AA is normocytic or mildly macrocytic
• Reticulocytes – 20 109 /L suggests severe aplastic anaemia
• Viral titres – hepatitis, Epstein–Barr, parvovirus (usually causes red cell aplasia) • Chromosomes for breakage analysis
• BM aspirate and trephine – to assess morphology and cellularity of the cells and to exclude infiltration. In AA it is hypocellular but the remaining cells are normal
Management pending a diagnosis and treatment is supportive. Haemorrhage and infection are her two major risks. However, there is a danger with multiple platelet transfusions of developing antibodies (alloimmunization). These can cause a typical transfusion reaction with fevers and rigors, but more importantly can diminish the increment in platelet count. This risk is minimized by restricting transfusions to episodes of active bleeding and/or a platelet count of 5 109 /L. Neutropenia, especially if prolonged, puts her at risk of serious life-threatening bacterial infections and the family should be given instructions about regular monitoring of her temperature and when to seek advice.
Spontaneous recovery of idiopathic aplastic anaemia is rare. The decision to embark on definitive treatment depends upon the severity. BM transplant (BMT) offers the best chance for those with a matched sibling donor. Otherwise, immunosuppressive treatment with antithymocyte globulin and cyclosporin is the main alternative. If this fails, a matched, unrelated-donor BMT is the only option.
KEY POINTS
• Pancytopenia can be due to bone marrow failure or bone marrow infiltration.
• The most important risks from pancytopenia are bleeding and infection.
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