Paediatrics chapters
Aplastic anaemia and the child with pancytopenia
How to approach a child whose red cells, white cells and platelets are all low: the causes (marrow failure, infiltration, destruction and sequestration), the viruses and systemic illnesses involved, and the diagnosis and treatment of acquired and inherited aplastic anaemia including Fanconi anaemia.
- Pancytopenia (low red cells, white cells and platelets) arises from marrow failure (aplastic anaemia), marrow replacement (leukaemia, neuroblastoma, storage disease), ineffective production (B12 or folate lack), peripheral destruction or splenic sequestration; children usually present with infection and bleeding rather than anaemia.
- Aplastic anaemia is pancytopenia with a hypocellular, fatty marrow and no organomegaly or lymph nodes; about half are idiopathic, others follow drugs (chloramphenicol), hepatitis, EBV, HIV, radiation or benzene; severe = two of neutrophils under 500, platelets under 20,000, reticulocytes under 1% with marrow cellularity under about 25%.
- Bone marrow biopsy is essential; treat with supportive care, HLA-matched sibling stem cell transplant (treatment of choice, over 80% long-term survival) or ATG plus ciclosporin; Fanconi anaemia is the main inherited form (absent thumbs, café-au-lait spots, chromosome breakage, leukaemia risk).
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Overview
Pancytopenia is a fall below normal of all three blood lines: red cells, white cells and platelets. It is a pattern, not a diagnosis. The causes range from a short-lived viral suppression to leukaemia and aplastic anaemia, and the most important single test is usually the bone marrow examination.
Because neutrophils live for hours and platelets for about a week, while red cells live for about 120 days, children with failing marrow often present first with fever and infection or bruising and bleeding, and only later with pallor.
Causes and pathophysiology of pancytopenia
| Mechanism | Examples |
|---|---|
| Marrow failure (aplasia) | Acquired aplastic anaemia (idiopathic, drugs, viruses, radiation, chemicals); inherited marrow failure (Fanconi anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome, amegakaryocytic thrombocytopenia) |
| Marrow replacement (infiltration) | Acute leukaemia, neuroblastoma and other metastatic tumours, lymphoma, storage diseases (Gaucher), osteopetrosis, myelofibrosis |
| Ineffective production | Vitamin B12 and folate deficiency, myelodysplasia |
| Peripheral destruction | Immune destruction (SLE), sepsis, DIC, haemophagocytic syndromes |
| Sequestration (hypersplenism) | Portal hypertension, thalassaemia, malaria, storage diseases, lymphoma, histiocytosis |
Telling production failure from destruction (Nelson)
| Favours marrow failure or replacement | Favours destruction or sequestration |
|---|---|
| Low reticulocytes | Reticulocytosis |
| Teardrop cells (marrow replacement) | Jaundice, raised bilirubin and LDH |
| Immature white cells on the film (blasts, myelocytes) | Immature red and white cells released in response |
| Small platelets | Large (young) platelets |
| High MCV with low reticulocytes | Big spleen (hypersplenism) |
Marrow failure is usually gradual: one or two lines fall first, then all three.
Viruses linked to pancytopenia
| Virus | Effect |
|---|---|
| Hepatitis viruses | Post-hepatitis aplastic anaemia, often severe, weeks to months after the hepatitis |
| Epstein-Barr virus | Marrow suppression, haemophagocytosis; severe in X-linked lymphoproliferative disease |
| HIV | Cytopenias, marrow suppression |
| Parvovirus B19 | Infects red cell precursors: pure red cell aplasia (aplastic crisis) in chronic haemolysis; occasionally wider suppression |
| CMV, HHV-6, EBV | Virus-associated haemophagocytic syndrome: fever, hepatosplenomegaly, pancytopenia |
Associated systemic disorders
- SLE and other autoimmune diseases (immune destruction).
- Sepsis and DIC.
- Malaria, chronic infections and portal hypertension (hypersplenism).
- Storage diseases and osteopetrosis (marrow crowding).
- Malnutrition and malabsorption (B12, folate deficiency).
- Thymoma and paroxysmal nocturnal haemoglobinuria (with aplastic anaemia).
- Malignancy: leukaemia, lymphoma, neuroblastoma.
Aplastic anaemia
Definition
Acquired aplastic anaemia is peripheral pancytopenia with a hypocellular bone marrow (Akbar: below about 30% cellularity), in which the blood-forming tissue is replaced by fat, with no abnormal infiltrate. It results from loss or damage of the pluripotent stem cell.
Classification of severity
| Grade | Criteria |
|---|---|
| Moderate | Neutrophils 500-1500/mm³, platelets 20,000-100,000/mm³ |
| Severe | At least two of: neutrophils below 500/mm³, platelets below 20,000/mm³, reticulocytes below 1% (corrected) or absolute reticulocytes below 50,000/µL; with marrow cellularity below about 25% |
| Very severe | As severe, with neutrophils below 200/mm³ |
Aetiology
- Idiopathic: about half of childhood cases (Akbar); the commonest type in developed countries (Nelson).
- Drugs:
- Chloramphenicol (about half of drug-related cases, Akbar), sulphonamides, phenylbutazone, metamizole (Novalgin), sodium valproate, felbamate, cimetidine, gold salts.
- Cytotoxic drugs cause dose-dependent, predictable aplasia; antibiotics and anticonvulsants cause idiosyncratic, unpredictable aplasia.
- Chemicals and radiation: benzene, insecticides, ionising radiation.
- Viruses: hepatitis, EBV, HIV, parvovirus B19.
- Others: thymoma, pre-leukaemia, PNH.
Pathophysiology
- Direct toxic damage to stem cells (radiation, cytotoxics).
- Immune-mediated suppression of the marrow by T lymphocytes is thought to be important in idiopathic and post-infective cases (about a third of patients have such an autoimmune process, Akbar). This is why immunosuppression works.
Clinical features
Features follow the cytopenias:
- Anaemia: pallor, fatigue, breathlessness, heart failure if severe.
- Neutropenia: fever, mouth ulcers, recurrent or severe infections.
- Thrombocytopenia: petechiae, bruising, epistaxis, gum bleeding.
- No hepatomegaly, splenomegaly or lymphadenopathy.
A pancytopenic child with a big liver, spleen or lymph nodes probably does not have aplastic anaemia; think of leukaemia, lymphoma, storage disease or hypersplenism.
Chloramphenicol is the classic drug cause; hepatitis is the classic viral cause (post-hepatitis aplasia).
Investigations
- Full blood count: normocytic (sometimes macrocytic) anaemia, reticulocytes below 1%, low white count with marked neutropenia, platelets usually below 50,000 and often below 20,000/mm³.
- Film: no blasts; no abnormal cells.
- Bone marrow aspiration and trephine biopsy (both are essential): hypocellular, with reduced erythroid, myeloid and megakaryocyte series and fat replacing marrow. Lymphocytes above about 70% of marrow cells suggest a poor outlook (Akbar). Biopsy measures cellularity and excludes infiltration.
- Tests for the cause: liver function and hepatitis serology, EBV, HIV, parvovirus.
- Chromosome breakage test to exclude Fanconi anaemia in every child; HbF and MCV.
- HLA typing of the patient and siblings early.
Differential diagnosis
- Acute leukaemia (blasts, organomegaly, packed marrow).
- Hypersplenism.
- Sepsis or DIC.
- Megaloblastic anaemia.
- Myelodysplasia, PNH.
Management
Supportive care
- Remove the cause: stop any suspect drug or toxin.
- Fever is an emergency: prompt evaluation and intravenous broad-spectrum antibiotics.
- Packed red cells for symptomatic anaemia; platelet transfusion for bleeding.
- Keep transfusions to what is needed: survival after transplant is best when the child has not been sensitised by many blood products.
- Avoid aspirin and other drugs that impair platelets, and avoid trauma.
Definitive treatment
| Option | When | Points |
|---|---|---|
| Haematopoietic stem cell transplant (HSCT) | Severe aplastic anaemia with an HLA-identical sibling | Treatment of choice; best done early; long-term survival above 80% |
| Immunosuppressive therapy | No matched sibling donor | Antithymocyte (antilymphocyte) globulin + ciclosporin + corticosteroids; complete or partial response in about 65% (Akbar); relapse can occur when stopped |
| Androgens | Selected cases, Fanconi anaemia | About 20% respond for a time; cause virilisation and liver toxicity |
| Growth factors (G-CSF), IVIG | Adjuncts | Do not cure |
| Unrelated or partially matched HSCT | No sibling donor | An evolving option |
For severe aplastic anaemia, HLA-identical sibling HSCT is first choice; ATG plus ciclosporin is the best option without a matched sibling.
Complications and prognosis
- Infection (bacterial and fungal) and haemorrhage (including intracranial) are the main causes of death.
- Without transplant or effective immunosuppression, severe aplastic anaemia has a very poor outlook: many die within 6-12 months (Akbar); about 20% survive with supportive care alone (Nelson).
- Transfusion-related problems: iron overload, alloimmunisation, transfusion-transmitted infection.
- Long-term survivors (after either treatment) have a higher risk of myelodysplasia, acute leukaemia and other cancers.
Fanconi anaemia (inherited aplastic anaemia)
- Autosomal recessive; defect in proteins that repair DNA, so chromosomes break easily.
- Marrow failure usually appears in the later part of the first decade (mean about 8 years), and evolves over years.
| Feature | Details |
|---|---|
| Skin | Café-au-lait spots, generalised hyperpigmentation |
| Upper limb | Absent or hypoplastic thumbs, radial defects |
| Growth | Short stature, microcephaly, microphthalmia |
| Kidney | Horseshoe or absent kidney |
| Others | Hypogonadism, deafness, hip dislocation, learning difficulty |
| Blood | Pancytopenia, high MCV and high HbF |
| Diagnosis | Increased chromosome breakage when cells are exposed to DNA-damaging agents |
| Cancer risk | Acute myeloid leukaemia (about 10%), head and neck and other solid tumours |
| Treatment | HSCT (only cure for the marrow), androgens, steroids |
Fanconi = Fragile chromosomes, Faulty thumbs, Freckle-like café-au-lait spots.
Fanconi anaemia has absent thumbs with pancytopenia; TAR syndrome has absent radii with thumbs present and only low platelets; Diamond-Blackfan has triphalangeal thumbs with red cell aplasia only.
Prophylactic vaccination and infection prevention
- Children who will receive repeated blood products should be immunised against hepatitis B.
- If splenectomy is planned for hypersplenism, give pneumococcal, Hib and meningococcal vaccines beforehand and penicillin afterwards.
- Live vaccines are avoided while a child is on intensive immunosuppression or chemotherapy; household contacts should be protected from measles and chickenpox exposure.
- Vaccine timing around transplant and immunosuppression follows the treating centre's protocol; check the current national guideline.
Expect: a child with pallor, fever and bleeding, pancytopenia and no organomegaly, where the next test is bone marrow aspiration and biopsy; the commonest cause (idiopathic) and drug cause (chloramphenicol); post-hepatitis aplasia and other viruses; severe aplastic anaemia criteria (neutrophils under 500, platelets under 20,000, reticulocytes under 1%); matched sibling HSCT as treatment of choice and ATG with ciclosporin as the alternative; Fanconi anaemia with absent thumbs, café-au-lait spots, chromosome breakage and AML risk; and causes of pancytopenia with organomegaly (leukaemia, hypersplenism, storage disease).
Quick revision
- Pancytopenia: failure, replacement, ineffective production, destruction, sequestration.
- Infection and bleeding come before anaemia (short-lived cells).
- Aplastic anaemia: hypocellular fatty marrow, no organomegaly.
- Half idiopathic; chloramphenicol, valproate, benzene, radiation; hepatitis, EBV, HIV, parvovirus.
- Severe: neutrophils under 500, platelets under 20,000, retics under 1%; very severe: neutrophils under 200.
- Marrow aspirate plus trephine biopsy is essential; screen chromosome breakage.
- HLA-identical sibling HSCT first; ATG + ciclosporin + steroids if no donor.
- Treat fever urgently; transfuse sparingly before transplant.
- Fanconi: AR, absent thumbs, café-au-lait, renal anomalies, high HbF, chromosome breaks, AML.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
What is the first investigation in a child with unexplained pancytopenia?
After a blood film and reticulocyte count, a bone marrow aspiration with trephine biopsy is needed to tell aplasia from infiltration such as leukaemia.
Why are the liver and spleen not enlarged in aplastic anaemia?
The problem is an empty, fat-filled marrow rather than an infiltrating disease or a sequestering spleen, so organomegaly suggests another diagnosis.
What is the best treatment for severe aplastic anaemia?
Stem cell transplantation from an HLA-identical sibling, done early; without a matched sibling, immunosuppression with antithymocyte globulin and ciclosporin is used.
How is Fanconi anaemia confirmed?
By showing increased chromosome breakage when the child's cells are exposed to DNA-damaging agents, supported by typical anomalies such as absent thumbs.