Medicine chapters
Aplastic anaemia
Bone marrow failure with pancytopenia and an empty, fatty marrow: its causes, presentation, how to confirm it and grade severity, and treatment with stem cell transplant or immunosuppression.
- Aplastic anaemia is pancytopenia with a hypocellular (fatty) marrow and no abnormal cells; most cases are idiopathic and immune (T-cell) mediated.
- Present with bleeding, infection and anaemia; no splenomegaly or lymphadenopathy; reticulocytes very low; trephine biopsy confirms.
- Severe disease (2 of: neutrophils below 0.5, platelets below 20, reticulocytes below 40 × 10^9/L): sibling stem cell transplant if young, otherwise ATG plus ciclosporin; steroids and growth factors are not effective treatment.
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Overview
Aplastic anaemia is failure of the bone marrow to make blood cells. It is defined as pancytopenia (low red cells, white cells and platelets) with a hypocellular ("aplastic") marrow in which fat replaces the blood-forming tissue, and no leukaemic, cancer or other abnormal cells.
The problem is a loss of haemopoietic stem cells. In most acquired cases this is caused by an immune attack by cytotoxic T cells on the stem cells. It is uncommon but serious: untreated severe disease often kills through infection or bleeding.
Causes
| Type | Causes |
|---|---|
| Idiopathic acquired (about two-thirds) | Immune (T-cell) destruction of stem cells |
| Drugs: predictable (dose-related) | Cytotoxic chemotherapy (e.g. busulfan, doxorubicin), radiotherapy |
| Drugs: idiosyncratic | Chloramphenicol, gold, penicillamine, carbimazole, phenytoin, carbamazepine, sulphonamides, chlorpromazine, NSAIDs, azathioprine |
| Chemicals | Benzene, toluene, glue sniffing, insecticides |
| Radiation | Ionising radiation |
| Viruses | Seronegative hepatitis (non-A to E), EBV, HIV, parvovirus (mainly red cell aplasia) |
| Other | Paroxysmal nocturnal haemoglobinuria, pregnancy, SLE, tuberculosis |
| Inherited (rare) | Fanconi anaemia, dyskeratosis congenita, Shwachman–Diamond syndrome |
Chloramphenicol is the classic drug: dose-related marrow suppression (reversible) and a rare idiosyncratic, often irreversible aplastic anaemia. Benzene is the classic chemical.
Fanconi anaemia
- Autosomal recessive defect in DNA repair (chromosomes break easily; diagnosed by a chromosome fragility test with diepoxybutane or mitomycin).
- Usually presents between 5 and 10 years of age.
- Physical features: short stature, absent or abnormal thumbs and radii, café-au-lait spots and skin pigmentation, microcephaly, renal and eye anomalies.
- High risk of AML, myelodysplasia and squamous cancers.
Pure red cell aplasia (related condition)
- Only the red cell line fails: anaemia with very low reticulocytes but normal white cells and platelets.
- Adult form linked to thymoma (5–15%) and autoimmune disease; thymectomy may help.
- Parvovirus B19 causes transient red cell aplasia in chronic haemolytic anaemias.
- Congenital form: Diamond–Blackfan anaemia.
Clinical features
The features of marrow failure from any cause:
- Anaemia: tiredness, breathlessness, pallor.
- Thrombocytopenia (bleeding): often the first sign: bruising, petechiae, gum bleeding, epistaxis, blood blisters in the mouth, menorrhagia, retinal haemorrhage.
- Neutropenia (infection): mouth ulcers and infections, fever, pneumonia, sepsis, fungal infection.
Important negative findings: no splenomegaly, no hepatomegaly, no lymphadenopathy and no bone tenderness.
Pancytopenia with splenomegaly or lymphadenopathy points away from aplastic anaemia: consider leukaemia, lymphoma, hypersplenism, myelofibrosis, visceral leishmaniasis or disseminated tuberculosis.
Investigations
Blood
- Pancytopenia.
- Anaemia is normocytic or mildly macrocytic.
- Reticulocytes very low or absent (shows failure of production).
- Film: no blasts or abnormal cells; neutrophils may show toxic granulation.
Bone marrow
- Aspirate: may be a dry or blood-only tap, with few cells and many fat spaces.
- Trephine biopsy is essential to assess cellularity: hypocellular marrow with increased fat and no infiltration or fibrosis.
The trephine biopsy, not the aspirate, is the key test, because only a core of bone shows true cellularity.
Other tests
- Flow cytometry for a PNH clone (loss of CD55 and CD59).
- Vitamin B12 and folate (megaloblastic anaemia can cause pancytopenia).
- Viral serology: hepatitis, EBV, HIV, parvovirus.
- Liver tests, autoantibodies (SLE).
- Chromosome fragility test for Fanconi anaemia in young patients.
- Cytogenetics to look for myelodysplasia (hypocellular MDS mimics aplastic anaemia).
- HLA typing of the patient and siblings early, for possible transplant.
Differential diagnosis of pancytopenia
| Group | Examples |
|---|---|
| Marrow failure | Aplastic anaemia, drugs, Fanconi anaemia |
| Marrow infiltration | Acute leukaemia, lymphoma, myeloma, metastatic cancer, myelofibrosis |
| Nutritional | Megaloblastic anaemia (B12, folate) |
| Peripheral destruction | Hypersplenism, SLE |
| Infection | Disseminated TB, visceral leishmaniasis (kala-azar), overwhelming sepsis, HIV, brucellosis |
| Others | PNH, myelodysplasia |
Diagnosis and severity
Severity guides treatment and predicts outcome.
| Grade | Criteria |
|---|---|
| Severe | Marrow cellularity reduced plus at least 2 of: neutrophils below 0.5 × 10^9/L, platelets below 20 × 10^9/L, reticulocytes below 40 × 10^9/L |
| Very severe | Severe criteria plus neutrophils below 0.2 × 10^9/L |
| Non-severe | Not meeting severe criteria |
Neutrophils 0.4, platelets 15, reticulocytes 55 (all × 10^9/L), marrow hypocellular
Neutrophils below 0.5 → yes; platelets below 20 → yes; reticulocytes below 40 → no
2 of 3 criteria met → severe aplastic anaemia (neutrophils not below 0.2, so not very severe)
Management
1. Remove the cause
- Stop any suspect drug and avoid further exposure to chemicals.
2. Supportive care (all patients)
- Red cell transfusion for symptomatic anaemia.
- Platelet transfusion for bleeding or when counts are very low.
- Use irradiated, leucocyte-depleted blood products and avoid transfusions from family members if a transplant is possible (to reduce sensitisation).
- Infection control: good hygiene, avoid risky foods; antifungal and other prophylaxis in severe cases.
- Neutropenic fever (neutrophils below 0.5 × 10^9/L): immediate broad-spectrum IV antibiotics without waiting for culture results.
- Iron chelation if heavily transfused.
- Hormonal suppression of periods in women with low platelets.
3. Specific treatment
| Patient | Treatment of choice |
|---|---|
| Severe disease, under 40 years, HLA-identical sibling donor | Allogeneic haemopoietic stem cell (bone marrow) transplant: long-term survival about 75–90% |
| Severe disease, over 40, or no matched sibling, or non-severe but transfusion-dependent | Immunosuppression: antithymocyte globulin (ATG) plus ciclosporin: response in about 60–80% |
| Failed immunosuppression, younger, no sibling | Matched unrelated donor transplant |
- Eltrombopag (a thrombopoietin receptor agonist) is now often added to ATG and ciclosporin to improve responses.
- Not effective as main treatment:
- Haemopoietic growth factors (G-CSF, erythropoietin): body levels are already high.
- Corticosteroids: should not be used to treat severe disease (only to cover serum sickness from ATG).
- Androgens are an older option in some patients, including Fanconi anaemia.
Do not treat aplastic anaemia with steroids alone. Steroids are given only to prevent serum sickness from ATG.
"Sibling and young: transplant. Old or no sibling: ATG and ciclosporin."
Transplant problems
- Graft rejection, graft-versus-host disease, viral infections.
Complications and prognosis
- Death from infection (bacterial and fungal) or haemorrhage (often intracranial).
- Transfusion-related iron overload and alloimmunisation.
- Clonal evolution after immunosuppression to PNH, myelodysplasia or acute myeloid leukaemia.
- Prognosis depends most on neutrophil count, platelet count, reticulocyte count and marrow cellularity. The course ranges from spontaneous recovery (especially drug-induced mild cases) to rapid death in very severe disease.
Expect: the definition (pancytopenia, hypocellular marrow, no abnormal cells); idiopathic immune cases as the commonest; chloramphenicol, carbimazole, anticonvulsants and benzene as causes; seronegative hepatitis as a viral cause; Fanconi anaemia features; absence of splenomegaly and lymphadenopathy; low reticulocytes; trephine biopsy as the diagnostic test; the severity criteria; transplant for young patients with a sibling donor versus ATG and ciclosporin for others; why steroids and growth factors are not used; and progression to PNH, MDS or AML.
Quick revision
- Pancytopenia + fatty hypocellular marrow + no abnormal cells.
- About two-thirds idiopathic, T-cell mediated.
- Drugs: chloramphenicol, gold, carbimazole, phenytoin, carbamazepine, cytotoxics; chemicals: benzene.
- Viruses: seronegative hepatitis, EBV, HIV.
- Fanconi: autosomal recessive, absent thumbs and radii, short stature, AML risk.
- Bleeding often presents first; no spleen, liver or node enlargement.
- Trephine biopsy confirms; reticulocytes very low.
- Severe: 2 of neutrophils below 0.5, platelets below 20, reticulocytes below 40 (× 10^9/L).
- Under 40 with matched sibling: stem cell transplant; others: ATG + ciclosporin.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
Why is a trephine biopsy needed in suspected aplastic anaemia?
An aspirate from an empty marrow may give few or no cells, so only a core biopsy shows the true reduction in cellularity and excludes infiltration.
Does aplastic anaemia cause splenomegaly?
No; an enlarged spleen, liver or lymph nodes suggests another cause of pancytopenia such as leukaemia, lymphoma or kala-azar.
Why are growth factors not the main treatment?
Patients already have high natural levels of growth factors; the problem is too few stem cells to respond.
What is the best treatment for a 20-year-old with severe aplastic anaemia and an HLA-identical brother?
An allogeneic haemopoietic stem cell transplant from the matched sibling.
What can aplastic anaemia evolve into?
A minority develop paroxysmal nocturnal haemoglobinuria, myelodysplasia or acute myeloid leukaemia.