Aplastic Anaemia
Bone marrow failure syndrome characterised by pancytopenia and hypocellular bone marrow. Autoimmune T-cell mediated destruction of haematopoietic stem cells in most cases. Treated with immunosuppression or stem cell transplant.
Key Facts
Pancytopenia with hypocellular bone marrow: reduced RBCs, WBCs, and platelets due to marrow failure Most cases autoimmune: T-cell mediated destruction of haematopoietic stem cells (~70% idiopathic) Causes: idiopathic (~70%), drugs (chloramphenicol, carbamazepine, NSAIDs, gold), viruses (hepatitis B/C, parvovirus B19, EBV, HIV), chemicals (benzene), radiation, inherited (Fanconi anaemia) Severity: severe aplastic anaemia (SAA) if ≥2 of: neutrophils <0.5 × 10⁹/L, platelets <20 × 10⁹/L, reticulocytes <20 × 10⁹/L Treatment <40 years: allogeneic SCT with matched sibling donor (first-line if available) Treatment >40 or no donor: ATG + ciclosporin (horse ATG preferred; response in ~60–70%) Eltrombopag: thrombopoietin receptor agonist; improves response rates when added to immunosuppression (NICE TA895) Association with PNH: ~30% of aplastic anaemia patients develop PNH clone; screen with flow cytometry
Overview
Key Facts
Aplastic anaemia is a bone marrow failure syndrome characterised by pancytopenia (anaemia, leucopenia, thrombocytopenia) with a hypocellular/empty bone marrow.
Epidemiology
- Incidence: ~2 per million per year in Europe
- Bimodal: peak 10–25 years and >60 years
- Higher incidence in East Asia (~5–7 per million)
Aetiology
- Idiopathic (~70%): presumed autoimmune
- Drugs: chloramphenicol, carbamazepine, phenytoin, sulfonamides, NSAIDs, gold, methotrexate (dose-dependent)
- Viral: hepatitis (seronegative — hepatitis-associated aplastic anaemia), parvovirus B19, EBV, HIV
- Chemical: benzene, pesticides
- Inherited: Fanconi anaemia (AR, childhood, skeletal anomalies, café-au-lait), dyskeratosis congenita
- Radiation
Pathophysiology
- Immune-mediated: oligoclonal CD8+ T cells → IFN-γ, TNF-α → apoptosis of haematopoietic stem/progenitor cells
- Result: empty/fatty marrow → failure of all cell lineages
- Clonal escape: surviving clones may acquire mutations → PNH, MDS, or AML
Clinical Presentation
Insidious Onset
- Anaemia: fatigue, pallor, dyspnoea
- Thrombocytopenia: bruising, petechiae, mucosal bleeding, menorrhagia
- Leucopenia (neutropenia): recurrent/severe infections
Examination
- Pallor
- Petechiae, bruising
- NO hepatosplenomegaly, NO lymphadenopathy (distinguishes from leukaemia/lymphoma)
Red Flags
- Severe bleeding (intracranial, GI)
- Severe neutropenic sepsis
- Pancytopenia in young patient
- Drug history (recent new drug)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| MDS | Elderly, dysplastic cells on film, may have increased blasts | Bone marrow (ring sideroblasts, blasts) |
| Acute leukaemia | Blasts on film/marrow, hepatosplenomegaly | Blood film, bone marrow |
| B12/folate deficiency | Megaloblastic, hypersegmented neutrophils, pancytopenia possible | B12, folate |
| Bone marrow infiltration | Leukoerythroblastic film, dry tap on aspiration | Bone marrow trephine |
| Hypersplenism | Splenomegaly, pancytopenia | Clinical, USS |
Diagnosis / Investigation
Bloods
- FBC: pancytopenia — low Hb, low WCC (neutropenia), low platelets
- Reticulocyte count: low (inappropriately for anaemia)
- Blood film: pancytopenia, no abnormal cells, no dysplasia
- B12, folate, iron studies: exclude deficiency
- LDH, bilirubin, haptoglobin: mild haemolysis markers if PNH clone
- Viral serology: hepatitis B/C, HIV, EBV, parvovirus
Bone Marrow
- Aspirate AND trephine biopsy: ESSENTIAL
- Hypocellular (<25% cellularity or <50% with <30% haem cells)
- Fat spaces replacing haematopoietic tissue
- No dysplasia, no increased blasts
- No fibrosis, no infiltration
Special Tests
- Flow cytometry: PNH clone screen (GPI-anchored proteins)
- Cytogenetics: exclude MDS (normal karyotype in aplastic anaemia)
- Chromosomal breakage (DEB/MMC test): if Fanconi anaemia suspected (<30 years, physical anomalies)
- Telomere length: dyskeratosis congenita
- HLA typing: for potential SCT
Management
Young Patient (<40 years) with Matched Sibling Donor
- Allogeneic SCT: first-line curative treatment
- ~75–90% long-term survival with matched sibling
- Conditioning: fludarabine + cyclophosphamide ± ATG
Older Patient (>40) or No Matched Sibling
- Horse ATG (ATGAM) + ciclosporin: first-line immunosuppression
- Response rate: ~60–70% at 6 months
- Horse ATG superior to rabbit ATG for aplastic anaemia
- Eltrombopag 150mg OD: added to ATG/ciclosporin improves response (NICE TA895)
Refractory:
- Matched unrelated donor SCT (MUD)
- Repeat immunosuppression with rabbit ATG
- Eltrombopag monotherapy
Supportive
- Transfusion: RBC and platelet support (irradiated if pre-SCT)
- Antibiotics: prompt treatment of febrile neutropenia
- Antifungals: if prolonged neutropenia
- G-CSF: may be used short-term for severe infection (not routine)
- Iron chelation: if transfusion-dependent
Referral Criteria
- Haematology: URGENT for all suspected aplastic anaemia
- Specialist bone marrow failure centre: for SCT assessment
Prognosis
- Untreated severe aplastic anaemia: ~70% mortality within 1 year
- Matched sibling SCT: 75–90% 5-year survival
- MUD SCT: 65–75% 5-year survival
- ATG + ciclosporin: 60–70% response; 5-year survival ~75%
- Eltrombopag addition: improves complete response rates
- ~15% develop clonal evolution (MDS, AML, PNH) over 10 years
- Relapse after immunosuppression: ~30–40%
Other Relevant Information
Severity Classification (Modified Camitta Criteria)
| Severity | Criteria |
|---|---|
| Non-severe (NSAA) | Hypocellular marrow + cytopenia not meeting SAA criteria |
| Severe (SAA) | Marrow cellularity <25% AND ≥2 of: neutrophils <0.5, platelets <20, reticulocytes <20 |
| Very severe (VSAA) | SAA criteria + neutrophils <0.2 |