Understand aplastic anemia, a bone marrow failure disorder causing pancytopenia. Explore causes including radiation, drugs, viruses, and congenital forms like F
HEATOLOGY CHAPTER 22: APLASTIC ANAEMIA AND BONE MARROW FAILURE Comprehensive Revision Notes Hoffbrand's Essential Haematology --- PANCYTOPENIA Reduction in blood count of all three major cell lines — red cells, white cells, and platelets. Causes — broadly divided into: - Decreased bone marrow production - Increased peripheral destruction Causes of decreased bone marrow production: - Aplasia (reduction of haemopoietic stem cells) - Acute leukaemia, myelodysplasia, myeloma - Infiltration with lymphoma, solid tumours, tuberculosis - Megaloblastic anaemia - Paroxysmal nocturnal haemoglobinuria - Myelofibrosis - Haemophagocytic syndrome - Splenomegaly - Increased peripheral destruction --- APLASTIC ANAEMIA Definition: Pancytopenia resulting from hypoplasia of the bone marrow Classification: Primary (congenital or acquired) or Secondary --- Causes Primary: - Congenital — Fanconi and non-Fanconi types - Idiopathic acquired Secondary: - Ionizing radiation — accidental exposure, radiotherapy, radioactive isotopes - Chemicals — benzene, organophosphates, DDT, pesticides, recreational drugs (ecstasy) - Drugs — two groups: - Those that regularly cause marrow depression: busulfan, melphalan, cyclophosphamide, anthracyclines, nitrosoureas - Those that occasionally/rarely cause depression: chloramphenicol, sulphonamides, gold, anti-inflammatory, antithyroid, psychotropic, anticonvulsant/antidepressant drugs - Viruses — viral hepatitis (non-A, non-B, non-C, non-G in most cases), EBV - Autoimmune diseases — systemic lupus erythematosus - Transfusion-associated GVHD - Thymoma — more usually associated with red cell aplasia --- Pathogenesis Underlying defect in all cases = substantial reduction in haemopoietic pluripotential stem cells + fault in remaining stem cells OR an immune reaction against them → unable to divide and differentiate to populate bone marrow. --- CONGENITAL APLASTIC ANAEMIA Fanconi Anaemia (FA) - Inheritance: Autosomal recessive - Usual age of presentation: 3–14 years - ~10% develop acute myeloid leukaemia Features: - Growth retardation - Congenital defects of the skeleton (microcephaly, absent radii or thumbs) - Defects of the renal tract (pelvic or horseshoe kidney) - Defects of the skin (hyper- and hypopigmentation) - Sometimes learning disability Genetics: - Genetically heterogeneous — 16 different genes involved (FANC A–Q) - FANCD1 is identical to BRCA2 (breast cancer susceptibility gene) - Genes cooperate in ubiquitination of FANCD2 → protects cells against genetic damage - FA cells show abnormally high frequency of spontaneous chromosomal breakage - Diagnostic test: elevated breakage after incubation with DNA cross-linking agent diepoxybutane (DEB test) Treatment: Androgens and/or SCT. Conditioning regimes are mild and irradiation avoided (cells sensitive to DNA damage). Remission rarely lasts 2 years; SCT may cure. --- Dyskeratosis Congenita (DC) - Rare, sex-linked disorder - Features: nail atrophy, skin atrophy, high risk of pulmonary fibrosis, cirrhosis, osteoporosis, cancer - Associated with mutations in DKC1 (dyskerin) or TERC (telomerase reverse transcriptase RNA template) → involved in telomere length maintenance --- Diamond–Blackfan Anaemia (DBA) - Congenital form of pure red cell aplasia - Rare autosomal recessive syndrome - Varying degrees of cytopenia, especially neutropenia - Propensity to transform to myelodysplasia or acute myeloid leukaemia - Exocrine pancreatic dysfunction is an invariable feature - Skeletal abnormalities, hepatic impairment, short stature are frequent - Results from inherited mutations in gene SD involved in ribosome synthesis --- IDIOPATHIC ACQUIRED APLASTIC ANAEMIA Most common type of aplastic anaemia; accounts for at least two-thirds of acquired cases. Pathogenesis: - Haemopoietic tissue = target of autoimmune process dominated by oligoclonal expansion of cytotoxic CD8+ T cells - Clonal haemopoiesis with somatic mutations of PIGA, ASXL1, DNMT3A — present in ~50% of cases - Must be distinguished from: late-onset congenital aplastic anaemia and hypoplastic myelodysplasia - Short telomeres may be present as acquired abnormalities - Favourable responses to ATG and ciclosporin support the autoimmune concept --- CLINICAL FEATURES - Onset at any age; peak incidence: 10–25 and over 60 years - More frequent in Asia (e.g. China) than Europe - Insidious OR acute onset with symptoms of anaemia, neutropenia, or thrombocytopenia Haemorrhagic manifestations (most frequent): - Bruising, bleeding gums, epistaxes, menorrhagia - Retinal haemorrhage may impair vision Infections: - Particularly of mouth and throat - Generalized infections frequently life-threatening Note: Lymph nodes, liver, and spleen are NOT enlarged --- LABORATORY FINDINGS At least two of the following must be present: 1. Anaemia — Hb 75% of marrow); trephine biopsy shows patchy cellular areas in a hypocellular background; main cells = lymphocytes and plasma cells; megakaryocytes severely reduced or absent 8. Cytogenetic and molecular analysis to exclude inherited forms and myelodysplasia --- DIAGNOSIS Must be distinguished from other causes of pancytopenia. PNH must be excluded by flow cytometry testing for CD55 and CD59. In older patients, hypoplastic myelodysplasia may appear similar — abnormalities of blood cells and clonal cytogenetic/molecular changes suggest myelodysplasia. --- TREATMENT Best carried out in a specialized centre . General (Supportive) - Remove any identifiable cause (e.g. drug) - Blood transfusions, platelet concentrates, prevention and treatment of infection - All blood products must be leucodepleted (prevent alloimmunisation, prevent grafting of live donor lymphocytes) - Antifibrinolytic agent (e.g. tranexamic acid) — reduces haemorrhage in severe prolonged thrombocytopenia - Granulocyte transfusions — rarely used; for severe bacterial/fungal infections not responding to antibiotics - Oral antibacterial and antifungal drugs to reduce infections Specific Tailored to severity of illness and availability of stem cell donors. 1. Antithymocyte Globulin (ATG) - Prepared by immunizing animals (horse or rabbit) with human thymocytes - Benefit in 50–60% of acquired cases - Given with ciclosporin to improve response rate - Corticosteroids given short term — reduce immediate allergic effects and serum sickness (fever, rash, joint pains) ~7 days after administration - Platelet count maintained 10 × 10⁹/L, if possible 20–30 × 10⁹/L - No response after 4 months → second course tried - Overall up to 80% of patients respond to combined ALG + ciclosporin 2. Ciclosporin - Effective agent, particularly valuable in combination with ALG - In older subjects sometimes used alone 3. Alemtuzumab (anti-CD52 antibody) - Effective in about 50% in small studies - Usually only used after ATG has failed 4. Eltrombopag (thrombopoietin mimetic) - Stimulates platelet production - May also result in durable improvement in red cell and neutrophil counts 5. Androgens - Beneficial in some FA patients and acquired aplastic anaemia - Overall improved survival NOT proven - Side-effects: virilization, salt retention, liver damage with cholestatic jaundice, rarely hepatocellular carcinoma - If no response in 4–6 months → stop. If response → withdraw gradually 6. Stem Cell Transplantation (SCT) - Allogeneic SCT offers chance of permanent cure in selected patients - Conditioning: cyclophosphamide without irradiation + ciclosporin (reduces graft failure and graft-versus-host disease) - Favoured in patients 40 years - SCT using umbilical cord blood and unrelated/mismatched donors used in carefully selected patients - In older/less severe patients — immunosuppression tried first 7. Haemopoietic Growth Factors - G-CSF — minor responses only; does NOT lead to sustained improvement - Other growth factors not proved helpful 8. Iron chelation therapy - May be needed in patients requiring regular transfusion --- PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH) Definition: Rare, acquired, c