Understand aplastic anemia, a bone marrow failure disorder causing pancytopenia. Explore causes including radiation, drugs, viruses, and congenital forms l
#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 <100 g/L ; normochromic, normocytic or macrocytic; MCV often 95–110 fL; reticulocyte count extremely low relative to degree of anaemia 2. Neutrophil count <1.5 × 10⁹/L 3. Platelet count <50 × 10⁹/L 4. Severe: neutrophils <0.5 × 10⁹/L, platelets <20 × 10⁹/L, reticulocytes <20 × 10⁹/L, marrow cel