Aplastic Anaemia Pathology
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Direct answer
Aplastic anaemia is pancytopenia with a hypocellular, fat-replaced bone marrow in which haematopoietic stem cells are destroyed or functionally silenced — most often by an immune T-cell attack (oligoclonal cytotoxic T cells producing TNF and interferon-gamma against progenitor CD34 cells), and in a majority of cases with no cause found (idiopathic). The trephine biopsy shows empty spicules, fat and stroma with cellularity below 25 per cent. Severity is graded on absolute neutrophil count, platelet count, corrected reticulocyte percentage and marrow cellularity; definitive treatment is allogeneic stem-cell transplantation for a young patient with a matched sibling donor, or immunosuppressive therapy with antithymocyte globulin and ciclosporin, with eltrombopag now added to both pathways.
What you must remember
- Severity criteria (Camitta): severe aplastic anaemia needs marrow cellularity under 25 per cent plus at least two of — absolute neutrophil count below 0.5 × 10⁹/L, platelets below 20 × 10⁹/L, corrected reticulocytes below 1 per cent; very severe disease means neutrophils below 0.2 × 10⁹/L.
- Cause list with anchors: idiopathic (largest group); drugs — dose-related (alkylators) versus idiosyncratic (chloramphenicol, the historical Indian viva favourite); benzene; ionising radiation; viral hepatitis (hepatitis-associated aplastic anaemia, typically months after a non-A non-B episode); parvovirus B19 (pure red-cell aplasia, not aplastic anaemia); Epstein-Barr virus and HIV.
- Inherited forms: Fanconi anaemia — autosomal recessive, defective DNA repair (FANC genes), radial ray and thumb anomalies, skin pigmentation, and a diepoxybutane chromosome-breakage test; dyskeratosis congenita — short telomeres (DKC1, TERT, TERC) with nail dystrophy, leukoplakia and reticular pigmentation; both evolve into marrow failure or myelodysplasia.
- The PNH overlap: a sizeable minority of aplastic patients have glycosylphosphatidylinositol-anchor deficiency (FLAER assay); aplastic anaemia, PNH and hypocellular MDS form a diagnostic triangle.
- Physical sign that steers you: no splenomegaly, no lymphadenopathy — an enlarged spleen in a pancytopenic patient points to hypersplenism, leukaemia or lymphoma instead.
- Supportive care discipline: leucodepleted and irradiated blood products, prompt broad-spectrum antibiotics for febrile neutropenia, and avoiding unnecessary transfusions before transplant to reduce alloimmunisation.
- Treatment outcomes to quote: matched-sibling transplant gives the best long-term survival in the young; immunosuppressive therapy benefits most treated patients, with relapse and late clonal evolution (MDS, AML) as the follow-up risks.
Approach to pancytopenia
A 19-year-old presents with gum bleeding, recurrent oral ulcers and exertional dyspnoea; haemoglobin 5.8 g/dL, total leucocyte count 1.6 × 10⁹/L, platelets 12 × 10⁹/L. Step one is the peripheral smear: no blasts (rules out aleukaemic leukaemia), no macro-ovalocytes or hypersegmented neutrophils (megaloblastic anaemia), no fragmented cells, and — critically — the spleen is not palpable. Step two confirms B12 and folate are normal, because a megaloblastic marrow is the great mimic that cures with vitamins. Step three is the bone marrow: the aspirate yields diluted material and the trephine shows fat with scattered lymphocytes and plasma cells — cellularity 10 per cent. Step four excludes the mimics: cytogenetics for hypocellular MDS (a hypocellular marrow with dysplastic forms or monosomy 7 behaves very differently), FLAER for PNH, and a diepoxybutane test plus skeletal survey if congenital stigmata surface. She meets severe criteria; without a matched sibling, ATG-based immunosuppression with ciclosporin and eltrombopag is the plan, transplant reserved for failure.
Where students slip
Calling parvovirus B19 a cause of aplastic anaemia is the standard error — it causes pure red-cell aplasia, erythroid precursors alone, classically in chronic haemolysis (aplastic crisis). Distinguishing aplastic anaemia from hypocellular MDS matters therapeutically: dysplasia, blasts above threshold or clonal cytogenetics point to MDS. Remember that the commonest cause overall is idiopathic — writing "chloramphenicol" reflexively in an Indian exam loses the mark unless the stem says so. Finally, Fanconi anaemia presents in childhood but may first declare itself in adolescence; the thumb anomaly is the giveaway on the clinical photograph.
Frequently asked questions
What defines severe aplastic anaemia?
Bone marrow cellularity below 25 per cent with at least two of: neutrophils below 0.5 × 10⁹/L, platelets below 20 × 10⁹/L, and corrected reticulocyte count below 1 per cent.
Which drug is classically linked with idiosyncratic marrow aplasia?
Chloramphenicol — dose-independent, rare, and historically over-prescribed; it remains the textbook example despite modern rarity.
How does Fanconi anaemia cause marrow failure?
Inherited FANC gene mutations disable DNA interstrand cross-link repair, leading to chromosomal instability, congenital anomalies and progressive stem-cell loss.
Why is the spleen not enlarged in aplastic anaemia?
The pathology is marrow hypoplasia, not extramedullary destruction or infiltration; splenomegaly with pancytopenia should prompt a search for another cause.
What first-line therapy suits a patient lacking a matched sibling donor?
Horse antithymocyte globulin with ciclosporin (eltrombopag often added), with allogeneic transplant reserved for failure or a suitable donor.