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PA17.1 | Aplastic Anemia & Bone Marrow Failure — PBL Case

CLINICAL SETTING

Meenakshi is a 14-year-old girl from a rural village in Tamil Nadu, brought to the district hospital by her parents with a six-month history of pallor, frequent nosebleeds, and recurrent boils on the skin. Her parents first noticed that she seemed tired even after a full night's sleep and had stopped growing — classmates of the same age had overtaken her in height. She has had three episodes of high fever with skin infections in the past four months, each requiring a course of antibiotics from the local PHC. Her mother mentions that Meenakshi was born with 'bent hands' (the parents show a photograph — both thumbs appear absent, and the radii are markedly foreshortened bilaterally). Two older siblings are healthy. On examination: short stature (height on the 3rd centile), multiple café-au-lait spots over the trunk (counted seven), absent thumbs bilaterally, hypoplastic radii, pallor +++, scattered petechiae on both lower legs. No hepatosplenomegaly and no lymphadenopathy. Temperature 37.8°C, pulse 110/min. CBC shows: Hb 5.4 g/dL, MCV 104 fL (macrocytic), TLC 1.6 × 10⁹/L (ANC 0.35 × 10⁹/L), Platelets 12 × 10⁹/L. Reticulocyte count: 0.3%. Peripheral smear: normochromic macrocytic red cells, no blasts, no hypersegmented neutrophils.

Trigger 1: Initial Presentation

The district hospital physician reviews Meenakshi's presentation: a 14-year-old girl with six months of progressive pallor, recurrent infections, and skin bleeding. She has congenital physical anomalies — absent thumbs, hypoplastic radii, café-au-lait spots — and short stature since childhood. CBC reveals pancytopenia (Hb 5.4 g/dL, WBC 1.6 × 10⁹/L, platelets 12 × 10⁹/L) with a very low reticulocyte count of 0.3%. There is no hepatosplenomegaly and no lymphadenopathy.

DISCUSSION POINTS

  • Pancytopenia means all three lineages are reduced — what specific complications arise from reduction of each lineage, and which complication in Meenakshi is most immediately life-threatening?
  • The reticulocyte count is 0.3% in the setting of severe anaemia — what does a low reticulocyte count tell you about the bone marrow's response, and how does this differ from haemolytic anaemia where the reticulocyte count is high?
  • Absent thumbs, hypoplastic radii, café-au-lait spots, and short stature are not typical of acquired aplastic anaemia — what category of aplastic anaemia should this combination of findings trigger you to consider, and what is the eponymous diagnosis?
  • The absence of hepatosplenomegaly and lymphadenopathy is an important negative finding — what diagnoses causing pancytopenia does this help exclude?
Click to reveal Trigger 2: Investigations (discuss previous trigger first!)

Trigger 2: Investigations

The haematology team at the referral centre reviews Meenakshi. A bone marrow trephine biopsy is performed from the posterior superior iliac crest. Histology shows 10% cellularity — the remainder is replaced by fat cells and fibrous stroma. No blast cells, no granulomas, no dysplasia, no infiltration. Aspiration yields scant material (hypoplastic fragments). Chromosomal fragility testing (diepoxybutane, DEB test) on peripheral blood lymphocytes shows markedly increased chromosomal breakage compared to controls. Renal ultrasound reveals a horseshoe kidney. HbF level: 22% (elevated above the normal adult level of <1%).

DISCUSSION POINTS

  • What is the difference between a bone marrow aspiration and a trephine biopsy — why are both needed here, and what unique information does the trephine provide that the aspirate cannot?
  • A cellularity of 10% in a 14-year-old — how do you interpret this, given that normal marrow cellularity is estimated as (100 minus age in years), and what severity grade does this correspond to?
  • The DEB chromosomal fragility test is positive — explain why Fanconi anaemia cells are hypersensitive to cross-linking agents like diepoxybutane, and what this reveals about the underlying molecular defect.
  • The elevated HbF (22%) in Meenakshi's case is a stress erythropoiesis marker — what does it indicate about the state of the bone marrow, and in which other conditions is HbF elevated as a compensatory or reactivated mechanism?
Click to reveal Trigger 3: Diagnosis & Management (discuss previous trigger first!)

Trigger 3: Diagnosis & Management

Meenakshi is diagnosed with Fanconi anaemia, a constitutional (hereditary) form of aplastic anaemia, based on the clinical triad of congenital anomalies, pancytopenia, and positive DEB test. She is referred to a paediatric haematology centre for further evaluation. The team explains that the definitive treatment is haematopoietic stem cell transplantation (HSCT) and begins sibling HLA-typing. While awaiting transplant, she is started on oxymetholone (androgen therapy) and supportive care (irradiated blood products, G-CSF, infection prophylaxis with cotrimoxazole and fluconazole). The family is counselled about the autosomal recessive inheritance pattern and the importance of genetic counselling before future pregnancies.

DISCUSSION POINTS

  • Compare Fanconi anaemia with acquired aplastic anaemia: what are the key differences in etiology, age of presentation, associated findings, and definitive treatment?
  • The pathogenesis of acquired aplastic anaemia involves T-cell mediated destruction of haematopoietic stem cells — what cellular and molecular mechanisms are involved, and why does immunosuppressive therapy (ATG + cyclosporin) work in acquired but not in Fanconi anaemia?
  • Design a systematic differential diagnosis for a 14-year-old presenting with pancytopenia and hypocellular marrow — include at least four conditions and the key distinguishing features for each.
  • Meenakshi will need red cell and platelet transfusions — what specific precaution is required for blood product preparation before transplant, and why?

Group Task Assignments

Group 1: Definition, etiology, and classification of aplastic anaemia

  • Write a precise definition of aplastic anaemia that includes the three necessary elements (pancytopenia, hypocellular marrow, exclusion of infiltration/fibrosis/dysplasia). Classify aplastic anaemia by etiology, placing Meenakshi's case correctly.
  • List five important drug or chemical causes of acquired aplastic anaemia and explain why chloramphenicol is the classic example — distinguish dose-dependent from idiosyncratic mechanisms.

Competencies: PA17.1

Group 2: Pathogenesis of aplastic anaemia — acquired vs inherited

  • Draw a flow diagram of the immune-mediated pathogenesis of acquired aplastic anaemia: from trigger (drug/virus/idiopathic) → T-cell activation → cytokine release (IFN-γ, TNF-α) → haematopoietic stem cell apoptosis → empty marrow.
  • Contrast with the pathogenesis of Fanconi anaemia: explain DNA repair deficiency (FANC pathway), chromosomal instability, and why this leads to progressive bone marrow failure and also increases cancer risk.

Competencies: PA17.1

Group 3: Bone marrow examination — procedures, indications, and findings

  • Create a comparison table: bone marrow aspiration vs trephine biopsy — covering what is obtained, what it shows, when each is essential, and what a 'dry tap' means.
  • Describe the normal bone marrow trephine appearance and how you estimate cellularity using the age-based formula. Sketch and compare: normal marrow (age 14) vs aplastic marrow (10% cellularity).

Competencies: PA17.1

Group 4: Differential diagnosis of pancytopenia

  • Build a differential diagnosis table for pancytopenia with hypocellular marrow: list aplastic anaemia, MDS (hypocellular variant), hairy cell leukaemia, PNH, and B12/folate deficiency — with one key distinguishing lab or morphological feature for each.
  • Explain why megaloblastic anaemia (B12/folate deficiency) causes pancytopenia even though the marrow is hypercellular — contrast the mechanism with aplastic anaemia's hypocellular marrow.

Competencies: PA17.1

Group 5: Clinical features, severity grading, and management principles

  • Apply the Camitta severity criteria to classify aplastic anaemia as moderate, severe, or very severe — state the specific CBC thresholds and cellularity cut-offs, and classify Meenakshi's case.
  • Outline the management framework for aplastic anaemia: supportive care, immunosuppression (ATG + cyclosporin), androgens, and HSCT — state the indications for each and why HSCT is preferred in young patients with a matched sibling donor.

Competencies: PA17.1

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PA17.1] What is the precise definition of aplastic anaemia, how is it classified by etiology (idiopathic, acquired secondary, inherited/constitutional), what are the pathogenetic mechanisms (T-cell immune destruction in acquired; DNA repair deficiency in Fanconi), what are the clinical and peripheral blood features (pancytopenia, no organomegaly, normocytic-normochromic or macrocytic red cells, low reticulocyte count), and what are the indications and findings of bone marrow aspiration and trephine biopsy in aplastic anaemia?