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

CLINICAL SCENARIO

A 19-year-old male college student presents to the outpatient department with a 6-week history of progressive fatigue, three episodes of fever with upper respiratory infections over the past 2 months, and multiple spontaneous bruises on his limbs. He has no significant past medical history. He takes no regular medications but admits to frequent use of an over-the-counter analgesic (diclofenac) for exam-related headaches. Family history is unremarkable. On examination: pallor ++, multiple ecchymoses on forearms and thighs, no hepatosplenomegaly, no lymphadenopathy. Investigations: Hb 6.2 g/dL, TLC 1.8 × 10⁹/L (ANC 0.4 × 10⁹/L), Platelets 18 × 10⁹/L. Peripheral blood film shows a hypocellular picture with no blast cells. Reticulocyte count: 0.2%.

Section 1 — Pancytopenia: Differential Diagnosis & Pathophysiological Framework

The blood counts reveal pancytopenia (anaemia + leucopenia + thrombocytopenia). Construct a systematic differential diagnosis for pancytopenia in this young adult, organised by the underlying pathophysiological mechanism. For each category, name at least one representative condition. Then apply the clinical and investigative data from this case to narrow the differential.

Guidance: Organise by mechanism: (a) hypoproduction — bone marrow failure (aplastic anaemia, myelodysplastic syndrome, infiltration, megaloblastic); (b) peripheral destruction/sequestration (hypersplenism, immune-mediated); (c) dilutional (massive transfusion — less relevant here). Use the absence of blast cells, the absence of hepatosplenomegaly, and the very low reticulocyte count as discriminators. Demonstrate that pancytopenia of hypoproductive origin is the most likely category here.

Section 2 — Bone Marrow Examination: Why Trephine Biopsy is Indispensable

The haematologist requests both a bone marrow aspirate AND a trephine biopsy. Explain the diagnostic rationale for each procedure. Critically, justify why the trephine biopsy (not the aspirate alone) is essential for the diagnosis of aplastic anaemia, and describe what findings you would expect on the biopsy in this case.

Guidance: Key teaching point: aplastic anaemia produces a 'dry tap' or hypocellular aspirate — the very pathology you are investigating causes the aspirate to fail. The trephine biopsy provides core architecture, cellularity assessment (% haematopoietic vs fat cells — normal 50% cellularity in adults), and confirms the hypocellular marrow filled with fat cells and stromal cells. Contrasts: aspirate gives cytology (morphology, cytochemistry, flow cytometry, cytogenetics); trephine gives architecture, cellularity, and detects focal lesions. Expected findings in aplastic anaemia: overall cellularity <25% (or <30% with <30% residual haematopoietic cells), fat cell replacement, residual lymphocytes, plasma cells and mast cells, no fibrosis, no infiltrate, no dysplasia.

Section 3 — Reaching the Diagnosis: Interpreting the Hypocellular Marrow

The bone marrow trephine biopsy report reads: 'Markedly hypocellular marrow with overall cellularity approximately 10%. Fat spaces predominate. Residual haematopoietic cells show no morphological dysplasia. No increase in blasts. No evidence of granuloma, fibrosis, or infiltration by abnormal cells.' Using this report and the peripheral blood findings, establish the diagnosis and fulfil the diagnostic criteria for aplastic anaemia.

Guidance: State the diagnostic criteria (modified Camitta criteria): severe AA requires at least 2 of: ANC <0.5 × 10⁹/L, platelets <20 × 10⁹/L, reticulocytes <1% (or <20 × 10⁹/L if corrected) — PLUS marrow cellularity <25% (or 25-50% with <30% residual haematopoietic cells). Apply criteria to this case: ANC 0.4, platelets 18, reticulocytes 0.2%, marrow cellularity 10% — all four criteria met → Severe Aplastic Anaemia. Distinguish from MDS (absence of dysplasia), from hypoplastic MDS (important differential — cytogenetics/FISH needed), from PNH (screen by flow cytometry for GPI-anchored proteins).

Section 4 — Aetiology Screening: Drug, Toxin, Viral and Inherited Causes

Once the diagnosis of aplastic anaemia is established, you must determine the cause. Describe the systematic aetiology screen you would initiate, covering drug/toxin exposure, viral triggers, and inherited bone marrow failure syndromes. Link the clinical history in this case to the most relevant aetiological suspects, and identify which investigations would differentiate idiopathic from secondary aplastic anaemia.

Guidance: Drug/toxin: NSAIDs (diclofenac — prominent in this history), chloramphenicol, antiepileptics (carbamazepine), chemotherapy agents, benzene. Viral: EBV, hepatitis viruses (non-A, non-B, non-C hepatitis — classically associated), CMV, HIV, Parvovirus B19. Inherited: Fanconi anaemia (FA — most important in a 19-year-old; screen with chromosomal breakage test with DEB/MMC; look for short stature, café-au-lait spots, thumb anomalies), dyskeratosis congenita (telomere length testing), Shwachman-Diamond. Investigations: LFTs, viral serology panel (EBV/CMV/HIV/Hepatitis A-C/Parvovirus B19), PNH screen (flow cytometry — up to 50% of acquired AA have a PNH clone), cytogenetics (rule out MDS/FA), DEB breakage test if clinical features or age suggest inherited cause. Conclusion: in this case, NSAIDs are suspicious but most acquired AA is ultimately idiopathic/immune-mediated.

Section 5 — Severity Grading and Management Principles

Grade the severity of this patient's aplastic anaemia using the standard classification. Then outline the management principles for his case, covering supportive care, definitive treatment options, and the rationale for the recommended first-line definitive treatment in a 19-year-old patient. Include the role of HLA typing at this point.

Guidance: Severity classification: Non-severe (nSAA), Severe (SAA), Very Severe (vSAA — ANC <0.2 × 10⁹/L). This patient has SAA (ANC 0.4 is borderline; platelets 18 and retic 0.2% meet two of three criteria). Management: (1) Supportive — infection prophylaxis/empirical antibiotics, platelet transfusions (threshold ~10–20 × 10⁹/L), packed red cells for anaemia, avoid live vaccines, avoid transfusions from family members (sensitisation risk pre-transplant). (2) Definitive — Allogeneic HSCT from a matched sibling donor is first-line for patients <40 with SAA/vSAA. HLA typing of patient AND siblings should begin immediately. If no matched sibling: immunosuppressive therapy (horse ATG + cyclosporine + eltrombopag). (3) NSAID must be stopped immediately. Emphasise: HLA typing is time-critical — do not delay.

PEER REVIEW

You will be assigned one peer submission to review anonymously. Your review should take approximately 20–25 minutes and will be graded for quality.

What to assess:
1. Accuracy — Are the differential diagnoses, diagnostic criteria, and management principles correct? Flag specific factual errors with a brief explanation.
2. Reasoning quality — Does your peer use case data to drive their reasoning, or do they simply list facts? Note where reasoning is strong and where it is absent.
3. Trephine biopsy justification — This is the key teaching point of the case. Did your peer clearly explain why the trephine (not just the aspirate) is essential? If not, explain what was missing.
4. Completeness — Were all five sections addressed? Were any aetiological categories or management steps omitted?
5. Constructive suggestion — Provide at least one specific, actionable suggestion for improvement.

What NOT to do: Do not rewrite your peer's answer. Do not grade harshly for word count alone. Do not provide vague praise ('Good job'). Your peer review must be at least 150 words to receive full credit.