Aplastic Anaemia

Meet the patient

A 19-year-old student walks into ED with a nosebleed that will not stop and a mouth full of ulcers. She looks well — chatting, afebrile, no lumps, no spleen to feel. Then the full blood count lands: haemoglobin 58, neutrophils 0.3, platelets 12, reticulocytes 4 (all x 10^9/L). The registrar reaches for "leukaemia." The examiner's first question is the one this whole topic answers: a well-looking patient with severe pancytopenia and no organomegaly — what is your top diagnosis, and what single specimen confirms it?[4]

What aplastic anaemia actually is (and isn't)

It is a marrow-failure syndrome — pancytopenia plus a hypocellular marrow plus nothing else. Two findings must coexist: peripheral-blood pancytopenia (anaemia, neutropenia and thrombocytopenia together) and a markedly hypocellular marrow replaced by fat, with no abnormal infiltrate, no dysplasia and no clonal population.[4]

The name is a misnomer that catches juniors. "Anaemia" sits in the title, but the defining failure is all three lineages at once — the triad of pancytopenia. Pure red cell aplasia (erythroid alone) and amegakaryocytic thrombocytopenia (platelets alone) are different diseases with different work-ups and different treatments; do not file them under aplastic anaemia.[1]

Cellularity in severe disease is under 25 percent (or 25 to 50 percent with under 30 percent residual haematopoiesis). It is not a malignancy — there is no neoplastic clone — yet it can turn into one: paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome and acute myeloid leukaemia all evolve out of aplastic marrow over the years. That is why "cured" is a word you use carefully here.[1]

The clinical skill is not the biopsy — anyone can order one. It is three judgements in order: recognise pancytopenia and do not dismiss the well-looking patient; separate aplastic anaemia from its mimics (hypoplastic MDS, megaloblastic anaemia, aleukaemic leukaemia, hypersplenism); then grade severity with the Camitta criteria to choose between transplant and immunosuppression.[1][4]

Severity and aetiology — the Camitta number rule (25 / 0.5 / 20 / 20)

Grade severity with one number rule: 25 / 0.5 / 20 / 20. Marrow cellularity under 25 percent, then at least two of neutrophils under 0.5, platelets under 20, reticulocytes under 20 (all x 10^9/L) — that is severe aplastic anaemia. Push the neutrophils under 0.2 and it becomes very severe. Two axes decide your management: how severe the marrow has failed, and what set it off.[1][4]

Severe AA (Camitta/modified criteria — learn it verbatim):[1]

By aetiology — acquired in adults, inherited in the young:[1]

Who gets it — epidemiology and the trigger list

About 2 per million per year in the West, two to three times higher across East and South Asia (China, Thailand, Indonesia, India) — blamed on agricultural chemicals, benzene and infectious triggers, with a likely genetic contribution (HLA-DR15, which also predicts a better ciclosporin response).[3]

Two age peaks — 15 to 25, and over 60. The young peak often unmasks an inherited predisposition (short telomeres, FANC mutations) under environmental or infectious stress; the older peak accumulates somatic clones and overlaps diagnostically with hypoplastic MDS.[4]

The trigger list — what to ask about:[1]

Why the marrow empties — the immune T-cell attack (and why IST works)

Three mechanisms contribute, but one dominates acquired disease: an immune T-cell attack on CD34+ stem cells. That single fact — the marrow being destroyed by its owner's own T cells — is why immunosuppression works, and it is the conceptual heart of the whole topic.[3]

1. The core mechanism — cytotoxic CD8+ T cells kill the stem cells. An oligoclonal expansion of cytotoxic CD8+ Th1 lymphocytes fires off interferon-gamma, tumour necrosis factor-alpha and interleukin-2. These cytokines do four things:[3]

• Induce apoptosis of CD34+ haematopoietic stem and progenitor cells via the Fas–Fas-ligand pathway — the death-receptor cascade that activates caspase-8 and downstream executioner caspases.
• Drive stem cells into cell-cycle arrest (loss of quiescence), exhausting the proliferative reserve — the stem cells are forced out of their protective G0/G1 resting state and into cycling, where they are vulnerable to cytokine-induced apoptosis.
• Down-regulate c-kit (the stem-cell factor receptor) and activate indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan in the marrow microenvironment, starving the very cells needed for recovery.
• The transcription factor T-bet, a master regulator of Th1 differentiation, is over-expressed in the T cells of aplastic anaemia patients, sustaining the pathogenic cytokine programme. [1]

This is why IST works. Remove the autoreactive T-cell clone and the surviving (often tiny) pool of stem cells repopulates the marrow. The proof: a 60 to 70 percent response to anti-thymocyte globulin plus ciclosporin, and the laboratory observation that depleting T cells from the marrow in vitro restores haematopoiesis.[1]

2. The intrinsic stem-cell defect — short telomeres hiding in 'acquired' disease. A subset of apparently acquired cases carries short telomeres from germline mutations in TERT, TERC, DKC1, RTEL1, NHP2, NOP10, CTC1, PARN — impairing self-renewal. When telomeres hit the Hayflick limit the cell senesces or dies, and the stem-cell pool drains over years. These patients respond less well to IST and carry a higher risk of clonal evolution (especially monosomy 7 MDS/AML). About 10 percent of apparently acquired aplastic anaemia hides a clinically significant telomerase mutation — often hypomorphic, which is why the family history looks normal.[1]

3. The marrow microenvironment — stromal dysfunction is a minor player but matters in the inherited syndromes. Mesenchymal stromal cells, endothelium and matrix form the niche that keeps stem cells quiescent; defects here can fail the marrow independently of the stem cells themselves.[1]

The PNH link — two faces of one immune attack. A small glycosylphosphatidylinositol (GPI)-deficient clone, born of a PIG-A mutation (absent CD55 and CD59), turns up on flow cytometry in up to half of acquired cases — even with no haemolysis. Here is the confession examiners love: PNH and aplastic anaemia are two faces of the same immune attack. The PNH clone survives only because stripping off its GPI-anchored proteins makes it invisible to the very T cells emptying the rest of the marrow — it is the cell that escaped by going dark. Over the years that clone (and others — monosomy 7, trisomy 8, del(13q)) can expand into overt PNH, MDS or AML, which is why surveillance is lifelong.[5]

Histological hallmarks on the trephine — fatty marrow scattered with islands of lymphocytes and plasma cells, markedly reduced haematopoiesis (cellularity under 25 percent), no fibrosis, no abnormal infiltrate. Everyone forgets: the aspirate is a 'dry tap' because there is nothing to suck out — the trephine, not the aspirate, decides cellularity.[4]

What you'll see at the bedside

The symptoms track whichever cell line is lowest — but all three cytopenias usually arrive together.[4]

Anaemia — the slow one. Progressive fatigue is the common opener: washed out, breathless on minimal effort, palpitations. Look for pallor in the conjunctivae, palmar creases and nail beds; older patients or those with a fast haemoglobin drop get angina and cardiac failure. The onset is gradual enough for physiological adaptation — patients walk in with haemoglobin of 40 to 60 g/L and yet look surprisingly well.[1]

Neutropenia — the one that kills first. Neutrophils under 0.5 x 10^9/L is the most dangerous cytopenia in the short term, and fever is the cardinal sign. A neutropenic patient with fever above 38.0 degrees Celsius has neutropenic sepsis — a medical emergency needing empirical broad-spectrum antibiotics within one hour. Other features: oral mucositis, perianal infection (often missed), recurrent bacterial infections, overwhelming sepsis, and invasive fungal infection (aspergillosis — pleuritic chest pain, haemoptysis, halo sign on CT; candidiasis — hepatosplenic lesions). A vital clue: neutrophils make pus, so infections here can look indolent yet run rapidly progressive — do not be reassured by a quiet-looking patient.[4]

Thrombocytopenia — the one that bleeds. Petechiae (pinpoint, non-blanching) and purpura appear first on the lower limbs (dependent capillary pressure), the pressure points (waistband, blood-pressure cuff) and the buccal mucosa. Mucosal bleeding follows — epistaxis (often bilateral, hard to control), gingival bleeding, menorrhagia (can be life-threatening), haematuria, melaena. The feared complication is intracranial haemorrhage — rare but catastrophic, presenting with severe headache, altered consciousness or a focal deficit.[4]

Onset is usually insidious over weeks to months — patients and families blame tiredness or easy bruising on stress until a blood test exposes the severity. Severe bleeding or sepsis is what precipitates the sudden presentation.[1]

Examination is the discriminator: the well patient with frightening bloods. The patient looks well despite profound cytopenias — pallor, petechiae and purpura, but characteristically no hepatosplenomegaly and no lymphadenopathy. That is the bedside clue to marrow failure, not leukaemia: a leukaemic patient with the same counts looks unwell, often has organomegaly, and may have tissue infiltration. Find a spleen or a lymph node in someone you thought had aplastic anaemia, and go hunting for something else — leukaemia, lymphoma, hypersplenism, megaloblastic anaemia, visceral leishmaniasis.[4]

Scenarios that change the picture:[1]

• Adolescents/young adults — the "well patient with frightening bloods"; a classic clue to bone marrow failure rather than leukaemia. The clinical contrast between how well the patient looks and how bad the blood count is can be striking.
• Elderly — may be misclassified as hypoplastic MDS; presentation overlaps with myelodysplasia and cytogenetic assessment is essential. The distinction has major treatment implications: MDS may need hypomethylating agents or supportive care, while aplastic anaemia needs IST or HSCT.
• Hepatitis-associated AA — typically young males, develops 1 to 6 months after an episode of seronegative hepatitis (negative for hepatitis A, B, C, E and all known hepatotropic viruses). The liver injury resolves but the marrow fails. Often fulminant and poorly responsive to IST — early HSCT is considered if a donor exists.[1]
• Pregnancy — rare; risk of severe haemorrhage and infection; managed supportively during pregnancy, with IST considered postpartum. May remit after delivery but can recur in subsequent pregnancies.
• Parvovirus B19 — classically pure red cell aplasia with giant proerythroblasts in the marrow (the virus directly infects and lyses erythroid progenitor cells through the P-antigen receptor); in the immunocompromised host can cause a more generalised aplasia because the virus cannot be cleared by neutralising antibodies.
• Aplastic-PNH syndrome — overlapping marrow failure and haemolysis (jaundice, dark urine), venous thrombosis (hepatic, portal, cerebral, dermal). The thrombosis of PNH is characteristically in unusual sites — Budd-Chiari syndrome (hepatic vein), portal/mesenteric/splenic vein thrombosis, cerebral venous sinus thrombosis — and should trigger a PNH work-up in any patient with aplastic anaemia.

The face-off — aplastic anaemia vs its mimics (the discriminator is marrow cellularity)

Sort the differential of pancytopenia by marrow cellularity — it splits the mimics in one move. A hypocellular marrow points at aplastic anaemia and its close cousins; a normo- or hypercellular marrow points everywhere else.[4]

Hypocellular marrow — the close differentials:[1]

• Hypoplastic myelodysplastic syndrome (MDS) — the single hardest distinction in bone marrow failure. Dysplastic morphology (micromegakaryocytes, hypogranular neutrophils, nuclear budding), clonal cytogenetics (monosomy 5/7, trisomy 8, del(20q)), and raised CD34+ blasts all favour MDS. Cytogenetics and next-generation sequencing increasingly inform this distinction, but some cases remain genuinely ambiguous ("hypoplastic MDS vs aplastic anaemia"). The clinical implication is large: MDS is managed differently (hypomethylating agents, supportive care, HSCT in selected cases) and carries a different prognosis.
• Aleukaemic leukaemia — acute leukaemia presenting with a low white cell count (no peripheral blasts); marrow is usually hypercellular with over 20 percent blasts but can occasionally be hypocellular.
• Advanced hairy-cell leukaemia — pancytopenia with dry tap on aspirate; marrow shows hairy cells (villose cytoplasmic projections), annexin-A1 and BRAF V600E positive on immunohistochemistry, and there is usually massive splenomegaly.
• Late myelofibrosis — tear-drop cells (dacryocytes) on the blood film, massive splenomegaly, and marked reticulin and collagen fibrosis on trephine — the marrow is hypocellular but fibrotic (fibrosis is absent in classic aplastic anaemia).
• Severe infection — miliary tuberculosis, visceral leishmaniasis (kala-azar), brucellosis. These are particularly relevant in endemic regions (India, South Asia) and should be excluded with appropriate cultures and serology.
• Paroxysmal nocturnal haemoglobinuria (aplastic-PNH syndrome) — see below; the marrow may be hypocellular early in the disease course. [1]

Normo- or hypercellular marrow — the rest of the pancytopenia list:[1]

• Megaloblastic anaemia (B12 or folate deficiency) — macro-ovalocytes, hypersegmented neutrophils (5 or more lobes), megaloblastic marrow (giant metamyelocytes, nuclear-cytoplasmic asynchrony), high LDH and indirect bilirubin, low B12 or folate. The key point: it causes pancytopenia with a hypercellular marrow, and it responds rapidly to supplementation within days to weeks. A common exam trap is to confuse megaloblastic anaemia with aplastic anaemia — the marrow cellularity and the film morphology are the decisive discriminators.
• Sepsis with marrow suppression — temporary, resolves with treatment of the underlying infection.
• Hypersplenism — portal hypertension (cirrhosis, portal/splenic vein thrombosis), storage disorders (Gaucher, Niemann-Pick); splenomegaly is dominant, marrow is hypercellular with maturation arrest.
• Systemic lupus erythematosus and other autoimmune cytopenias — may present with pancytopenia from autoantibodies or from secondary marrow involvement; ANA and anti-dsDNA are positive.
• Disseminated (miliary) tuberculosis — particularly in endemic regions; may cause marrow infiltration and secondary haemophagocytic syndrome.
• Infiltrative malignancy — metastatic carcinoma (breast, lung, prostate, stomach), lymphoma, myelophthisis (marrow replacement). The film may show nucleated red cells and immature myeloid precursors (leukoerythroblastic picture).
• Gaucher disease, visceral leishmaniasis — storage or parasitic infiltration of the marrow; organisms visible on marrow aspirate in kala-azar (Leishman-Donovan bodies). [1]

The one-line discriminator: marrow cellularity plus what is in it. Aplastic anaemia is hypocellular and empty; hypoplastic MDS is hypocellular but dysplastic; leukaemia is hypercellular and full of blasts; megaloblastic is hypercellular and megaloblastic; hypersplenism comes with a big spleen.[1]

At the bedside and on the form

Bedside examination must cover four things:[4]

• Vital signs — fever in a neutropenic patient is neutropenic sepsis until proven otherwise and requires immediate empirical antibiotics. Do not wait for blood cultures to return before starting treatment — the window for effective intervention is the first hour.
• Skin — pallor (conjunctival, palmar, nail-bed), petechiae and purpura (especially lower limbs, pressure points, buccal mucosa). Look carefully at the lower legs and buccal mucosa — these are dependent and traumatised areas where petechiae first appear.
• Fundoscopy — retinal haemorrhage (flame-shaped or dot-blot), a sign of severe thrombocytopenia and a bleeding risk. Roth spots (white-centred haemorrhages) suggest additional infection.
• Lymph nodes, liver and spleen — characteristically absent in aplastic anaemia; their presence argues for leukaemia, lymphoma, hypersplenism, or megaloblastic anaemia. Carefully examine the cervical, axillary and inguinal nodes, and palpate and percuss for hepatosplenomegaly. [1]

In the young, hunt the inherited marrow-failure syndromes — missed diagnoses that change the transplant conditioning regimen:[4]

• Fanconi anaemia — short stature, café-au-lait spots, radial ray anomalies (absent thumb, triphalangeal thumb, radial hypoplasia), microcephaly, renal anomalies (horseshoe kidney, duplicated collecting system), hypogonadism, strabismus. The physical features may be subtle — café-au-lait spots can be mistaken for ordinary pigmentation, and thumb anomalies may have been surgically corrected in childhood. A careful family history of early-onset cancers, congenital anomalies or unexplained cytopenias is essential.
• Dyskeratosis congenita — the classic triad of dystrophic nails (ridged, split, atrophic), reticular skin pigmentation (neck, chest, axillae — a lace-like pattern), and oral leukoplakia (whitish patches on the tongue and buccal mucosa). These appear in childhood to early adolescence. Also look for premature greying and dental abnormalities.
• Shwachman-Diamond — skeletal anomalies (metaphyseal chondrodysplasia, rib abnormalities), growth failure, and steatorrhoea from pancreatic exocrine insufficiency (ask about greasy, foul-smelling stools from childhood).
• GATA2 deficiency — warts (persistent, extensive HPV infection due to monocytopenia), opportunistic infection (atypical mycobacteria, fungal), lymphoedema (Emberger syndrome), and a family history of MonoMAC (monocytopenia, dendritic cell deficiency, B-cell and NK-cell deficiency). [1]

Search for the trigger: jaundice or hepatomegaly (recent hepatitis — ask about a febrile illness with deranged liver enzymes in the preceding 1 to 6 months), thyroid goitre (autoimmune polyglandular syndrome), pregnancy, occupation (benzene in petrochemical workers, pesticides in agricultural workers, radiation), and drugs (chloramphenicol — still used in places; antiepileptics; NSAIDs; sulphonamides; gold).[3]

Look for PNH clues: jaundice (haemolytic — an indirect bilirubin out of proportion to the anaemia), dark urine from haemoglobinuria (worse in the morning — hence "nocturnal"), abdominal pain or Budd-Chiari (ascites, abdominal-wall collaterals, hepatomegaly), and neurological deficit from cerebral venous sinus thrombosis (headache, papilloedema, seizures).[1]

The well-looking patient with severe pancytopenia and absent organomegaly is the bedside signature of aplastic anaemia. Those same counts in a patient who looks unwell, is febrile with localising signs, or has organomegaly point instead to leukaemia, lymphoma or infection.[4]

Signs that move you from clinic to resus:

• Fever with neutropenia → neutropenic sepsis bundle (cultures and empirical antibiotics within 1 hour).
• Uncontrolled bleeding, severe headache or altered consciousness → suspected intracranial haemorrhage — urgent platelet transfusion, CT imaging, neurosurgical consultation.
• Retinal haemorrhage with visual change → urgent platelet support and ophthalmology review. [1]

The investigations that decide it — trephine first, aspirate second

First-line tests:[4]

• Full blood count with differential — confirms pancytopenia: low haemoglobin, low neutrophils (absolute neutrophil count under 0.5 in severe AA), low platelets, low reticulocytes. The MCV is often normal or mildly raised (macrocytosis is common in marrow failure and in telomere biology disorders). A high MCV with pancytopenia should always prompt consideration of megaloblastic anaemia, but a normal MCV does not exclude it.
• Peripheral blood film — no abnormal cells, no blasts (the key finding that excludes leukaemia). May show anisocytosis, macrocytes, and mild poikilocytosis. The absence of blasts, dysplastic neutrophils, and nucleated red cells is itself diagnostic information. In megaloblastic anaemia, you would see macro-ovalocytes and hypersegmented neutrophils; in leukaemia, you would see blasts.
• Reticulocyte count — inappropriately low for the degree of anaemia (the marrow is not compensating). Absolute reticulocytes under 20 x 10^9/L is part of the severe criteria. A high reticulocyte count in the setting of pancytopenia suggests haemolysis or recovery rather than aplastic anaemia.
• Bone marrow aspirate AND trephine biopsy — the diagnostic cornerstone. The trephine is essential because the aspirate can be misleadingly dilute (a "dry tap" or blood-only aspirate is common when the marrow is severely hypocellular). On the trephine: cellularity under 25 percent (or 25 to 50 percent with under 30 percent residual haematopoietic cells), no dysplasia, no abnormal infiltrate, no significant fibrosis. The cellularity should be assessed on the trephine biopsy, not the aspirate, because the aspirate is prone to dilution artefact. [1]

Severe AA — Camitta criteria (reproduced verbatim, examinably verbatim):[4]

Marrow cellularity under 25 percent (or 25 to 50 percent with under 30 percent residual haematopoietic cells), AND at least two of the following:

• Neutrophils under 0.5 x 10^9/L
• Platelets under 20 x 10^9/L
• Reticulocytes under 20 x 10^9/L [1]

Very severe AA: meets the severe criteria AND neutrophils under 0.2 x 10^9/L. Non-severe AA: hypocellular marrow with cytopenias that do not meet severe criteria. [1]

Severity grading is not academic — it is the treatment fork. Severe and very severe AA need definitive therapy (HSCT or IST); non-severe AA may be watched. Very severe AA (neutrophils under 0.2) carries the worst prognosis — fast-track it to definitive treatment.[1]

Second-line and aetiological work-up — what to send before you treat:[1]

• Cytogenetics (conventional karyotyping plus FISH for chromosomes 5, 7, 8, 20) — normal in idiopathic AA; clonal abnormalities (monosomy 7, trisomy 8, del(20q)) suggest MDS or clonal evolution. A normal karyotype supports the diagnosis of aplastic anaemia; an abnormal karyotype with a hypocellular marrow shifts the diagnosis toward hypoplastic MDS.
• Flow cytometry for a PNH clone (FLAER test on granulocytes and monocytes; CD55/CD59 on red cells) — detect a small PNH clone in up to half of acquired cases. FLAER (fluorescent aerolysin) binds to GPI-anchored proteins; GPI-deficient cells (PNH clone) fail to bind. This is more sensitive than CD55/CD59 alone and is now the preferred method.[5]
• Exclude triggers and mimics: liver function tests (hepatitis-associated AA); viral serology (hepatitis A/B/C/E, EBV, CMV, HIV, parvovirus B19 PCR); vitamin B12 and folate (to exclude megaloblastic anaemia); serum copper (deficiency causes a reversible pancytopenia with neurological signs and myelodysplastic features — easily missed and treatable); autoimmune screen (ANA, anti-dsDNA, rheumatoid factor — SLE can cause secondary aplastic anaemia); serum immunoglobulins.
• Telomere length assay (flow-FISH) and directed germline gene testing (TERT, TERC, DKC1, RTEL1, SAMD9/SAMD9L, GATA2, FANC genes) when an inherited disorder is suspected — i.e., young patients, family history of cytopenias/cancers, physical stigmata, or poor response to IST. Telomere length below the first percentile for age is highly suggestive of a telomere biology disorder.
• Chromosomal breakage test (DEB or MMC) — diepoxybutane (DEB) or mitomycin C (MMC) induced chromosomal breakage testing is the diagnostic test for Fanconi anaemia: Fanconi cells show increased chromosomal breakage and radial figures when exposed to cross-linking agents. This should be performed in all young patients with aplastic anaemia, because undiagnosed Fanconi anaemia changes the HSCT conditioning regimen (must avoid radiation and alkylators) and carries implications for family members.
• HLA typing of the patient and full siblings at diagnosis — early donor identification informs the first-line choice between HSCT and IST. HLA-A, -B, -C, -DRB1, -DQB1 (10/10 match) is the minimum for sibling assessment.
• Imaging — chest X-ray or CT if tuberculosis or fungal infection suspected (halo sign, air-crescent sign for invasive aspergillosis); abdominal ultrasound for splenomegaly (which would argue against aplastic anaemia). Not diagnostic of aplastic anaemia itself.
• Iron studies and ferritin before the transfusion programme — iron overload is a late complication of repeated transfusions and needs chelation when ferritin exceeds 1000 micrograms/L.

[1]

Resuscitation — bleeding and neutropenic sepsis first

[1]

ABCDE first. The two immediate threats are bleeding (severe thrombocytopenia) and infection (neutropenia) — and neutropenic sepsis is the one that kills before you have finished making the diagnosis.[1]

Neutropenic fever — the one-hour bundle (this is a preventable death: do NOT wait for cultures):[4]

1. Blood cultures from every lumen of any central line and a peripheral site — before antibiotics if possible, but do not delay antibiotics beyond 1 hour from presentation.
2. Empirical broad-spectrum IV antibiotics within 1 hour per local policy — typically piperacillin-tazobactam 4.5 g IV 8-hourly, or ceftazidime 2 g IV 8-hourly / cefepime 2 g IV 8-hourly as monotherapy. Add vancomycin 1 g IV 12-hourly (or 15 to 20 mg/kg) or teicoplanin 400 mg IV 12-hourly for suspected line infection, haemodynamic instability, severe mucositis, or known MRSA colonisation. The rationale is to cover Gram-negative bacilli (Pseudomonas, E. coli, Klebsiella — the most rapidly lethal organisms in neutropenia) and Gram-positive cocci (Staphylococcus, Streptococcus viridans — increasingly common with central lines).
3. Reassess at 48 to 72 hours; escalate to antifungal cover (liposomal amphotericin B 3 mg/kg/day, caspofungin 70 mg loading then 50 mg/day, voriconazole 6 mg/kg loading then 4 mg/kg 12-hourly) for persistent fever — which raises suspicion of invasive fungal infection (aspergillosis, candidiasis). A galactomannan assay (serum or BAL) and high-resolution CT chest should be considered.
4. Reverse barrier nursing, strict hand hygiene, neutropenic diet (avoid raw foods, unpasteurised dairy). G-CSF (granulocyte colony-stimulating factor) may be considered in severe sepsis, though its routine use in aplastic anaemia is debated. [1]

Severe anaemia — transfuse leucodepleted packed red cells to haemoglobin over 70 g/L (over 80 to 90 g/L if symptomatic, pregnant or with cardiovascular disease); each unit raises haemoglobin by about 10 g/L in an adult without active bleeding.[1]

Severe thrombocytopenia or bleeding:[1]

• Prophylactic platelet transfusion when platelets under 10 x 10^9/L (or under 20 if febrile or with active bleeding). One adult therapeutic dose raises the count by approximately 20 to 40 x 10^9/L.
• Therapeutic transfusion for active bleeding or before invasive procedures — aim for platelets over 50 x 10^9/L for active bleeding or major procedures, and over 100 for neurosurgery or ophthalmic procedures.
• Tranexamic acid 1 g IV 8-hourly for mucosal bleeding (avoid in haematuria — risk of clot obstruction in the urinary tract).
• Avoid NSAIDs, intramuscular injections, rectal examinations, hard tooth-brushing, razors in thrombocytopenic patients — these can precipitate life-threatening bleeding. [1]

Use CMV-safe (leucodepleted) blood products in anyone who may proceed to HSCT — to prevent CMV transmission and alloimmunisation. Alloimmunisation (especially anti-HLA antibodies) makes future platelet transfusions useless (platelet refractoriness) and complicates HSCT conditioning.[1]

Prophylaxis during the cytopenias: co-trimoxazole 480 mg orally daily (or 960 mg three times weekly) for Pneumocystis jirovecii; aciclovir 200 to 400 mg orally daily for HSV/VZV; posaconazole 300 mg orally daily (or itraconazole) for antifungal cover; iron chelation with deferasirox 20 mg/kg/day orally once ferritin exceeds 1000 micrograms/L.[1]

Rapidly refer severe or very severe disease to a haematology centre with transplant capability — definitive therapy must start within days, not weeks. Untreated severe aplastic anaemia carries a 70 percent one-year mortality from infection or bleeding.[2]

Definitive therapy — the age-and-donor fork

This is the topic's mantra: grade the severity, then fork by age and donor. Young (under 40) with an HLA-matched sibling donor gets an allogeneic stem cell transplant; everyone else gets horse ATG plus ciclosporin. The whole strategy turns on that single decision.[1][4]

The decision rule:[1]

• Severe or very severe AA AND age under 40 years AND an HLA-matched sibling donor available → allogeneic haematopoietic stem cell transplant (HSCT) as first-line curative therapy. This offers the best chance of long-term cure (80 to 90 percent survival in young patients).
• Severe or very severe AA in patients over 40, OR no matched sibling donor → immunosuppressive therapy (IST): horse anti-thymocyte globulin plus ciclosporin. This is not curative but achieves a haematological response in 60 to 70 percent, allowing transfusion independence.
• Non-severe AA — observation plus supportive care; treat with IST only if transfusion-dependent or progressing to severe criteria. [1]

Why age 40? Transplant-related mortality climbs sharply with age (GVHD, infection, conditioning toxicity), so IST becomes the safer bet in older patients. The cut-off is a guideline, not a cliff — a fit 50-year-old with a matched sibling may still go to HSCT; a frail 35-year-old may be better served by IST.[1]

Immunosuppressive therapy (IST) — drug, dose, route, timing, rationale, monitoring: [1]

Response assessment at 3 to 6 months:[1]

• Complete response (CR) — haemoglobin over 100 g/L, neutrophils over 1.5 x 10^9/L, platelets over 100 x 10^9/L, transfusion-independent.
• Partial response (PR) — no longer meeting severe AA criteria, transfusion-independent.
• No response — consider second-line therapy. [1]

Responses begin at 3 months (the first sign is a rising neutrophil and reticulocyte count) and are maximal by 6 months. No response at 6 months means move to second-line. Responders still risk relapse (10 to 30 percent) and clonal evolution (10 to 15 percent at 10 years) — hence lifelong surveillance.[5]

Refractory or relapsed severe AA — second-line options:[2]

• Matched unrelated donor HSCT (younger patients with a suitable donor — outcomes approaching matched sibling HSCT with modern conditioning).
• Eltrombopag monotherapy for refractory disease (response in approximately 40 percent of refractory patients).[6]
• A second course of IST (rabbit ATG if first course was horse ATG; alemtuzumab — anti-CD52 — in selected cases).
• Haploidentical HSCT (half-matched family donor — post-transplant cyclophosphamide conditioning) is an emerging option for patients without a matched donor.

Allogeneic HSCT — conditioning and procedure:[1][5]

• Donor preference: HLA-matched sibling first (lowest GVHD risk, best outcomes); matched unrelated donor if no sibling and the patient is young (8/8 or 10/10 HLA match).
• Conditioning: fludarabine plus cyclophosphamide plus ATG (with or without low-dose total-body irradiation 2 Gy or alemtuzumab for in vivo T-cell depletion). Avoid heavy alkylators and total-body irradiation in inherited marrow-failure syndromes (Fanconi anaemia — extreme radiosensitivity and chromosomal fragility; dyskeratosis congenita — sensitivity to alkylators and radiation).
• Source: peripheral blood stem cells (faster engraftment) or bone marrow (lower chronic GVHD in some studies).
• Outcomes: long-term survival about 80 to 90 percent in young patients with matched sibling donors; 70 to 80 percent with matched unrelated donors; lower in older or heavily pretreated patients.
• Late complications: graft-versus-host disease (acute — skin rash, diarrhoea, cholestatic jaundice in the first 100 days; chronic — sicca syndrome, scleroderma-like skin changes, bronchiolitis obliterans after 100 days), veno-occlusive disease/sinusoidal obstruction syndrome (weight gain, tender hepatomegaly, jaundice — from conditioning toxicity), infections, secondary malignancy (solid tumours, post-transplant lymphoproliferative disorder), infertility, endocrine failure (growth hormone deficiency, hypothyroidism, gonadal failure).[5]

PNH clone surveillance — flow cytometry every 6 to 12 months; start eculizumab (anti-C5 monoclonal antibody, 1200 mg IV every 2 weeks after loading) or ravulizumab (longer-acting anti-C5, every 8 weeks) if overt haemolysis or thrombosis develops. Both require meningococcal vaccination and prophylactic penicillin because they block complement-mediated defence against Neisseria. [1]

Subtypes and special situations

Inherited/congenital aplastic anaemia — these syndromes are missed at the candidate's peril, because they change the conditioning regimen and carry family implications:[4]

• Fanconi anaemia — the commonest inherited marrow-failure syndrome. Autosomal recessive (FANC gene family — at least 22 genes involved in DNA cross-link repair). The diagnostic test is the DEB (diepoxybutane) chromosomal breakage test: Fanconi cells show increased chromosomal breakage, gaps and radial figures when exposed to DEB or mitomycin C. Physical stigmata: short stature, café-au-lait spots, radial ray anomalies (absent or hypoplastic thumbs, radial hypoplasia), microcephaly, renal anomalies, hypogonadism. Bone marrow failure typically develops in the first decade. HSCT is the only cure for the marrow failure, but conditioning must avoid total-body irradiation and alkylators (extreme chromosomal fragility — use fludarabine-based reduced-intensity conditioning). Lifelong cancer surveillance is needed (head and neck, gynaecological, skin cancers).[2]
• Dyskeratosis congenita — a telomere biology disorder (X-linked DKC1, or autosomal dominant TERC/TERT, or autosomal recessive RTEL1, NHP2, NOP10, CTC1, PARN, TCAB1). The classic mucocutaneous triad — dystrophic nails, reticular skin pigmentation, oral leukoplakia — appears in childhood. Marrow failure develops in the teens to twenties. Telomere length is markedly shortened (below first percentile for age). Pulmonary fibrosis and hepatic cirrhosis are non-haematological complications of the short-telomere syndrome. HSCT conditioning should be reduced-intensity with fludarabine; patients are sensitive to radiation and alkylators.
• Shwachman-Diamond syndrome — autosomal recessive (SBDS gene). Features: pancreatic exocrine insufficiency (steatorrhoea, failure to thrive from infancy — distinguish from cystic fibrosis by normal sweat chloride), neutropenia (often the first haematological sign), skeletal dysplasia (metaphyseal chondrodysplasia), and marrow failure. MDS/AML risk is increased. HSCT is the only cure for marrow failure.
• GATA2 deficiency — includes MonoMAC syndrome (monocytopenia, dendritic cell deficiency, B-cell and NK-cell deficiency) and Emberger syndrome (primary lymphoedema with MDS/AML). Presents with persistent warts (HPV), opportunistic infection (atypical mycobacteria, fungal), and progression to MDS/AML. HSCT is curative for the immunodeficiency and marrow failure.
• Congenital amegakaryocytic thrombocytopenia (MPL gene) — presents with isolated thrombocytopenia at birth (absent megakaryocytes in the marrow), progressing to trilineage marrow failure. HSCT is the only cure.

Hepatitis-associated AA — young males, 1 to 6 months after seronegative hepatitis (negative for all known hepatotropic viruses — A, B, C, E); fulminant course; poor response to IST (response rate lower than idiopathic); early HSCT if a donor is available. The mechanism is thought to be immune cross-reactivity between liver and marrow antigens, but the exact trigger is unknown.[1]

Pregnancy-associated AA — rare; support with transfusions during pregnancy (leucodepleted, CMV-safe); defer IST until postpartum where possible (ciclosporin is relatively safe in pregnancy — category C, but ATG is generally avoided); HSCT deferred until delivery. Risk of miscarriage, preterm birth, and maternal haemorrhage. May remit postpartum but can recur in subsequent pregnancies. Multidisciplinary obstetric–haematology–anaesthesia care is essential.[4]

Post-EBV / post-mononucleosis AA — rare; usually self-limited or responds to IST. The virus infects and lyses haematopoietic progenitors in the immunocompromised host. [1]

Drug-induced AA — withdraw the offending drug (chloramphenicol, carbamazepine, NSAIDs, sulphonamides, gold, penicillamine, ticlopidine); supportive care; IST for severe cases. Dose-related causes (benzene, chemotherapy, radiation) may recover after withdrawal, though benzene exposure carries a long-term leukaemia risk.[3]

Parvovirus B19 — pure red cell aplasia in immunocompetent hosts (the virus infects and lyses erythroid progenitors via the P-antigen receptor, causing a transient reticulocytopenia); generalised aplasia in the immunocompromised (who cannot mount a neutralising antibody response to clear the virus). Marrow shows giant proerythroblasts with viral inclusions. Treat with intravenous immunoglobulin (IVIG 0.4 g/kg/day for 5 days) — provides neutralising antibodies — and reduce concomitant immunosuppression where possible. [1]

Aplastic-PNH syndrome — overlapping marrow failure and haemolysis; treat marrow failure with IST, and haemolysis/thrombosis with complement inhibition (eculizumab, ravulizumab). The two conditions coexist because the PNH clone (GPI-deficient) survives the immune attack that causes aplastic anaemia, and over time may expand. [1]

Refractory severe AA — second-line options: matched unrelated donor HSCT, eltrombopag, repeat IST (rabbit ATG if first was horse). Haploidentical HSCT is an emerging option for patients without a matched donor.[2]

Complications and the pitfalls that cost marks

Bleeding: severe thrombocytopenia → mucocutaneous bleeding (epistaxis, gingival, menorrhagia, gastrointestinal, urinary), intracranial haemorrhage (rare but fatal — the most feared bleeding complication), retinal haemorrhage (may threaten vision). Manage with platelet transfusion (aim over 50 for active bleeding), tranexamic acid 1 g IV 8-hourly for mucosal bleeding, and general haemostatic measures. Avoid antiplatelet drugs and NSAIDs. Menorrhagia can be controlled with norethisterone 5 mg orally three times daily or a levonorgestrel intrauterine system. [1]

Infection: neutropenia → bacterial sepsis (Gram-negative bacilli — Pseudomonas, E. coli, Klebsiella — the most rapidly lethal; Gram-positive cocci — Staphylococcus, Streptococcus viridans — increasingly common with central lines) and invasive fungal infection (aspergillosis — pulmonary infiltrates, pleuritic pain, haemoptysis; candidiasis — hepatosplenic, bloodstream) — the leading early cause of death in aplastic anaemia.[4]

Iron overload: cumulative transfusions → hepatic (cirrhosis, hepatitis), cardiac (dilated cardiomyopathy, arrhythmia) and endocrine (diabetes, hypothyroidism, hypogonadism) dysfunction. Each unit of packed red cells delivers approximately 200 mg of iron, and the body has no physiological mechanism for excreting excess iron. Manage with deferasirox (oral, 20 mg/kg/day — monitor renal function and LFTs) or deferoxamine (subcutaneous infusion 40 mg/kg over 8 to 12 hours — less convenient but effective). Start chelation when ferritin exceeds 1000 micrograms/L or after approximately 20 units of red cells. [1]

Alloimmunisation and platelet refractoriness: from repeated transfusions — the patient develops anti-HLA or anti-platelet antibodies that rapidly clear transfused platelets. Diagnosed by a post-transfusion platelet increment less than expected (1-hour corrected count increment under 7500). Manage with HLA-matched or antigen-negative platelets and, in severe cases, intravenous immunoglobulin. [1]

Clonal evolution: development of MDS, AML (especially monosomy 7, trisomy 8), or overt PNH over years — the cumulative risk is approximately 15 percent at 10 years after IST. Higher risk with short telomeres (telomere biology disorders), older age at IST, and addition of eltrombopag (some studies suggest a slight increase in cytogenetic abnormalities — monitoring is essential). This is why lifelong surveillance with blood counts, cytogenetics and PNH flow cytometry is mandatory.[5]

Ciclosporin toxicity: nephrotoxicity (the dose-limiting toxicity — monitor creatinine, reduce dose if it rises by more than 30 percent from baseline), hypertension, gum hypertrophy, tremor, hirsutism, hepatotoxicity, hyperkalaemia, hypomagnesaemia, and opportunistic infection (PJP — hence co-trimoxazole prophylaxis; BK virus nephropathy). [1]

ATG toxicity: serum sickness (a Type III hypersensitivity reaction — fever, rash, arthralgia, myalgia, proteinuria around days 7 to 14 after infusion; managed with corticosteroids), anaphylaxis (immediate hypersensitivity — test dose is mandatory; have adrenaline, antihistamines and oxygen ready), and viral reactivation (CMV, EBV, HBV — prophylactic antivirals and monitoring). [1]

Post-HSCT complications: graft-versus-host disease (acute — skin rash, diarrhoea, cholestatic jaundice; chronic — sicca syndrome, scleroderma-like skin, bronchiolitis obliterans), veno-occlusive disease/sinusoidal obstruction syndrome (weight gain, tender hepatomegaly, jaundice, ascites — from sinusoidal endothelial injury by conditioning), infections (bacterial, viral, fungal — particularly in the first 100 days), graft failure/rejection (primary — no engraftment; secondary — loss of donor cells after initial engraftment), secondary malignancy (solid tumours, post-transplant lymphoproliferative disorder), infertility, and endocrine failure (growth hormone deficiency, hypothyroidism, gonadal failure).[5]

The pitfalls that cost marks:

• Misclassifying hypoplastic MDS as aplastic anaemia (or vice versa) — cytogenetics, CD34 counts and next-generation sequencing are decisive. The distinction changes the treatment from IST to hypomethylating agents or supportive care.
• Failing to recognise neutropenic sepsis and delaying antibiotics beyond 1 hour — the single most preventable cause of early death.
• Under-transfusing platelets in active bleeding — the target is over 50 x 10^9/L for active bleeding, not just over 20.
• Missing an occult PNH clone at diagnosis — leads to missed haemolysis, thrombosis, and delayed complement-directed therapy.
• Overlooking inherited marrow-failure syndromes in young patients — leads to inappropriate conditioning (radiation, alkylators) and avoidable toxicity, and misses the opportunity for family counselling and genetic testing.
• Premature taper of ciclosporin → relapse. The taper must be slow (over 1 to 2 years) after maximal response.
• Using non-leucodepleted blood products → alloimmunisation and CMV transmission, complicating future HSCT. [1]

Prognosis and disposition

Untreated severe AA is fatal within 6 to 12 months from infection or bleeding — that is the baseline every treatment is measured against.[1]

• HSCT (HLA-matched sibling donor): long-term survival about 80 to 90 percent in young patients; best outcomes in children and adolescents (over 90 percent survival in children with matched siblings). The curative potential of HSCT is its great advantage — a successful transplant eliminates the disease and the risk of clonal evolution (though it introduces GVHD and other transplant-related risks).
• IST (horse ATG + ciclosporin): overall response 60 to 70 percent at 6 months; 5-year survival 70 to 85 percent; 10-year survival approximately 70 percent. Relapse rate 10 to 30 percent (hence the slow ciclosporin taper). Clonal evolution (MDS/AML/PNH) 10 to 15 percent at 10 years — this is the major long-term threat after IST.[5]
• Adding eltrombopag to first-line IST (RACE trial) improved the complete response rate at 6 months from approximately 10 percent to over 50 percent (response defined as haematological improvement).[6]

Worse prognosis: age over 40 (higher transplant mortality, lower IST response), very severe AA (neutrophils under 0.2) — the single most powerful adverse prognostic factor, short telomeres (germline telomerase mutations — worse IST response, higher clonal evolution), hepatitis-associated AA (poor IST response), no response at 6 months, infection at presentation (a marker of severe immunocompromise).[1]

Better prognosis: young age, no infection at diagnosis, absence of clonal cytogenetic abnormality (normal karyotype), higher baseline reticulocyte and lymphocyte counts (indicating more residual stem-cell reserve), presence of a PNH clone (paradoxically — patients with a small PNH clone respond better to IST, perhaps because the clone proves the immune mechanism). [1]

Lifelong follow-up is required for clonal evolution (PNH/MDS/AML) and late effects of HSCT (secondary malignancy, endocrine, chronic GVHD). This is not a disease that is "cured and forgotten" — even after successful HSCT or IST response, surveillance continues indefinitely.[5]

Disposition: severe AA requires admission to a haematology centre; referral to a transplant-capable unit at diagnosis (HLA typing of patient and siblings done early); survivors need long-term haematology follow-up with annual blood counts, PNH flow cytometry every 6 to 12 months, and cytogenetics if counts change. [1]

Special populations

• Children — higher response to IST and HSCT; matched sibling HSCT is preferred first-line if available (survival over 90 percent in children with matched siblings). Conditioning regimens should avoid total-body irradiation to preserve growth, development and fertility — fludarabine-based reduced-intensity conditioning is preferred. Always exclude inherited marrow-failure syndromes before transplant (DEB test for Fanconi, telomere length for dyskeratosis congenita) because they change the conditioning and prognosis.[2]

• Pregnancy — rare; supportive transfusions are the mainstay during pregnancy (leucodepleted, CMV-safe; aim haemoglobin over 80 g/L, platelets over 20, over 50 near term or for delivery). IST deferred until postpartum where possible (ciclosporin is relatively safe — category C — but ATG is generally avoided in pregnancy). HSCT deferred until delivery. Risks: miscarriage, preterm birth, maternal haemorrhage (especially postpartum with thrombocytopenia). Multidisciplinary care (obstetrics, haematology, anaesthesia) with delivery planned in a unit with haematology and transfusion support. May remit postpartum.[4]

• Elderly (over 40 to 50) — less likely to respond to IST (response rate falls with age); higher transplant-related mortality; comorbidities favour IST over HSCT. If HSCT is needed, reduced-intensity conditioning is used. Differentiation from hypoplastic MDS is critical in this age group — the two conditions overlap and the wrong diagnosis leads to the wrong treatment. [1]

• Immunocompromised host (HIV, post-transplant) — exclude parvovirus B19 (PCR) and drug-related marrow suppression (ganciclovir, valganciclovir, trimethoprim-sulfamethoxazole, linezolid); IST modified (ciclosporin alone may be tried); higher infectious risk requires aggressive prophylaxis and early treatment of infection. [1]

• Inherited marrow-failure syndromes — avoid total-body irradiation and alkylator-heavy conditioning; HSCT is the only cure for the marrow failure but does not correct the non-haematological manifestations (Fanconi — cancer risk; dyskeratosis congenita — pulmonary fibrosis, hepatic cirrhosis). Chromosomal breakage testing (DEB) and telomere length should be performed in young patients with suggestive features or family history. Family counselling and genetic testing are essential.[4]

• Patients with established PNH clone — complement-directed therapy (eculizumab 1200 mg IV every 2 weeks, ravulizumab every 8 weeks) for haemolysis or thrombosis; IST for the marrow-failure component. Vaccinate against Neisseria meningitidis and give prophylactic penicillin (anti-C5 therapy blocks complement-mediated defence against encapsulated organisms). [1]

• Resource-limited settings (relevant for India/South Asia) — incidence is 2 to 3 fold higher; donor registries are smaller and transplant access is limited — IST is the realistic first-line for most patients; emphasis on supportive care, infection prevention and iron chelation. Access to eltrombopag and transplantation is variable and often determined by economics rather than clinical need.[2]

Evidence, Guidelines & Regional Differences

• Bacigalupo A. 'How I treat acquired aplastic anemia' (Blood 2017) — the practical framework that most clinicians follow: IST for older patients and those without donors; HSCT for young patients with matched sibling donors. Emphasises the immune mechanism and the rationale for IST.[1]
• Killick SB et al, BCSH Guidelines for the diagnosis and management of adult aplastic anaemia (British Journal of Haematology 2016) — the UK diagnostic criteria, severity grading and treatment recommendations. Defines the work-up (FBC, film, reticulocytes, trephine biopsy, cytogenetics, PNH flow, telomere length, DEB test in young patients) and the treatment algorithm (HSCT under 40 with matched sibling; IST otherwise).[4]
• Scheinberg P et al (NEJM 2011): horse ATG is superior to rabbit ATG for first-line treatment of severe AA (6-month response: 68 percent vs 37 percent; survival: 96 percent vs 76 percent) — horse ATG remains first choice. This is a frequently tested exam point.[7]
• Olnes MJ et al (NEJM 2012) and the subsequent RACE trial: eltrombopag improves trilineage haematopoiesis in refractory and treatment-naïve severe AA — now incorporated into first-line IST for selected patients. The RACE trial showed a significant improvement in complete response rate when eltrombopag was added to horse ATG plus ciclosporin.[6]
• Young NS & Maciejewski J (NEJM 1997): the foundational description of immune-mediated destruction of CD34+ stem cells as the core pathophysiology — established the cytokine cascade (IFN-gamma, TNF-alpha) and the Fas–FasL apoptosis pathway. Still widely cited as the mechanism reference.[3]
• Wingard JR et al (JCO 2011): long-term outcomes after allogeneic HSCT, including late deaths from secondary malignancy and chronic GVHD — informs the need for lifelong surveillance after transplant.[5]

Controversy: the boundary between hypoplastic MDS and aplastic anaemia is debated; some cases are genuinely ambiguous on morphology alone. Cytogenetics, flow cytometry (CD34 counts) and next-generation sequencing (mutations in ASXL1, RUNX1, TP53 favour MDS) increasingly inform classification and prognosis, but a grey zone remains.[1]

Guideline bodies: British Society for Haematology (BCSH), European Society for Blood and Marrow Transplantation (EBMT), Asian Hematology Alliance, Indian Society of Hematology and Blood Transfusion. All agree on the Camitta severity criteria and the age-and-donor treatment algorithm, but differ on access to eltrombopag and transplantation in resource-limited settings. [1]

The PAINT mnemonic and exam pearls

• Pancytopenia (anaemia + neutropenia + thrombocytopenia) with a HYPOCELLULAR marrow and NO abnormal cells is aplastic anaemia until proven otherwise. The trephine biopsy (not the aspirate) is the diagnostic specimen.
• Most common form is idiopathic (autoimmune); classical drug cause is chloramphenicol (idiosyncratic, now rare); classical virus is seronegative hepatitis.
• Severe AA (Camitta criteria): marrow cellularity under 25 percent AND at least two of neutrophils under 0.5, platelets under 20, reticulocytes under 20 (all x 10^9/L). Very severe AA adds neutrophils under 0.2.
• First-line for a young patient (under 40) with an HLA-matched sibling donor: allogeneic HSCT. First-line for older patients or no donor: horse ATG plus ciclosporin.
• Horse ATG is superior to rabbit ATG (Scheinberg NEJM 2011) — a frequent exam point. Dose: 40 mg/kg/day IV x 4 days.[7]
• Ciclosporin 5 mg/kg/day orally, target trough 200 to 400 micrograms/L, tapered over 1 to 2 years to limit relapse. Side effects: nephrotoxicity, hypertension, gum hypertrophy, tremor, hirsutism.
• Eltrombopag (TPO-receptor agonist) 150 mg orally daily for 6 months — is an adjunct to IST and a treatment for refractory disease. Monitor LFTs and for clonal evolution.[6]
• Always check a PNH clone (FLAER / CD55-CD59 flow cytometry) at diagnosis — aplastic anaemia, PNH and MDS can overlap. A small PNH clone is found in up to half of cases.[5]
• Hepatitis-associated AA: young male, seronegative hepatitis, poor response to IST — consider early HSCT.[1]
• Inherited marrow-failure syndromes: Fanconi (café-au-lait, radial ray, chromosomal breakage — DEB test) vs dyskeratosis congenita (nail dystrophy, leukoplakia, reticular pigmentation, short telomeres). Always test in young patients.
• Absent hepatosplenomegaly in a well-looking patient with severe pancytopenia is a bedside clue to aplastic anaemia rather than leukaemia or hypersplenism.
• Clonal evolution to MDS/AML (especially monosomy 7) and PNH is a recognised late complication (15 percent at 10 years after IST) — lifelong surveillance.[5]
• Parvovirus B19 causes pure red cell aplasia with giant proerythroblasts; treat with intravenous immunoglobulin.
• Telomere shortening (TERT/TERC/DKC1 mutations) identifies a subset with worse outcome and higher clonal risk — relevant to apparently 'acquired' disease. About 10 percent of apparently acquired AA has a clinically significant telomerase mutation.[3]
• Serum copper deficiency causes a reversible pancytopenia with neurological signs — easily missed, easily treated (copper supplementation). Check in patients with risk factors (bariatric surgery, parenteral nutrition, zinc excess).
• Neutropenic fever = sepsis until proven otherwise — cultures and empirical IV antibiotics (piperacillin-tazobactam or ceftazidime/cefepime) within 1 hour. Do not wait for results.
• Platelet transfusion thresholds: prophylactic under 10 (under 20 if febrile or bleeding); therapeutic over 50 for active bleeding or procedures.

Ward-round test — four stems, thirty seconds each

Stem 1 — the well patient with frightening bloods (answer)

A 19-year-old with a nosebleed and mouth ulcers looks well, is afebrile, and has no spleen or nodes — but haemoglobin 58, neutrophils 0.3, platelets 12, reticulocytes 4 (all x 10^9/L). Top diagnosis, and the single specimen that confirms it? Model: Aplastic anaemia — the well-looking patient with severe pancytopenia and no organomegaly is the bedside signature. Confirm with a trephine biopsy (not the aspirate): hypocellular marrow under 25 percent, no abnormal infiltrate.[4]

Stem 2 — grade it, then fork (answer)

Cellularity 15 percent, neutrophils 0.3, platelets 12, reticulocytes 4. Severity grade? And the definitive treatment at age 19 with an HLA-matched sister, versus age 45 with no donor? Model: Severe AA — cellularity under 25 percent plus at least two of neutrophils under 0.5, platelets under 20, reticulocytes under 20 (she meets all three). Had her neutrophils been under 0.2 it would be very severe. At 19 with a matched sibling donor: allogeneic HSCT. At 45 with no donor: horse ATG 40 mg/kg/day IV for 4 days plus ciclosporin 5 mg/kg/day orally, with eltrombopag in selected protocols.[1][7]

Stem 3 — horse or rabbit? (answer)

A 50-year-old with severe AA and no donor starts IST. The pharmacy offers rabbit ATG because it is cheaper. What do you say, and on what evidence? Model: Insist on horse ATG. Scheinberg (NEJM 2011) showed horse ATG beats rabbit ATG — 6-month haematological response 68 percent vs 37 percent, survival 96 percent vs 76 percent. Horse ATG 40 mg/kg/day IV for 4 days remains first choice.[7]

Stem 4 — fever at 3 am (answer)

The same patient spikes 38.5 three weeks into treatment; neutrophils 0.2. Night cover wants to wait for blood cultures before antibiotics. What do you do? Model: Do not wait. Fever in a neutropenic patient is neutropenic sepsis until proven otherwise. Take cultures from every lumen and a peripheral site, then give empirical broad-spectrum IV antibiotics (piperacillin-tazobactam, or ceftazidime or cefepime) within one hour. Delaying antibiotics beyond the first hour is the single most preventable cause of early death.[4]

Exam application bank (NEET-PG / INICET)

One-line answer

Aplastic anaemia is a life-threatening bone marrow failure syndrome defined by pancytopenia (anaemia + neutropenia + thrombocytopenia) with a markedly hypocellular marrow and no abnormal infiltrate. Most cases are acquired and idiopathic (immune-mediated); recognised triggers include drugs (chloramphenicol, carbamazepine, NSAIDs), toxins (benzene, radiation), and viruses (seronegative hepatitis, EBV, parvovirus B19, HIV); inherited forms include Fanconi anaemia and dyskeratosis congenita. Presents with fatigue, bleeding and infection in a well-looking patient without organomegaly. Diagnose with full blood count, film, reticulocyte count and a trephine biopsy (cellularity under 25 percent). Severe AA (Camitta criteria): cellularity under 25 percent plus at least two of neutrophils under 0.5, platelets under 20, reticulocytes under 20 (all x 10^9/L). Treat young patients (under 40) with an

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. [1]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. [1]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. [1]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. [1]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. [1]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Aplastic Anaemia.

References

1. [1]Bacigalupo A. How I treat acquired aplastic anemia Blood, 2017.PMID 28096088
2. [2]Piekarska A, Pawelec K, Szmigielska-Kapłon A, et al. The state of the art in the treatment of severe aplastic anemia: immunotherapy and hematopoietic cell transplantation in children and adults Front Immunol, 2024.PMID 38646536
3. [3]Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia N Engl J Med, 1997.PMID 9134878
4. [4]Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia Br J Haematol, 2016.PMID 26568159
5. [5]Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation J Clin Oncol, 2011.PMID 21464398
6. [6]Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia N Engl J Med, 2012.PMID 22762314
7. [7]Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia N Engl J Med, 2011.PMID 21812672