Anaemias: eight teaching cases.

Topic Thalassaemia trait·Curriculum Red Cell Disorders 3(i) — Thalassaemia: screening strategies, genetic counselling, laboratory diagnosis of alpha and beta thalassaemia syndromes

Model answer

Diagnosis. Beta thalassaemia trait, with iron replete status (ferritin 42 µg/L, transferrin saturation 26%). She is not iron deficient and has never been.

How the picture fits together. A haemoglobin of 11.3 g/dL with an MCV of 63 fL is a degree of microcytosis out of all proportion to the anaemia — the discriminating observation. Iron deficiency severe enough to produce an MCV in the low 60s would ordinarily be accompanied by a haemoglobin well below 9 g/dL, a red cell count under 4 × 10¹²/L and a raised RDW. Here the red cell count is 5.6 × 10¹²/L and the RDW is normal: the marrow is producing large numbers of small, uniform cells. The Mentzer index is 11.3 (<13 favours trait). Basophilic stippling and target cells support the impression. Quantitative HbA2 of 4.9% strongly supports it.

What to do. Stop the iron. Explain that this is a lifelong, benign carrier state, not a disease, and that her haemoglobin will always sit a little below the reference range — she should not be treated for it, and she should not accept repeated iron courses. Give her a written carrier card. Offer folic acid only if there is an additional demand such as pregnancy.

The consequential step. Screen her prospective partner with an FBC and HPLC before conception. If he is also a carrier of beta thalassaemia, HbE or HbS, refer both for genetic counselling with a discussion of prenatal diagnosis (chorionic villus sampling at 10–12 weeks). This is the point of the whole consultation.

Common trap. Where iron deficiency and thalassaemia trait coexist — very common in India — the HbA2 may be falsely normal. If a patient with this red cell picture is iron deficient, replace iron first and repeat the HPLC after three months before calling the screen negative.

Key learning points

• Microcytosis out of proportion to the degree of anaemia points to thalassaemia trait rather than iron deficiency.
• Mentzer index = MCV ÷ RBC; below 13 favours trait, above 13 favours iron deficiency. Useful, but never a substitute for iron studies plus HPLC.
• Iron deficiency lowers HbA2 and can mask beta thalassaemia trait — correct the iron, then re-test.
• The trait itself needs no treatment; the action that matters is partner screening and counselling before pregnancy.
• Repeated empirical iron in an iron-replete carrier is a real and avoidable harm.

Further reading

• BSH — Guideline for the laboratory diagnosis of iron deficiency in adults and children (2021)
• TIF — Guidelines for the Management of Transfusion-Dependent Thalassaemia, 4th edition
• ASH Image Bank — blood film morphology

Topic Iron deficiency·Curriculum Red Cell Disorders 1 — Iron deficiency anaemia: evaluation of the individual patient, interpretation of serum iron, TIBC, transferrin and ferritin; management including iron replacement

Model answer

Diagnosis. Absolute iron deficiency anaemia — ferritin 8 µg/L with a transferrin saturation of 7% and a normal CRP leaves no ambiguity. The reactive thrombocytosis and pencil cells are supporting features.

Interpreting the iron studies. Ferritin below 30 µg/L is diagnostic of iron deficiency in an adult. Above 30 it becomes unreliable in inflammation, because ferritin is an acute phase protein; that is when transferrin saturation (<20% supports deficiency) and, where available, soluble transferrin receptor or reticulocyte haemoglobin content earn their place. Here the CRP is normal and the picture is unambiguous, so no further iron testing is needed.

The real task is finding the cause. In a 68-year-old man, iron deficiency is a gastrointestinal blood loss until proven otherwise. Arrange bidirectional endoscopy with duodenal biopsies and send coeliac serology. Do not let the aspirin and the PPI provide a comfortable explanation — aspirin increases the likelihood of a bleed from a lesion, it does not tell you the lesion is benign. Check the urine for blood if the GI tract is clear.

Replacement. Ferrous sulphate 200 mg once daily, or on alternate days, on an empty stomach. Counsel him that dark stools are expected. Review the omeprazole — is it still needed? Recheck the full blood count at four weeks: expect a rise of about 2 g/dL. Continue iron for three months after the haemoglobin normalises to reload stores, then check ferritin.

Escalation. Intravenous iron (ferric carboxymaltose or ferric derisomaltose) if he cannot tolerate oral iron, cannot absorb it, or is losing blood faster than he can absorb replacement. Transfusion is for haemodynamic compromise or symptomatic anaemia with cardiac disease, not for a number.

If endoscopy is negative. Roughly a third of patients have no cause found at bidirectional endoscopy. Reassess adherence and absorption first; then consider capsule endoscopy or CT enterography, particularly if he remains transfusion or iron dependent.

Key learning points

• Ferritin <30 µg/L is diagnostic of iron deficiency; above that, in inflammation, use transferrin saturation <20% alongside it.
• Iron deficiency in a man or a postmenopausal woman should be investigated with screening for coeliac disease with appropriate serology, and upper and lower GI tract investigation according to current IDA/endoscopy guidance; duodenal biopsy should be performed where indicated.
• Alternate-day or once-daily iron beats three-times-daily dosing: hepcidin blocks the later doses.
• Expect a reticulocytosis by day 5–10 and a 2 g/dL rise by four weeks. No response means adherence, absorption, ongoing loss, or wrong diagnosis.
• Continue iron for three months after the haemoglobin normalises to refill stores.

Further reading

• BSG — Guidelines for the management of iron deficiency anaemia in adults (2021)
• BSH — Laboratory diagnosis of iron deficiency in adults and children

Topic Megaloblastic anaemia·Curriculum Red Cell Disorders 2 — Megaloblastic anaemia: clinical recognition, evaluation and management of complications of vitamin B12 deficiency; the role of B12 and folate in cellular metabolism

Model answer

Diagnosis. Severe vitamin B12 deficiency due to pernicious anaemia, with subacute combined degeneration of the spinal cord. The dorsal column signs (vibration and proprioceptive loss, positive Romberg) combined with corticospinal signs (extensor plantars) and absent ankle jerks from a peripheral neuropathy is the classic mixed picture.

Reading the numbers. Pancytopenia with an MCV of 112 fL and hypersegmented neutrophils on the film is megaloblastic until proven otherwise. The raised LDH, unconjugated bilirubin and low haptoglobin with a low reticulocyte count is ineffective erythropoiesis, not haemolysis — precursors are dying in the marrow. A bone marrow, if performed, would show a hypercellular marrow with megaloblastic erythroid change and giant metamyelocytes; it is not required when the picture is this clear.

Establishing the cause. Diet contributes — she is a lifelong vegetarian, and dietary B12 deficiency is genuinely common in India — but a positive anti-intrinsic factor antibody makes pernicious anaemia the operative diagnosis and changes the treatment from dietary advice to lifelong replacement. Screen for associated autoimmune disease: thyroid function, HbA1c, coeliac serology. Note the long-term association with gastric carcinoid and adenocarcinoma; investigate new upper GI symptoms rather than screening routinely.

Treatment. Hydroxocobalamin 1 mg IM on alternate days until no further neurological improvement, then 1 mg IM every two months indefinitely. Do not give folate first. Check potassium in the first week — brisk erythropoiesis can cause hypokalaemia. Expect a reticulocytosis at 3–5 days and a falling MCV over weeks; failure to respond should prompt a search for coexisting iron deficiency, which the rising marrow demand often unmasks and which can leave the MCV misleadingly normal.

Prognosis. Haematological recovery is reliable and complete. Neurological recovery depends on duration — improvement continues for 6–12 months and residual deficit is common if treatment has been delayed by more than six months. That single fact is the argument for treating on suspicion.

Key learning points

• High LDH + high bilirubin + low haptoglobin + LOW reticulocytes = ineffective erythropoiesis, not haemolysis.
• Anti-IF antibody: specific but only ~50% sensitive. A negative result does not exclude pernicious anaemia.
• MMA rises in B12 deficiency only; homocysteine rises in both B12 and folate deficiency.
• Do not treat suspected B12 deficiency with folate alone. Folate may correct the haematological abnormality while neurological B12 deficiency continues or progresses.
• Watch for hypokalaemia in the first week of treatment, and for unmasked iron deficiency if the response stalls.
• A normal MCV does not exclude B12 deficiency when iron deficiency or thalassaemia trait coexists.

Further reading

• BSH — Guidelines for the diagnosis and treatment of cobalamin and folate disorders (BJH)
• NICE — Vitamin B12 deficiency in over 16s: diagnosis and management (NG239)

Topic Autoimmune haemolytic anaemia·Curriculum Red Cell Disorders 3(iv) — Acquired haemolytic disorders: immune haemolytic anaemia, management with immunosuppression, role of IVIg, plasmapheresis and splenectomy

Model answer

Diagnosis. Warm autoimmune haemolytic anaemia. The evidence of haemolysis is complete — anaemia with reticulocytosis, raised unconjugated bilirubin, raised LDH, undetectable haptoglobin — and the DAT establishes it as immune. Spherocytes without schistocytes point to immune rather than microangiopathic destruction. The macrocytosis is reticulocytosis, not a nutritional deficiency.

The question that must be answered next: primary or secondary? Roughly half of adult warm AIHA is secondary. Take a careful drug history (including over-the-counter and herbal preparations). Send an autoimmune screen (ANA, dsDNA, complement), immunoglobulins and serum electrophoresis, HIV, hepatitis B and C, and a peripheral blood lymphocyte immunophenotype to look for a low-level clonal B-cell population. Examine carefully for lymphadenopathy and consider CT of chest, abdomen and pelvis in adults, particularly over 50 or where anything on the screen is abnormal. A young woman with a preceding viral illness may well have primary disease, but CLL and lymphoma present this way and must be excluded rather than assumed away.

Immediate management. Prednisolone 1 mg/kg/day. Folic acid 5 mg daily — the reticulocytosis consumes folate and a superimposed megaloblastic arrest is a real hazard. Add a proton pump inhibitor and bone protection. Give thromboprophylaxis: active AIHA is strongly prothrombotic and VTE is a leading avoidable cause of death here.

Transfusion. Do not withhold blood from a symptomatic patient because the crossmatch is difficult. The autoantibody is usually panreactive, so fully compatible units may not exist; the laboratory should exclude an underlying alloantibody and issue the best-matched units, phenotype-matched for Rh and K. Transfuse slowly, in small aliquots, and reassess.

Response and escalation. Expect a haemoglobin rise within 1–2 weeks. Taper prednisolone slowly over 3–6 months once above 10 g/dL. Second line — for steroid failure, relapse on taper, or an unacceptable steroid requirement — is rituximab. Third-line options include splenectomy (with pre-splenectomy vaccination and counselling about lifelong sepsis and thrombosis risk) and immunosuppressants such as azathioprine, mycophenolate or ciclosporin.

Key learning points

• DAT IgG ± C3d = warm AIHA (extravascular, spherocytes). DAT C3d alone = cold agglutinin disease (agglutination on the film).
• Half of adult warm AIHA is secondary — look for lymphoproliferative disease, SLE, drugs, infection, immunodeficiency.
• Thromboprophylaxis is part of the treatment, not an afterthought. VTE risk is high and frequently missed.
• Add folic acid: brisk reticulocytosis consumes folate.
• Never withhold transfusion from a symptomatic patient for want of a perfect crossmatch — talk to the transfusion laboratory.
• IVIg and plasma exchange are of little value in warm AIHA, unlike in ITP and TTP respectively.

Further reading

• BSH — The diagnosis and management of primary autoimmune haemolytic anaemia
• BSH — Management of drug-induced immune and secondary autoimmune haemolytic anaemia
• ASH Education Program — Management of autoimmune hemolytic anemia (2025)

Topic G6PD deficiency·Curriculum Red Cell Disorders 3(iii) — Inherited enzymopathies (G6PD deficiency): evaluation and management of acute haemolytic crises

Model answer

Diagnosis. Acute drug-induced oxidative intravascular haemolysis on a background of G6PD deficiency, precipitated by primaquine. The X-linked inheritance fits the affected maternal uncle.

Reading the case. Haemoglobinuria with no red cells on urine microscopy, undetectable haptoglobin and a very high LDH indicate an intravascular process. The negative DAT excludes an immune mechanism. The film — bite cells, blister cells, irregularly contracted cells, Heinz bodies on supravital staining — is diagnostic of oxidative injury. The timing, four to five days after starting primaquine, is textbook.

The trap. The G6PD assay is normal, and this must not be allowed to overturn the diagnosis. During a crisis the deficient older cells have already been destroyed and the circulation is full of reticulocytes with near-normal enzyme activity. Repeat the assay in steady state at three months, or after any transfused cells have cleared. Treat on the clinical picture now.

Management. Stop the primaquine immediately. Supportive care: maintain good hydration and urine output to protect the kidneys from free haemoglobin, monitor renal function, and transfuse only if he is symptomatic or the haemoglobin is falling rapidly. Most episodes are self-limiting over 7–10 days once the drug is withdrawn, because the surviving young cell population is relatively resistant. Folic acid supports the reticulocyte response.

The lasting intervention. A written trigger list and a patient-held card. Counselling that infection alone can precipitate haemolysis. Testing of at-risk relatives, particularly before oxidant drugs are prescribed. And an entry in his records so that primaquine is not prescribed again — a point of some practical weight in a malaria-endemic setting, where the WHO recommends G6PD testing before radical cure with primaquine or tafenoquine wherever it is feasible.

Key learning points

• Bite cells + blister cells + Heinz bodies on supravital stain = oxidative haemolysis.
• A normal G6PD assay during an acute crisis is common and does not exclude the diagnosis — retest at 3 months in steady state.
• Haemoglobinuria with no red cells on microscopy distinguishes intravascular haemolysis from haematuria.
• The episode is self-limiting once the trigger is withdrawn; management is supportive plus prevention.
• Test for G6PD deficiency before primaquine or tafenoquine for radical cure of P. vivax where possible.

Further reading

• WHO — Guidelines for malaria (radical cure and G6PD testing)
• ASH Image Bank — bite cells and Heinz bodies

Topic Thalassaemia major·Curriculum Red Cell Disorders 3(i) — Management of thalassaemia intermedia and major: transfusion regimes, chelation, role of splenectomy and bone marrow transplantation

Model answer

The problems, in order of urgency. (1) Moderate cardiac iron loading (T2* 11 ms) in an asymptomatic child — the finding that could kill him and the one that must drive management. (2) Heavy hepatic iron loading (LIC 14 mg/g dw) with a raised ALT. (3) Chronic undertransfusion (pre-transfusion Hb 7.4 g/dL) with the skeletal and growth consequences that follow. (4) Endocrine complications of iron overload: growth failure, delayed puberty, and an impaired fasting glucose. (5) Underlying all of it, poor adherence to chelation.

Transfusion. Restore an adequate regime: transfuse to a pre-transfusion haemoglobin of 9.5–10.5 g/dL, generally 2–3 weekly or 4-weekly depending on his consumption, with leucodepleted, extended phenotype-matched (at minimum Rh and Kell) units. Adequate transfusion suppresses marrow expansion, halts the bone changes and reduces gut iron absorption. Record transfusion volume per kilogram per year — it is the denominator for judging whether chelation is keeping pace.

Chelation. A T2* of 11 ms with a normal ejection fraction demands intensification now. Move to a deferiprone-containing regimen — deferiprone with desferrioxamine is the best-evidenced combination for myocardial iron — with weekly FBC monitoring for agranulocytosis, and repeat cardiac T2* in 6–12 months. Intensified or combination deferasirox regimens are a reasonable alternative where deferiprone is not tolerated or monitoring is not feasible. None of this works without adherence: involve the family directly, explore cost and access barriers (a major real-world determinant in India), simplify the regimen where possible, and consider a day-care supervised model.

Complications to address in parallel. Formal endocrine review for growth failure and delayed puberty — growth hormone axis, sex steroids, bone age. Annual OGTT given the impaired fasting glucose; iron-related diabetes is common in the second decade. Annual thyroid and parathyroid function, vitamin D, DEXA from adolescence. Annual echocardiogram and T2*. Continue viral screening. Give folic acid; hepatitis B vaccination if not immune.

Definitive treatment. Assess suitability for curative therapy, including allogeneic HSCT where an appropriate donor is available, in discussion with a specialist thalassaemia/transplant centre. He is young, which is in his favour: outcomes are best in children under 14 with a matched sibling donor and low Pesaro risk. Hepatomegaly, portal fibrosis and a history of irregular chelation define the Pesaro classes, and irregular chelation places him at higher risk — a further argument for improving control now and typing siblings without delay. Where transplant is not available, gene therapy is an emerging but currently inaccessible option for most patients in this setting.

Key learning points

• Pre-transfusion haemoglobin target in thalassaemia major is 9.5–10.5 g/dL. Undertransfusion causes marrow expansion AND increases gut iron absorption.
• Cardiac T2*: >20 ms normal, 14–20 ms mild, 10–14 ms moderate, <10 ms severe. Ferritin and liver iron do not predict cardiac iron.
• Cardiac iron overload is the leading cause of death; symptoms appear late, so monitor by MRI, not by echo alone.
• Deferiprone has the strongest evidence for myocardial iron removal; monitor FBC weekly for agranulocytosis.
• Adherence — and the cost and access barriers behind it — is usually the real problem, not the choice of chelator.
• Pesaro risk classification (hepatomegaly, portal fibrosis, quality of prior chelation) predicts transplant outcome.

Further reading

• TIF — Guidelines for the Management of Transfusion-Dependent Thalassaemia, 4th edition (2021)
• TIF guidelines — full text via NCBI Bookshelf

Topic Aplastic anaemia·Curriculum Red Cell Disorders 4 — Aplastic anaemia: aetiology, evaluation and management including immunosuppression and supportive therapy; role of bone marrow transplantation

Model answer

Diagnosis. Acquired severe aplastic anaemia (modified Camitta criteria: cellularity <25% plus neutrophils <0.5, platelets <20 and reticulocytes <20 × 10⁹/L), with a small PNH clone. No cause has been identified — as in around 70% of cases — after exclusion of drugs, chemicals, viruses and inherited marrow failure.

What the workup must exclude before treatment. Hypoplastic MDS is the key differential: a careful trephine review for dysplasia and reticulin, cytogenetics, and increasingly a myeloid mutation panel. Inherited bone marrow failure must be excluded in any young patient — chromosome breakage testing for Fanconi anaemia (negative here), telomere length for telomere biology disorders, and a careful look for the physical clues (nail dystrophy, oral leucoplakia, skin pigmentation, short stature, thumb and radial anomalies) that may be absent. Getting this wrong has direct consequences: patients with Fanconi anaemia cannot tolerate standard conditioning. Also exclude a large granular lymphocyte population, hepatitis-associated aplasia, and nutritional deficiency.

Definitive treatment. He is 22 with severe disease and an HLA-identical sibling: proceed to allogeneic HSCT from that donor without delay. Survival exceeds 90% in this group and it removes the risks of relapse and clonal evolution. Type the sibling urgently and refer to a transplant centre — time to transplant matters, and outcomes are worse once patients are heavily transfused or infected.

If there were no matched sibling. First-line immunosuppression with horse ATG plus ciclosporin plus eltrombopag; horse ATG is superior to rabbit. Response takes 3–6 months, so supportive care must hold the line meanwhile. Matched unrelated donor transplant is the next option for non-responders, and increasingly is considered upfront in young patients with a well-matched unrelated donor.

Supportive care from today. Irradiated, leucodepleted, CMV-safe blood products — irradiated because he is a potential transplant candidate and will receive ATG. Avoid family donors to prevent sensitisation against a potential donor. Platelet transfusion for bleeding or a threshold of 10 × 10⁹/L (20 if febrile). Neutropenic precautions with antibacterial and antifungal prophylaxis; treat fever as a neutropenic emergency. Avoid NSAIDs and intramuscular injections. Counsel on fertility preservation before conditioning.

Key learning points

• Modified Camitta severe AA: cellularity <25% plus two of — neutrophils <0.5, platelets <20, reticulocytes <20 × 10⁹/L (or <60 × 10⁹/L by automated count). Very severe adds neutrophils <0.2.
• Under 40 with a matched sibling donor: transplant first. Otherwise horse ATG + ciclosporin + eltrombopag.
• Horse ATG is superior to rabbit ATG as first-line therapy.
• Always exclude inherited marrow failure in a young patient — chromosome breakage and telomere length — before conditioning.
• A small PNH clone is found in ~50% of AA, supports immune pathogenesis, and needs monitoring not treatment.
• Use irradiated, leucodepleted products and avoid family donors in any potential transplant candidate.

Further reading

• BSH — Guidelines for the diagnosis and management of adult aplastic anaemia (2024)
• BSH guideline full text (BJH 2024)

Topic Anaemia of chronic disease·Curriculum Red Cell Disorders — Clinical evaluation of a patient with anaemia; interpretation of iron studies in the presence of inflammation

Model answer

Diagnosis. Anaemia of chronic kidney disease with functional iron deficiency. Two mechanisms are operating together: reduced renal erythropoietin production (the inappropriately low reticulocyte count for the degree of anaemia) and hepcidin-mediated iron restriction driven by inflammation and impaired renal hepcidin clearance.

Interpreting the iron studies — the teaching point. Ferritin 260 µg/L would normally reassure. It should not here. Ferritin is an acute phase protein and the CRP is 22 mg/L; the transferrin saturation of 12% tells you what the marrow can actually access, and it is inadequate. In CKD, iron deficiency is diagnosed at a much higher ferritin threshold than in the general population, and the thresholds have moved upwards: KDIGO 2026 supports starting iron in non-dialysis CKD at a ferritin below 100 µg/L with a saturation below 40%, or a ferritin of 100–300 µg/L with a saturation below 25%, and withholding iron only above a ferritin of 700 µg/L or a saturation of 40% or more. Her ferritin of 260 µg/L with a saturation of 12% therefore falls squarely inside the band in which iron is indicated. Between a ferritin of 300 and 700 µg/L with a low saturation the guideline gives no threshold and the decision becomes one of clinical judgement. Where available, reticulocyte haemoglobin content or percentage of hypochromic red cells gives a more direct read of iron supply to the erythron.

What to exclude first. Do not attribute the anaemia to the kidneys without looking elsewhere. B12 and folate are normal. Check for blood loss — she is on no antiplatelet, but occult GI loss in a diabetic patient is not rare, and a saturation of 12% warrants iron whichever label is attached to it. The label matters less than the habit of not letting ‘anaemia of CKD’ close the case. Review for myeloma (paraprotein, light chains, calcium) in an older patient with renal impairment and anaemia — an important and regularly missed diagnosis in this exact presentation. Check thyroid function and PTH.

Management sequence. Give intravenous iron and reassess in four to six weeks; oral iron is poorly absorbed at this eGFR. Many patients need nothing more. If she remains symptomatically anaemic with a corrected iron status, start an ESA targeting a sub-normal haemoglobin of roughly 10–11.5 g/dL, with iron maintained throughout, and monitor blood pressure. Avoid transfusion where possible if she is a potential transplant candidate. Escalating ESA doses without response should trigger a re-evaluation, not a further dose increase.

Key learning points

• Ferritin is an acute phase protein — a normal ferritin does not exclude iron deficiency when CRP is raised.
• Functional iron deficiency = adequate/high ferritin with transferrin saturation <20%. It responds to IV iron. KDIGO 2026 now calls this 'iron-restricted erythropoiesis'.
• In CKD, iron thresholds are higher than in the general population, and IV iron is often preferred in advanced CKD when rapid or reliable repletion is required. Oral iron is an acceptable option to try in selected patients.
• Iron first, ESA second. An ESA started in a functionally iron-deficient patient works poorly and the dose escalates.
• Target a sub-normal Hb of about 10–11.5 g/dL. Normalising Hb with ESAs increased stroke and cardiovascular events in randomised trials.
• Anaemia + renal impairment in an older patient: always consider myeloma.

Further reading

• NICE NG8 — Chronic kidney disease: managing anaemia
• KDIGO 2026 — Clinical Practice Guideline for the Management of Anemia in CKD
• KDIGO 2026 anaemia guideline — executive summary (PDF)