Thalassaemia syndromes: Viva

Opening question

The candidate is expected to start with the molecular mechanism. Beta-thalassaemia major is an autosomal recessive disorder of beta-globin synthesis, so the unpaired alpha chains precipitate in the red cell precursors and the cells die in the marrow, a process called ineffective erythropoiesis that is the dominant cause of the anaemia. The candidate who explains why the newborn is well, because fetal haemoglobin compensates until it falls at six to twelve months, has the clinical timeline as well as the mechanism. [12]

Branch 1 — Diagnosis and the electrophoresis

The examiner may hand over a haemoglobin electrophoresis trace. The expected answer is a markedly raised haemoglobin F, often over 70 percent, with haemoglobin A absent in the beta-zero form or greatly reduced in the beta-plus form, and a raised haemoglobin A2. The candidate should explain that the diagnosis is most reliable before the first transfusion, because a transfused child carries the donor haemoglobin A, and that a microcytosis with a high red cell count on the index full blood count points away from iron deficiency, which has a low red cell count and a low ferritin. [12]

Branch 2 — Transfusion and chelation

The examiner may press for the exact numbers. The pre-transfusion haemoglobin target is 90 to 100 g per litre, given every two to five weeks with leucodepleted, extended-phenotype-matched red cells at 10 to 20 mL per kg. Chelation starts once the ferritin exceeds 1000 micrograms per litre, and the first-line oral agent is deferasirox at 20 mg per kg per day, established by the phase 3 trial of Cappellini. Deferiprone at 75 mg per kg per day in three divided doses is the agent of choice for cardiac iron and demands a weekly absolute neutrophil count for the risk of agranulocytosis. [4][11]

Branch 3 — Cardiac surveillance and the curative pathway

The examiner may ask how the child is kept alive into adulthood. The annual cardiac T2 star magnetic resonance imaging is the key surveillance: a value over 20 milliseconds is normal and a value under 10 milliseconds marks severe myocardial loading and a high risk of heart failure. The candidate should link the improving survival to the T2 star detection of myocardial iron and name intensive combined chelation as the response to a low value. The curative options are an allogeneic transplant from a matched sibling donor, the standard of cure, and betibeglogene gene therapy, which adds a functional beta-globin gene and removes the donor barrier, with luspatercept the non-curative burden-reducing drug alongside both. [8][1][2]