Thalassaemia syndromes: SAQ

Part A — Pathophysiology and diagnosis (10 marks)

Beta-thalassaemia major is an autosomal recessive disorder in which the beta-globin chain is made too slowly or not at all, while the alpha chain continues at the normal rate. The unpaired alpha chains are unstable, they precipitate inside the developing red cell precursors, and the precursors die in the marrow, a process called ineffective erythropoiesis that is the dominant cause of the severe microcytic anaemia. The red cells that reach the circulation are fragile and are destroyed in the spleen, adding chronic haemolysis. The child is well at birth because fetal haemoglobin, made of alpha and gamma chains, carries the oxygen, and the disease declares itself only as the fetal haemoglobin falls between six and twelve months. [12][6]

The diagnosis is made by haemoglobin separation. Before any transfusion, the electrophoresis or high-performance liquid chromatography shows 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 full blood count shows a severe microcytic, hypochromic anaemia with a high red cell count, target cells, and an inappropriately low reticulocyte count for the degree of haemolysis. The diagnosis is most reliable when it is made before the first transfusion, because a transfused child carries the donor haemoglobin A. [12]

Part B — Transfusion, chelation and surveillance (10 marks)

The first pillar of care is the regular transfusion programme, begun at diagnosis. The aim is to keep the pre-transfusion haemoglobin at 90 to 100 g per litre, given every two to five weeks using leucodepleted, extended-phenotype-matched red cells at 10 to 20 mL per kg over two to four hours. This level suppresses the ineffective erythropoiesis, halts the marrow expansion and skeletal change, and allows the child to grow. The child is phenotyped for the major red cell antigens before the first transfusion to prevent alloimmunisation, and the blood is screened for transfusion-transmitted infection. [6]

The second pillar is iron chelation, because each unit of red cells loads about 200 mg of iron that the body cannot excrete. Chelation is started once the ferritin exceeds 1000 micrograms per litre or after about 10 to 20 transfusions, usually around two to three years. The first-line oral chelator is deferasirox, started at 20 mg per kg per day once daily and titrated to the iron load, established by the phase 3 trial of Cappellini. Deferiprone at 75 mg per kg per day in three divided doses is the chelator of choice for cardiac iron, with a weekly absolute neutrophil count because of the risk of agranulocytosis, and deferoxamine at 20 to 40 mg per kg per day by subcutaneous infusion is the older agent. [4][11]

The third pillar is the surveillance of iron and its target organs. The cardiac T2 star magnetic resonance imaging is done annually from around five years: a value over 20 milliseconds is normal and a value under 10 milliseconds marks severe myocardial loading and a high short-term risk of heart failure. The analysis of Modell linked the improving survival directly to the T2 star detection of myocardial iron. The liver iron and the ferritin are tracked at each visit, and the annual endocrine review tracks the growth, pubertal, gonadal and glucose axes that iron slowly erodes. The curative options of allogeneic transplant and betibeglogene gene therapy are discussed as the child grows. [8][11]