In beta-thalassaemia major, the primary mechanism of anaemia is:

• A Reduced iron absorption from the gastrointestinal tract
• B Increased red cell destruction by autoimmune antibodies against beta-globin fragments
• C Defective haem synthesis due to porphyrin pathway enzyme deficiency
• D Ineffective erythropoiesis due to precipitation of excess alpha-globin chains causing intramedullary red cell destruction ✓

Explanation

In beta-thalassaemia major, absent or severely reduced beta-globin production leads to excess unpaired alpha-globin chains. These alpha chains precipitate within developing erythroblasts in the bone marrow, causing massive intramedullary destruction of erythroblasts (ineffective erythropoiesis — the primary cause of anaemia). Peripheral haemolysis of the few surviving cells is secondary. Compensatory erythropoietic expansion causes extramedullary haematopoiesis (skull bossing, hepatosplenomegaly, the 'hair-on-end' skull X-ray). Iron overload is secondary to transfusion and increased GI absorption driven by hepcidin suppression.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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