In a case of β-thalassemia major, which imbalance primarily causes anemia?

• A. Decreased production of α-globin chains
• B. Increased production of β-globin chains
• C. Imbalance in the synthesis of α- and β-globin gene products
• D. Increased production of alpha-4 tetramers

Answer: (C)

In β-thalassemia major, the underlying pathology involves a significant reduction in the production of β-globin chains due to mutations in the β-globin gene. This impaired synthesis creates an imbalance between the production of α-globin and β-globin chains. As β-globin production decreases, excess α-globin chains accumulate, leading to several pathological consequences.

The imbalance in globin chain synthesis results in ineffective erythropoiesis, as the excess α-globin chains precipitate and form unstable tetramers or aggregates. These aggregates can form α4 (also known as tetramers of α-globin), which are toxic to the developing erythroid precursors. Consequently, this leads to apoptosis of these precursors in the bone marrow and contributes to the severe anemia characteristic of β-thalassemia major.

This imbalance is central to the pathophysiology of the disease, making it the primary cause of the anemia observed in affected individuals. The severe deficiency of β-globin directly leads to a lack of functional hemoglobin and the production of ineffective red blood cells, further compounding the anemia and its clinical manifestations.