A 25-year-old woman of Mediterranean origin has HbH disease (three alpha-globin gene deletions). Peripheral smear shows hypochromic microcytic red cells with Heinz bodies after brilliant cresyl blue staining (HbH inclusions). What is the molecular basis of HbH formation?

• A Excess beta-globin chains form soluble tetramers (β4) with high oxygen affinity that precipitate on aging ✓
• B Excess beta-globin chains form tetramers (β4) that precipitate in acidic conditions
• C Excess gamma chains form soluble Hb Barts (γ4) with extremely high oxygen affinity
• D Excess delta-globin chains form HbA2 tetramers causing thalassemia intermedia

Explanation

In HbH disease (three alpha-gene deletions), severely reduced alpha-chain synthesis results in marked excess of beta-globin chains. These beta-chains form soluble tetramers called HbH (β4), which have extremely high oxygen affinity (left-shifted ODC) causing tissue hypoxia, and are unstable — precipitating in older red cells to form Heinz body-like inclusions demonstrable with brilliant cresyl blue. This leads to hemolysis and a moderate hemolytic anemia. Hb Barts (γ4) excess occurs in hydrops fetalis (four alpha-gene deletions).

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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