Introduction (p2)

In the thalassemia patient, a mutation or deletion of the genes that control globin production occurs. This leads to a decreased production of the corresponding globin chains and an abnormal hemoglobin ratio (a:non-a). This abnormal ratio leads to decreased synthesis of hemoglobin and the expression of thalassemia. The globin that is produced in normal amounts winds up in excess and forms red cell aggregates or inclusions. These aggregates become oxidized and damage the cell membrane, leading either to hemolysis, ineffective erythropoiesis, or both. The quantity and properties of these globin chain aggregates determine the characterstics and severity of the thalassemia.

Beta thalassemia results in an excess of alpha globins, which leads to the formation of alpha globin tetramers (a⁴) that accumulate in the erythroblast (immature red blood cell). These aggregates are very insoluble and precipitation interferes with erythropoiesis, cell maturation and cell membrane function, leading to ineffective erythropoiesis and anemia.

Alpha thalassemia results in an excess of beta globins, which leads to the formation of beta globin tetramers (b⁴) called hemoglobin H. These tetramers are more stable and soluble, but under special circumstances can lead to hemolysis, generally shortening the life span of the red cell. Conditions of oxidant stress cause Hgb H to precipitate, interfering with membrane function and leading to red cell breakage. Hemoglobin H-Constant Spring disease is a more severe form of this hemolytic disorder. The most severe thalassemia is alpha thalassemia major, in which a fetus produces no alpha globins, which is generally incompatible with life.

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