The major hemoglobin in adults is hemoglobin A, which is a tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha chains; and one pair of beta chains. In normal subjects, globin chain synthesis is very tightly controlled so that the ratio of production of alpha to non-alpha chains is 1.00 ± 0.05. There are two copies of the alpha globin gene on chromosome 16. A single beta globin gene resides on chromosome 11 adjacent to genes encoding the beta-like globin chains, delta and gamma (figure 1). (See "Structure and function of normal human hemoglobins".)
Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains. Beta thalassemia is due to impaired production of beta globin chains, which leads to a relative excess of alpha globin chains. These excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. The degree of alpha globin chain excess determines the severity of subsequent clinical manifestations, which are profound in patients homozygous for impaired beta globin synthesis and much less pronounced in heterozygotes who generally have minimal or mild anemia and no symptoms. (See "Clinical manifestations and diagnosis of the thalassemias".)
Alpha thalassemia, in comparison, is due to impaired production of alpha globin chains, which leads to a relative excess of beta globin chains. (See "Pathophysiology of alpha thalassemia".) The toxicity of the excess beta globin chains in alpha thalassemia on the red cell membrane skeleton appears to be less than that of the excess partially oxidized alpha globin chains in beta thalassemia . This probably explains why the clinical manifestations are generally less severe in alpha compared with beta thalassemia of comparable genetic severity (except for homozygous alpha (0) thalassemia, which is incompatible with extrauterine life, leading to hydrops fetalis and/or death shortly after delivery).
The pathophysiology of the anemia in beta thalassemia will be reviewed here. This discussion will focus on the mechanisms by which unbalanced alpha globin chain synthesis leads to hemolysis of red cells in the peripheral circulation and, more importantly, to the extensive destruction of erythroid precursors within the bone marrow and in extramedullary sites, such as the liver and spleen (ineffective erythropoiesis). The molecular pathology of the thalassemias is discussed separately. (See "Molecular pathology of the thalassemic syndromes".)
The thalassemias are profoundly heterogeneous from a genetic standpoint ; however, certain clinical terms are available to describe the phenotypic expression of this disorder: