Pathophysiology of thalassemia

Haema 2011; 2(3): 235-243

by Dimitris Loukopoulos

Professor, Medical School, University of Athens

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The term thalassemia encompasses the conditions where one of the two types of globin chains, which fill the human erythrocytes in the form of tetramers (HbA, α2β2) ceases being synthesized (partially or totally) as a result of a defect in the respective gene. The condition is characterized as a- or β-thalassemia according to the affected chain, is inherited as an autosomal codominant character, and may be present in the heterozygous or homozygous form, according to whether the defect involves one or more allelic genes (2 for the β-chains and four for the α-chains). The β-thalassemias are most frequent and constitute a major problem for Greece. In double dose (homozygous) thalassemia (when both β genes are defective) the erythroid cells are empty because the deficiency of β-chains does not allow formation of complete HbA tetramers (α2β2), while the a-chains, whose synthesis is not inhibited, accumulate and precipitate intracellularly causing release of abundant free radicals, which readily destroy the cellular components and lead to premature cellular death in the marrow (which expands dramatically in an attempt to compensate the anemia; ineffective erythropoiesis) and severe hemolytic anemia in the peripheral blood. Reactivation of HbF synthesis is useful but never adequate. As a result, the patients develop anemia, severe bone deformities, jaundice, liver disease and cholecystitis, growth failure and other endocrine deficiencies, as well as heart failure not only because of hyperactive circulation, but also because of hemosiderosis due to blood transfusions and increased iron absorption; moreover, increased numbers of platelets along with vasoconstriction due to NO depletion, aggravate the pulmonary hypertension and lead to right heart failure.