Overview of β thalassemia

β thalassemia is an autosomal recessive disease with mutations within the β gene cluster located on chromosome 11. More than 200 different mutations, mostly point mutations and rarely deletions, causing a thalassemic phenotype have been described, with a poor genotype-phenotype correlation. Any of these genetic changes results in a synthesis imbalance between the α and β globin chains and results in an accumulation of excess unpaired α chains leading to oxidative damage of the erythrocyte membrane and hemolysis. The severity of anemia cannot be conferred from the genetic change.

Anemia in β thalassemia is the result of 2 pathologic processes: hemolysis and ineffective erythropoiesis. In β thalassemia the patient’s excessive erythropoiesis, combined with a high rate of erythroid precursor cell apoptosis, results in a hypercellular bone marrow.

Ineffective erythropoiesis can be a result of maturation failure, apoptosis during maturation, or unstable erythrocytes with a severely shortened lifespan. The exact mechanisms leading to ineffective erythropoiesis are elusive. Iron metabolism in thalassemia is affected by the level of ineffective erythropoiesis, hypoxia, and the number of transfusions (causing iron overload).

Clinical sequelae of thalassemia include delay in growth and development, deformity of bones because of ectopic marrow expansion, osteopenia, and, most importantly, iron overload. The latter results in serious organ damage and can have fatal consequences if not treated adequately with iron-chelating therapy. Desferrioxamine has been the mainstay of iron chelation since its introduction in the 1980s. However, patient acceptability and compliance have been limited by the discomfort associated with the need for daily subcutaneous infusions. The introduction of oral iron chelators, deferasirox and deferiprone, has dramatically improved the patients’ acceptability of chelation. It remains to be seen whether these will consistently translate into improved compliance and optimal iron chelation.

Treatment is focused on maintaining pretransfusion hemoglobin levels of more than 9 to 10 g/dL to allow normal growth and development and suppress endogenous erythropoiesis, diminish intravascular hemolysis, and therefore lessen the enhanced endogenous iron accumulation. Although the implementation of hypertransfusion regimens has substantially improved the survival and quality of life of patients with thalassemia major, this approach comes at a price. This price includes transfusional hemosiderosis with multiorgan involvement, complications related to exposure to multiple donors (allosensitization, transmission of viruses and other pathogens), cost, discomfort, and inconvenience of a chronic intensive treatment regimen. Another treatment approach is the use of hydroxyurea, an agent that seems to raise hemoglobin F levels, and thereby prolongs the erythrocyte lifespan. In some patients hydroxyurea reduces the need for transfusions dramatically, whereas in others no effect is observed. This may be related to the individual’s genetic makeup.