The anatomic changes in β-thalassemia major are similar in kind to those seen in other hemolytic anemias but are profound in degree. Ineffective erythropoiesis and hemolysis result in a striking hyperplasia of erythroid progenitors, with a shift toward early forms. The expanded erythropoietic marrow may completely fill the intramedullary space of the skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities. Extramedullary hematopoiesis and hyperplasia of mononuclear phagocytes result in prominent splenomegaly, hepatomegaly, and lymphadenopathy. The ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia reminiscent of that seen in cancer patients. Unless steps are taken to prevent iron overload, during the span of years severe hemosiderosis develops (Fig. 12.5 ). HbH disease and β-thalassemia intermedia are also associated with splenomegaly, erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β-thalassemia major.
Clinical Features. β-Thalassemia trait and α-thalassemia trait are typically asymptomatic. There is usually only a mild microcytic hypochromic anemia; generally, these patients have a normal life expectancy. Iron deficiency anemia is associated with a similar red cell appearance and must be excluded by appropriate laboratory tests  (described later).
β-Thalassemia major manifests postnatally as HbF synthesis diminishes. Affected children suffer from growth retardation that commences in infancy. They are sustained by blood transfusions, which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis. With transfusions alone, survival into the second or third decade is possible, but systemic iron overload gradually develops owing to inappropriate uptake of iron from the gut and the iron load in transfused red cells. Unless patients are treated aggressively with iron chelators, cardiac dysfunction from secondary hemochromatosis inevitably develops and often is fatal in the second or third decade of life. When feasible, hematopoietic stem cell transplantation at an early age is the treatment of choice. HbH disease and β-thalassemia intermedia are not as severe as β-thalassemia major, because the imbalance in α-and β-globin chain synthesis is not as great and hematopoiesis is more effective. Anemia is of moderate severity and patients usually do not require transfusions. Thus, the iron overload that is so common in β-thalassemia major is rarely seen.