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Thalassemia syndromes result from deficiencies in the production of either alpha-globin (alpha-thalassemia) or beta-globin (beta-thalassemia) chains. The disease becomes apparent when production of the affected globin is first required during development. alpha-Thalassemia is thus symptomatic during gestation. Because beta globin is not required before birth, beta-thalassemia is asymptomatic until 6 to 12 months after birth.

An obvious consequence of the biosynthetic defect in thalassemia is the microcytosis and hypochromia owing to reduced amounts of hemoglobin tetramer in each red blood cell. However, the major pathologic process in the thalassemias is caused by the imbalance of alpha and non-alpha chain accumulation. Aggregation of the unaffected chains produced in normal amount occurs because the surplus chains are unable to find a heterologous counterpart to which to bind; these precipitate during erythropoiesis because free globin is far less soluble than intact tetramers. In beta-thalassemia, the precipitated alpha globin forms inclusion bodies that damage the red blood cell membrane and cause cell death (ineffective intramedullary erythropoiesis); decreased red blood cell survival also occurs.

In alpha-thalassemic fetuses, excessive gamma globin forms tetramers (gamma4 = hemoglobin Bart's) during the fetal and neonatal period; excess beta globin (beta4 = hemoglobin H) accumulates after birth. Hemoglobin Bart's and hemoglobin H are somewhat more soluble.

The alpha-globin gene is duplicated. There is a good correlation between the number of abnormal alpha-globin loci inherited.


The diagnosis of severe thalassemia is usually straight-forward. The family history, especially in ethnic groups at high risk (Italian, Greek, black, Asian, North African), is often a solid lead. Thalassemia major or thalassemia intermedia is marked by microcytic anemia.



In heterozygous alpha- or beta-thalassemias, close monitoring of the hematocrit is necessary during pregnancy to avoid a harmful drop, but patients are otherwise asymptomatic.

Transfusion Therapy

In beta-thalassemia major, red blood cell transfusion is the mainstay of supportive therapy. Transfusions should be administered in sufficient quantity and frequency to achieve a hemoglobin level of at least 9.3 grams per dL; this level partly suppresses the erythropoietic drive.

With regard to initiation of chronic transfusions, one can safely follow the recommendations of the guide of the Cooley's Anemia Foundation.


Massive splenomegaly is usually avoided or delayed by a proper hypertransfusion regimen. However, splenic sequestration of donor cells can eventually cause an excessive transfusion requirement. A 50% or greater increase in the transfusion requirements during a 1-year period.

Treatment of Iron Overload

Each unit of blood contains approximately 250 mg of iron. A typical hypertransfusion regimen encumbers each patient each year with an average of four times the normal total body iron burden. There is no compensatory mechanism of sufficient magnitude to eliminate this iron.

Before effective iron chelation therapy was developed, the dramatic multiorgan toxicity of iron was the major determinant.

The iron chelator deferoxamine mesylate is an effective agent when it is administered as a continuous subcutaneous or intravenous infusion. This maneuver markedly improves urinary iron excretion in comparison with intramuscular injections. When given as a continuous infusion in high enough doses in most patients, the drug maintains a negative iron balance despite continuing blood transfusions. When started before 5 to 8 years of age, these regimens are proving to be effective in delaying cardiac disease in some patients, potentially prolonging survival.

In the presence of a significant iron burden before the onset of therapy, complete reversibility of the lesions by deferoxamine cannot be reliably predicted. If therapy is started after 10 years of age, progressive cardiac dysfunction may not be completely prevented. Early initiation of therapy is thus advocated.

Iron overload should be documented first in candidates for iron chelation by a deferoxamine test. The 24-hour urinary excretion after injection.

Thalassemia Intermedia

A number of patients with symptomatic beta-thalassemia do not develop a debilitating anemia. These patients should not be committed to a lifelong transfusion regimen. In general, when the hemoglobin level remains above 8 grams per dL, patients lead a relatively normal life.


Often no treatment is indicated with this disorder. The homozygous form is usually lethal in utero. Cases have been described of neonates who were kept alive with exchange transfusions. Patients with hemoglobin H disease usually present with moderate anemia. They should be monitored for worsening of the anemia during infections. If it is persistent and is associated with increasing splenomegaly, splenectomy should be performed.


Bone Marrow Transplantation

Allogeneic bone marrow transplantation can be curative by replacing stem cells harboring defective globin genes with normal cells. Transplantation is associated with significant mortality and morbidity resulting from the toxicity of the conditioning regimen and from the pancytopenia and acute and chronic graft-versus-host disease after the procedure.

Gene Transfer

Many are investigating the biologic mechanisms necessary to achieve the long-term goal of correcting the defective genes in the stem cells of a thalassemic patient. At present, the most efficient system for transferring globin genes in hematopoietic stem cells is the retroviral vector, but many alternative systems are being studied because of disappointing results with this vector.