BETA THALASSEMIA PATHOPHYSIOLOGY

BETA THALASSEMIA THERAPY

IRON OVERLOAD AND CHELATION

ALLOGENEIC STEM CELL TRANSPLANT

MONITORING

NEW THERAPEUTIC APPROACHES

SUMMARY

REFERENCES

INTRODUCTION

Beta thalassemias represent a class of disorders with a high global prevalence and significant health and economic impact.1 Since the elucidation of the molecular mechanism in the 1960s, there has been significant progress in treatment of disease complications. With increasing use of transfusion therapy, iron overload has become a pressing problem, and chelation therapy is a key component of treatment. The first part of this review focuses on monitoring of disease complications, transfusion therapy, iron overload, and chelator toxicity. In the second part, the authors review new developments in therapy for beta thalassemia.

BETA THALASSEMIA PATHOPHYSIOLOGY

Thalassemias are a class of disorders caused by imbalance of the alpha (a) and beta (b) globin chains that make up the principal adult oxygen transporter hemoglobin A (a2b2). Beta thalassemias result from a relative excess of a chains due to reduced production of b globin chains and, in some instances, increased dosage of a globin genes.2 In addition to reduced functional hemoglobin production, red blood cells (RBCs) and their precursors are damaged by a globin, which is unstable in the absence of a binding partner. Free a globin forms precipitates, leads to formation of reactive oxygen species, and damages RBC membranes leading to hemolysis and abnormal erythroid maturation. The beta thalassemia phenotype is determined by the degree of the imbalance and ranges from minimal effects in beta thalassemia trait to severe transfusion-dependent anemia. Symptoms in beta thalassemia are due to a combination of anemia and ineffective erythropoiesis. Increased erythropoietin levels due to anemia drive erythroblast proliferation through JAK2-STAT5 signaling; additional RBC extrinsic and intrinsic factors have been implicated in this process and are reviewed elsewhere.3 Complications of beta thalassemia are numerous and include growth failure, bone disease, cardiac abnormalities (pulmonary hypertension, heart failure, arrhythmias), predisposition to thrombosis, extramedullary hematopoiesis (splenomegaly, masses with compression), and a broad range of endocrinopathies.