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Transfusion‑Dependent Beta‑Thalassemia (TDT) Is A Severe Genetic Disease That Impacts Patients for Life1,2

Beta-Thalassemia Around the World Is Changing4,5

Beta-thalassemia is primarily found in South Asia, the Middle East, North Africa, and Southern Europe, but global migration patterns are changing the global distribution of the disease.5,6

Beta thalassemia US estimated prevalence
  • According to the CDC (Centers for Disease Control and Prevention), beta-thalassemia major (a subset of TDT) affects at least 1000 people in the US; however, the exact prevalence of TDT in the US is not known.4,6
  • In both Europe and the US, the prevalence of thalassemia has risen as a result of immigration from endemic countries.4,7,8,9
  • About 1.5% of the global population (80-90 million people) are carriers of beta-thalassemia.
  • 60,000 symptomatic individuals are born annually.5

How Beta-Thalassemia is Inherited

Beta-thalassemia is inherited as an autosomal recessive disease; however, dominant mutations have also been reported in rare cases. The beta-globin gene (HBB gene) is located on the short arm of chromosome 11. Over 200 disease-causing HBB gene mutations have been identified, most of which are point mutations.4,10

The Pathophysiology of Beta-Thalassemia

Beta-thalassemia is caused by reduced or absent synthesis of the beta-globin chains of the adult hemoglobin tetramer (HbA), which is made up of two α-globin and two β-globin chains (α2β2).11 When beta-globin chains are absent, alpha-globin chains and their degradation products precipitate, causing ineffective erythropoiesis and hemolysis, which leads to anemia. Anemia, in turn, stimulates erythropoietin synthesis, resulting in intense proliferation of the bone marrow, skeletal deformities, and a variety of growth and metabolic abnormalities. Splenomegaly is typically seen in patients with beta-thalassemia as a result of extramedullary hematopoiesis or as a response to extravascular hemolysis.1

How Genetic Defects in
Beta-Thalassemia Lead to
Ineffective Erythropoiesis
and Hemolysis12

Beta-thalassemia pathophysiology: ineffective erythropoiesis and hemolysis Beta-thalassemia pathophysiology: ineffective erythropoiesis and hemolysis
While currently available treatment with transfusion and chelation addresses beta-thalassemia symptomatically, it does not correct the genetic mutations that lead to ineffective erythropoiesis and hemolysis.11,13,14

Adapted from Rachmilewitz E, Giardina P. How I treat thalassemia. Blood. 2011;118(13):3479-88.

Beta-Thalassemia:

Range of Severity11

Historically, beta-thalassemia has been classified into three groups: minor (trait), intermedia, and major.

1. Beta-thalassemia minor (trait)
Clinically asymptomatic; patients are heterozygous for beta-thalassemia.

2. Beta-thalassemia intermedia
Clinically and genotypically heterogeneous disorders, ranging in severity from mild to the severe transfusion-dependent state.

3. Beta-thalassemia major
Severe, transfusion-dependent anemia.

  1. These terms—major, intermedia and minor—continue to be used by patients and some clinicians today. However, current Thalassaemia International Federation (TIF) guidelines characterize the clinical severity of beta-thalassemia as:1

  2. TDT transfusion-dependent

    NTDT non-transfusion-dependent

How is Transfusion-Dependent 
Beta-Thalassemia Diagnosed?

Beta-thalassemia major will usually present clinically between the ages of 6 and 24 months. Affected infants have severe microcytic anemia, fail to thrive, become progressively pale, develop hepatosplenomegaly that may distend the abdomen, have mild jaundice, and may also have feeding problems and recurrent fevers due to hypermetabolic state or inter-current infection.1

  • Left untreated—that is, without a chronic transfusion regimen—infants with transfusion-dependent beta-thalassemia usually die within the first few years of life.1

Beta-thalassemia intermedia usually presents at a later age with a milder form of these clinical findings. Those on the more severe end of the spectrum may show slow development and retarded growth, while those on the mild end may be completely asymptomatic, with just mild anemia. People with beta-thalassemia carrier state (heterozygous) show no important clinical effects since the activity of their normal beta-globin gene makes enough stable globin.1

Hb Electrophoresis And Molecular Analysis

Hemoglobin electrophoresis or high pressure liquid chromatography can reveal hemoglobin types and their amounts. In patients with TDT, HbF constitutes the majority of total hemoglobin. Additionally, mutations of the beta-globin gene can be detected by polymerase chain reaction (PCR) methods or gene sequencing.1

How is Transfusion-Dependent
Beta-Thalassemia Treated?

Until effective therapy for its management was developed, beta-thalassemia major was considered a pediatric condition: in the absence of a chronic transfusion regimen, children with the disease usually died within the first few years of life.1

Patients with transfusion-dependent beta-thalassemia typically require regular transfusions every two to five weeks, with the goal, according to TIF guidelines, of maintaining a pre-transfusion hemoglobin level above 9‑10.5 g/dL.1

Each unit of whole blood contains approximately 200 mg of iron, and receiving regular blood transfusions makes iron overload unavoidable since there is no dedicated iron excretion pathway that can increase the excretion of iron.16 While iron chelation treatment can help control iron overload, many patients experience iron overload-associated complications.16,17

  • Red blood cell transfusions, which are central to the treatment of severe disease, correct the anemia characteristic of beta‑thalassemia and limit bone marrow expansion, but also lead to iron overload.1,11

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Consider Asking Your Patients:

"Can you describe any changes made to your life because of your symptoms or treatment?"

Actor portrayals throughout. Not real patients.

Take the Beta-Thalassemia Challenge

Which of the following might be seen in a patient with beta-thalassemia intermedia?

E.

The clinical presentation of beta-thalassemia intermedia can vary widely, from asymptomatic to severe. At the mildest end of the clinical spectrum, patients are asymptomatic with only mild anemia until adulthood. At the severe end, patients present between age 2 and 6, and show growth retardation and slowed development. Clinical features may include deformities of the bones and face. In both beta-thalassemia major and intermedia, intestinal absorption of iron is increased. Chronic transfusions are the main source of iron overload in patients who are regularly transfused, but patients with beta-thalassemia can develop iron overload, even in the absence of transfusion, due to this increased intestinal absorption.1,11

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