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Transfusion-Dependent β-Thalassaemia (TDT) Is A Severe Genetic Disease That Impacts Patients for Life1,2

β-Thalassaemia Around the World 
Is Changing4,5

The incidence and prevalence of β-thalassaemia varies around the world. Endemic populations are primarily found in south Asia, the middle east, north Africa and southern Europe. While migration is changing the global distribution of the disease, β-thalassaemia is a rare disease in most of Europe and the United States.5,6

  • TDT prevalence is variable in Europe, with <1000 patients in most non-endemic countries.7,8,9,10
  • In Italy, TDT affects an estimated 6500 patients.11
  • According to the CDC (Centers for Disease Control and Prevention), β-thalassaemia 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 United States, the prevalence of thalassaemia 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 β-thalassaemia.
  • 60,000 symptomatic individuals are born annually.5

How β-Thalassaemia Is Inherited

β-thalassaemia is inherited as an autosomal recessive disease; however, dominant mutations have also been reported in rare cases. The beta-globin gene is located on the short arm of chromosome 11. Over 200 disease-causing mutations have been identified, most of which are point mutations.5,12

The Pathophysiology of β-Thalassaemia

β-thalassaemia is caused by reduced or absent synthesis of the beta-globin chains of the adult haemoglobin (HbA) tetramer, which is made up of two alpha- and two beta-globin chains (α2β2).13 When beta-globin chains are absent, alpha-globin chains and their degradation products precipitate, causing ineffective erythropoiesis and haemolysis, which leads to anaemia. Anaemia, 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 β-thalassaemia as a result of extramedullary haematopoiesis or as a response to extravascular haemolysis.1

Ineffective Erythropoiesis and Haemolysis in β-Thalassaemia14

Diagram for Ineffective Erthropoiesis and Haemolysis in β-Thalassaemia

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


Range of Severity13

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

1. β-thalassaemia minor (trait)
Clinically asymptomatic; patients are heterozygous for β-thalassaemia.

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

3. β-thalassaemia major
Severe, transfusion-dependent anaemia.

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

  2. TDT transfusion-dependent

    NTDT non-transfusion-dependent

How is Transfusion-Dependent 
β-Thalassaemia Diagnosed?

β-thalassaemia major will usually present clinically between the ages of 6 and 24 months. Affected infants have severe microcytic anaemia, 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 β-thalassaemia usually die within the first few years of life.1

β-thalassaemia 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 anaemia. People with β-thalassaemia carrier state (heterozygous) show no important clinical effects since the activity of their normal β gene makes enough stable globin.1

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

Hb Electrophoresis And Molecular Analysis

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

How Is Transfusion-Dependent β-Thalassaemia Treated?

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

  • Red blood cell transfusions, which are central to the treatment of severe disease, correct the anaemia characteristic of β-thalassaemia and limit bone marrow expansion, but also lead to iron overload.1,13

Each unit of blood contains approximately 200 mg of iron, and receiving regular blood transfusions makes iron overload unavoidable. Unfortunately, there is no dedicated iron excretion pathway that can increase the excretion of iron in response to iron loading.16 While iron chelation treatment can help control iron overload, many patients experience iron overload-associated complications.1,17,18

Take the β-Thalassaemia Challenge

Which of the following might be seen in a patient with β-thalassaemia intermedia?


The clinical presentation of β‑thalassaemia intermedia can vary widely, from asymptomatic to severe. At the mildest end of the clinical spectrum, patients are asymptomatic with only mild anaemia until adulthood. At the severe end, patients present between age 2 and 6, and show growth retardation and slowed development. Deformities of the bones and face can occur. In both β‑thalassaemia 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 β‑thalassaemia can develop iron overload even in the absence of transfusion, due to this increased intestinal absorption.1,13


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