Thalassaemia

Introduction

Thalassaemia is a group of inherited blood disorders causing anaemia. It is one of the most common genetic disorders globally, particularly prevalent in regions such as the Mediterranean, parts of Africa, and Southeast Asia including Hong Kong.

There is a wide spectrum of severity for patients with thalassaemia, ranging from totally asymptomatic carriers to severe forms of thalassaemia in which patients are dependent on regular transfusion to sustain life. In the most severe form known as Hb Barts, it can cause death of a fetus during pregnancy.

Causes

Thalassaemia is a genetic condition leading to abnormal production of haemoglobin, the protein in red blood cells responsible for transporting oxygen throughout the body.

Mode of Inheritance

Thalassaemia major is inherited in an autosomal recessive pattern, which means inheriting both copies of faulty genes, one from each asymptomatic parent who usually does not have the condition.

Types of Thalassaemia

Haemoglobin is made of two types of protein subunits—alpha (α) and beta (β) globin chains. A fine balance in the production of α and β chains is essential for the synthesis of normal haemoglobin. In patients with thalassaemia, there is either a deficiency in the production of the α or β chains or an abnormality in these protein chains manufactured. This results in the formation of abnormal Hb and leads to an ineffective red blood cells production. The red blood cells of patients with thalassaemia are smaller and paler with a shorter life-span compared with normal people.

Depending on which protein chain is being affected, thalassaemia is classified into two main types: alpha-thalassaemia (problem with alpha chain production) and beta-thalassaemia (problem with beta chain production).

Alpha thalassaemia

Each person has two copies of chromosome 16 and four functional copies of the alpha-globin gene (with two copies on each chromosome 16). Alpha thalassaemia results from mutations in the alpha-globin genes. The severity of alpha thalassaemia depends on how many of these four alpha genes are affected:

• Silent carrier: One out of four alpha-globin genes is affected; usually asymptomatic and usually identified by the presence of small red blood cells on blood testing
• Alpha thalassaemia trait: Two alpha-globin genes are affected; mild anaemia may occur.
• HbH disease, HbH-constant spring: Three alpha-globin genes are affected; moderate to severe anaemia.
• Alpha thalassaemia major (Hb Bart’s): All four alpha-globin genes are affected; with severe anaemia of the affected fetus during pregnancy that can result in heart failure, hydrops fetalis and in-uterine death if untreated.

Beta thalassaemia

Each person also has two copies of chromosome 11 and two functional copies of the beta-globin gene (with one copy on each chromosome 11). Beta thalassaemia occurs due to mutations in the beta-globin gene. The severity of beta-thalassemia depends on the amount of functional beta-globin chains produced, which can range from a mild deficiency to a total absence.

• Beta thalassaemia minor: One beta-globin gene is affected; the patients are typically asymptomatic or have mild anaemia.
• Beta thalassaemia intermedia: Both genes are affected but with some beta-globin production; the patients can be affected by moderate anaemia, and some may require transfusion in the later part of life.
• Beta thalassaemia Major (Cooley’s Anaemia, named after Dr. Thomas Benton Cooley who first described this condition in the 1920s): both genes are severely affected with a minimal or no functional beta-globin chains; affected individuals require regular and life-long blood transfusions for survival.

Signs and Symptoms

Patients with thalassaemia exhibit a range of symptoms depending on the severity of their condition. Typical timing of presentation for beta-thalassaemia intermedia and major is usually at six to nine months of age. Common clinical manifestations include:

• Anaemia: Symptoms such as fatigue, pallor, weakness, poor exercise tolerance, poor feeding and weight gain in infants and children.
• Splenomegaly: Enlargement of the spleen due to increased destruction of abnormal red blood cells. This can be felt as a mass over the left upper abdomen and can manifest as a distended abdomen in severe cases.
• Skeletal changes: In severe cases, bone deformities can occur due to marrow expansion in response to the severe anaemia, leading to the typical thalassaemia facial features with frontal and maxilla bone expansion and dental malocclusion.
• Growth delays: Children may experience delayed growth and sexual maturation due to chronic anaemia and iron overload from frequent blood transfusions.

Diagnosis

Diagnosis of thalassaemia is made by blood tests:

• Full blood count: red blood cells appear smaller and paler than usual (hypochromic and microcytic).
• Haemoglobin pattern: analysis can show what type of haemoglobin is present in the blood.
• Genetic tests: in some cases, genetic tests are needed to diagnose the exact type of thalassaemia, and help to test other family members.

Management

Management of thalassemia major focuses on alleviating anaemia and preventing complications. Regular transfusions, however, can lead to iron overload as the transfused red cells carry lots of iron. The excess iron accumulates in vital organs, including the heart, liver and endocrine glands, causing tissue and organ damage. This iron accumulation can result in life threatening events (e.g., heart failure, liver cirrhosis) and a shortening of life-span if untreated, therefore it is also important to remove excess iron from the body. Key treatment strategies include:

• Regular blood transfusions: Patients with severe forms of thalassaemia require regular packed red blood cells transfusions at intervals of approximately every three to five weeks to maintain adequate trough haemoglobin levels. This helps to alleviate anaemia, prevent the spleen from enlarging and bony changes.
• For fetuses diagnosed to have Hb Barts, in-uterine transfusion is a potential treatment option to support the growth of the fetus till birth.
• Iron chelation therapy: There are effective medications known as iron-chelators that can remove excess iron from the body. This prevents organ damage and complications from iron overload. In the old days, subcutaneous infusion of desferrioxamine was the only available agent in the market and its administration was tedious and difficult to comply with. Nowadays, orally administered iron chelators (Deferiprone and deferasirox) are available which greatly facilitates drug administration and treatment compliance. An optimal iron chelation therapy and compliance to treatment is crucial to prevent complications and maintain a long-term survival of patients with transfusion dependent thalassaemia.
• Haematopoietic stem cell transplantation (HSCT): This is a curative treatment for patients with transfusion dependent thalassaemia. A suitable stem cell donor is required for the transplantation. Potential suitable donors include matched siblings of the patients, unrelated matched donors, and more recently the use of half-matched family donors. With successful transplantation, the patient will become transfusion independent. It is a complex procedure and has treatment related risk, some of which can be fatal. Nevertheless, the reported rate of successful HSCT among young patients is high.
• Gene therapy: There are emerging therapies aiming to correct genetic defects and restore the capability to produce adequate Hb. Recently, a gene therapy product for treating beta-thalassaemia major is approved by drug authorities including FDA and EMA but it is not widely available in most parts of the world due to its extremely high cost.
• Preventive screening programmes: Carrier screening for couples and prenatal diagnosis are crucial for reducing the incidence of thalassaemia through informed reproductive choices.

Special treatment options available in HKCH

With the hub-and-spoke model, the HKCH offers a thalassaemia annual review clinic which provides regular review of paediatric patients with transfusion dependent thalassaemia and advises on the transfusion regimen, monitoring and surveillance of complications while the patients receive regular transfusion in regional hospitals.

HKCH is the only centre in Hong Kong providing hematopoietic stem cell transplantation for suitable paediatric patients with transfusion dependent thalassaemia.

Useful Resources

Children’s Thalassemia Foundation

Acknowledgement

Principal author: Dr Alex Leung on behalf of Haematology & Oncology team, HKCH

Initial posting: Nov 2025

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