Thalassemia: Understanding Types and Treatment Options

Thalassemia, a genetic blood disorder, is more common in certain parts of the world, but anyone can carry the gene. Understanding thalassemia, its causes, symptoms, and treatments, is key to managing the condition and improving quality of life.

What Is Thalassemia?  

Thalassemia is an inherited blood disorder that affects about 5% of the world’s population. In people with this condition, the body cannot make enough hemoglobin and healthy red blood cells. Hemoglobin is a protein in red blood cells that carries oxygen to cells throughout the body. 

As a result of less hemoglobin and fewer healthy red blood cells, people with thalassemia experience anemia symptoms. 

What is the Main Cause of Thalassemia?

Thalassemia occurs due to gene mutations and is inherited from parents to their children. It is not due to something the parents did before or during pregnancy. 

These gene mutations (sometimes referred to as alterations) are responsible for producing hemoglobin in the body and remained in our DNA as a protection against malaria. Thalassemia is therefore prevalent in populations with ancestral links to Africa, Asia, and Southern Europe, regions where malaria is also prevalent. 

Genetics

Alpha and beta-thalassaemia are inherited in an autosomal recessive pattern, which means a person needs to inherit only one copy of a faulty gene from each parent to develop the condition. 

If a person only gets a faulty gene from one parent, they are a carrier for thalassaemia. Carriers usually do not have any signs or symptoms of thalassemia. However, they can pass on the faulty gene to future offspring. 

If both partners are genetic carriers for the same type of thalassaemia, they have a 25% (1 in 4) chance of having a baby with thalassaemia, a 25% of having a baby who does not have thalassemia and is not a carrier, and a 50% chance of having a baby who is a carrier.

Types

Hemoglobin is made up of four protein chains: two alpha-globin chains, consisting of 4 genes (two from each parent), and two beta-globin chains, consisting of 2 genes (one from each parent). Thalassemia is classified as alpha-thalassemia (α-thalassemia) or beta-thalassemia (β-thalassemia) based on which of these protein chains is missing or defective.

Both alpha- and beta-thalassemia are also classified based on the severity: minor, intermediate, and major thalassemia. People with a thalassemia trait have no symptoms or very mild anemia symptoms.

People with thalassemia intermedia experience moderate to severe symptoms. People with thalassemia major have severe anemia and require frequent blood transfusions. Blood transfusions for chronic anemia can lead to excessive iron accumulation in the body, requiring additional treatments such as iron chelation.

Thalassemia Symptoms  

Common Symptoms

Some people with thalassemia are asymptomatic (they have no symptoms). 

Others have mild to moderate symptoms such as:

• Fatigue

• Weakness

• Pale skin

• Dizziness

• Feeling cold

Due to decreased oxygen supply to cells in the body, thalassemia can also cause signs and symptoms such as:

• Growth delays

• Delayed puberty

• Osteoporosis (weak bones)

• Enlarged spleen

People with severe thalassemia can have the above symptoms as well as:

• Decreased appetite.

• Jaundice (yellowing of the skin and whites of the eyes).

• Dark or tea-colored urine.

• Abnormal facial bone structure

• Abdominal swelling.

Alpha Thalassemia Symptoms  

Beta-Thalassemia Symptoms 

Diagnosis and Tests 

Detection and Medical Evaluation

Mild thalassemia typically does not cause symptoms and might only be detected when a person undergoes tests for other reasons.

Moderate and severe thalassemia are usually diagnosed during the first two years of a child’s life, as they cause signs and symptoms that lead to a medical evaluation.

Blood Tests  

Doctors can diagnose thalassemia based on blood tests such as:

• Complete Blood Count (CBC) is a test that measures the number and size of red blood cells and the amount of hemoglobin in red blood cells. People with thalassemia have fewer healthy red blood cells, smaller-than-normal red blood cells, and low levels of hemoglobin. 

• Peripheral Blood Smear, which is a microscopic examination of a thin layer of blood on a glass slide. It is done to evaluate the appearance, number, and types of blood cells.

• Reticulocyte count is a test that measures the number of immature (young) red blood cells. A low reticulocyte count indicates that the bone marrow isn’t making enough red blood cells.

• Iron studies to evaluate the cause of anemia (iron deficiency versus thalassemia). Iron levels are usually normal or high in thalassemia, which helps distinguish it from iron-deficiency anemia.

Additional Tests

In addition to the routine blood tests mentioned above, thalassemia can be diagnosed with structural hemoglobin tests, such as high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF).

Genetic Testing  

If initial tests such as HPLC and IEF identify thalassemia, genetic testing can provide a definitive diagnosis by identifying missing or defective genes.

What Is The Difference Between Anemia and Thalassemia?

Anemia and thalassemia are both conditions affecting red blood cells, but they are distinct conditions. 

Anemia is a condition in which a person has low levels of healthy red blood cells to carry oxygen throughout the body. Many factors can cause anemia, including iron deficiency, chronic illnesses, and excessive bleeding.

Thalassemia is a genetic condition in which a person has inherited faulty hemoglobin genes, resulting in anemia.

Iron studies can help in differentiating between anemia versus thalassemia.

How Does Beta-Thalassemia Differ From Sickle Cell Disease?  

Beta-thalassemia and sickle cell disease (also called sickle cell anemia or sickle cell trait) are both inherited disorders that affect hemoglobin. But they are not the same. 

People with beta-thalassemia have a missing or defective beta-globin gene, resulting in low hemoglobin levels and an insufficient number of healthy red blood cells. 

People with sickle cell anemia have a gene mutation that affects the hemoglobin molecule itself. It causes their red blood cells to be abnormally sickle-shaped or crescent-shaped rather than the normal disc-shaped. As a result, the red blood cells are less flexible and more sticky, causing problems in blood flow throughout the body.

Note: Some people have sickle cell beta-thalassemia (Hb S/B Th). This condition is an inherited form of sickle cell disease that affects red blood cells by producing abnormal hemoglobin and decreasing the synthesis of beta-globin protein chains. 

How is Thalassemia Treated?

Regular Blood Transfusions 

People with thalassemia are treated with blood transfusions to restore normal levels of healthy red blood cells and hemoglobin. 

• People with hemoglobin H disease or beta-thalassemia intermedia may require occasional blood transfusions, such as when they have an infection. 

• People with moderate to severe thalassemia may need blood transfusions every 4 months. 

• Those with transfusion-dependent beta-thalassemia major may need frequent blood transfusions every 2-4 weeks. 

Iron Chelation Therapy  

Frequent blood transfusions can lead to an iron overload in the body. Too much iron can lead to serious complications, including heart problems. Iron chelation therapy in the form of a pill taken by mouth helps to remove excess iron from the body.

Folic Acid Supplementation

People with thalassemia may be prescribed a folic acid supplement to support the formation of healthy red blood cells.

Bone Marrow and Stem Cell Transplants  

A bone marrow and stem cell transplant from a matching donor can cure thalassemia. This treatment may be recommended for individuals with more severe forms of thalassemia, such as β-thalassemia major. The donor should have the same human leukocyte antigens (HLA) on their cell surface as the recipient. The donor’s transplanted blood cells help to make healthy new red blood cells in the thalassemia patient’s body.

Luspatercept

A drug called luspatercept (brand name Reblozyl) is an FDA-approved treatment for people with transfusion-dependent beta-thalassemia. It is an erythroid maturation agent that helps the body make more red blood cells. Luspatercept injections are given every 3 weeks.

Emerging Treatments and Research  

Casgevy is a gene therapy that uses CRISPR/Cas9 gene editing technology. This personalized one-time treatment for thalassemia involves taking the patient's own stem cells from the bone marrow. 

The CRISPR gene-editing tool then attaches to a specific DNA sequence in the stem cells and uses molecular scissors to make precise cuts, adding, removing, or altering the genetic material at specific locations in the DNA. 

Casgevy edits the stem cells at the erythroid-specific enhancer region of the BCL11A gene that prevents the formation of fetal hemoglobin (HbF). The modified stem cells are reintroduced into the patient’s body with reduced BCL11A gene transcription. This drug leads to increased fetal hemoglobin HbF formation and the availability of more functional hemoglobin.

Living With Thalassemia  

Management

The need for frequent blood transfusions and iron chelation therapy in transfusion-dependent thalassemia can affect a person’s quality of life. Even those with non-transfusion-dependent thalassemia require frequent tests, including a complete blood count (CBC), iron studies, assessments of heart and liver function, and tests for viral infections. 

The need for multiple lifelong healthcare visits, tests, and treatments can significantly impact a person’s quality of life. However, red blood cell transfusions and other treatments are necessary to restore healthy blood cells in people with thalassemia syndromes.

Can You Get Pregnant With Beta Thalassemia?

Yes, you can get pregnant with both beta- and alpha-thalassemia. But people who have thalassemia, are reproductive partners of known carriers of thalassemia, have a family history of thalassemia, or belong to populations where thalassemia is highly prevalent should consider genetic screening and counseling before a pregnancy. 

Carrier screening and genetic counseling can lead to informed reproductive choices, better maternal care during pregnancy, and timely diagnosis in the newborn.

What is the Life Expectancy of a Person with Thalassemia?

People with mild thalassemia usually have a normal life expectancy. Even those with moderate or severe thalassemia have a good chance of long-term survival if they follow their healthcare team’s thalassemia treatment plan carefully (blood transfusions and iron chelation therapy). In many people with thalassemia, heart disease due to iron overload is the leading cause of death.

Can Beta-Thalassemia Trait Be Cured?

Beta-thalassemia trait (thalassemia minor) causes mild anemia and typically does not require treatment. People with moderate or severe beta thalassemia (called beta-thalassemia intermedia and beta-thalassemia major, respectively) have more than one missing or defective beta-globin chain. They can develop severe anemia, requiring frequent blood transfusions. The more severe forms of beta thalassemia can be cured with a stem cell transplant or bone marrow transplant.

What Is The Survival Rate For Beta-Thalassemia Major?

According to American Family Physician, people with beta-thalassemia major live to an average age of 17 years and typically die by 30 years of age. Most deaths are caused by excess iron, leading to cardiac complications.