Thalassemia

What Is Thalassemia?

Thalassemia refers to a group of genetic blood disorders in which the body produces abnormal hemoglobin or not enough hemoglobin. Hemoglobin is the protein in red blood cells responsible for transporting oxygen throughout the body.

There are several forms of thalassemia. They're categorized by which component of hemoglobin is affected and how severe the resulting anemia is. In more serious cases, anemia can lead to organ damage.

Thalassemia tends to occur more often in people from specific ancestral backgrounds.

People at risk include those with a family history of the inherited blood disorder or people in certain ethnic groups, including:

• African
• Asian
• Greek
• Italian
• Middle East

What are hemoglobinopathies?

Thalassemia belongs to a group of several related blood diseases called hemoglobinopathies. These are characterized by structural variations in the hemoglobin molecule.

Hemoglobin is a protein found on every erythrocyte (red blood cell) in the bloodstream. In healthy people, each hemoglobin molecule has one iron (Fe) ion on each of its four heme structures.

Iron is a vital compound that performs several essential functions:

• Binds to oxygen (O2) in the lungs.
• Carries O2 to all tissues and parts of the body.
• Releases life-sustaining O2.
• Removes carbon dioxide (CO2) waste.
• Sends CO2 back to the lungs for exhalation.

Imagine hemoglobin as a lock, and oxygen as the key. Iron is the metal pin inside the lock that allows the key to turn and open the door. Without iron, the lock (hemoglobin) can’t grab onto the key (oxygen), so the door to oxygen delivery stays shut.

The importance of hemoglobin cannot be overstated. A person whose hemoglobin levels are consistently too low is most likely unable to take in and use enough oxygen to sustain life.

What are the types of thalassemia?

Alphathalassemia and beta thalassemia represent the two main types of the disorder.

The alpha or beta designation depends on which gene chain associated with hemoglobin structural protein production fails to function:

• Alpha globin — Four genes help control production of this protein.
• Beta globin — Two genes help control production of this protein.

The genetic symptoms and clinical severity of thalassemia is another way to classify this disorder depending on the type and subtype inherited.

Alpha thalassemia (thal)

Alpha thal occurs when one or more of the genes associated with production of the alpha globin protein are defective or missing. It’s more common in people of African, Asian, and Middle Eastern ancestry.

Alpha thal genetic variants:

• Loss of one gene — People with this type have no symptoms and no signs of the disease but are silent carriers.
• Loss of two genes — People with this type have mild alpha thalassemia andmay experience the mildest anemia but usually look and feel healthy. Their bodies produce abnormally small red blood cells, a thalassemia called microcytosis.
• Loss of three genes — Hemoglobin H disease results in severe, life-threatening anemia. People often need frequent blood transfusions for survival. Left untreated, most people with this type die in childhood or as adolescents.
• Loss of four genes — This mutation produces thalassemia that cannot sustain life. Most people with this type die in the womb.

Beta thalassemia (thal)

Beta thal differs from alpha thal in that it rarely arises due to the complete deletion of the beta globin gene. Instead, the gene has a suppressed function in varying degrees. It may produce very little beta globin protein or none at all.

Beta thal mostly affects those with Mediterranean heritage. It can sometimes affect those of African and Asian heritage.

The severity of symptoms and the impact of the disorder depend on the type of beta thal variant a person has inherited.

• One-gene beta thalassemia — When one normal beta globin gene and one suppressed gene produce diminished levels of beta globin in varying degrees, people have abnormally small red blood cells and mild anemia.
• Two-gene beta thalassemia — This variant of beta thal results in severe anemia. It gives rise to potentially fatal thalassemia.

Beta thal effects include:

• Thalassemia minor (also called thalassemia trait) — Refers to people whose only symptoms include small red blood cells and mild to no anemia. Often, these people don’t realize they have the trait until their blood is tested.
• Thalassemia intermedia — People with thal intermedia experience anemia that approaches a severe level. However, many do not need blood transfusions to live. With close monitoring, some people may rarely, or never, need a transfusion.
• Thalassemia major (also called Cooley’s anemia) — The life-threatening form of beta thal in which both beta genes have suppressed function or none at all. People with this form need chronic blood transfusions throughout their lives. The transfusions may cause too much iron to build up and damage vital organ systems. Iron chelation therapy may be necessary to remove the excess iron.

How common is thalassemia?

Thalassemia is historically rare in the United States. But the prevalence has increased due to immigration from regions in the Mediterranean, Middle East, and Southeast Asia where it's more common.

An estimated 1.25 million Americans carry the gene responsible for thalassemia.

About 1,000 to 1,500 people in the U.S. have the most severe transfusion-dependent form of the disease.

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What Are the Signs and Symptoms of Thalassemia?

People with thalassemia have had it from birth, even though it may sometimes not be clear.

Doctors usually diagnose moderate to severe thalassemia during infancy. The signs and symptoms typically occur within the first 24 months of life.

People with milder forms of thalassemia may not discover their status until much later. A routine blood test may indicate that they have anemia.

The signs and symptoms vary, depending on the type and subtype of thalassemia.

Babies and children with one of the severe forms — like Cooley’s anemia (thalassemia major) or hemoglobin H disease — usually exhibit symptoms of severe anemia within the first 12 months of life. The spleen often enlarges to several times its normal size, causing intense pain and potentially leading to rupture.

Other symptoms for moderate to severe thalassemia variants include:

• Facial bone deformities (abnormal bone protrusions in the face and forehead).
• Fatigue (a symptom of anemia).
• Failure to reach growth milestones.
• Heart failure from unmanaged severe thalassemia.
• Jaundice (yellow-tinged skin and whites of eyes).
• Shortness of breath.

People with minor forms of alpha thal and beta thal have minimal or no symptoms but do have microcytosis (small red blood cells). A look at a blood sample under a microscope reveals abnormally small blood cells. In asymptomatic people, this usually means they have the thalassemia trait, but not the disorder itself.

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How Do You Diagnose Thalassemia?

Your medical provider will do an exam and ask about your health history. They may also order tests to diagnose the condition.

Tests to diagnose thalassemia

Tests you may need include:

• Complete blood count (CBC) — Measures the size, maturity, and number of the various blood cells in a specific amount of blood.
• Free erythrocyte protoporphyrin (FEP) and ferritin — Helps doctors rule out anemia caused by iron deficiency in anemia patients.
• Genetic test – Checks to see if you have the genes that cause thalassemia.
• Hemoglobin electrophoresis — Determines the types of hemoglobin in the blood. The procedure uses A2 and F quantitation for alpha thalassemia and A2 quantitation for beta thalassemia (Cooley’s anemia).

If you learn that you have thalassemia, your family members should talk to their providers about testing.

Prenatal diagnosis of thalassemia

Doctors use chorionic villus sampling (CVS) or amniocentesis tests to determine if a fetus has thalassemia.

Since children inherit the thalassemia gene from their parents, family genetic studies can also help diagnose the type and severity of the disease.

People who have a family member with thalassemia might want to consider genetic counseling. This can determine their risk of passing the disease on to their offspring if they want to have children.

Almost everyone with thalassemia will need continued treatment and support throughout their lives:

• People diagnosed with mild forms of thalassemia may never need treatment or need very little.
• People with moderate to major thalassemia often need treatment very early in life.
• Thalassemia trait (silent carriers) should consider genetic counseling when planning a family or consult a doctor if already pregnant.

Thalassemia prognosis

• Thalassemia minor typically doesn’t cause symptoms and has a positive outlook. It usually doesn’t lead to serious health problems or affect life expectancy.
• Thalassemia major is a much more serious condition. How well a person does over time depends on how closely they follow their treatment plan.

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How Do You Treat Thalassemia?

Medical technology has transformed a once-fatal genetic blood disease into a chronic illness. Comprehensive treatment models and medical advances have made it possible for many people with thalassemia to experience full, productive lives.

Treatment strategies depend on the type and severity of the disease.

Blood transfusions

Blood transfusions are the primary treatment for those with moderate to severe thalassemia.

Transfusions provide healthy red blood cells with normal hemoglobin. They also help people with thalassemia feel well, take part in normal daily activities, and live to adulthood.

• Most people with thalassemia are transfusion-independent. This means they do not need regular transfusions at all.
• Some only need intermittent transfusions. People with alpha (hemoglobin H) or beta thalassemia intermedia may need occasional blood transfusions if anemia becomes severe and causes fatigue.
• A small number of people are transfusion-dependent, meaning they need regular transfusions. Those with beta thalassemia major (Cooley’s anemia) usually need blood transfusions every two to four weeks.

Treatment for transfusion-independent people

Adults who do not depend on regular or intermittent blood transfusions to manage their thalassemia usually visit their provider two to six times a year.

At each visit, the doctor will check:

• Gallbladder function.
• Nutrition.
• Orthopaedic concerns.
• Spleen size and activity.

Treatment for transfusion-dependent people

Transfusion-dependent people have more health care needs and need a comprehensive exam once a year. They also need to have a battery of diagnostic tests before their annual visit.

These tests may include:

• Cardiac assessment (like an echocardiogram).
• Dental health exam.
• Endocrine assessment (thyroid, glucose tolerance, bone density, sex hormone levels).
• Hepatic (liver function) panel.
• Nutritional screening.
• Quantitative iron staging (liver biopsy, ferritin).
• Vision health exam.

Based on the results, the health care team assesses how the person’s needs may have changed and adjusts treatment strategies.

For people with transfusion-dependent thalassemia, care focuses on the most common complications:

• Cardiac issues.
• Endocrine system failure.
• Excess iron levels — Iron toxicity is the leading cause of death for people with thalassemia in the western world.
• Hepatitis.
• Infectious disease.
• Psychosocial concerns.
• Splenomegaly (enlarged spleen).
• Transfusion.

Chelation therapy — desferal infusion

Chronic blood transfusion therapy causes excessive iron buildup.

The spleen, liver, heart, and endocrine systems are the primary storage sites for the large amounts of exogenous (from an outside source) iron received from frequent blood transfusions. The body has no way of excreting this excess iron. This can lead to organ system failure, including the heart and liver.

Doctors must track body iron levels to help the survival and wellness of the transfusion-dependent person.

Testing for excess iron

At UPMC, we test iron burden using one of two procedures:

• Ferritin test — Measures gross iron burden or drastic iron level reduction.
• Liver biopsy — Measures iron storage in the liver by taking a direct sample of liver tissue.

Removing excess iron

People who have excessive body iron levels must have chelation therapy to remove the excess iron. Iron chelation therapy involves daily intravenous infusions of Desferal (deferoxamine). Desferal binds to iron in the body, which then passes out in urine and stool.

Bone marrow and cord blood transplants

Proteins called human leukocyte antigens (HLAs) are on the surface of every human body cell. They help the immune system determine whether cells belong to foreign invaders (like viruses or bacteria) or to the person’s own cells and tissue.

HLA typing plays a critical role when trying to find a transplant donor. Proper HLA matching helps prevent transplant rejection and graft-versus-host disease (GVHD).

People with Cooley’s anemia are possible candidates for bone marrow transplants. Unfortunately, most people cannot find a perfect match (HLA-identical) donor.

Siblings who share both parents provide the best chance of an appropriate match. Even then, a sibling only represents a 25% chance of providing the required perfect match.

Those who overcome the significant hurdle of finding an HLA-identical donor will undergo chemotherapy to remove all, or almost all, of the stem cells from their own bone marrow. Doctors then replace these removed cells with the donor’s healthy stem cells.

In successful transplants, donor stem cells repopulate the recipient’s bone marrow and create new, normal blood cells.

Generally, the younger the person, the better the outcome of bone marrow transplantation. But older adults can undergo the therapy, provided they meet certain criteria.

Cord blood refers to the umbilical cord blood that remains in the umbilical cord and placenta after birth. Cord blood contains an abundance of stem cells.

Cord blood transplants offer some advantages over bone marrow transplants. The biggest advantage is that recipients show a greater tolerance for a partial match (HLA-partial) donor.

As with bone marrow transplants, siblings who share both parents represent the optimal donors. Parents can arrange to collect and store their newborn’s stem cell-rich cord blood for potential future use.

Other treatment options

Other thalassemia treatment options include:

• Daily folic acid supplements.
• Gallbladder removal (only when necessary).
• Spleen removal (only when necessary).

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