Thalassemia

What thalassemia is

Adult hemoglobin (HbA) is made of four protein chains: two alpha and two beta. Each chain is built from instructions in specific genes. You inherit:

• four alpha-globin genes (two from each parent) on chromosome 16
• two beta-globin genes (one from each parent) on chromosome 11

In thalassemia, one or more of these genes is missing or altered, so fewer chains are made. The resulting red blood cells are small, pale and fragile, and unpaired chains damage developing red cells in the bone marrow. The result is anemia from both reduced production and early destruction of red cells.

Types of thalassemia

Alpha thalassemia

Alpha thalassemia is most common in people of Southeast Asian, Chinese, African, Mediterranean and Middle Eastern ancestry.

Beta thalassemia

Beta thalassemia is most common in people of Mediterranean, Middle Eastern, South Asian and Chinese ancestry.

Doctors now often group severe forms by need for blood: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT).

Combined conditions

Thalassemia can combine with other hemoglobin variants. Hemoglobin E/beta thalassemia, common in Southeast Asia, varies from mild to severe. Sickle beta thalassemia behaves like sickle cell disease.

Thalassemia trait

Most people with thalassemia are carriers, with trait or minor forms. Trait:

• usually causes no symptoms, or mild tiredness
• shows up on a routine blood count as small red cells (low MCV) with a normal or high red cell count
• is often mistaken for iron deficiency anemia
• does not turn into thalassemia major and needs no treatment
• matters mainly for family planning

Do not take iron supplements for thalassemia trait unless tests show you are also iron deficient, because extra iron is not needed and can build up.

Symptoms of moderate and severe thalassemia

• Fatigue, weakness and breathlessness
• Pale skin and sometimes a yellow tinge (jaundice)
• Enlarged spleen and liver, causing a swollen belly
• Poor growth and delayed puberty in children
• Bone changes: the marrow expands to make more blood, widening the skull and cheekbones and thinning bones, which can fracture
• Dark urine
• Gallstones from breakdown of red cells

Babies with beta thalassemia major usually appear well at birth, because they still make fetal hemoglobin, then develop symptoms between 6 months and 2 years.

How thalassemia is inherited

Thalassemia is autosomal recessive. If both parents carry beta thalassemia trait, each pregnancy has:

• a 1 in 4 chance of a child with beta thalassemia major or intermedia
• a 2 in 4 chance of a child with the trait
• a 1 in 4 chance of a child with neither

Alpha thalassemia inheritance is more complex, because the four genes can be affected in different combinations on each chromosome. A genetic counselor can explain the specific risks for a couple.

Diagnosis

• Complete blood count: low hemoglobin, small red cells (low MCV and MCH) and often a normal or high red cell count.
• Peripheral blood smear: target cells and fragmented, irregular red cells.
• Iron studies: to rule out iron deficiency.
• Hemoglobin electrophoresis or HPLC: measures types of hemoglobin. A raised HbA2 (above about 3.5%) indicates beta thalassemia trait. Alpha thalassemia trait usually shows a normal pattern.
• DNA testing: confirms alpha thalassemia and identifies the exact gene changes, which helps predict severity and counsel families.
• Newborn screening: US newborn screening detects some forms, such as beta thalassemia major and hemoglobin H disease.
• Prenatal testing: chorionic villus sampling or amniocentesis for at-risk pregnancies.

Treatment

Thalassemia trait

No treatment is needed. Genetic counseling and partner testing are recommended before pregnancy.

Blood transfusions

People with transfusion-dependent thalassemia receive red cell transfusions every 2 to 5 weeks to keep hemoglobin at a level that allows normal growth and activity and suppresses the overactive marrow.

Iron chelation

Each unit of transfused blood adds iron, which the body cannot get rid of. Iron overload damages the heart, liver and hormone glands. Chelation medicines bind iron so it can be excreted:

• deferoxamine, given as an infusion under the skin
• deferasirox and deferiprone, taken by mouth

Iron levels are tracked with blood ferritin and MRI scans of the heart and liver. People with NTDT can also build up iron from increased absorption in the gut and may need chelation.

Other medicines

• Folic acid supplements to support red cell production
• Luspatercept: an injection every 3 weeks that improves red cell maturation and can reduce transfusion needs in adults with beta thalassemia
• Hydroxyurea in some people with NTDT, to raise fetal hemoglobin

Curative treatments

• Stem cell (bone marrow) transplant from a matched donor, usually a sibling, can cure thalassemia. Results are best in children.
• Gene therapy: FDA-approved therapies use a person's own modified blood stem cells, either adding a working beta-globin gene or editing a gene to switch fetal hemoglobin back on. They can free many people with transfusion-dependent beta thalassemia from transfusions, but require chemotherapy beforehand and are available only at specialist centers.

Spleen removal

Splenectomy is now used less often. It may help when an enlarged spleen destroys too many cells, but it increases the risk of serious infections and blood clots.

Complications

• Heart problems: iron in the heart can cause heart failure and irregular rhythms, the main cause of death in transfusion-dependent thalassemia historically
• Liver damage from iron and transfusion-related infections
• Hormone problems: diabetes, underactive thyroid, delayed puberty, infertility
• Osteoporosis and fractures
• Gallstones
• Blood clots, particularly after splenectomy
• Serious infections after splenectomy

Outlook

People with thalassemia trait have a normal life expectancy. With modern transfusion, chelation and specialist care, many people with thalassemia major live into their 50s and beyond, work and have families. Stem cell transplant and gene therapy offer the chance of a cure.

Frequently asked questions

What is thalassemia trait?

Thalassemia trait means you carry one altered beta-globin gene or two altered alpha-globin genes. It usually causes no symptoms or only mild anemia with small red blood cells. It does not need treatment but can be passed on, so partner testing before pregnancy is recommended.

Is thalassemia the same as anemia?

Thalassemia is one cause of anemia. Anemia simply means a low red blood cell or hemoglobin level. In thalassemia, the anemia comes from an inherited problem making hemoglobin. Unlike iron deficiency anemia, it does not improve with iron, and iron can be harmful if not needed.

What is the difference between alpha and beta thalassemia?

Alpha thalassemia affects the genes for the alpha chains of hemoglobin, of which there are four; beta thalassemia affects the two beta-chain genes. Both range from silent carriers to severe disease. Severity depends on how many genes are affected and the type of change.

Can thalassemia be cured?

Yes, for some people. A stem cell transplant from a matched donor can cure it, and recently approved gene therapies can make many people with transfusion-dependent beta thalassemia independent of transfusions. Most people are managed long term with transfusions and iron chelation.

Can two people with thalassemia trait have a healthy baby?

Yes. Each pregnancy has a 1 in 4 chance of a child with severe thalassemia, a 1 in 2 chance of a child with the trait, and a 1 in 4 chance of a child with neither. Genetic counseling, prenatal testing and IVF with embryo testing are options.

Is thalassemia minor serious?

Usually not. Thalassemia minor typically causes no symptoms or mild anemia and does not shorten life. It may cause mild tiredness, especially in pregnancy. The main importance is knowing you are a carrier and avoiding unnecessary iron supplements.