Hemoglobinopathies (he-muh-glo-buh-NA-puh-thees) are inherited disorders caused by defects in the genes that code for hemoglobin (Hb). Hemoglobinopathies are characterized by low levels of hemoglobin protein or low production and high turnover of red blood cells, resulting in anemia and body tissues that are starved for oxygen. The most common hemoglobinopathies are sickle cell anemia and thalassemia.

Sophia's Story

Sophia was resting on the sofa when her teacher called her mother. Sophia had fallen asleep in class again. “I couldn't help it, Mom. I was just so tired and my legs hurt,” Sophia explained. Sophia's mother reached for the telephone to schedule a blood transfusion * . “No,” cried Sophia. “I hate those. And there are other kids who need that blood a lot more than I do.” Sophia's mother reminded her that all their friends had donated blood so it would be available for Sophia when she needed it.

Initially, her parents had thought Sophia was just small for her age. Then the doctor diagnosed Sophia with anemia and prescribed iron supplements to increase her red-blood-cell (RBC) count. The iron did not help. Sophia's growth was delayed and she tired very easily. Then her liver * and spleen * became enlarged and her skin yellowed with jaundice * .

Her parents were mystified when a blood specialist diagnosed Sophia with a genetic * disease—beta-thalassemia, or Mediterranean anemia. No one in either of their large Greek and Italian families had ever had anemia. And Sophia's older brother was perfectly healthy. But blood tests showed that both of Sophia's parents carried genes for a beta-thalassemia trait. They each had one normal gene coding for the beta-globin protein chain in hemoglobin and one abnormal thalassemia gene. The normal gene made enough beta-globin, so their mild anemia had never been detected. Sophia had inherited an abnormal thalassemia gene from each of her parents. Her brother had inherited two normal genes.

Immediately after her blood transfusion Sophia returned to school and resumed her normal activities. Her condition could have been much worse. Sophia had beta-thalassemia intermedia. Her body made enough beta-globin that, with occasional blood transfusions, she could remain healthy and live a normal life. Had she been diagnosed with the more serious form of beta-thalassemia called beta-thalassemia major, she would have needed transfusions every two to four weeks to stay alive.

What Are Hemoglobinopathies?

Hemoglobinopathies cause anemia, which means that the blood does not contain enough properly functioning RBCs to carry required oxygen to cells in the body. Hemoglobinopathies can be autosomal dominant * or autosomal recessive * * , so defects in these genes affect males and females equally. Recessive traits usually do not cause serious problems unless two copies—one inherited from each parent—of the recessive genes are present.


Hemoglobin is the protein that carries oxygen from the lungs to cells throughout the body and transports carbon dioxide * from the cells back to the lungs. RBCs, or erythrocytes (e-RITH-ro-sites), are the most abundant cells in the blood. Each RBC contains about 280 million hemoglobin molecules.

Normal RBCs survive about 120 days. Cells called macrophages (MAK-ro-fayj-ez) engulf and chew up dying or dead RBCs in the spleen and liver. More than 2 million RBCs die every second and must be replaced at exactly the same rate by the bone marrow * .

Hemoglobin is made up of four protein chains called globins—two alpha-globins and two beta-globins. Defects, or mutations, in the genes that code for the production of these globins cause hemoglobinopathies. These altered genes result in abnormal hemoglobin proteins that are inefficient at transporting oxygen. They may also slow down the rate of hemoglobin production in the bone marrow and speed up the destruction of RBCs, a condition called hemolytic * anemia.

Sickle cell anemia

Sickle cell anemia is the most familiar hemoglobinopathy and the most serious type of sickle cell disease. People with sickle cell disease have an abnormal type of hemoglobin known as HbS. HbS makes RBCs sickle, or form a crescent shape, rather than being disc-shaped. These cells carry less oxygen than normal RBCs. They are fragile, more easily destroyed than normal RBCs, and have a life span of only 10 to 20 days. The rapid destruction of these RBCs makes it impossible for the bone marrow to replace them fast enough. It also causes an accumulation of the hemoglobin breakdown product bilirubin, which can lead to jaundice. In addition, the sickle shape prevents these RBCs from flowing easily. They tend to bunch up and clog small blood vessels. Oxygen starvation and blood vessel blockages can cause severe inflammation * , pain, and tissue damage, precipitating several types of sickle cell crises that can affect any of a number of organs.

Only those who inherit two HbS genes (SS), one from each parent, have sickle cell anemia. Those with one HbS gene and one normal HbA gene (SA) have sickle cell trait. Only about 45 percent of their hemoglobin is HbS, and only a small percentage of their RBCs are sickled. SA individuals are not only usually healthy, but they have increased resistance to malaria * , an often fatal disease in Africa where HbS is common.


Normal adult hemoglobin is designated HbA. People with sickle cell anemia have only hemoglobin S (HbS) in their red blood cells. In the late 1940s, using a procedure called electrophoresis (e-lek-tro-fo-REE-sis), Linus Pauling and Harvey Itano at the California Institute of Technology showed that HbS moves more slowly toward the positive electrode than HbA does in an electric field. They concluded that HbS was slightly less negatively charged than HbA. Later, Vernon Ingram of the Medical Research Council in London demonstrated that the difference between HbS and HbA comes from a structural change in the beta-globin chain. An uncharged amino acid (protein building block) replaces a negatively charged amino acid. Electrophoresis continues to be used to identify different types of hemoglobin.

Hundreds of unusual hemoglobins are now known. Several common ones are:

The distinction between beta-thalassemias intermedia and major is usually based on the latter's requirement for regular life-sustaining blood transfusions.

Rare hemoglobinopathies

There are many relatively rare subtypes of hemoglobinopathies, including hemoglobin C and hemoglobin E diseases. In these disorders, abnormally shaped RBCs are subject to excessive destruction, resulting in chronic * hemolytic anemia. Whereas hemoglobin C disease is similar to mild forms of sickle cell anemia, hemoglobin E disease rarely causes symptoms other than anemia. HbE is common among Southeast Asians.

Other hemoglobinopathies result from gene combinations in which an individual inherits one sickle cell-related gene mutation and/or one thalassemia-related mutation from each parent:

How Common Are Hemoglobinopathies?

Thalassemia affects about 1,000 Americans. Alpha-thalassemias occur most often in Chinese and Southeast Asians. Beta-thalassemias occur most often in people of Mediterranean origin and, to a lesser extent, in Chinese and other Asians and in blacks.

What Are the Symptoms of Hemoglobinopathies?

The symptoms of serious hemoglobinopathies usually develop in infancy, as the bone marrow switches production from fetal to adult hemoglobin. Symptoms depend on the severity of the anemia caused by the specific genetic defect and on the rate of RBC destruction. Symptoms such as jaundice and an enlarged spleen reflect the excessive destruction of RBCs. Babies with severe disease, such as hemoglobin H disease or betathalassemia major, develop serious anemia during the first two years of life. This results in abnormally slow growth and abnormal bone development, particularly in the facial bones. Other symptoms may include an enlarged liver, spleen, and heart. Many such babies are also pale and tired and have a poor appetite. In contrast, less serious disease, like that in thalassemia minor, may produce no symptoms.

Common symptoms of sickle cell disease include the following:

How Are Hemoglobinopathies Diagnosed and Treated?

Severe hemoglobinopathies are usually diagnosed in early childhood. Most doctors make a diagnosis using a combination of laboratory tests. These tests include hemoglobin electrophoresis, which measures different types of hemoglobin in the blood, and may also include:


Severe hemoglobinopathies require intensive lifelong medical care. Bone marrow or stem cell * transplants * , especially in children, can sometimes cure sickle cell disease and thalassemias. But it is often very difficult to find a suitable bone marrow donor. Other treatments for hemoglobinopathies include:

Other treatments for sickle cell and hemoglobin E diseases are directed at managing and controlling symptoms and preventing crises. These include:

Periodic RBC transfusions alleviate symptoms and improve the quality of life for those with moderately severe hemoglobinopathies like betathalassemia intermedia. Treatment of beta-thalassemia major requires transfusions as often as every two to four weeks throughout life. Because frequent blood transfusions can lead to a dangerous accumulation of iron in the body (since hemoglobin binds to iron), patients must undergo iron chelation therapy with chelating drugs that bind the iron and remove it from the body. In the past this procedure was difficult and painful, and many thalassemia patients shortened their lives significantly by failing to receive this therapy. Fortunately, the use of oral chelating drugs replaced older chelation therapies, which required patients to undergo slow, prolonged drug injections that lasted many hours.

Complications of sickle cell disease

Sickle cell disease and other hemoglobinopathies render people very susceptible to infections. In the United States and many other countries, babies are tested for HbS as part of routine newborn screenings, regardless of their ethnic background. Before screening became commonplace, many infants with sickle cell disease died from infections. The use of preventive antibiotics and a full immunization regimen significantly reduced this infant mortality.


In the late 20th and early 21st centuries, scientists hoped to cure hemoglobinopathies by replacing the defective genes with normal ones. Because they were among the best-understood genetic disorders, sickle cell disease and thalassemia were early targets of gene therapy experiments. In 1980 Martin Cline, the California scientist who created the first transgenic mouse, performed unauthorized gene therapy experiments on two individuals with beta-thalassemia. Cline was censured by scientific regulatory boards, and, although these experiments did not worsen these patients' condition, his attempts showed that much research was needed before gene therapy could be used to cure genetic diseases.

In addition to the symptoms and complications of anemia, most people with serious forms of sickle cell disease experience critical illnesses called crises. These begin suddenly when clumping of sickled RBCs obstructs the normal blood flow, depriving tissues and organs of oxygen. Specific types of sickle cell crises are:

Sickle cell crises can last for hours or days. Many people experience long periods of remission * during which they may feel relatively well. Others experience pain on a daily basis and may be hospitalized with crises multiple times each year.

Sickle cell crises can damage almost any part of the body. People with sickle cell disease are particularly susceptible to the following:

In the past, most people with sickle cell disease died from organ failure between the ages of 20 and 40, but with better treatment and disease management, the average life expectancy in the United States has risen to almost 50 years.


If “A” represents a normal hemoglobin gene and “X” represents a gene causing a hemoglobinopathy, normal adults are designated AA, with two normal hemoglobin genes. Carriers are designated AX, with one gene encoding a normal hemoglobin and one encoding an abnormal hemoglobin. Carriers may have no symptoms and may be unaware that they have a gene for abnormal hemoglobin. Children of an AA adult and an AX adult have a 50 percent chance of being AA and a 50 percent chance of being AX. Offspring of two AX parents have a 50 percent chance of being an unaffected carrier (AX) and a 25 percent chance of either being AA or XX. XX children will have the hemoglobinopathy. Children of an AA adult and an XX adult will have a 100 percent chance of being AX carriers, and children of two XX parents have a 100 percent chance of being XX and developing the hemoglobinopathy.

Complications of thalassemia

Beta-thalassemia major has a great many potential complications, including:

In addition, the frequent transfusions people with severe thalassemias receive often result in iron accumulation throughout the body, which can damage glands * and organs, especially the heart and liver. Heart failure * at a young age is the leading cause of death among people with betathalassemia major. Infections are also a major cause of death. But with improved medical treatments, many children with this disease are living well into adulthood.

Can Hemoglobinopathies Be Prevented?

Prospective parents who may be carrying a hemoglobinopathy gene can choose to be tested and receive genetic counseling before having children. Prenatal * screening is also available for fetuses at high risk for hemoglobinopathies.

Couples at risk for these genetic diseases can also use preimplantation genetic diagnosis to reproduce without passing on the mutated genes that cause hemoglobinopathies. This technology was developed in the 1980s and involves in vitro * fertilization, followed by placing the fertilized egg in a laboratory culture * * and test the sample for specific gene abnormalities. The parents may then choose whether or not to have the embryo (sometimes two embryos) implanted into the female's uterus.

See also Anemia, Bleeding, and Clotting • Genetic Diseases: Overview • Sickle Cell Anemia • Thalassemia


Books and Articles

Bjorklund, Ruth, Sickle Cell Anemia. Tarrytown, NY: Marshall Cavendish, 2012.

Mooney, Carla, Genetics. White River Junction, VT: Nomad Press, 2014.

Parks, Peggy J., Genetic Disorders. San Diego, CA: ReferencePoint Press, 2010.


Centers for Disease Control and Prevention. “Sickle Cell Disease (SCD).” CDC.gov . http://www.cdc.gov/ncbddd/sicklecell/index.html (accessed March 12, 2016).

MedlinePlus. “Hemoglobinopathy.” U.S. National Library of Medicine. https://wwwqa.nlm.nih.gov/medlineplus/qa3/ency/article/001291.htm (Accessed June 9, 2016).


Cooleyys Anemia Foundation. 330 Seventh Ave., No. 200, New York, NY 10001. Telephone: 212-279-8090. Website: http://www.thalassemia.org (accessed March 12, 2016).

National Heart, Lung, and Blood Institute. PO Box 30105, Bethesda, MD 20824-0105. Telephone: 301-592-8573. Website: http://nhlbi.nih.gov/health/health-topics (accessed March 12, 2016).

Sickle Cell Disease Association of America. 3700 Koppers St., Suite 570, Baltimore, MD 21227. Telephone: 410-528-1555. Website: http://www.sicklecelldisease.org (accessed March 12, 2016).

* blood transfusion is the process of giving blood (or certain cells or chemicals found in the blood) to a person who needs it due to illness or blood loss.

* liver is a large organ located beneath the ribs on the right side of the body. The liver performs numerous digestive and chemical functions essential for health.

* spleen is an organ in the upper left part of the abdomen that stores and filters blood. As part of the immune system, the spleen also plays a role in fighting infection.

* jaundice (JAWN-dis) is a yellowing of the skin, and sometimes the whites of the eyes, caused by a buildup of bilirubin, a chemical produced in and released by the liver or created when hemoglobin breaks down. An increase in bilirubin may indicate liver disease or certain blood disorders.

* genetic (juh-NEH-tik) refers to heredity and the ways in which genes control the development and maintenance of organisms.

* autosomal dominant mode of inheritance is one in which only one copy of an abnormal gene is necessary to cause disease.

* recessive describes a gene that is not dominant. A second identical recessive gene must be present for the associated trait to show in an individual. When a recessive gene is paired with a normal one, the individual is said to be a carrier of the trait.

* chromosomes (KRO-muh-somz) are threadlike chemical structures inside cells on which genes are located. There are 46 (23 pairs) of chromosomes in normal human cells. Genes on the X and Y chromosomes (known as the sex chromosomes) help determine whether a person is male or female. Females have two X chromosomes; males have one X and one Y chromosome.

* carbon dioxide (CAR-bon dy- OK-side) is an odorless, colorless gas that cells release as a waste product after using oxygen for energy. Hemoglobin molecules in red blood cells carry this carbon dioxide to be breathed out by the lungs.

* bone marrow is the soft tissue inside bones where red blood cells are made.

* hemolytic (he-muh-LIH-tik) refers to the destruction of red blood cells and the subsequent release of hemoglobin into the bloodstream.

* inflammation (in-fla-MAY-shun) is the body's reaction to irritation, infection, or injury that often involves swelling, pain, redness, and warmth.

* malaria (mah-LAIR-e-uh) is a disease spread to humans by the bite of an infected mosquito. Several species of parasites in the genus Plasmodium cause malaria, which may involve fever, chills, vomiting, headache, and other symptoms and can be fatal.

* chronic (KRAH-nik) means lasting a long time or recurring frequently.

* puberty (PU-ber-tee) is the period during which sexual maturity is attained.

* abdominal (ab-DAH-mih-nul) refers to the area of the body below the ribs and above the hips that contains the stomach, intestines, and other organs.

* stem cells are immature cell precursors that can develop into a variety of cells types. Stem cells can be implanted into people with certain diseases to replace diseased cells.

* transplants (TRANS-plantz) are organs or tissues from another body or made artificially and are used to replace a poorly functioning organ or tissue.

* antibiotics (an-tie-by-AH-tiks) are drugs that kill or slow the growth of bacteria.

* vaccines (vak-SEENS) are preparations of killed or weakened germs, or parts of a germ or product it produces, given to prevent or lessen the severity of the disease that can result if a person is exposed to the germ itself. Use of vaccines for this purpose is called immunization.

* hydroxyurea is a drug that was originally used to treat certain cancers by interfering with cancer cell growth. It is used to treat some hemoglobinopathies and works by decreasing the amount of HbS and increasing the amount of fetal hemoglobin the body produces.

* dehydration (dee-hi-DRAY-shun) is a condition in which the body is depleted of water, usually caused by excessive and unreplaced loss of body fluids, such as through sweating, vomiting, or diarrhea.

* remission is an easing of a disease or its symptoms for a prolonged period.

* gallstones (GAWL-stonz) are hard masses that form in the gallbladder.

* pulmonary refers to the lungs.

* hypertension (HI-per-ten-shun) is abnormally high blood pressure in the arteries.

* heart attack is a general term that refers to a sudden, intense episode of heart injury. It is usually caused by a blockage in a coronary artery, which stops blood flow to the heart, depriving it of oxygen.

* stroke is a reduction or interruption of blood flow to the brain. A stroke may occur when a blood vessel supplying the brain becomes clogged or bursts, depriving brain tissue of oxygen. As a result, nerve cells in the affected areas of the brain, and the specific body parts they control, may not function properly.

* osteoporosis (os-te-o-por-O-sis) is the loss of bone mass. This makes the bones thinner, weak, and brittle.

* glands are organs that produce substances such as hormones and other chemicals that regulate body functions.

* heart failure is a medical term used to describe a condition in which a damaged heart cannot pump enough blood to meet the oxygen and nutrient demands of the body. People with heart failure may find it hard to exercise due to the insufficient blood flow, but some people live a long time with heart failure.

* prenatal (pre-NAY-tal) refers to the time before a fetus is born.

* in vitro (in-VEE-tro) means in the laboratory or other artificial environment rather than in the living body, which is referred to as in vivo.

* culture (KUL-chur) refers to a laboratory dish containing material that supports the growth of certain living cells. Doctors often use cultures to identify cell abnormalities or to determine which microorganisms are causing a disease.

* biopsy (BI-op-see) is a test in which a small sample of body tissue is removed and examined for signs of disease.

Disclaimer:   This information is not a tool for self-diagnosis or a substitute for professional care.

(MLA 8th Edition)