Sickle Cell Disease

People who have sickle cell disease have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells. Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. People who have sickle cell disease inherit two abnormal hemoglobin genes, one from each parent.

The types of sickle cell disease include the following:

• Hemoglobin Sβ0 thalassemia
• Hemoglobin Sβ+ thalassemia
• Hemoglobin SC
• Hemoglobin SD
• Hemoglobin SE
• Hemoglobin SS

In all types of sickle cell disease, at least one of the two abnormal genes causes a person’s body to make hemoglobin S. When a person has two hemoglobin S genes (hemoglobin SS), the disease is called sickle cell anemia. This is the most common and often most severe type of sickle cell disease. Hemoglobin SC disease and hemoglobin Sβ thalassemia are two other common types of sickle cell disease. Hemoglobin SD and hemoglobin SE are much less common.

Abnormal hemoglobin, called hemoglobin S, causes sickle cell disease.

Sickle cell disease is a genetic disorder caused by mutations in the beta globin gene that leads to faulty hemoglobin protein, called hemoglobin S. Hemoglobin S changes flexible red blood cells into rigid, sickle-shaped cells. These sickle cells can block blood flow, and result in pain and organ damage. Medical Animation Copyright © 2020 Nucleus Medical Media, All rights reserved.

Hemoglobin S gene

Sickle cell disease is an inherited disease caused by defects, called mutations, in the beta globin gene that helps make hemoglobin. Normally, hemoglobin in red blood cells takes up oxygen in the lungs and carries it through the arteries to all the cells in the tissues of the body. Red blood cells that contain normal hemoglobin are disc-shaped and flexible so that they can move easily through large and small blood vessels to deliver oxygen.

Sickle hemoglobin is not like normal hemoglobin. The mutations in the gene cause a problem when oxygen levels in the blood are lower, which occurs once the hemoglobin has delivered oxygen to the cells in the body’s tissues. With less oxygen, the abnormal hemoglobin S gene can cause rigid, nonliquid protein strands to form within the red blood cell. These rigid strands can change the shape of the cell, causing the sickled red blood cell that gives the disease its name.

Sickle-shaped cells are not flexible and can stick to vessel walls, causing a blockage that slows or stops the flow of blood. When this happens, oxygen is unable to reach nearby tissues. The lack of oxygen in tissue can cause attacks of sudden severe pain, called pain crises. These pain attacks can occur without warning, and a person who has them often needs to go to the hospital for effective treatment.

Because sickle cells cannot change shape easily, they tend to burst apart. Normal red blood cells live about 90 to 120 days, but sickle cells last only 10 to 20 days. The body is always making new red blood cells to replace the old cells. However, in sickle cell disease, the body may have trouble keeping up with how fast the cells are being destroyed. Because of this, the number of red blood cells is usually lower than normal. This condition, called anemia, can cause a person to have less energy.

How is the hemoglobin S gene inherited?

When the hemoglobin S gene is inherited from only one parent, and a normal hemoglobin gene—hemoglobin A—is inherited from the other, that person will have sickle cell trait. People who have sickle cell trait are generally healthy.

Only rarely do people who have sickle cell trait have complications similar to those seen in people who have sickle cell disease. But people who have sickle cell trait are carriers of a defective hemoglobin S gene, so they can pass it on when they have a child.

If the child’s other parent also has sickle cell trait or another abnormal hemoglobin gene, such as beta-thalassemia, hemoglobin C, hemoglobin D, or hemoglobin E, that child has a chance of having sickle cell disease.

In the image above, each parent has one normal hemoglobin A gene and one hemoglobin S gene, which means each of their children has:

• A 25% chance of inheriting two normal hemoglobin A genes. In this case, the child does not have sickle cell trait or disease.
• A 50% chance of inheriting one normal hemoglobin A gene and one hemoglobin S gene. This child has sickle cell trait.
• A 25% chance of inheriting two hemoglobin S genes. This child has sickle cell disease.

It is important to keep in mind that each time this couple has a child, the chances of that child having sickle cell disease remain the same. In other words, if the firstborn child has sickle cell disease, there is still a 25% chance that the second child will also have the disease. Both boys and girls can inherit sickle cell trait, sickle cell disease, or normal hemoglobin.

If a person wants to know whether he or she carries a sickle hemoglobin gene, a doctor can order a blood test to find out.

In the United States, most people who have sickle cell disease are of African ancestry or identify themselves as Black.

• About 1 in 13 Black or African American babies is born with sickle cell trait.
• About 1 in every 365 Black or African American babies is born with sickle cell disease.

There are also many people who have sickle cell disease who come from Hispanic, southern European, Middle Eastern, or Asian Indian backgrounds.

About 100,000 Americans have sickle cell disease.

People who do not know whether they carry an abnormal hemoglobin gene can ask their doctor to have their blood tested.

Couples who are planning to have children and know that they are at risk of having a child with sickle cell disease may want to meet with a genetics counselor. A genetic counselor can answer questions about the risk and explain the choices that are available.

If a person has sickle cell disease, it is present at birth. But most newborns do not have any problems from the disease until they are about 5 or 6 months of age.

The symptoms of sickle cell disease can vary from person to person and can change over time. Over time, you may experience symptoms depending on how sickle cell disease affects your health.

Early signs and symptoms

Early symptoms of sickle cell disease may include:

• A yellowish color of the skin, known as jaundice, or whites of the eyes, known as icterus, that occurs when a large number of red cells undergo hemolysis
• fatigue or fussiness from anemia
• Painful swelling of the hands and feet, known as dactylitis

Complications

Complications of sickle cell disease include:

• Acute chest syndrome. Sickling in blood vessels of the lungs can deprive lungs of oxygen. This can damage lung tissue and cause chest pain, fever, and difficulty breathing. Acute chest syndrome is a medical emergency.
• Acute pain crisis. Also known as sickle cell or vaso-occlusive crisis, this can happen without warning when sickle cells block blood flow. People describe this pain as sharp, intense, stabbing, or throbbing. Pain can strike almost anywhere in the body and in more than one spot at a time. Common areas affected by pain include the abdomen, chest, lower back, or arms and legs. A crisis can be brought on by high altitudes, dehydration, illness, stress, or temperature changes. Often a person does not know what triggers the crisis.
• Chronic pain. Chronic pain is common, but it can be difficult to describe, but it is usually different from crisis pain or the pain that results from organ damage.
• Delayed growth and puberty. Children who have sickle cell disease may grow and develop more slowly than their peers because of anemia. They will reach full sexual maturity, but this may be delayed.
• Eye problems. Sickle cell disease can injure blood vessels in the eye, most often in the retina. Blood vessels in the retina can overgrow, get blocked, or bleed. This can cause the retina to detach, which means it is lifted or pulled from its normal position. These problems can lead to vision loss.
• Gallstones. When red blood cells break down, in a process called hemolysis, they release hemoglobin. Hemoglobin then gets broken down into a substance called bilirubin. Bilirubin can form stones, called gallstones, that get stuck in the gallbladder. The gallbladder is a small sac-shaped organ beneath the liver that helps with digestion.
• Heart problems, including coronary heart disease and pulmonary hypertension. Frequent blood transfusions may also cause heart damage from iron overload.
• Infections. The spleen is important for protection against certain kinds of infections. If you have sickle cell disease, a damaged spleen raises the risk for certain infections, including chlamydia, haemophilus influenzae type B, salmonella, and staphylococcus.
• Joint problems. Sickling in the hip bones and, less commonly, the shoulder joints, knees, and ankles, can decrease oxygen flow and result in a condition called avascular or aseptic necrosis, which severely damages the joints. Symptoms include pain and problems with walking and joint movement. Over time, you may need pain medicines, surgery, or joint replacement.
• Kidney problems. Sickle cell disease may cause the kidneys to have trouble making the urine as concentrated as it should be. This may lead to a need to urinate often and to bedwetting or uncontrolled urination during the night. This often starts in childhood.
• Leg ulcers. Sickle cell ulcers are sores that usually start small and then get larger and larger. Some ulcers will heal quickly, but others may not heal and may last for long periods of time. Some ulcers come back after healing. People who have sickle cell disease usually do not get ulcers until after age 10.
• Liver problems. Sickle cell intrahepatic cholestasis is an uncommon but severe type of liver damage that happens when sickled red cells block blood vessels in the liver. This blockage prevents enough oxygen from reaching liver tissue. These episodes are usually sudden and may happen more than once. Children often recover, but some adults may have chronic problems that lead to liver failure. Frequent blood transfusions can lead to liver damage from iron overload.
• Pregnancy problems. Pregnancy can increase the risk for high blood pressure and blood clots in women who have sickle cell disease. The condition also increases the risk of miscarriage, premature birth, and low birth weight babies. Learn more about pregnancy and sickle cell disease.
• Priapism. Priapism is an unwanted, sometimes prolonged, painful erection. This happens when blood flow out of the erect penis is blocked by sickled cells. Over time, priapism can cause permanent damage to the penis and lead to impotence. Priapism that lasts for more than 4 hours is a medical emergency.
• Severe anemia. People who have sickle cell disease usually have mild to moderate anemia. At times, however, they can have severe anemia, which is life-threatening.
• Stroke or silent brain injury. Silent brain injury, also called silent stroke, is damage to the brain without showing outward signs of stroke. This injury is common and can be detected on magnetic resonance imaging (MRI) scans. Silent brain injury can lead to difficulty in learning, making decisions, or holding down a job.

Severe anemia complications

People who have sickle cell disease also usually have mild to moderate anemia. At times, however, they can have severe anemia. Severe anemia can be life-threatening. Severe anemia in a newborn or child who has sickle cell disease may be a result of:

• Aplastic crisis. Aplastic crisis is usually caused by a parvovirus B19 infection, also called fifth disease or slapped cheek syndrome. Parvovirus B19 is a very common infection, but in sickle cell disease, it can cause the bone marrow to stop producing new red cells for a while, leading to severe anemia.
• Splenic sequestration crisis. Your spleen filters your blood and destroys old blood cells. In people who have sickle cell disease, red blood cells may get trapped in the spleen, making it quickly grow larger than normal. With red blood cells trapped in the spleen, fewer are available to circulate in the blood, and this can lead to severe anemia. A large spleen may also cause pain in the left side of the belly. A parent can usually feel a spleen that is larger than normal in a child’s belly.

Aplastic crisis and splenic sequestration crisis most commonly occur in newborns and children who have sickle cell disease. Adults who have sickle cell disease may also experience episodes of severe anemia, but these usually have other causes. Babies and newborns who have severe anemia may not want to eat and may seem very sluggish.

Your doctor may use a number of tests to diagnose sickle cell disease if various screening tests show that you might have the condition.

Screening tests

People who do not know whether they make sickle hemoglobin or another abnormal hemoglobin, such as SC, Sβ thalassemia, and SE, can find out by having their blood tested. This way, they can learn whether they carry a gene—or have the trait—for an abnormal hemoglobin that they could pass on to a child.

With this information, parents can be better informed about the chances of having a child with some type of sickle cell disease, such as hemoglobin SS or SC, Sβ thalassemia, or others.

Newborn screening

When a child has sickle cell disease, early diagnosis is important to better prevent complications.

Every state in the United States, the District of Columbia, and the U.S. territories require that every baby be tested for sickle cell disease as part of a newborn screening program. In newborn screening programs, blood from a heel prick is collected in “spots” on a special paper. The hemoglobin from this blood is then analyzed in special labs. Newborn screening results are sent to the doctor who ordered the test and to the child’s primary doctor.

If a baby is found to have sickle cell disease, health providers from a special follow-up newborn screening group contact the family directly to make sure that the parents know the results. The child is always retested to be sure that the diagnosis is correct.

Newborn screening programs also find out whether the baby has an abnormal hemoglobin trait. If so, the parents are informed, and counseling is offered. Remember that when a child has sickle cell trait or sickle cell disease, a future sibling or the child’s own future child may be at risk.

Prenatal screening

Doctors can also diagnose sickle cell disease before a baby is born. This is done using a sample of amniotic fluid, the liquid in the sac surrounding a growing embryo, or of tissue taken from the placenta, the organ that attaches the umbilical cord to the mother’s womb.

Testing before birth can be done as early as 8 to 10 weeks into the pregnancy. This testing looks for the sickle hemoglobin gene rather than the abnormal hemoglobin.

A blood and bone marrow transplant is currently the only cure for some patients who have sickle cell disease. After early diagnosis, your doctor may recommend medicines or transfusions to manage complications, including chronic pain.

Babies who have sickle cell disease may see a hematologist, a doctor who specializes in blood diseases such as sickle cell disease. For newborns, the first sickle cell disease visit should take place before 8 weeks of age.

Medicines

Voxelotor

The U.S. Food and Drug Administration (FDA) approved a new medicine in 2019 to treat sickle cell disease in adults and children 12 years and older. The oral medicine prevents red blood cells from forming the sickle shape and binding together. This may decrease the destruction of some red blood cells, which in turn lowers the risk for anemia and improves blood flow to your organs.

Possible side effects include headache, diarrhea, abdominal pain, nausea, fatigue, and fever. Rarely, allergic reactions may occur, causing rashes, hives, or mild shortness of breath. Talk to your doctor about other medicines you take.

Crizanlizumab-tmca

In 2019, the FDA also approved a new medicine to reduce the number of pain crises experienced by adults and children 16 years and older who have sickle cell disease. The medicine, which is given through an IV in the vein, helps prevent blood cells from sticking to blood vessel walls and causing blood flow blockage, inflammation, and pain crises.

Possible side effects include nausea, joint pain, back pain, and fever.

Penicillin

In children who have sickle cell disease, taking penicillin two times a day has been shown to reduce the chance of having a severe infection caused by the pneumococcus bacteria. Newborns need to take liquid penicillin. Older children can take tablets.

Many doctors will stop prescribing penicillin after a child has reached the age of 5. Some prefer to continue this antibiotic throughout life, particularly if a person has hemoglobin SS or hemoglobin Sβ0 thalassemia, since people who have sickle cell disease are still at risk. All people who have had surgical removal of the spleen, called a splenectomy, or a past infection with pneumococcus should keep taking penicillin throughout life.

Hydroxyurea

Hydroxyurea is an oral medicine that has been shown to reduce or prevent several sickle cell disease complications.

• Use in adults. Many studies of adults with hemoglobin SS or hemoglobin Sβ thalassemia showed that hydroxyurea reduced the number of episodes of pain crises and acute chest syndrome. It also improved anemia and decreased the need for transfusions and hospital admissions.
• Use in children. Studies in children with severe hemoglobin SS or Sβ thalassemia showed that hydroxyurea reduced the number of vaso-occlusive crises and hospitalizations. A study of children between the ages of 9 and 18 months with hemoglobin SS or Sβ thalassemia also showed that hydroxyurea reduced the number of pain episodes and dactylitis. There is no information about how safe or effective hydroxyurea is in children under 9 months of age
• Pregnant women should not use hydroxyurea.

Since hydroxyurea can decrease several complications of sickle cell disease, most experts recommend that children and adults with hemoglobin SS or Sβ0 thalassemia who have frequent painful episodes, recurrent chest crises, or severe anemia take hydroxyurea daily.

Hydroxyurea can cause the blood’s white cell count or platelet count to drop. Rarely, it can worsen anemia. These side effects usually go away quickly if a patient stops taking the medicine. When the patient restarts it, the doctor usually prescribes a lower dose.

It is still unclear whether hydroxyurea can cause problems later in life in people who have sickle cell disease and take the medicine for many years. Studies so far suggest that it does not put people at a higher risk of cancer and does not affect growth in children, but further studies are needed.

Read more about hydroxyurea.

Transfusions

Your doctor may recommend transfusion to treat and prevent certain sickle cell disease complications. These transfusions may include:

• Acute transfusion to treat complications that cause severe anemia. Doctors may also use transfusions when a patient has an acute stroke, in many cases of acute chest crises, and in multi-organ failure. A patient who has sickle cell disease usually receives blood transfusions before surgery, to prevent complications.
• Red blood cell transfusions to increase the number of red blood cells and provide normal red blood cells that are more flexible than red blood cells with sickle hemoglobin.
• Regular or ongoing blood transfusions for people who have had an acute stroke, to reduce the chances of having another stroke. Doctors also recommend blood transfusions for children who have abnormal transcranial Doppler (TCD) ultrasound results, because transfusions can reduce the chance of having a first stroke. Some doctors use this approach to treat complications that do not improve with hydroxyurea. Doctors may also use transfusions in people who have too many side effects from hydroxyurea. Possible complications include alloimmunization, which can make it hard to find a matching unit of blood for a future transfusion; infection; and iron overload.

Blood and bone marrow transplant

A blood and bone marrow transplant is currently the only cure for sickle cell disease, but it is not for everyone. Most patients who have sickle cell disease either are too old for a transplant or do not have a relative who is a good enough genetic match to be a donor. A well-matched donor is needed for a patient to have the best chance for a successful transplant.

Most sickle cell disease transplants are currently performed in children who have had complications such as strokes, acute chest crises, and recurring pain crises. These transplants usually use a matched donor. Blood and bone marrow transplants are riskier in adults.

Several medical centers are looking into new ways to help more people who have sickle cell disease get a transplant. These include blood and bone marrow transplant techniques in children and adults who do not have a matched donor in the family or who are older than most recipients.

Blood and bone marrow transplants are successful in about 85% of children when the donor is related and HLA (human leukocyte antigen)-matched. Even with this high success rate, transplants still have risks. Complications can include severe infections, seizures, and other clinical problems. About 5% of people who have received such transplants have died. Sometimes transplanted cells attack the recipient’s organs. This is called graft-versus-host disease. You will get medicine to prevent many of the complications, but they still can happen.

Learn more about blood and bone marrow transplants.

Potential genetic therapy treatments for sickle cell disease

Researchers at the NHLBI are exploring ways genetic therapies may help develop new treatments or find a cure for sickle cell disease. Genetic therapies aim to treat or cure conditions by adding new DNA or changing existing DNA.

Watch this video to learn about how genome editing works and how it could be used to treat sickle cell disease. Medical Animation Copyright © 2020 Nucleus Medical Media, All rights reserved.

Genetic therapy involves either restoring a faulty or missing gene or adding a new gene that improves the way the cell works. Researchers take blood or bone marrow from a patient and modify their stem cells in a laboratory using genetic therapies.

Genetic therapies that modify a person’s own hematopoietic stem cells may provide a cure for people who have sickle cell disease and do not have a well-matched donor. Modified stem cells can be injected into the blood, then the cells travel in the bloodstream to the marrow spaces inside the bones. Once inside the bone marrow, the cells can produce healthy red blood cells that do not sickle.

Follow these steps to help relieve symptoms and reduce your chances of serious problems, such as pain crises and other complications of sickle cell disease.

Receive routine follow-up care

• See your doctor regularly. Most people who have sickle cell disease should see their doctor every 3 to 12 months, depending on their age.
• Get regular vaccines, including an influenza or flu shot every year. Your doctor may also recommend a second pneumococcus (PPSV23), in addition to the pneumococcus one (PCV13) that all children get as part of their regular immunizations. This second vaccine is given after 24 months of age and again 5 years later. Adults who have sickle cell disease and have not received any pneumococcal vaccine should get a dose of the PCV13 vaccine. They should later receive the PPSV23 if they have not already received it or if it has been more than 5 years since they did. Follow these guidelines even if you or your child is still taking penicillin.

Learn how to manage pain

• When an acute crisis is just starting, drink lots of fluids and take a nonsteroidal anti-inflammatory (NSAID) pain medicine, such as ibuprofen. If you have kidney problems, acetaminophen is often preferred.
• If you cannot control the pain at home, go to a sickle cell disease day hospital/outpatient unit or an emergency room to receive additional, stronger medicines and intravenous (IV) fluids. You may be able to return home once your pain is under better control. You may need to be admitted to the hospital to fully control an acute pain crisis.

Learn more about how to manage pain.

Adopt a healthy lifestyle

• Get regular physical activity. You may tire easily, so be careful to pace yourself and avoid very strenuous activities.
• Choose heart-healthy foods, including limiting alcohol. Drink extra water to avoid dehydration.
• Quit smoking. Visit Smoking and Your Heart and the National Heart, Lung, and Blood Institute’s Your Guide to a Healthy Heart. Although these resources focus on heart health, they include basic information about how to quit smoking. For free help and support to quit smoking, you can call the National Cancer Institute’s Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848).

Prevent problems over your or your child’s lifetime

• Avoid situations that may set off a crisis. Extreme heat or cold, as well as abrupt changes in temperature, are often triggers. When going swimming, ease into the water rather than jumping right in.
• Do not travel in an aircraft cabin that is unpressurized.
• If you experience priapism (prolonged, painful erection), you may be able to relieve your symptoms by doing light exercise, emptying your bladder by urinating, drinking more fluids, and taking medicine recommended by your doctor.
• If your child attends daycare, preschool, or school, speak to his or her teacher about the disease. Teachers need to know what to watch for and how to accommodate your child.
• Learn how to palpate, or feel, your child’s spleen. Because of the risk of splenic sequestration crisis, caretakers should learn how to palpate a child’s spleen. They should try to feel for the spleen daily and more often when the child is ill. If the spleen feels larger than usual, they should call the care provider.
• Seek help if you have feelings of depression or anxiety. Supportive counseling and, sometimes, antidepressant medicines may help.

Get more tips for healthy living with sickle cell disease.

Know when to seek emergency medical care

Sickle cell disease can lead to serious and life-threatening health problems. If you think you or someone else is having any of the following symptoms or complications, seek medical care or call 9–1–1 right away.

• Symptoms of severe anemia, including extreme tiredness (fatigue), shortness of breath, dizziness, or irregular heartbeat. Splenic sequestration crisis or an aplastic crisis can cause severe anemia symptoms. These conditions can be life-threatening.
• Fever. All children and adults who have sickle cell disease and a fever of more than 101.3 degrees Fahrenheit or 38.5 degrees Celsius must be seen by a doctor and treated with antibiotics right away. Some people will need to be hospitalized.
• Symptoms of acute chest syndrome, including chest pain, coughing, fever, and shortness of breath. You will need to be admitted to the hospital, where you may receive antibiotics, oxygen therapy, or a blood transfusion.
• Signs and symptoms of a stroke, such as sudden weakness, numbness on one side of the body, confusion, or trouble speaking, seeing, or walking.
• Priapism. If you experience priapism that lasts for 4 hours or more, go to the hospital to see a hematologist and urologist.

Pregnancy and sickle cell disease

Pregnant women who have sickle cell disease are at greater risk for problems. If you are pregnant or planning for pregnancy, meet with a doctor who specializes in high-risk pregnancies and has experience with patients who have sickle cell disease.

Your doctor may prescribe certain vitamins and will be careful to prescribe pain medicines that are safe for you and your baby. You should not use hydroxyurea during pregnancy.

You may need to have one or more blood transfusions during pregnancy to treat problems, such as anemia symptoms that get worse. You may also experience more pain crises or be at higher risk of having acute chest syndrome. Your doctor will talk to you about how to help prevent these complications.