Sickle Cell Disease

What is sickle cell disease?

Sickle cell disease is the name of a group of inherited blood disorders that is characterized by chronic anemia, periodic episodes of pain and other complications.

The disease affects the red blood cells. Sickle cell disease results when red blood cells make mostly hemoglobin S instead of the normal hemoglobin A. Normal red blood cells are smooth, round and soft; their shape and softness enable them to move easily through the blood vessels to carry oxygen to all parts of the body.

In sickle cell disease, the abnormal hemoglobin S causes the red blood cells to become hard, pointed and sticky and shaped like crescents or sickles. When these hard and pointed red cells go through the small blood vessels, they often get stuck and block the vessels. They also stick to and damage the lining of larger blood vessels. The damaged vessels become scarred, narrowed and sometimes completely closed. The blockage of blood flow through blood vessels can lead to pain, stroke and damage to many organs.

Sickle cells also break up too easily and survive for only 10 to 20 days compared to 120 days for normal red blood cells. The rapid destruction of sickle cells leads to anemia — a shortage of red blood cells and hemoglobin. It becomes difficult for the body to make new red blood cells fast enough to keep up with the needed supply.

Causes

Sickle cell conditions are inherited. People who make hemoglobin S in their red blood cells have inherited the sickle cell gene from one or both parents. Children who inherit the sickle cell gene from both parents will have sickle cell disease (SS). The sickle cell gene tells the body to make a variant (different from normal) hemoglobin. Children who inherit the sickle cell gene (S) from one parent and another abnormal hemoglobin gene from the other parent may have different types of sickle cell disease.

There are four common types of sickle cell disease: SS, SC, S/beta-plus thalassemia, and S/beta-zero thalassemia. A person who is SS has inherited a double dose of the sickle cell gene (S), one from each parent. People with any other type of sickle cell disease have inherited the S gene from one parent and another abnormal hemoglobin gene from the other parent.

Children who inherit the sickle cell (S) gene from only one parent and the normal genes for hemoglobin A from the other parent will not have the disease, but will have the sickle cell trait (AS). People with AS generally have no symptoms of the disease and lead normal lives, but can pass the gene on to their children.

When two people with the sickle cell trait have a baby, they can have a child with normal hemoglobins (AA), sickle cell trait (AS), or the SS type of sickle cell disease. These possibilities exist with each pregnancy.

Risk factors

Sickle cell disease affects millions of people throughout the world. It is common in people whose origins are:

  • African
  • Mediterranean
  • Arabian
  • Indian (Asian)

People with sickle cell conditions predominantly live in countries in Africa, the Americas (North, Central and South), the Caribbean region, Mediterranean region, the Middle East, India and Western Europe.

In the United States, sickle cell disease affects:

  • 1 in approximately 360 African-American newborns
  • 1 in approximately 16,300 Hispanic-American newborns

It has been estimated that more than 2 million Americans carry the sickle cell "trait" (which means they don't have the disease themselves but could potentially pass it on to their children). About 1 in 12 African-Americans has the sickle cell trait.

(Source: Newborn screening for sickle cell diseases in the United States: A review of data spanning 2 decades. Therrell BL Jr, Lloyd-Puryear MA, Eckman JR, Mann MY. Semin Perinatol. 2015 Apr;39(3):238-51.)

Signs and symptoms

Anemia is the most common feature of sickle cell disease. Anemia may cause fatigue, paleness, yellowing of the skin and eyes (jaundice), or shortness of breath.

Pain is the most common symptom of sickle cell disease. Some people have few or no severe pain episodes a year while others have 15 or more. Pain may last a few hours to a few days, and, in some cases, it can last for weeks. Some people have chronic, almost daily pain.

The pain occurs in organs or joints and results from tissue damage caused when sickle cells block blood flow. Mild pain episodes may be treated with over-the-counter pain medications such as acetaminophen and ibuprofen. Pain that is severe may require treatment in the hospital with strong pain medicines given intravenously (into a vein).

Complications of sickle cell disease may be acute or or chronic.

Acute complications

  • Anemia. It is the most common feature of sickle cell disease. Anemia may cause fatigue, paleness, yellowing of the skin and eyes (jaundice), or shortness of breath.
  • Pain. It is the most common symptom of sickle cell disease. Some people have few or no severe pain episodes a year while others have several. The duration of pain can vary, and some people have chronic, almost daily pain. This is the result from tissue damage caused when sickle cells block blood flow. Mild pain episodes may be treated with heat (warm baths or compresses) and over-the-counter pain medications such as acetaminophen and ibuprofen. Pain that is severe may require treatment in the hospital with strong pain medicines given intranasal (into the nose) and intravenously (into a vein).
  • Infection. Repeated red cell sickling within the spleen causes it to lose the ability to remove bacteria from the blood. Infants and young children are susceptible to blood infections, pneumonia, meningitis, and bone and other serious infections. Individuals are given twice-daily penicillin and vaccines to prevent serious infection and death. Fever should be immediately evaluated by a healthcare provider.
  • Splenic sequestration. Sickled red blood cells can become trapped in the spleen. The spleen becomes larger and is frequently painful. The blood in the spleen is no longer in the circulation, and the patient can become pale and tired from the anemia. This is a life-threatening emergency and requires immediate evaluation by a healthcare provider.
  • Aplastic crises. Infection with parvo virus B19 can cause an aplastic crisis. The bone marrow temporarily stops making red blood cells and the patient becomes more anemic. Sometimes patients may need a red blood cell transfusion.
  • Dactylitis (hand-foot syndrome). Swollen and/or painful hands or feet may be the first symptom of sickle cell disease in infants and should be evaluated by a doctor immediately.
  • Acute chest syndrome. This life-threatening complication of sickle cell disease is caused by trapped sickle cells or infection in the lung. People who have chest pain and fever must be seen by a doctor immediately.
  • Stroke. Sickled cells damage and block blood vessels that supply blood to the brain; this may result in a stroke. About 10 percent of children with sickle cell disease develop stroke. Another 20 percent develop scars in the brain without stroke. The damage to brain tissue can cause learning problems and disabilities. Doctors can sometimes identify children who are at increased risk of stroke by using a special type of ultrasound test.
  • Priapism. This refers to painful and unwanted erections, which occur because sickled red blood cells cause blood to be trapped in the vessels of the penis. Immediate medical attention is needed when the erection lasts for more than an hour. Recurrent priapism can lead to erectile dysfunction.

Chronic complications

  • Gallstones. These stones form in the gallbladder when there is too much of a substance called bilirubin in the body; bilirubin is made when red blood cells are destroyed. People with gallstones may have pain episodes in the upper right side of the belly, under the right shoulder or between the shoulder blades. They may also experience yellowing of the eyes or skin. Eating a large or fatty meal may trigger gallstone attacks.
  • Pulmonary hypertension. This is high blood pressure of the main artery to the lungs (pulmonary artery); this artery carries blood from the heart to the lungs where it becomes oxygenated. Pulmonary hypertension is a common complication of adults with sickle cell disease and has become more widely recognized in children. Early diagnosis and treatment may reverse or prevent progress of this condition.
  • Joint disease. Aseptic necrosis (death of tissue not related to infection) of bone is the most common problem of bones and joints related to sickle cell disease. It is caused by sickled cells blocking blood flow. This condition can begin in childhood but is more common later in life.
  • Eye problems. When the retina does not get enough blood, it can weaken and result in problems, including blindness. Children with sickle cell disease need regular eye exams, as tiny blood vessels in the eye may become blocked with the sickled cells. Early detection of these problems can allow treatment to prevent poor vision or complete blindness.
  • Kidney problems. The inability to maximally concentrate urine is the most common renal abnormality in sickle cell disease. One result is enuresis (bedwetting). Another is an increased susceptibility to dehydration, which can initiate vaso-occlusive events (painful episodes). To compensate, people with sickle cell disease should drink large amounts of fluids; this is particularly important for children at play in warm weather.
  • Neuropsychological effects. Silent strokes and cerebral vessel narrowing are common in young children with sickle cell disease, and it puts them at increased risk for cognitive deficits. These can lead to learning difficulties. Neuropsychological testing of children with poor academic performance should be conducted, so appropriate interventions can be started. Also, early brain imaging studies can provide information so that interventions can be started as soon as possible.

Testing and diagnosis

There are several tests suitable for determining what type of hemoglobin is made by a person's red blood cells. These include:

  • Hemoglobin electrophoresis
  • Isoelectric focusing
  • Chromatography

These tests can determine whether a person has a type of sickle cell disease or sickle cell trait.

DNA analysis is used to determine changes in the genes for making hemoglobin. This test indirectly predicts the type of hemoglobin made in the red cells.

Tests that are not suitable for determining sickle cell disease or sickle cell trait include:

  • Solubility tests (e.g., Sickledex®)
  • Sickling test

A "positive" result from these tests simply indicates the presence of hemoglobin S in a person's blood; this occurs in both sickle cell trait and all types of sickle cell disease.

Other tests that are not useful by themselves for diagnosing sickle cell conditions include:

  • Blood count. This test may detect anemia, but there are many other causes of anemia in infants and others with mild types of sickle cell disease, and there may be little or no anemia.
  • Blood smear. Sickled cells can be easily seen on a blood smear examined under a microscope. However, even in some people with severe sickle cell disease and particularly in young children and in others with milder types of sickle cell disease, there may be no sickled cells on the regular blood smears.

When is the best time to diagnose sickle cell disease?

Sickle cell conditions can be accurately diagnosed at any age. However, the newborn period is the best time. Newborn diagnosis enables healthcare providers to start preventive treatment (penicillin prophylaxis) and family health education before the start of symptoms.

Forty-nine U.S. states, the District of Columbia, Puerto Rico and the Virgin Islands currently screen all newborns for sickle cell disease through blood tests. These tests use blood from the same samples taken for other routine newborn screening tests and can determine if the child has the disease itself or only the trait. It is also possible to identify sickle cell disease before birth by getting a sample of amniotic fluid or tissue taken from the placenta; this test can be done as early as the first few months of pregnancy.

Treatment

The goals of treatment are to prevent infections, relieve pain, and prevent or control complications. Infections are the leading cause of death in sickle cell disease. Pain attacks are the leading cause of emergency room visits and hospitalizations.

Because infections may lead to death, special measures are taken to prevent or reduce the severity of infections. This includes twice-daily penicillin for children for at least the first five years of life, special vaccines, and aggressive evaluation and treatment when patients develop fever or other signs of infection.

Vaccinations against certain dangerous bacteria (pneumococcus, haemophilus influenza type B, and meningococcus) and viruses (hepatitis B and influenza) are especially important for people with sickle cell disease. For more information about what vaccinations your child needs, visit the Children's Hospital of Philadelphia Vaccine Education Center.

Blood transfusions are used to treat some acute complications and to prevent the occurrence or recurrence of other complications. Children who have had a stroke or are at high risk for initial stroke are given blood transfusions on a regular and long-term basis to prevent stroke.

Pain is most often treated with acetaminophen, nonsteroidal anti-inflammatory drugs (also known as NSAIDs) and opioids, which are the strongest pain medications and include substances such as morphine, oxycodone and hydrocodone.

Outlook and follow-up care

Important health maintenance measures in sickle cell disease include:

  • Doctor visits every two or three months for children up to 2 years of age, then at least every three to four months after age 2
  • Regular well visits to a sickle cell clinic or primary healthcare provider
  • All recommended well child immunizations with the addition of Prevnar® and Pneumovax® vaccines, which protect against pneumococcus
  • Blood tests to monitor blood counts when well
  • Antibiotic (penicillin) prophylaxis in young children
  • Folic acid supplementation
  • TCD (an ultrasound of the brain known as transcranial doppler) at least once a year in children with SCD-SS and SCD-SB0thalassemia starting at 2 years and until 16 years of age
  • Hydroxyurea therapy beginning at 9 months of age in children with SCD-SS and SCD-SB0 thalassemia
  • Eye (retina) examination for early detection of retina disease

Researchers are investigating new medications, bone marrow transplants and gene therapy to treat and possibly provide a universal for cure sickle cell disease. Fortunately, a child may live a full, productive life with the disease as doctors know a great deal about the disease and how to manage it.