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Sickle Cell Disease (Sickle Cell Anemia)

  • Medical Author: William C. Shiel Jr., MD, FACP, FACR

Sickle cell anemia (SCD) definition and facts

  • Sickle cell anemia (SCD) is an inherited disorder of the hemoglobin in blood.
  • Sickle cell anemia requires the inheritance of two sickle cell genes.
  • Sickle cell trait, which is the inheritance of one sickle gene, almost never causes problems.
  • Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped sickled red blood cells blocking the flow of blood.
  • The current treatment of sickle cell anemia is directed primarily toward managing the individual features of the illness as they occur.

What is sickle cell anemia?

Sickle cell anemia (sickle cell disease) is a disorder of the blood caused by an inherited abnormal hemoglobin (the oxygen-carrying protein within the red blood cells). The abnormal hemoglobin causes distorted (sickled appearing under a microscope) red blood cells. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. This condition is referred to as sickle cell anemia. The irregular sickled cells can also block blood vessels causing tissue and organ damage and pain.

Sickle cell anemia is one of the most common inherited blood anemias. The disease primarily affects Africans and African Americans. It is estimated that in the United States, some 90,000 to 100,000 Americans are afflicted with sickle cell anemia. Overall, current estimates are that one in 500 U.S. African American births is affected with sickle cell anemia.

What are the symptoms and signs of sickle cell anemia?

Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped, sickled red blood cells blocking the flow of blood that circulates through the tissues of the body. The tissues with impaired circulation suffer damage from lack of oxygen. Damage to tissues and organs of the body can cause severe disability in patients with sickle cell anemia. The patients endure episodes of intermittent "crises" of variable frequency and severity, depending on the degree of organ involvement.

The major features and symptoms of sickle cell anemia include:

  1. Fatigue and anemia
  2. Pain crises
  3. Dactylitis (swelling and inflammation of the hands and/or feet) and arthritis
  4. Bacterial infections
  5. Sudden pooling of blood in the spleen and liver congestion
  6. Lung and heart injury
  7. Leg ulcers
  8. Aseptic necrosis and bone infarcts (death of portions of bone)
  9. Eye damage

Some features of sickle cell anemia, such as fatigue, anemia, pain crises, and bone infarcts can occur at any age. Many features typically occur in certain age groups.

Sickle cell anemia usually is apparent in the first year of life. Infants and younger children can suffer with fever, abdominal pain, pneumococcal bacterial infections, painful swellings of the hands and feet (dactylitis), and splenic sequestration. Adolescents and young adults more commonly develop leg ulcers, aseptic necrosis, and eye damage. Symptoms in adult typically are intermittent pain episodes due to injury of bone, muscle, or internal organs.

Affected infants do not develop symptoms in the first few months of life because the hemoglobin produced by the developing fetus (fetal hemoglobin) protects the red blood cells from sickling. This fetal hemoglobin is absent in the red blood cells that are produced after birth so that by 5 months of age, the sickling of the red blood cells is prominent and symptoms begin.

How is sickle cell anemia inherited?

Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition. This means that the gene can be passed on from a parent carrying it to male and female children. In order for sickle cell anemia to occur, a sickle cell gene must be inherited from both the mother and the father, so that the child has two sickle cell genes.

The inheritance of just one sickle gene is called sickle cell trait or the "carrier" state. Sickle cell trait does not cause sickle cell anemia. Persons with sickle cell trait usually do not have many symptoms of disease and have hospitalization rates and life expectancies identical to unaffected people. When two carriers of sickle cell trait mate, their offspring have a one in four chance of having sickle cell anemia. (In some parts of Africa, one in five persons is a carrier for sickle cell trait.)

Picture of Sickle Cell Red Blood Cell
Picture of Sickle Cell Red Blood Cell

What conditions promote distortion of red blood cells?

Sickling of the red blood cells in patients with sickle cell anemia results in cells of abnormal shape and diminished flexibility. The sickling is promoted by conditions associated with low oxygen levels, increased acidity, or low volume (dehydration) of the blood. These conditions can occur because of injury to the body's tissues, dehydration, or anesthesia.

Certain organs are predisposed to lower oxygen levels or acidity, such as when blood moves slowly through the spleen, liver, or kidney. In addition, organs with particularly high metabolism rates (such as the brain, muscles, and the placenta in a pregnant woman with sickle cell anemia) promote sickling by extracting more oxygen from the blood. These conditions make these organs susceptible to injury from sickle cell anemia.

How is sickle cell anemia diagnosed?

Sickle cell anemia is suggested when the abnormal sickle-shaped cells in the blood are identified under a microscope. Testing is typically performed on a smear of blood using a special low-oxygen preparation. This is referred to as a sickle prep. Other prep tests can also be used to detect the abnormal hemoglobin S, including solubility tests performed on tubes of blood solutions. The disease can be confirmed by specifically quantifying the types of hemoglobin present using a hemoglobin electrophoresis.

Prenatal diagnosis (before birth) of sickle cell anemia is possible using amniocentesis or chorionic villus sampling. The sample obtained is then tested for DNA analysis of the fetal cells.

The hemoglobin electrophoresis test precisely identifies the hemoglobins in the blood by separating them. The separation of the different hemoglobins is possible because of the unique electrical charges they each have on their protein surfaces, causing them each to move characteristically in an electrical field as tested in the laboratory.

What treatments manage symptoms of fatigue and anemia?

Fatigue is a common symptom in persons with sickle cell anemia. Sickle cell anemia causes a chronic form of anemia, which can lead to fatigue. The sickled red blood cells are prone to breakage (hemolysis) which causes reduced red blood cell life span (the normal life span of a red blood cell is 120 days). These sickled red blood cells are easily detected with a microscope examination of a smear of blood on a glass slide.

Typically, the site of red blood cell production (bone marrow) works overtime to produce these cells rapidly, attempting to compensate for their destruction in the circulation. Occasionally, the bone marrow suddenly stops producing the red blood cells, which causes a very severe form of anemia (aplastic crises). Aplastic crises can be promoted by infections that otherwise would seem less significant, including viruses of the stomach and bowels and the flu (influenza).

Sickle cell anemia tends to stabilize without specific treatments. The degree of anemia is defined by measurement of the blood hemoglobin level. Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues to the lungs. Blood hemoglobin levels in persons with sickle cell anemia are generally between 6 to 8 gms/dl (normal levels are above 11 gms/dl). Occasionally, there can be a severe drop in hemoglobin requiring a blood transfusion to correct the anemia (such as in patients suffering splenic sequestration). Blood transfusion is usually reserved for those patients with other complications, including pneumonia, lung infarction, stroke, severe leg ulceration, or late pregnancy. (Among the risks of blood transfusion are hepatitis, infection, immune reaction, and injury to body tissues from iron overload.) Transfusions are also given to patients to prepare them for surgical procedures. Folic acid is given as a supplement. Sometimes a red blood cell exchange is performed. This process removes some of the sickle blood cells and replaces them with normal (non-sickle) blood cells. It is done when the sickle cell crisis is so severe that other forms of treatment are not helping.

What treatments help manage symptoms of pain, arthritis, and dactylitis?

Pain crises

Pain crises in persons with sickle cell anemia are intermittent painful episodes that are the result of inadequate blood supply to body tissues. The impaired circulation is caused by the blockage of various blood vessels from the sickling of red blood cells. The sickled red blood cells slow or completely impede the normal flow of blood through the tissues. This leads to excruciating pain, often requiring hospitalization and opiate medication for relief. The pain typically is throbbing and can change its location from one body area to another. Bones are frequently affected. Pain in the abdomen with tenderness is common and can mimic appendicitis. Fever frequently is associated with the pain crises.

A pain crisis can be promoted by preceding dehydration, infection, injury, cold exposure, emotional stress, or strenuous exercise. As a prevention measure, persons with sickle cell anemia should avoid extremes of heat and cold.

Pain crises require analgesia for pain and increased fluid intake. Dehydration must be prevented to avoid further injury to the tissues and intravenous fluids can be necessary. Other modalities, such as biofeedback, self-hypnosis, and/or electrical nerve stimulation may be helpful.

Hydroxyurea is a medication that is currently being used in adults and children with severe pain from sickle cell anemia. It is also considered for those with recurrent strokes and frequent transfusions. This drug acts by increasing the amount of fetal hemoglobin in the blood (this form of hemoglobin is resistant to sickling of the red blood cells). The response to hydroxyurea is variable and unpredictable from patient to patient. Hydroxyurea can be suppressive to the bone marrow.

Dactylitis and arthritis

Swelling and inflammation of the hands and/or feet is often an early sign of sickle cell anemia. The swelling involves entire fingers and/or toes and is called dactylitis. Dactylitis is caused by injury to the bones of the affected digits by repeated episodes of inadequate blood circulation. Dactylitis generally occurs in children with sickle cell anemia from age 6 months to 8 years.

Joint inflammation (arthritis) with pain, swelling, tenderness, and limited range of motion can accompany the dactylitis. Sometimes, not only the joints of the hands or feet are affected, but also a knee or an elbow.

The inflammation from dactylitis and arthritis can be reduced by anti-inflammation medications, such as ibuprofen and aspirin.

What is the outlook for sickle cell anemia? Can it be cured?

The life expectancy of persons with sickle cell anemia is reduced. Some patients, however, can remain without symptoms for years, while others do not survive infancy or early childhood. Nevertheless, with optimal management patients can now survive beyond the fourth decade.

Most patients suffer intermittent pain crises, fatigue, bacterial infections, and progressive tissue and organ damage. Impaired growth and development is the result of the physical and emotional trauma that is endured by children with sickle cell anemia.

Causes of death include bacterial infection (the most common cause), stroke or bleeding into the brain, and kidney, heart, or liver failure. The risk of bacterial infections does diminish after three years of age. Nevertheless, bacterial infections are the most common cause of death at any age. Therefore, any signs of infection in a person with sickle cell anemia must be reviewed with a doctor to prevent damage and save lives.

Interestingly, the sickle cell gene somewhat protects against malaria infection. This makes those with sickle cell trait (gene carriers) at least partially resistant to malaria. Furthermore, the geographic distribution of the sickle cell gene is similar to that of malaria infection. Sickle cell anemia is a lethal condition that threatens life. However, there may be a selective advantage to being a sickle cell carrier (trait) if the person resides in an area of the world where malaria is very common. The advantage a person with sickle cell trait has over a non-carrier of the gene may explain why sickle cell anemia did not disappear from the world even though it is lethal.

The sickle cell gene is not a "black gene." It just happens to disproportionately occur in the black population. When a black person who carries a sickle cell gene has children with a non-black person, the children may inherit the sickle cell gene regardless of race. There are also people of all races who carry the sickle cell gene.

Recent research is examining further ways to promote the development of the fetal hemoglobin that delays the development of sickle cell in the newborn. Bone marrow transplantation is being used for patients with severe sickle cell anemia who have a sibling donor. Future treatments may involve genetic engineering where cures might be achieved.

Finally, genetic counseling can be helpful for parents and families to prevent sickle cell anemia. Sickle cell anemia is an inherited illness. Both parents must be carriers of the sickle cell gene for a child to be affected with sickle cell anemia. If each parent is a carrier, any child has a one chance in two (50%) of also being a carrier and a one in four (25%) chance of inheriting both genes from the parents and being affected with sickle cell anemia.

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Reviewed on 11/15/2018

REFERENCE:

Bunn, HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762.
Jameson, JL, et al. Harrison's Principles of Internal Medicine, 20th ed. (Vol.1 & Vol.2). McGraw-Hill Education 2018.

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