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Sickle cell disease

Highlights

NIH Consensus Statement: Hydroxyurea Underused

  • In 2008, a panel convened by the U.S. National Institutes of Health (NIH) released a consensus statement recommending that more adults and adolescents with sickle cell disease receive drug treatment with hydroxyurea (Droxia).
  • Hydroxyurea is a drug that can help reduce the frequency of painful sickle cell crises and episodes of acute chest syndrome. It is currently approved for adults, but is increasingly being used to treat younger patients.
  • The NIH panel also concluded that the risks of serious side effects appear to be lower than previously thought, and that the risks of untreated sickle cell disease outweigh those of the drug.

Complications of Sickle Cell Disease

Sickle cell disease can block the flow of blood in arteries in many parts of the body, causing many complications. The hallmark of sickle cell disease is the sickle cell crisis, which causes sudden attacks of severe pain. Acute chest syndrome, which is triggered by infection or blockage of blood vessels in the lungs, is also a common and serious occurrence. Other medical complications include:

  • Infections
  • Pulmonary hypertension (increased pressure in the arteries of the lungs)
  • Stroke
  • Anemia
  • Kidney problems
  • Priapism (prolonged and painful erections)
  • Liver problems
  • Gallbladder disease
  • Spleen damage
  • Bone and joint problems
  • Leg sores and ulcers
  • Eye damage in the retina

Introduction

Sickle cell disease (also called sickle cell anemia) is an inherited blood disorder that affects red blood cells. The sickle cell gene causes the body to produce abnormal hemoglobin. In sickle cell disease, the hemoglobin clumps together, which causes red blood cells to become stiff and develop a C-shaped (sickle) form. These sickled red blood cells can block blood vessels, reducing blood flow in many parts of the body. This process results in tissue and organ damage.

Hemoglobin and Iron

Each red blood cell contains about 280 million hemoglobin molecules. Hemoglobin is the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component takes up oxygen and releases carbon dioxide. The red blood cells carry the oxygen to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is essential for all cells in the body to function.

Sickle cell disease reduces or denies adequate oxygen to many parts of the body. This contributes to the severe pain experienced as a sickle cell crisis and both short- and long-term organ damage.

Sickle Cell Disease and Hemoglobin

Sickle cell disease occurs from genetic changes which causes a portion of the hemoglobin molecules to be abnormal:

  • Hemoglobin A (HbA). HbA is the hemoglobin molecule found in normal red blood cells during childhood and adulthood. People without sickle cell anemia have primarily this type of hemoglobin in their blood cells.
  • Hemoglobin S (HbS). HbS (S is for sickle) is the abnormal variant of hemoglobin A, which occurs in sickle-red blood cells and is the primary characteristic of the disease. The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about 300 that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.
Hemoglobin
Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

The Sickle Cell Disease Process

The symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:

  • When the sickle hemoglobin molecule loses its oxygen, it forms rigid rods called polymers that change the red blood cells into a sickle or crescent shape.
  • These sickle-shaped cells stick to the walls and cannot squeeze through the capillaries. Blood flow through tiny blood vessels becomes slowed or stopped in many parts of the body. This deprives tissues and organs of oxygen.
  • When this blood flow slows or stops suddenly in a certain part of the body, the decrease in oxygen (hypoxia) can cause severe pain (the sickle cell crisis). Over time, it leads to gradual destruction in organs and tissues throughout the body.
Red blood cells, sickle cell

Click the icon to see an image of sickle cells.
  • The higher the concentration of sickle hemoglobin and the more acidic the environment, the faster the sickle cell process.
  • When blood cells dry out (dehydrate), the density of hemoglobin S within the cell increases, thereby speeding the sickling process.
  • Sickle cells also have a shorter life span (10 - 20 days) than that of normal red blood cells (90 - 120 days). Every day the body produces new red blood cells to replace old ones, but sickle cells become destroyed so fast that the body cannot keep up. The red blood cell count drops, which results in anemia. This gives sickle cell disease its more common name, sickle cell anemia.

Risk Factors

Sickle cell disease is inherited. People at risk for inheriting the gene for sickle cell descend from people who are or were originally from Africa and parts of India and the Mediterranean. The sickle cell gene also occurs in people from South and Central America, the Caribbean, and the Middle East. The high incidence of the sickle cell gene in these regions of the world is due to the sickle cell's ability to make red blood cells resistant to the malaria parasite:

  • People who inherit just a single gene are referred to as having the sickle trait. These people are protected against malaria and do not develop sickle cell disease. About 40% of people in certain parts of Africa and about 9% of African-Americans have the trait.
  • Those who inherit both copies of the HbS gene develop sickle cell disease. They are not protected from malaria, however. In fact, malaria is more serious in these individuals. An estimated 1 in 500 African-Americans and 1 in 1,000 - 1,400 Hispanic Americans are born with sickle cell disease.

Risk of Inheritance

The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in the United States. About 70,000 - 100,000 Americans -- mostly African-Americans -- have sickle cell disease. About 2 million Americans have sickle cell trait.

People inherit a pair of genes that regulate hemoglobin, with one gene coming from each parent. If two sickle genes are inherited, a person will have sickle cell disease. If a one normal hemoglobin gene and one sickle cell gene are inherited, a person will have sickle cell trait. People who have sickle cell trait are healthy and do not develop themselves sickle cell disease, but they are carriers who can pass the disease on to their children.

The risk of a child inheriting sickle cell disease or sickle cell trait is as follows:

  • If both parents have sickle cell trait (each have one normal hemoglobin gene and one sickle cell gene), the child has a 50% chance of inheriting sickle cell trait (one normal gene, one sickle cell gene), 25% chance of inheriting sickle cell disease (two sickle cell genes), and 25% chance of not inheriting either the trait or the disease (two normal genes).
  • If one parent has sickle cell trait (one normal gene and one sickle cell gene) and the other parent has two normal hemoglobin genes, the child has a 50% chance of inheriting sickle cell trait (one normal gene and one sickle cell gene) and a 50% of inheriting neither the trait nor the disease (two normal genes). The child is not at risk of inheriting sickle cell disease.
  • If one parent has sickle cell disease (two sickle cell genes) and the other parent has sickle cell trait (one normal gene, one sickle cell gene), the child has a 50% chance of inheriting sickle cell trait and a 50% chance of inheriting sickle cell disease.
  • If one parent has sickle cell disease and the other parent has two normal hemoglobin genes, the child has a 100% chance of inheriting sickle cell trait, but not the disease.
  • If both parents have sickle cell disease, the child has a 100% chance of inheriting the disease.

Symptoms

General Symptoms in Infants. In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:

  • Fever
  • Swelling of the hands and feet
  • Pain in the chest, abdomen, limbs, and joints
  • Nosebleeds and frequent upper respiratory infections

General Symptoms in Children. Pain is the most common complaint. It can be acute and severe or chronic, usually from orthopedic problems in the legs and low back. Other symptoms include:

  • Fatigue and shortness of breath (signs of anemia)
  • Irritability
  • Jaundice (yellowish discoloration of the skin and eyes)

Additional Symptoms in Adolescence or Adulthood. Symptoms of childhood continue in adolescence and adulthood. In addition, patients may experience:

  • Delayed puberty (in young teenagers)
  • Severe joint pain
  • Progressive anemia
  • Leg sores
  • Gum disease
  • Vision problems

Sickle Cell Crisis

The hallmark of sickle cell disease is a group of devastating symptoms known collectively as a sickle cell crisis (also sometimes known as a vaso-occlusive crisis). Sickle cell crises are episodes of pain that occur with varying frequency and severity in different patients and are usually followed by periods of remission. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. It most commonly occurs in the lower back, leg, abdomen, and chest, usually in two or more locations. Episodes usually recur in the same areas.

The risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half the cases, however, the trigger is unknown. Acute chest syndrome is a particularly serious complication of sickle cell crisis. It occurs in the lungs and can be extremely serious and even life threatening.

Diagnosis

Blood tests can determine whether an individual has sickle cell trait or sickle cell disease.

Screening Tests for Newborns

In the United States, hospitals routinely screen newborn babies for sickle cell disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. Early detection of sickle cell disease can help reduce the risk for life-threatening infections and increase the odds for survival. Babies who are diagnosed with sickle cell disease are given daily antibiotics to help prevent infections.

Prenatal diagnosis is also possible through amniocentesis. The amniotic fluid is tested for the presence of the sickle cell gene.

Diagnostic Tests for Stroke

Unfortunately, no tests can definitely determine which children are at highest risk for a stroke and, therefore, would be candidates for ongoing blood transfusions. The following are diagnostic tools currently used or under investigation:

  • Transcranial Doppler (TCD) ultrasonography measures the speed of blood flow in the brain. It can be used for identifying children at risk for stroke. However, high-risk children are still vulnerable to stroke even if the TCD screening diagnosed normal blood flow velocities.
  • The use of follow-up magnetic resonance imaging (MRI) to detect small blockages in blood vessels may help confirm high risk in patients identified by TCD ultrasound.
  • Some patients may need to undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.
  • Researchers are also beginning to uncover possible genetic markers that may eventually be used to help identify sickle cell patients at higher risk for stroke.

Prognosis

New and aggressive treatments for sickle cell disease are prolonging life and improving its quality. As recently as 1973, the average lifespan for people with sickle cell disease was only 14 years. Currently, life expectancy for these patients can reach 50 years and over. Women with sickle cell live longer than their male counterparts.

The damage of sickle cell disease occurs because the logjam that sickle cells cause in the capillaries slows the flow of blood and reduces the supply of oxygen to various tissues. Not only does pain occur when body tissues are damaged by lack of oxygen, but serious and even life-threatening complications can result from severe or prolonged oxygen deprivation. Sickle cell disease is referred to in some African languages as "a state of suffering," but the disease has a wide spectrum of effects, which vary from patient to patient. In some people, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks.

Children with sickle cell disease are very susceptible to infections, usually because their damaged spleens are unable to protect the body from bacteria. Signs of impaired lung function may occur even in very early years. As children with sickle cell disease live longer, older patients are now facing medical problems related to the long-term adverse effects of the disease process. The most serious dangers are acute chest syndrome, long-term damage to major organs, stroke, and complications during pregnancy such as high blood pressure in the mother and low birth weight in the infant.

Complications

There is still no cure for sickle cell disease other than experimental transplantation procedures, but treatments for complications of sickle cell have prolonged the lives of many patients who are now living into adulthood.

Pain and Acute Sickle Cell Crisis

The hallmark of sickle cell disease is the sickle cell crisis (also sometimes known as a vaso-occlusive crisis), which is an episode of pain. It is the most common reason for hospitalization in sickle cell disease. The pattern may occur as follows:

  • In general, the risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half of episodes, however, the trigger is unknown.
  • Episodes typically begin at night and last 3 - 14 days, accelerating to a peak over several days and then declining.
  • The pain is typically described as sharp, intense, and throbbing. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. Shortness of breath is common.
  • Pain most commonly occurs in the lower back, leg, hip, abdomen, or chest, usually in two or more locations. Episodes usually recur in the same areas. Pain in the bones (usually occurring symmetrically on both sides) is common because blood obstruction can directly damage bone and because bone marrow is where red blood cells are manufactured.
  • The liver or spleen may become enlarged, causing pain in the upper right or upper left sides of the abdomen. Liver involvement may also cause nausea, low-grade fever, and increasing jaundice.
  • Males of any age may experience prolonged, often painful erections, a condition called priapism.

Episodes cannot be predicted, and they vary widely among different individuals. Episodes sometimes become less frequent with increasing age. Generally, people can resume a relatively normal life between crises. Most patients are pain-free between episodes although pain can be chronic in some cases.

Acute Chest Syndrome (ACS)

Acute chest syndrome (ACS) occurs when the lung tissues are deprived of oxygen during a crisis. It can be very painful, dangerous, and even life threatening. It is a leading cause of illness among sickle cell patients and is the most common condition at the time of death. At least one whole segment of a lung is involved, and the following symptoms may be present:

  • Fever of 101.3F degrees (38.5C) or above
  • Rapid or labored breathing
  • Wheezing or cough
  • Acute chest pain

Pain often lasts for several days. In about half of patients, severe pain develops about 2 - 3 days before there are any signs of lung or chest abnormalities. Acute chest syndrome is often accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi. Pneumonia is often present. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises.

Respiratory system
Air is breathed in (inhaled) through the nasal passageways, and travels through the trachea and bronchi to the lungs.

Causes of Acute Chest Syndrome. Primary causes of acute chest syndrome include:

  • Infection. Infection from viruses or small atypical organisms (Chlamydia and Mycoplasma) is the most common cause of the oxygen deprivation that leads to acute chest syndrome.
  • Blockage of blood vessels. Blockage in the blood vessels (called infarction) that cuts off oxygen in the lungs is another important cause of acute chest syndrome. Blockage may be produced by blood clots or fat embolisms. (Fat embolisms are particles formed from fatty tissue in the bone marrow that enter and travel through the blood vessels.)
  • Asthma. Asthma can increase the frequency and pain of acute chest syndrome episodes in children. Children with sickle-cell disease who have frequent acute chest syndrome attacks should be evaluated for asthma.

In about half of cases, the cause cannot be established. Some cases of acute chest syndrome may result from treatments of the crisis, including from administration of opioids (which reduce oxygen) or excessive use of intravenous fluids. Other lung diseases may also trigger ACS.

Severity of Acute Chest Syndrome. The mortality rates for ACS are around 2% in children and 4% in adults. The syndrome and its long-term complications are the major causes of death in older patients. The longer a patient survives, the greater is the damage done by repetitive sickle cell crises in the chest and lungs.

The following destructive effects can occur:

  • Damage in the chest area from recurrent episodes increases susceptibility to invading infections, even those that are ordinarily not harmful.
  • Lung damage over time can lead to obstruction in the airways in lungs, causing asthma-like conditions.

Infections

Infections are common and an important cause of severe complications in sickle cell patients. Before early screening for sickle cell disease and the use of preventive antibiotics in children, 35% of infants with sickle cell died from infections. Fortunately, with screening tests for sickle cell now required for newborns, and with the use of preventive antibiotics and immunizations in babies who are born with the disease, this terrible mortality rate has dropped significantly.

Infections in Infants and Toddlers with Sickle Cell Disease. The most common organisms causing infection in children with sickle cell disease include:

  • Streptococcus pneumoniae (can cause pneumonia, blood infections, or meningitis)
  • Haemophilus influenza (also a cause of pneumonia, blood infections, and meningitis)

Such infections pose a grave threat to infants and very young children with sickle cell disease. They can progress to fatal pneumonia with devastating speed in infants, and death can occur only a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.

Infections in Children and Adults. Infections are also common in older children and adults with sickle cell disease, particularly respiratory infections such as pneumonia, kidney infections, and osteomyelitis, a serious infection in the bone. (The organisms causing them, however, tend to differ from those in young children.) Infection-causing organisms include:

  • Chlamydia and Mycoplasma pneumoniae. These are the important infections in acute chest syndrome (see above).
  • Gram-negative bacteria. This group of bacteria mostly infects hospitalized patients and can cause serious pneumonias and other infections.

Pulmonary Hypertension

About 30% of patients with sickle cell disease have pulmonary hypertension. Pulmonary hypertension is a serious and potentially deadly condition that develops when pressure in the arteries of the lungs increases. It is an often unrecognized complication and cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease undergo echocardiographic testing to identify if they are at risk for pulmonary hypertension and require treatment.

The primary symptom of pulmonary hypertension is shortness of breath, which is often severe. Pulmonary hypertension can be very serious and life threatening in the short- and long-term. If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening. Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

Core pulmonale

Click the icon to see an image of cor pulmonale.

Stroke

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than 3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Patients may also suffer small strokes that may not be immediately noticeable. However, patients who have many of these small strokes may over time start behaving differently or have worsening mental functioning.

Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Patients with sickle cell disease are also at high risk for stokes caused by aneurysm, a weakened blood vessel wall that can rupture and hemorrhage. Multiple aneurysms are common in sickle cell patients, but they are often located where they cannot be treated surgically.

Stroke

Click the icon to see an image of stroke.

Anemia

Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia).

Severe worsening of anemia. Children, adolescents, and possibly young adults may experience what is called splenic sequestration. This happens when a large amount of the sickled red blood cells collect in the patient's spleen. Symptoms may include pain in the right abdomen below the ribs and a large mass (the swollen spleen) may be felt.

Chronic Anemia. Because of the short lifespan of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes a particular form of anemia called hemolytic anemia. Most patients with sickle cell disease have a hemoglobin levels of 8 g/dL, much lower than people without sickle cell anemia. Chronic anemia reduces oxygen and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to become dangerously enlarged, with an increased risk for heart attack and heart failure.

On occasion, patients may experience what is called an aplastic crisis. This happens when the cells in the bone marrow that are normally trying to make new red blood cells suddenly stop working. This sudden stopping is often triggered by a virus called human parvovirus B19.

Kidney Problems

The kidneys are particularly susceptible to damage from the sickling process. Persistent injury can cause a number of kidney disorders, including infection. Problems with urination are very common, particularly uncontrolled urination during sleep. Patients may have blood in the urine, although this is usually mild and painless and resolves without damaging consequences. Kidney failure is a major danger in older patients and accounts for 10 - 15% of deaths in sickle cell patients. Renal medullary carcinoma is an aggressive, rapidly destructive tumor in the kidney that is rare but can occur as a result of sickle cell disease.

Kidney anatomy

Click the icon to see an image of kidney anatomy.

Priapism

A reported 38 - 42% of males, including children, with sickle cell disease suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. If priapism is not treated, partial or complete erectile dysfunction can occur in 80% of cases.

Male reproductive anatomy

Click the icon to see an image of the male reproductive anatomy.

Liver Problems

Enlargement of the liver occurs in over half of sickle cell patients, and acute liver damage occurs in up to 10% of hospitalized patients. Because sickle cell patients often need transfusions, they have been at higher risk for viral hepatitis, an infection of the liver. This risk, however, has decreased since screening procedures for donated blood have been implemented.

Gallbladder Disease

About 30% of children with sickle cell disease have gallstones, and by age 30, 70% of patients have them. In most cases, gallstones do not cause symptoms for years. When symptoms develop, patients may feel overly full after meals, have pain in the upper right quadrant of the abdomen, or have nausea and vomiting. Acute attacks can be confused with a sickle cell crisis in the liver. Ultrasound is usually used to confirm a diagnosis of gallstones. If the patient does not have symptoms, no treatment is usually necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [For more information, see In-Depth Report #10: Gallstones.]

Cholelithiasis

Click the icon to see an image of cholithiasis.

Spleen Damage

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroy it. Injury to spleen increases the risk for serious infection. Acute splenic sequestration crisis (sudden spleen enlargement) can occur when the spleen suddenly becomes enlarged from trapped blood.

Enlarged spleen

Click the icon to see an image of an enlarged spleen.

Bone and Joint Problems

In some children with sickle cell disease, excessive production of blood cells in the bone marrow causes bones to grow abnormally, resulting in long legs and arms or misshapen skulls. Sickling that blocks oxygen to the bone can also cause bone loss and pain. Sickling that affects the hands and feet of children causes a painful condition called hand-foot syndrome. A condition called avascular necrosis of the hip occurs in about half of adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may require surgery to remove diseased and dead bone tissue. Joint replacement may be required in severe cases. X-rays are not very useful for detecting early disease in the bones. MRI may be important.

Blood supply to bone

Click the icon to see an image of the blood supply to bone.

Leg Sores and Ulcers

Leg sores and ulcers occur in up to 10% of sickle cell patients and usually affect patients older than 10 years.

Eye Problems

Sickle cell disease can damage blood vessels in the eye and cause scarring and detachment of the retina, which can lead to blindness.

Pregnancy and Sickle Cell Disease

Women with sickle cell disease who become pregnant are at higher risk for complications such as miscarriage, premature birth, and low birth weight. Sickle cell disease symptoms often worsen during pregnancy and pain crises become more frequent. However, with careful prenatal care and monitoring, serious problems can be avoided. Maternal mortality rates have dropped significantly over the past decades. Most women with sickle cell disease can now anticipate favorable pregnancy outcomes.

Other Medical Complications

Older children and adult patients with sickle cell are subject to other medical problems, including impaired physical development and gum disease. In severe cases, sickle cell disease can cause multiple organ failure.

Treatment

Treatment goals for sickle cell disease aim to relieve pain, prevent infections, and manage complications. [For specific information on complications, see Treatment of Complications section in this report.] Patients should seek care from a doctor who specializes in blood disorders (hematologist) or a clinic that is experienced in treating sickle cell disease.

Bone marrow transplantation is the only potential cure, but it is used in only a small number of cases as few patients are able to find donors who are suitable genetic matches. Blood transfusions are given to prevent worsening anemia and prevent stroke.

Drug treatments for sickle cell disease include:

  • Antibiotics, usually penicillin, are commonly given to infants and young children, as well as adults, to help prevent infections.
  • Pain relief medication ranging from nonprescription nonsteroidal anti-inflammatory drugs (NSAIDs) to opiods are given to control pain.
  • Hydroxyurea is prescribed for patients with moderate-to-severe sickle cell disease to help reduce the frequency of pain episodes and acute chest syndrome. It is approved

Hydroxyurea

HbF, also called fetal hemoglobin, is the form of hemoglobin present in the fetus and small infants. Most HbF disappears early in childhood, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells. Because of this, infants with sickle cell disease do not develop symptoms of the illness until. HbF levels have dropped. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Hydroxyurea (Droxia) is a drug that reduces the severity of sickle cell disease by stimulating production of HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is recommended as frontline therapy to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces the frequency of acute pain crises and episodes of acute chest syndrome. It is taken daily by mouth. Hydroxyurea can be taken indefinitely and the benefits appear to be long-lasting.

Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Many patients who can benefit from it are not receiving it. Hydroxyurea is still being investigated for younger patients. To date, the response to the drug in children with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe for infants.

Side effects include constipation, nausea, drowsiness, hair loss, and inflammation of the mouth. More severe side effects include reduction of white blood cells (neutropenia) and clot-forming platelets (thrombocytopenia). Hydroxyurea should not be taken by pregnant patients as it can cause birth defects. There have been concerns that long-term use of hydroxyurea may increase the risk of developing leukemia, but the significance of this risk remains unclear. Still, for some patients the risks of untreated sickle cell disease may outweigh the risks of hydroxyureas side effects.

Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Transfusion

Blood transfusions are often critical for treating sickle cell disease. Transfusions may be used either as treatment for specific episodes or as chronic transfusion therapy to prevent life-threatening complications Ongoing transfusions can also help improve height and weight in children with sickle cell disease. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/dL after transfusion.

Episodic Transfusions. Episodic transfusions are needed in the following situations:

  • To manage sudden severe events, including acute chest syndrome, stroke, widespread infection (septicemia), and multi-organ failure.
  • To manage severe anemia, usually caused by splenic sequestration (dangerously enlarged spleen) or aplasia (halting of red blood cell production, most often caused by parvovirus). Transfusions are generally not required for mild or moderate anemia.
  • Before major surgeries. Transfusions are generally not required for minor surgeries.

Chronic Transfusions. Chronic (on-going) transfusions are used for:

  • Stroke prevention for first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. The U.S. National Institutes of Health strongly recommends that doctors do not stop regular transfusions for children with sickle cell disease who are at high risk for stroke.
  • Pulmonary hypertension and chronic lung disease
  • Heart failure
  • Chronic kidney failure and severe anemia
  • To reduce episodes of pain and acute chest syndrome

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

  • Simple Transfusion. Simple transfusions involve the infusion of one or two units of donor blood to restore blood volume levels and oxygen flow. It is used for moderately severe anemia, severe fatigue, and nonemergency situations when there is a need for increased oxygen. It is also used for acute chest syndrome.
  • Exchange Transfusion. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done as manual procedure or as automatic one called erythrocytapheresis. Exchange transfusions may be used when there is any evidence that the patient's condition is deteriorating. It prevents stroke and also may be used in patients with severe acute chest syndrome. It reduces the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels.

Iron Overload and Chelation Therapy. Iron overload increases risk for damage to the liver, heart, and other organs. A liver biopsy accurately determines whether excess iron levels are present.

Chelation therapy is used to remove excess iron stores in the body. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. In 2005, the drug deferasirox (Exjade) was approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

  • Immune reactions. An immune reaction may occur in response to donor blood. In such cases, the patient develops antibodies that target and destroy the transfused cells. This reaction, which can occur 5 - 20 days after transfusion, can result in severe anemia and may be life-threatening in some cases. It can be generally prevented with careful screening and matching of donor blood groups before the transfusion.
  • Hyperviscosity. With this condition, a mixture of hemoglobin S and normal hemoglobin causes the blood to become sticky. The patient is at risk for high blood pressure, altered mental status, and seizures. Careful monitoring can prevent this condition.
  • Transmission of viral illness. Before widespread blood screening, transfusions were highly associated with a risk for hepatitis and HIV. This complication has decreased considerably.

Bone Marrow or Stem Cell Transplantation

At this time, the only chance for cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced. Clinical studies using a few carefully selected patients have reported very successful results.

Up to 80 - 85% of patients who meet criteria for receiving a transplant receive remain disease free. Unfortunately, only about 7% of patients with sickle cell meet the criteria for transplantation, including those who:

  • Are age 16 or younger (generally considered the better candidates, but patients in their 20s have had successful transplants)
  • Have severe symptoms but no long-term organ or neurologic damage
  • Have a genetically matched brother or sister who will donate their marrow

Complications. Bone marrow transplant carries its own dangers and limitations, especially for patients who do not receive a bone marrow transplant from a well-matched brother or sister donor. About 10% of those who have bone marrow transplants die from the treatment. Some complications include:

  • In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.
  • Other very serious complications include bleeding, pneumonia, and severe infection.
  • Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
  • Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease may be reduced.

Early clinical trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Investigational Treatments

Nitric Oxide. Nitric Oxide. Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Patients with sickle cell disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. It is difficult to administer, however. More studies are needed. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Arginine. Arginine is involved in producing nitric oxide. Because a lack of arginine may contribute to the development of pulmonary hypertension, (a leading cause of death in patients with sickle cell disease), arginine is being studied as a potential drug treatment. Some research is also being conducted on arginine nutritional supplements. Patients should talk to their doctors before taking these or any other supplements.

Drugs To Prevent Dehydration. Researchers are studying various drugs, as well as mineral supplements such as magnesium pidolate and zinc sulfate, that may help prevent potassium loss and red blood cell dehydration.

Treatment of Complications

Treatment of Pain

The basic objectives for managing a sickle cell crisis are control of pain and rehydration by administration of fluids. Oxygen is typically given for acute chest syndrome. Pain medications can help reduce the severe pain of sickle cell crises. These medications can range from non-prescription pain relievers such as acetaminophen or nonsteroidal anti-inflammatory drugs, to more powerful narcotics such as the opioid drug morphine. Corticosteroid drugs may also be prescribed.

All patients should have a treatment plan that helps guide them and their families during a pain episode. Plans should outline which medicines to take and when to seek medical help. Patients and families should learn to recognize symptoms early and begin managing with an appropriate amount of pain medication.

Treatment of Acute Chest Syndrome (ACS)

Acute chest syndrome can be fatal and must be treated immediately. Basic treatments include:

  • Supplementary oxygen -- this is critical and life saving.
  • Administration of fluids -- overhydration should be avoided to reduce the risk of fluid in the lungs.
  • Pain relievers
  • Bronchoscopy (a diagnostic procedure involving insertion of a tube into the lower airways) may be needed to identify infection.

Other treatments include:

  • High-dose intravenous corticosteroids (usually dexamethasone) may hasten recovery from acute chest syndrome and reduce the duration of hospitalization.
  • Antibiotics that specifically target the organisms ( Chlamydia, Mycoplasma) that commonly trigger acute chest syndrome. Such antibiotics include erythromycin, azithromycin, clarithromycin, and various tetracyclines.
  • Transfusions are important early on for rapid improvement in severe cases, especially if fat embolisms have developed.

Treatment of Infections

Fever in any sickle cell patient should be considered an indication of infection. Temperatures over 101 F in children warrant a call to the doctor. Adults with sickle cell should call the doctor if they have a have fever over 100 F and any signs of infection, including chest pain, productive cough, urinary problems, or any other symptoms. Pneumonia is common among patients with sickle cell disease, as are meningitis, influenza, and hepatitis. Bone infections (osteomyelitis) can develop.

When patients with sickle cell develop infections, they are nearly always hospitalized immediately and treated with intravenous or high-dose injections of antibiotics in order to prevent septicemia, the dangerous spread of the infection throughout the body. Antibiotics are also given on an outpatient basis.

It is important for patients with sickle cell disease, especially children, to receive vaccinations to protect against infections. [For more information, see Prevention and Lifestyle Changes section in this report.]

Treatment of Anemia

Blood transfusions are given for suddenly worsening anemia. However, transfusions can increase the risk for infections and cause a build-up of iron in the blood. [For more information, see "Transfusion Therapy" in Treatment section of this report.]

Folic acid and possibly iron supplements are often given. However, iron supplements should be avoided by patients who are given multiple transfusions. Also, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12.

Treatment of Kidney Complications

Kidney damage in patients with sickle cell disease can cause bleeding into the urine. Mild episodes can usually be treated with bed rest and fluids. Severe bleeding may require transfusions.

Treatment of Priapism

Priapism causes prolonged and painful erections that can last from several hours to days. It is best to relieve this problem within 12 hours. Relief within 36 hours is important to avoid permanent erectile dysfunction. Pain relief and intravenous fluids are the initial steps. Drugs used to prevent priapism include terbutaline and phenylephrine, which help restrict blood flow to the penis. A surgical procedure that implants a shunt to redirect blood flow is sometimes performed.

Treatment of Acute Splenic Sequestration (Damaged Spleen)

The spleen is often removed (splenectomy) in children who have one or two acute splenic sequestration crises. Transfusion therapy is an alternative for preventing acute splenic sequestration in high-risk patients.

Treatment of Leg Ulcers

Leg ulcers are difficult to treat. Simple treatment with a moist dressing usually provides the best results. To treat mild ulcers, the leg should be gently washed with cotton gauze soaked in mild soap or a solution of one tablespoon of household bleach to one gallon of water. A dressing soaked in diluted white vinegar may be applied every 3 - 4 hours.

More severe ulcers require debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means. Hydrogels are helpful in healing ulcers and are noninvasive and soothing. Topical antibiotics, saline or zinc oxide dressings, or cocoa butter or oil are also used depending on severity. The leg should be elevated. Bed rest for a week or more is sometimes required for severe ulcers. Skin grafts and transfusions may be helpful in extreme cases.

Treatment of Sickle Cell Disease During Pregnancy

Women who are pregnant should be treated at a high-risk clinic. They should take folic acid in addition to multivitamins and iron. Standard treatment is given for sickle cell crises, which may occur more frequently during pregnancy. However, certain drugs (such as hydroxyurea) should not be taken during pregnancy. The benefits of transfusions to prevent crises during pregnancy are not yet clear and doctors recommend them only for women who experience frequent complications during pregnancy.

Prevention and Lifestyle Changes

No proven methods prevent either sickle cell crises or long-term complications of sickle cell disease. By taking precautions and aggressively managing problems that occur, however, patients are now living longer, with a better quality of life.

General Precautions

To prevent or reduce the severity of long-term complications, a number of precautions may be helpful:

  • Have regular physical examinations every 3 - 6 months.
  • Have periodic and careful eye examinations.
  • Have sufficient rest, warmth, and increased fluid intake. (These are critical precautions for reducing oxygen loss and the risk for dehydration.)
  • Avoid conditions, such as crowds, that increase risk for infections.
  • Avoid excessive demands on the body that would increase oxygen needs (physical overexertion, stress). Low impact exercise (leg lifts, light weights) may be useful and safe for maintaining strength, particularly in the legs and hips, but patients should consult their doctor about any exercise program.
  • Avoid high altitudes if possible. If flying is necessary, be sure that the airline can provide oxygen.
  • Do not smoke, and avoid exposure to second-hand smoke. Both active and passive smoking may promote acute chest syndrome in patients with sickle cell disease.

Preventing Infections

Vaccinations. Everyone with sickle cell disease should have complete regular immunizations against all common infections. Children should have all routine childhood vaccinations. The following are important vaccinations for everyone with sickle cell disease:

  • Pneumococcal vaccines. All sickle cell patients should be vaccinated with the pneumococcal vaccine. There are two types of pneumococcal vaccines; the choice between them depends on the age of the patient. Infants and children less than 2 years of age should receive 4 doses of the pneumococcal conjugated vaccine (Prevnar) between 2 - 15 months of age. The pneumococcal polysaccharide vaccine should be administered at age 2 years or older, repeated after 3 - 5 years for patients younger than age 10, or in 5 years for patients older than age 10.
  • Vaccination against Haemophilus influenza, the major cause of childhood meningitis, starting at age 2 months.
  • Influenza vaccines ("flu shots") should be given every winter, starting at age 6 months.
  • Meningococcal vaccination for patients age 5 and older.
  • Hepatitis B vaccine. All children should receive this vaccine.

Tuberculosis skin testing should be performed every year.

Antibiotics. In addition to regular immunizations, preventive (prophylactic) antibiotics are the best approach for protection against pneumonia and other serious infections among children with sickle cell disease. Babies diagnosed with sickle cell are given daily antibiotics, starting at 2 months of age and continuing through 5 years of age. Penicillin is usually the antibiotic given, unless a child is allergic to it.

Nutrition and Dietary Supplements

Foods. Good nutrition, while essential for anyone, is critical for patients with sickle cell disease. Some dietary recommendations include:

  • Fluids are number one in importance. The patient should drink as much water as possible each day to prevent dehydration.
  • Diet should provide adequate calories, protein, fats, and vitamins and minerals. Patients and families should discuss vitamin and mineral supplements with their doctors and nurses.
  • Some studies claim that omega-three fatty acids, found in fish and soybean oil as well as dietary supplements, might make red blood cell membranes less fragile and possibly less likely to sickle, although no studies have proven this definitively.

Vitamins. Patients should take daily folic acid and vitamin B12 and B6 supplements. Vitamin B6 may have specific anti-sickling properties. Some doctors recommend 1 mg folic acid, 6 microgram vitamin B12, and 6 mg vitamin B6. Foods containing one or all of these vitamins include meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast. Of note, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.

Vitamin B6 source

Click the icon to see an image of vitamin B6 sources.

Note on Iron. Although sickle cell disease is often referred to as anemia, patients should avoid iron supplements or iron rich foods when receiving multiple transfusions, which increase the risk for iron-overload.

Managing the Emotional and Social Impact

In assessing the seriousness of this disease, no one should underestimate its emotional and social impact. For the family, nothing is more heartbreaking than watching their child endure extreme pain and life-threatening medical conditions. The patient endures not only the pain itself but also the emotional strain from unpredictable bouts of pain, fear of death, and lost time and social isolation at school and work. Academic grades among patients average less than C, even in children with a low frequency of hospitalization (averaging 17 days a year).

These problems continue over the years, and both children and adults with sickle cell disease often suffer from depression. The financial costs of medical treatments combined with lost work can be very burdensome.

Any chronic illness places stress on the patient and family, but sickle cell patients and caregivers often face great obstacles in finding psychological support for the disease. Communities in which many sickle cell patients live generally lack services that can meet their needs, and professionals who work in their medical facilities are often overworked. In a study comparing patients with different kinds of long-term illnesses, those with sickle cell disease gave the lowest scores to their doctors and other professional caregivers for compassion, and were least satisfied with their medical care.

It is very important for patients and their caregivers to find emotional and psychological support. No one should or can endure this life-long disease alone. Unfortunately, studies indicate that most patients do not receive even basic supportive care that could help reduce the anxiety and intensity of pain that occurs when a sickle cell crisis erupts.

The following are some measures that some people find helpful in dealing with this disease:

  • Stress Reduction. Stress reduction techniques and relaxation methods appear to be helpful. Breathing and mediation techniques may be very helpful.
  • Cognitive-Behavioral Therapy. Studies suggest that cognitive behavioral therapies that teach coping skills can result in less negative thinking and even less pain. Coping skills refer to the patient's ability to respond to symptoms, such as pain.
  • On-Line Support Help. Computer on-line services are now valuable sources of support groups and access to research. They are particularly valuable for patients who cannot easily leave home or for patients who are ill.
  • Support Associations. Parent and professional support associations still offer the best and least expensive sources of help.

Other important factors are those that help maintain positive attitudes including spirituality, humor, or having important life goals (such as having children or pursuing a career).

Resources

References

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Bernaudin F, Socie G, Kuentz M, et al Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. Epub 2007 Jul 2.

Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008 Jun 17;148(12):932-8. Epub 2008 May 5.

Caboot JB, Allen JL. Pulmonary complications of sickle cell disease in children. Curr Opin Pediatr. 2008 Jun;20(3):279-87.

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Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007 Jun 1;44(11):1428-33. Epub 2007 Apr 18.

Lanzkron S, Strouse JJ, Wilson R, Beach MC, Haywood C, Park H, et al. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med. 2008 Jun 17;148(12):939-55. Epub 2008 May 5.

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Mehta SR, Afenyi-Annan A, Byrns PJ, Lottenberg R. Opportunities to improve outcomes in sickle cell disease. Am Fam Physician. 2006 Jul 15;74(2):303-10.

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Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008 Sep;39(9):2644-91. Epub 2008 Jul 17.

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Review Date: 2/18/2009
Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
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