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Detailed Medical Information On Sickle-Cell Anemia
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An inherited disorder, primarily seen in African Americans and others of African descent, sickle cell anemia is a serious but increasingly manageable disorder. This article is a comprehensive look at the genetics and diagnosis of, and treatments for Sickle-Cell Disease.

What Is Sickle-Cell Disease?
Red blood cells carry oxygen throughout the body to nourish tissues and sustain life. They are the most abundant cells in the human body. When they are healthy, they look like tiny flexible inner-tubes. This unique shape and small size serve many functions. The tubular shape provides a large surface area to absorb oxygen. It also offers the flexibility necessary to squeeze through the capillaries -- the tiny blood vessels that connect arteries to veins.

Oxygen is carried within the red blood cells by hemoglobin, a complicated molecule composed of proteins and iron. Sickle-cell disease is caused by a genetic defect in this important hemoglobin molecule. A normal red blood cell contains a molecule called hemoglobin A; in a sickle red blood cell, a variant of this molecule exists and is called hemoglobin S (S for sickle). The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about three hundred that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.

The sickle-cell disease process is triggered when red blood cells become deprived of oxygen. In everyone -- both those with and without the disease -- hemoglobin loses its oxygen in a number of ways. To sustain life, oxygen regularly passes from red blood cells to the tissues where it is needed to perform vital functions. Hemoglobin loses oxygen if blood cells become too acidic, for example, after strenuous exercise. Going to high altitudes or any stressful activity or situation that increases the body's demand for oxygen depletes its supply in red blood cells. Such situations do not affect normal red blood cells that contain hemoglobin A. Oxygen loss from hemoglobin S, however, causes the molecules to form rigid rods called polymers that distort the red blood cell into a sickle or crescent shape. The sickle cell also has a chemical on its surface that sticks to blood vessel walls. As a result, these abnormally sickle-shaped, rigid, and sticky blood cells cannot squeeze through the capillaries. They block the flow of blood, depriving tissues and organs of oxygen. Loss of oxygen contributes to episodes of pain called sickle-cell crises and to both short- and long-term organ damage. Excessive acidity and the abnormal shape of the sickle cell also cause water and potassium loss from the cell, resulting in dehydration -- another destructive outcome of this process. Fortunately, because it takes a relatively long time to form the sickle-cell shape, most blood cells have traveled out of the capillaries before they have time to be affected. Only about 20% of all red blood cells polymerize and become sickle-shaped. Sickle cells also have a shorter life span (10 to 20 days) than that of normal red blood cells (90 and 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.

The severity of sickle-cell disease generally depends on three factors: the extent of oxygen loss; the concentration of hemoglobin within the cell (the lower the better); and the presence of a protective molecule called hemoglobin F (for fetal). Hemoglobin F is produced in everyone during fetal development and for a short time after birth. Some persists throughout life. In sickle-cell patients, hemoglobin F does not polymerize and form sickle-shapes, so its red blood cells continue to function normally. People with the sickle-cell gene who continue to carry some fetal hemoglobin are better protected, therefore, from severe forms of the disease.

Who Gets Sickle-Cell Disease?
The sickle-cell gene for hemoglobin S (HbS) is the most common inherited blood condition in America. Fortunately most people with a high genetic risk inherit only one copy of the gene for HbS; the other hemoglobin gene is normal. The normal hemoglobin gene is sufficient to override HbS and to block the development of the disease. Such people have the sickle-cell trait, but not the disease, and they lead normal lives. To inherit the full-blown disease, children must inherit the hemoglobin S gene from both parents. If one parent has one copy of the gene and the other parent has two normal hemoglobin genes, then the child will not have the disease. If each parent has one copy of the gene, the child has a 25% chance of acquiring the disease. Some people inherit one hemoglobin S gene and one abnormal hemoglobin gene; in such cases, they usually develop a form of sickle-cell disease, although it is often a milder variant.

Approximately 80,000 Americans have sickle-cell disease. About 9% of African Americans have the trait, and an estimated one in 500 African American and one in every 1,000 to 1,400 American Hispanic children are born with sickle-cell disease itself. The high incidence of the sickle-cell gene in these and other specific populations is due to its ability to make red blood cells resistant to the malaria parasite. This natural protection has made the HbS gene common in malaria-infested areas, particularly Africa and parts of India and the Mediterranean. (About 40% of people in certain parts of Africa have the trait.) The sickle-cell gene occurs also in people from South and Central America, the Caribbean, and the Middle East. This protection against malaria, however, is bestowed only on people who have the sickle trait and have inherited just a single gene. Those who inherit both copies of the HbS gene and develop sickle-cell disease are not even protected from malaria; in fact, malaria is more serious in these individuals.

What Are the Symptoms of Sickle-Cell Disease?

General Symptoms
In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they are fever, swelling of the hands and feet, pain in the chest, abdomen, limbs and joints, and enlargement of the heart, liver, and spleen. Infants also may have nosebleeds and frequent upper respiratory infections. After infancy, patients develop symptoms of anemia -- fatigue, irritability, and jaundice (yellowish discoloration of the skin and eyes). Pain is the most common complaint. In adolescence and young adulthood, symptoms often also include severe joint pain, as well as delayed puberty, progressive anemia, leg sores, and gum disease.

Symptoms of Sickle-Cell Crisis
The hallmark of sickle-cell anemia 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. Although they cannot be predicted, 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.

The first day of the crisis is usually the worst, with pain in the arms, legs, and back that is described as sharp, intense, and throbbing. Shortness of breath is common. Children also often experience pain in the abdomen, which is probably caused by spasm or gas. Pain in the bones is common because blood obstruction can directly damage bone and because bone marrow is where red blood cells are manufactured. Sudden attacks of pain also commonly occur in the fingers or toes and in other bones and joints. The liver may become enlarged, causing pain in the upper right side of the abdomen. Nausea, abdominal pain, low-grade fever, and increasing jaundice may occur when the liver is affected. Males of any age may experience prolonged, sometimes painful erections, a condition called priapism. Acute chest syndrome is a particularly serious complication of sickle-cell crisis. Symptoms may include rapid or labored breathing. Acute chest syndrome is usually accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi; pneumonia is often present. Acute pain often lasts for several days. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises. Generally, people can resume a relatively normal life between crises.

Some patients have few painful events; others may need to hospitalized many times a year. Some patients can go months without a crisis and then have a cluster of severe attacks. Painful episodes sometimes become less frequent with increasing age.

How Serious Is Sickle-Cell Disease?
Sickle-cell disease is referred to in some African languages as "a state of suffering," but the disease affects people very differently, and new and aggressive treatments are prolonging life and improving its quality. As recently as 1960, most people with sickle-cell disease were not expected to survive childhood. Yet, a major 1994 study reported that 85% of children with full-blown sickle-cell disease and 95% of those with a less serious variation were living into adulthood. A 1997 study reports that the mortality rate for African American children with sickle cell disease has decreased by up to 53%, perhaps due to preventive treatment with penicillin, newborn screening, aggressive research, and improved medical care. Currently, about half of sickle-cell patients live beyond 50 years. Early studies showed that women had a greater risk for death from sickle-cell disease than men, but experts now believe this was due to high mortality during pregnancies before the mid 1970s. Women with sickle-cell disease now actually live longer than their male counterparts.

The damage and durability of sickle-cell disease occurs because the log jam 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 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.

Major Problems in Infants and Young Children with Sickle-Cell Disease
Sickle-cell patients are susceptible to infections, usually because their damaged spleens are unable to protect the body from bacteria. The most common organisms causing infection in children with sickle-cell disease are Streptococcus pneumoniae and Haemophilus influenza. 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 36 times greater than for African-American children and 314 times greater than for white children without sickle cell disease. Before early screening for sickle-cell disease and the use of preventive antibiotics in children, 35% of sickle-cell infants were lost to infections. Fortunately, with screening tests for sickle-cell now required for newborns in most states and with the use of preventive antibiotics in babies who are born with the disease, this terrible mortality rate is dropping significantly. The lung damage caused by sickle cell disease in children can lead to asthma-like bronchial hyperreactivity (an exaggerated response to certain stimuli) in the airways in the lungs.

Problems in Older Children and Adults
As medical progress has increased the lifespan of children with sickle-cell disease, older patients are now facing medical problems related to long-term damage. Physicians are just developing ways to treat these complications effectively. In older children and adults, 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.

Acute Chest Syndrome. Acute chest syndrome, a very dangerous component of the sickle-cell crisis, is associated with the highest risk for 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. Blockage of blood vessels cuts off oxygen to the bones and tissues in the chest and lung. Injuries in the bone can cause severe pain. The airways in the lungs may narrow, causing severe reductions in oxygen delivery. Destructive changes in the chest area increase susceptibility to invading infectious agents, such as viruses, bacteria, fungi, and parasites. Acute chest syndrome can be fatal, particularly if the patient is not immediately given supplementary oxygen. Infections frequently clear up if they are limited to small areas of the lung, but if they spread, they can progress very quickly and become life threatening.

Stroke. After acute chest syndrome, stroke is the most common killer of patients with sickle-cell disease who are older than three. Between 8% and 10% of patients suffer strokes, typically at about age seven. Transfusions are proving to prevent a first stroke as well as recurrence. Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Studies indicate that sickle-cell patients 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 can be treated surgically. Some experts, therefore, believe that any patients who have neurologic symptoms should undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.

Complications from Anemia. Because of the short life span of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes the anemia that gives this disease its more common name. Although the anemia may occasionally become severe and require transfusions, it is usually manageable. Chronic anemia, however, 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.

Kidney Failure. The kidneys are particularly susceptible to damage from the sickling process. Kidney failure is another major danger in older patients and accounts for 10% to 15% of deaths in sickle-cell patients.

Infections. Infections are also common in older children and adults with sickle-cell disease, particularly respiratory infections such as pneumonia and osteomyelitis, a serious infection in the bone. The organisms causing them, however, tend to differ from those in young children. The incidence of pneumococcal infections decrease and those caused by E. coli and bacteria known as gram negative organisms increase, which can still be extremely serious.

Problems in the Genital-Urinary Tract. 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. Males, including children, with sickle-cell disease may also suffer from priapism, which is a prolonged and painful erection. If priapism is not treated, partial or complete impotence can occur in 80% of cases.

Problems in the Liver. Enlargement of the liver occurs in over half of sickle-cell patients, and acute damage to this organ occurs in up to 10% of hospitalized patients. People with sickle-cell disease who receive transfusions may also contract viral hepatitis, an infection of the liver, although screening of donated blood has reduced this risk considerably.

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.

Problems in the Bones and Joints. 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 can also cause bone loss -- particularly the top of the thigh bone -- and pain in the hands and feet of children, which is known as the hand-foot syndrome.

Other Medical Complications. Patients who survive infancy are subject to other medical problems, including impaired physical development, gum disease, scarring of the retina, and leg sores.

Emotional and Social Impact
In assessing how serious this disease is, no one should underestimate the emotional and social impact of this disease. For the family, there is nothing more heartbreaking than to watch 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 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 physicians and other professional caregivers for compassion and satisfaction with medical care.

How Is Sickle-Cell Disease Diagnosed?

Prenatal Testing
Prenatal diagnosis of sickle-cell disease is now possible using amniocentesis for women who may be at risk for having a child with the disease. A positive result for sickle-cell disease when a fetus is already four months old (once the opportunity for early-term abortion has passed) poses extremely difficult questions for which there are no easy solutions. Some cases of sickle-cell disease can be mild, but the parents and physicians have no way of knowing this from test results. When faced with raising a child with sickle-cell disease, parents should educate themselves as fully as possible. Parents must weigh the benefits of current treatments and pain management against the likelihood of suffering and a shorter life span for their child. They must be prepared to be vigilant and aggressive partners with their physicians, and in spite of their own emotional anguish, they must be loving and fully supportive when their child is suffering a sickle-cell crisis. Energy, time, and money are necessary expenditures in raising any child; they are significantly increased when a child has this severe and life-threatening illness.

Tests for Newborns
In 1987, the National Institutes of Health recommended that all newborns, regardless of country of origin or ethnic background, be tested for sickle-cell disease. Most states, though not all, now screen infants for the disease. The earlier a child is diagnosed with sickle-cell disease, the higher the survival rate. States where screening is now required report survival rates in children with sickle-cell disease that are equal to those of African-Americans without the disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. If an infant is diagnosed with sickle-cell disease, the parents should be offered genetic counseling and information on the problem.

Ruling Out Other D iseases
As part of the diagnosis, the physician will rule out other conditions that resemble sickle-cell disease. It is sometimes difficult to distinguish between abnormalities in the bone caused by infection and those caused by a sickle-cell crisis. Bone scans may be performed to help diagnose possible bone infections. Other disorders that might mimic certain stages of sickle-cell disease include some types of anemia, rheumatic fever, hepatitis and liver disease, and infections of the kidney or heart. Other genetic abnormalities can cause sickling of the red blood cells, including hemoglobin C, hemoglobin I, and high levels of Bart's hemoglobin.

How Can Sickle-Cell Crises and Long Term Complications Be Prevented?
There are no proven methods for preventing 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.

Preventive Measures for Children and Adults
General Precautions. To prevent or reduce the severity of long-term complications, regular physical examinations should be scheduled every three to six months. Periodic and careful eye examinations are also critical. Everyone with sickle-cell disease should have complete regular immunizations against infections and annual influenza vaccinations. Children over two should be vaccinated against pneumonia.

To help reduce the frequency and severity of a sickle-cell crisis, patients and their caregivers should take constant precautions to avoid oxygen loss and dehydration. Sufficient rest, warmth, and increased fluid intake are the most important ongoing measures for reducing pain and managing the disease. The patient should drink as much water as possible each day to prevent dehydration. Female patients may want to include cranberry juice to help prevent urinary tract infections. Other conditions that contribute to crises include illness, physical exertion, stress, increased oxygen needs (such as from exercise, air travel, or being at high altitudes), and environmental toxins and chemicals. When flying, the patient or caregiver should be sure that the airline can provide oxygen.

Psychologic and Emotional Support. Stress reduction techniques and relaxation methods appear to be helpful. One study showed that when adult patients were trained in coping skills, they had less negative thinking and reported less pain. 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.

Diet. Good nutrition is essential. It is important to have five to nine daily servings of green, red, and yellow vegetables, fruits, or juices that are rich in antioxidants and other important nutrients. Studies on fish oil and soybean oil show they might make red blood cell membranes less fragile, and possibly less likely to sickle, although no studies have proven this definitively. Although the benefits of vitamin and mineral supplements are also unproven, some research indicates that zinc and magnesium may help. Patients should take folic acid daily and may wish to take supplements of the antioxidant vitamins E and C if the diet does not adequately supply them.

Relief for Mild Pain. For mild pain relief, common medications such as acetaminophen (Tylenol) or the class of drugs known as nonsteroidal anti*inflammatory drugs (NSAIDs) are often sufficient. Aspirin is the most common NSAID, but there are many others, including ibuprofen (Advil, Motrin) and naproxen (Naprosyn, Aleve). Aspirin is not usually recommended for children because it can aggravate abdominal pain.

How Are Sickle-Cell Crises and Long-Term Complications Managed and Treated?
There is still no cure for sickle-cell disease other than experimental transplantation procedures, but treatments have prolonged the lives of many patients who are now living into adulthood.

Treatment of Sickle-Cell Crisis
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.

Treatment of Pain. Effective pain medications are available to help reduce the severe pain of sickle-cell crises. Often, however, patients are not given the treatment they require. Many patients, their families, and even physicians are hesitant to use opioids aggressively because of fear of addiction. This fear, however, is nearly always unwarranted. Studies indicate that less than one in a thousand people who take long-term narcotics to alleviate chronic pain develop an addiction to the drug. A problem for adult patients is that early phases of sickle-cell crisis can cause severe pain before test results confirm the crisis. In such cases, health professionals may question the patient's response and may withhold appropriate pain medication and not repeat tests later on that would confirm the crisis. Adult patients and parents of children with the disease should insist on aggressive pain-relief treatment. If physicians show any reluctance to administer medications after the onset of pain, they should not hesitate to seek a more responsive health care professional.

For severe pain, the patient must be hospitalized and treated with strong painkillers, usually opioids. Opioids are generally given orally to adults and adolescents and intravenously to children, although older patients with severe pain may also require intravenous administration. Often the opioid meperidine (Demerol) is used for sickle-cell crises, although some experts believe that it is not adequate and prefer morphine for frequent or prolonged episodes of pain. Meperidine is not as powerful as morphine, and, if used for prolonged periods, may cause twitches, tremors, and disturbed mental states including seizures. The most dangerous side effect of high doses of opioids, especially morphine, is depression of breathing function. This can occur some time after the drug has been administered, and so patients must be watched closely and monitored during treatment. Other side effects opioids are vomiting and nausea, itching, and problems urinating. If the patient vomits or becomes nauseated, the physician may administer prochlorperazine (Compazine). Devices are being tested to allow patients to administer their own painkillers as needed.

Because of the potentially serious side effects of opioids, physicians are constantly searching for safer and easier ways of reducing the severity of pain of sickle-cell crises. Because experts believe that inflammation is a major contributor to the pain of sickle-cell disease, drugs that reduce inflammation are being studied. Prescription-strength NSAIDs, including diflunisal (Dolobid) and ketorolac (Toradol), have shown promise. Steroid hormone drugs are commonly used to treat pain caused by inflamed muscles and joints, and studies using these drugs along with opioids are reporting some success with sickle-cell patients. Such drugs include methylprednisolone (Medrol) and dexamethasone (Decadron, Hexadrol). In one study, children who were given methylprednisolone and morphine had a shorter period of severe pain and required less morphine to control the pain than those given morphine alone. These children, however, had more recurrent attacks after medication was withdrawn than those treated with opioids alone. Because steroids can suppress the body's infection fighters, they should not be given to patients with bacterial infections or any serious medical complication.

Treatment of Acute Chest Syndrome. Acute chest syndrome is associated with a partially collapsed lung and infection, both of which can be dangerous and even life threatening. Blockage of blood vessels in the chest wall causes injury to the bones, serious lung infections, and loss of oxygen. Basic treatments include administration of fluids, pain-relievers, and oxygen. Exchange transfusion, which involves drawing out the patient's blood while exchanging it for donor blood, may be used to reduce hemoglobin S levels. This treatment might also reduce the risk of heart failure and help prevent fat embolism, a rare life-threatening condition in which fatty tissue from the bone marrow travels to blood vessels in the lungs and cuts off oxygen. Transfusions may also be indicated for patients with progressive lung damage from acute chest syndrome. Regular transfusions are also proving to significantly reduce the risk for a first stroke in high-risk children.

To increase oxygen levels in children hospitalized for acute chest syndrome, a simple breathing technique known as incentive spirometry may be beneficial. A spirometer is a hand-held plastic device commonly used by asthma patients to measure their lung capacity and by patients after surgery to increase intake of oxygen. In one trial, children with sickle-cell disease were asked to inhale and exhale into this device every two hours during the day and when they were awake at night until their chest pain subsided. This device forces more air into the lungs, and researchers hoped it would prevent the serious drop in oxygen levels and the risk for infection caused by acute chest syndrome. Results were encouraging: children who used spirometry had significantly lower rates of collapsed lung tissue and infections than those who did not. This very inexpensive and simple treatment might have beneficial long-term effects.

Treatment of Infection. When sickle-cell patients develop infections, they are nearly always hospitalized immediately and treated with high dose injections of antibiotics in order to prevent septicemia -- the dangerous spread of the infection throughout the body. Repeated hospitalizations are very disruptive for both children and adults. Studies have found that older children whose fever is below 38.5 degrees Celsius (101 degrees Fahrenheit) and who have no serious infection or other complications may not need hospitalization. Children who have more serious complications (higher fevers, severe infection and pain, a history of pneumonia, and signs of dehydration) should remain in the hospital. If osteomyelitis, an infection in the bone, occurs, a six-week antibiotic course is needed, most of it intravenous. An accurate diagnosis of osteomyelitis is sometimes difficult to make, because bone damage from sickling can cause similar symptoms. It is important, however, to confirm the presence of an actual infection before administering antibiotics, because the antibiotic treatment required for osteomyelitis is so intensive and prolonged. Urinary tract infections may be difficult to manage and can be a serious problem for pregnant women with sickle-cell disease. Physicians should take a urine culture before beginning antibiotic treatment and another culture one to two weeks after treatment to be sure the infection has cleared up.

Treatment for Other Complications of Sickle-Cell Disease
Stroke. Compelling data from a recent study called the Stroke Prevention Trial in Sickle-Cell Anemia (STOP), supported by the National Institutes of Health, show that regular blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. The objective is to reduce hemoglobin S concentrations to less than 30% of total hemoglobin. Some children at high risk for a first stroke who are candidates for transfusion may be identified using ultrasound, a noninvasive imaging technique. Studies indicate that as many as 90% of patients do not experience another stroke after five years of transfusions. Most centers give children transfusions for only three years, however, and when they are stopped, strokes occur in 50% of patients. Some centers are administering transfusion therapy indefinitely. Ongoing transfusion therapy can have severe consequences including iron overload, which increases the risk for liver cancer and requires treatments known as chelation therapy. The drug deferoxamine is commonly used for this purpose. Unfortunately, deferoxamine must be infused using a pump for 20 hours each day, and because of this, many patients fail to continue with the treatment. It also has some severe side effects. An oral form of iron-chelation therapy -- deferiproneis currently in trials and may help to make the regimen less arduous, although it also has serious complications and requires careful monitoring.

Many physicians are concerned about giving continual transfusions to every sickle-cell patient whose ultrasounds indicate risk. Because ultrasound is not accurate enough to predict which patients will have a stroke, many who would never experience one will endure transfusions and iron chelation therapy for years. An automated procedure for exchanging red blood cells called erythrocytapheresis may limit iron overload and provide an alternative to transfusions in some patients. More research on this procedure is needed, however. Until diagnostic tests can be more precise in determining risk, or there are effective alternative treatments to transfusions, patients and their caregivers and physicians must make the best decisions they can.

In children who have had a stroke, rehabilitation and rehydration are extremely important. Transfusions are administered at regular intervals to prevent further damage and recurrence.

Kidney Problems. ACE inhibitors are drugs commonly used to control high blood pressure that have been known to slow progression of kidney failure in people with diabetes. Studies are now reporting that these drugs might be beneficial in preventing hypertension and kidney failure in sickle-cell patients. Such drugs include captopril (Capoten), enalapril (Vasotec), quinipril (Accupril), benazepril (Lotensin), and lisinopril (Prinivil, Zestril).

Anemia. Folic acid is given to help treat the anemia that occurs in patients with sickle-cell disease.

Leg Sores Leg sores occur in up to 10% of sickle-cell patients and usually affect patients older than 10 years. They are difficult to treat, and, at this time, simple treatment with a moist dressing 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 household bleach to one gallon of water. A dressing soaked in diluted white vinegar may be applied every 3 to 4 hours. The leg should be elevated and bed rest for a week or more is sometimes required for severe ulcers. Topical antibiotics, saline or zinc oxide dressings, or cocoa butter or oil are also used depending on severity. Skin grafts and transfusions have been helpful in some extreme cases.

Priapism. Priapism -- prolonged and sometimes painful erections -- must be treated to prevent partial or complete impotence, which can result from erections that last several hours to days. Exchange transfusions may be used to reduce the hemoglobin S and sickling that cause this condition. A surgical procedure that implants a shunt to redirect blood flow is sometimes performed. Inflatable penile implants may help maintain potency without causing priapism. One study suggests that treatment with the drug leuprolide can prevent repetitive and prolonged episodes of priapism in severely affected teenage boys with sickle-cell disease; further research is required, however.

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.

Emotional Support
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. 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. Computers and the monthly charges for on-line services are still costly, however. Parent and professional support associations still offer the best and least expensive sources of help.

What Are the Treatments Aimed at Sickle-Cell Disease Itself?
Research is ongoing toward identifying the biologic and chemical activities that promote or protect against the sickle-cell process. Currently, experimental treatments focus on the basic processes that cause the red blood cells to sickle in the first place. There are three basic modes of treatment:

1. stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process
2. blocking dehydration in the cells
3. transplantation of bone marrow from healthy donors so that normal hemoglobin is produced rather than hemoglobin S

Gene therapy is also being studied, although effective treatments of this kind are still years away.

Stimulation of Fetal Hemoglobin
In all people, the hemoglobin in the fetus and young infant called hemoglobin F is different from the hemoglobin in the growing child and adult. Infants with sickle-cell disease do not develop symptoms of the illness while they still have hemoglobin F. Adults who have sickle-cell disease but still retain high levels of hemoglobin F generally have mild disease. Fetal hemoglobin blocks the sickling action of red blood cells, and studies are now reporting that the severity of sickle-cell disease can be reduced by using drugs that stimulate production of hemoglobin F.

Hydroxyurea. To date, the most promising drug is hydroxyurea (Droxia), which is currently used to prevent acute sickle-cell crises, though it does not help once pain has begun. One trial reported that hydroxyurea reduced the intensity and frequency of sickle-cell crises by nearly 50%. Small studies of patients who have been using the treatment for several years indicate that the drug may also may improve spleen function, which aids in the immune process, particularly in children. Hydroxyurea also increases water content in red cells, which may add to its beneficial qualities. The drug also reduces the number of neutrophils -- the white blood cells that contribute to the process causing sickled cells to stick to the blood vessel walls. This effect may actually be more protective against sickle-cell crises over time than an increase in hemoglobin F. In some patients, the drug may cause dark discoloration of the nails. Continued monitoring of hemoglobin F has been recommended by some experts who believe that the drug should be discontinued if there is no increase in hemoglobin F within six months. Successful results appear to depend on a number of conditions: the ability of the bone marrow's ability to withstand the stress of the treatment; genetic factors that affect hemoglobin F production; patient compliance; and other biologic factors.

Experts currently recommend that hydroxyurea be limited to adults with moderate to severe recurrent, painful crises and to those who have experienced at least three crises during the last year. Although small studies show promise for the drug's use in children, its long term benefits, risks, and effects on longevity are not yet known. Laboratory studies indicate that it causes genetic changes and so may increase the risk for cancer and birth defects. It should be pointed out that one five-year follow-up study found no difference in survival rates between those taking hydroxyurea and those on placebo (dummy pills). In addition, one survey reported that there was no difference over one month in how patients on hydroxyurea and those on placebo recalled their experiences of pain.

Butyrate. Another drug, arginine butyrate, induces expression of a gene known as gamma-globin, which stimulates hemoglobin F. Results of early trials have been conflicting. In one 1998 study, administration of butyrate using intermittent pulses increased HbF levels to over 20% from a starting point of 2% of baseline.

Drugs to Prevent of Dehydration
Cell dehydration is a major factor in the sickling process of red blood cells. Dehydration itself is destructive. It also increases the density of hemoglobin S within the cell, thereby increasing the speed of the sickling process. To maintain the proper inflow and outflow of water, a cell uses a pump controlled by calcium and potassium. These minerals have electric charges that open and close a channel known as the Gardos channel in the cell membrane. If there is too little potassium and too much calcium in the bloodstream, the channel doesn't close and water flows out resulting in dehydration. Potassium can be lost and calcium increased through a number of mechanisms. The swollen sickle-cell membrane is easily injured, and abnormal iron deposits in the hemoglobin S can also damage the membrane.

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Clotrimazole, commonly used in ointments (Lotrimin, Mycelex) to treat fungal skin infections, stops potassium from leaving red blood cells and prevents the entry of calcium. Very early studies using an oral form of clotrimazole have been promising, but much more research is needed. Nitrendipine (Baypress), another drug being studied, prevents dehydration by blocking calcium's entry to red blood cells. In laboratory studies, magnesium protected against potassium and water loss in sickle-cells; small patient and animal studies are reporting promise for its use in preventing dehydration and increases in the hemoglobin S concentration.

Bone-Marrow or Stem-Cell Transplantation
The only true cure for sickle-cell disease at this time is bone-marrow transplantation. The bone marrow nurtures stem cells -- 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, or allogenic, donor, normal hemoglobin may be produced. Trials using a few carefully selected patients have reported very successful results. Candidates include those with a history of stroke or recurrent acute chest syndrome, sickle pulmonary disease, or vaso-occlusive crises.

Bone marrow transplant carries its own dangers and limitations. About 10% of those treated die from the treatment. 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. Nonetheless, transplanted cells which come from a donor (called allogenic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). 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. To be a candidate for bone marrow transplant, patients must be under age sixteen and have severe symptoms but no long term organ or neurologic damage and genetically matched siblings who will donate their marrow. At this time only 1% to 2% of all sickle-cell patients meet all these criteria. Experts hope that better diagnostic techniques will identify more patients at an early age who are at high risk for developing serious sickle-cell disease and in whom the benefits of transplantation would outweigh the risks.

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 (GVHD) may be reduced.

Other Investigative Treatments for Sickle-Cell Disease
Progesterone. Women with sickle-cell disease are often denied oral contraception that contains estrogen and progesterone because of a concern that the hormones may exacerbate the blood disorder. A laboratory study found no evidence that they would influence the sickling process, and, in fact, some studies are indicating that injected and implanted contraceptives that contain progesterone may be very effective in reducing symptoms in women. In one European study that used progesterone implants, symptoms were reduced and fetal hemoglobin levels increased.

L-Glutamine. L-glutamine is an ordinary amino acid that is heavily used by sickle cells. One study using supplements of this substance reported that after a month it caused changes in the blood that might prove to have benefits for sickle-cell patients.

Gene Therapy. Some researchers are focusing on therapies that transfer certain genes to bone marrow that might prevent the sickling process. One unique form of gene therapy for sickle-cell disease involves actually repairing existing defective genetic material to restore production of healthy hemoglobin. Even if any of these therapies are successful, however, widely available treatments are still years away.

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