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Sickle cell disease

Description

An in-depth report on the causes, diagnosis, and treatment of sickle cell disease.

Alternative Names

Sickle cell anemia

Treatment

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:

• Stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process
• Blocking dehydration in the cells
• Transplantation of bone marrow or stem cells from healthy donors so that normal hemoglobin is produced rather than hemoglobin S

Drugs that Stimulate Fetal Hemoglobin

Hemoglobin F (HbF, also called fetal hemoglobin) is the form of hemoglobin that exists in the fetus and small infants. Most HbF is later replaced by the hemoglobin that is present in the growing child and adult, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells so that 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.

Studies now suggest that the severity of sickle cell disease can be reduced by using drugs that stimulate production of HbF. Even increases as modest as 4% may have a significant benefits for these patients.

Hydroxyurea. Hydroxyurea (Droxia, Hydrea) destroys cells in the bone marrow, which results in an increase in special cells that can produce HbF. It is currently the only drug in general use to prevent acute sickle cell crises. It appears to have a number of effects on sickle cell:

• Hydroxyurea reduces the intensity and frequency of sickle cell crises by nearly 50%. (It does not have any effect on pain, however, once it starts.)
• Over time, the drug may improve spleen function, which aids in the immune process, particularly in children.
• Hydroxyurea increases water content in red blood cells.
• The drug reduces the number of neutrophils, the white blood cells that contribute to the process causing sickle cells to stick to the blood vessel walls. This effect may actually be more protective over time than its effect on increasing levels of hemoglobin F.

Hydroxyurea is used to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). The drug is proving to reduce sickling crises and pain, priapism, the number of transfusions, and life-threatening complications in this group. The benefits appear to be long-lasting. For example, a 2002 study reported that after 4 years patients who had taken the drug for at least 2 years experienced 30% fewer hospitalizations and 58% fewer transfusions than before they took hydroxyurea. In a 9-year study, the drug also reduced mortality rates by about 40%. Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Small studies have reported no protection from damage in the spleen or bones and joints. Effects on stroke and complications in the eye or kidney are not yet known.

Hydroxyurea is still being investigated in young people. To date, the response to the drug in children and teenagers 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 and beneficial for infants. A 2005 study indicated that long-term hydroxyurea treatment can improve height, weight, and spleen function, and reduce episodes of acute chest syndrome. Patients in the study started the treatment as babies, and most patients took the drug for at least 4 years. The drug was given by mouth in a flavored liquid form.

Side effects include gastrointestinal problems, headache, drowsiness, and skin and nail changes. In rare cases, there have been reports of hallucinations and seizures. The drug may also cause leg ulcers and gangrene in some patients. 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.

Cytidine Analogues. Cytidine analogues increase HbF production by affecting the genes that regulate it. Decitabine is one such drug that was developed to treat leukemia and other blood malignancies. Early studies are suggesting that it significantly increases HbF production, even in patients in whom treatment with hydroxyurea failed. Only minor toxic side effects have been reported to date.

Butyrates. Butyrates are natural fatty acids, the end-products of fermented carbohydrates in the intestinal tract that are also metabolized from fiber. One derivative, arginine butyrate, has been under investigation for some time in sickle cell for its role in stimulating production of HbF. Intermittent therapy using intravenous administration has achieved increased levels. In a promising 2002 study, administering arginine butyrate improved ulcer healing by ten-fold. Because its actions are different from hydroxyurea, experts hope the two drugs may eventually be used in combination. However, arginine butyrate is difficult to administer, and experts are looking for different forms that might make it simpler to use.

Nitric Oxide

Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Hemoglobin removes nitric oxide. Because sickle cells release hemoglobin, patients with the 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. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Arginine

Sickle cell disease can cause red blood cells to break apart. This process is called hemolysis. Hemolysis causes a lack of the amino acid arginine. Arginine is involved in producing nitric oxide. Recent research suggests that a lack of arginine may contribute to the development of pulmonary hypertension, a leading cause of death in patients with sickle cell disease. Pulmonary hypertension causes high blood pressure in the arteries that carry blood to the lungs.

A 2005 study found that patients with sickle cell who had low levels of arginine were 3.6 times more likely to die than patients with high arginine levels. Most patients in the study died from pulmonary hypertension. Scientists are working on developing a blood test that could measure amino acid levels and help identify patients at greatest risk of death. They are also working on developing drugs that could block arginase, a protein in cells that is released during hemolysis, which consumes arginine. Doctors are not yet sure whether arginine nutritional supplements are helpful or harmful for patients with sickle cell disease. Patients should talk to their doctor before taking these or other supplements.

Drugs to Prevent Dehydration

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Promising drugs under investigation are those that specifically block the Gardos channel, which is an important route for potassium loss and dehydration. They include magnesium pidolate and clotrimazole and its derivatives.

Clotrimazole. Clotrimazole (a common ingredient in ointments such as Lotrimin or Mycelex, which are used to treat fungal skin infections) stops potassium from leaving and calcium from entering red blood cells. This prevents water loss in the cells. Early studies using an oral form of clotrimazole have been promising, but more research is needed.

Magnesium. Small studies have reported some benefits from the use of supplements containing magnesium pidolate to improve potassium and calcium interactions. Research is still ongoing.

Zinc. Zinc sulphate appears to help reduce red blood cell dehydration. Important studies are reporting that it helps prevent sickle cell crises and reduce pain and life-threatening complications.

Piracetam. Piracetam (Nootropil) prevents water loss, and important studies suggest that it may reduce sickle cell crises and pain. It also may improve rehabilitation in people who have had strokes.

Bone Marrow or Stem Cell Transplantation

At this time, the only true 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.

Candidates. Possible candidates for transplantation are patients with the following conditions:

• A history of stroke
• Sickle pulmonary disease
• Recurrent acute chest syndrome or vaso-occlusive crises

Up to 80 - 85% of patients who receive transplants remain disease free. Unfortunately, only about 7% meet the criteria for transplantation, include those who:

• Are age 16 or younger
• 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. About 10% of those treated die from the treatment. Some complications include:

• 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.

Investigational Approaches. Experts hope that better diagnostic techniques will identify at an early age more patients who are at high risk for developing serious sickle cell disease and in whom the benefits of transplantation would outweigh the risks. Researchers are also investigating regimens that might be suitable for adult patients and less toxic regimens.

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.

Transfusion Therapy in Sickle Cell Disease Transfusions are often critical for treating sickle cell disease. In some cases they may be given on a regular basis to prevent stroke or other life-threatening complications of the disease. Ongoing transfusions can reduce episodes of pain and acute chest syndrome. They can also help improve height and weight in children with sickle cell disease. Regular transfusions, however, can have severe side effects. Transfusions may be required by sickle cell patients either for specific episodes (used only for specific events) or as chronic transfusions (ongoing transfusions). 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. Some evidence suggests that a conservative transfusion regime is as effective as aggressive transfusions in these cases, but more research is needed. Transfusions are generally not required for minor surgeries. Chronic Transfusions. Chronic (on-going) transfusions are used in patients who have:: Pulmonary hypertension and chronic lung disease Heart failure Chronic kidney failure and severe anemia Unusually severe and protracted episodes of pain Transfusions are also used to prevent first or recurrent strokes. Evidence indicates that chronic transfusions reduce the risk for stroke in children by over 90%. The important 2004 STOPII trial showed that stopping transfusions in high-risk children definitely increases their stroke risk. At this time, experts recommend that children at high risk for stroke continue to receive regular blood transfusions. 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 should be used promptly if 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 and to reduce the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels. Exchange transfusion may also reduce the risk of heart failure and help prevent fat embolism, a life-threatening condition in which fatty tissue from the bone marrow travels to blood vessels in the lungs and cuts off oxygen. Iron Overload and Chelation Therapy. Iron overload increases risk for complications including liver cancer and heart failure. A liver biopsy accurately determines whether excess iron levels are present. A non-invasive test called a superconducting quantum interference device (SQUID) should be used if available. Chelation therapy is used to remove excess iron stores in the body that can harm the liver, heart, and other organs. 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.

• Review Date: 1/17/2007
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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