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 hydroxyureaâ ' s 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.