Sickle cell disease is an inherited blood disorder in which the body produces abnormally shaped red blood cells. In sickle cell disease, the hemoglobin in red blood cells clumps together. This causes red blood cells to become stiff and C-shaped. These sickle cells block blood and oxygen flow in blood vessels. Sickle cells break down more rapidly than normal red blood cells, which results in anemia.
Sickle cell disease is a genetic disorder. People who have sickle cell disease are born with two sickle cell genes, one from each parent. If one normal hemoglobin gene and one sickle cell gene are inherited, a person will have sickle cell trait. People who have sickle cell trait do not develop sickle cell disease, but they are "carriers" who can pass the abnormal gene on to their children.
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. An infection or by blockage of blood vessels in the lungs can trigger acute chest syndrome, another common and serious occurrence. Additional medical complications include:
Hydroxyurea is being studied to replace transfusion therapy in select patients for the prevention of stroke. Sildenafil (Viagra), taken on a daily basis, may actually help reduce the frequency of priapism.
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, causing 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.
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. Hemoglobin is a protein in red blood cells that carries oxygen.
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 occurs from genetic changes that cause abnormalities in hemoglobin molecules:
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 symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:
The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in the United States. About 70,000 to 100,000 Americans -- mostly African-Americans -- have sickle cell disease. About 2 million Americans have sickle cell trait.
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 or 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 prevalence 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 inherit a pair of genes that regulate hemoglobin, with one gene coming from each parent:
The risk of a child inheriting sickle cell disease or sickle cell trait is as follows:
In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:
Pain, which can be very severe, is the most common complaint. It can be acute (short-term) or chronic (long-term). The pain usually arises from orthopedic problems in the legs and low back. Other symptoms can include:
Symptoms from childhood continue in adolescence and adulthood. In addition, patients may have:
Sickle cell crises are sudden and unpredictable 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. (See "Sickle Cell (Vaso-Occlusive) Crisis" in Complications section of this report.)
The hallmark complication of sickle cell disease is the
The pattern of a sickle cell crisis may occur as follows:
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.
Acute chest syndrome (ACS) is a sudden condition that occurs when the lung tissues are deprived of oxygen. ACS can occur when:
ACS can be very painful, dangerous, and even life threatening. Once ACS occurs, it is likely to happen again. ACS is a leading cause of illness among patients with sickle cell disease. Children with asthma are at particular risk for having ACS.
Symptoms of ACS include:
Infections are common and an important cause of severe complications. Before early screening for sickle cell disease and the use of preventive antibiotics in children, many infants with sickle cell died from infections. Fortunately, the use of required sickle cell screening tests for newborns, and the use of preventive antibiotics and immunizations in babies who are born with the disease, have significantly reduced mortality rates.
The most common organisms causing infection in children with sickle cell disease include:
Such infections pose a serious threat to infants and very young children with sickle cell disease. They can rapidly progress to fatal pneumonia in infants, and death can occur within a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.
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:
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 a significant cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease have echocardiographic testing to identify if they are at risk for pulmonary hypertension and need 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
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% to 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.
Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia). People with sickle cell disease have a chronic shortage of healthy red blood cells, which leads to persistent 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 hemoglobin levels of about 8 g/dL, much lower than hemoglobin levels in healthy people. Chronic anemia reduces oxygen levels and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to enlarge dangerously, with an increased risk for heart attack and heart failure.
Sometimes patients may experience 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 and are unable to form new red cells. This leads to a sudden drop in the red blood cell count (hemoglobin level). This sudden stopping is often triggered by a virus called human parvovirus B19.
Children, adolescents, and possibly young adults may experience splenic sequestration, which can be a life-threatening condition. This happens when a large number of sickled red blood cells collect in the patient's spleen. In addition to pain and abdominal swelling, splenic sequestration can cause a sudden drop in hemoglobin levels.
Many males with sickle cell disease, including children, suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. If priapism is not treated, permanent partial or complete erectile dysfunction can occur.
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% to 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 in association with sickle cell disease.
Enlargement of the liver (hepatomegaly) occurs in many sickle cell patients, which can lead to permanent liver damage and failure. In addition, because sickle cell patients often need blood transfusions, they are at higher risk for acquiring hepatitis C. This risk, however, has decreased since screening procedures for donated blood have been implemented.
Gallstones are a common complication of sickle cell disease. 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, usually no treatment is necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed.
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.
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 adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may need surgery to remove diseased and dead bone tissue. Patients with severe cases may need joint replacement.
Leg sores and ulcers may occur. They usually affect patients older than 10 years.
Sickle cell disease can damage blood vessels in the eye and cause scarring and detachment of the retina, which can lead to blindness.
Women with sickle cell disease who become pregnant are at higher risk for complications such as miscarriage and premature birth, and their babies may have 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.
Older children and adult patients with sickle cell are subject to other medical problems, including delayed growth and physical development. In severe cases, sickle cell disease can cause multiple organ failure.
New and better 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. Today, life expectancy for these patients can reach 50 years and beyond. Women with sickle cell usually live longer than their male counterparts.
The damage of sickle cell disease occurs because of the logjam that sickle cells cause in the capillaries. Sickle cell disease 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, mostly because their damaged spleens are unable to protect the body from bacteria. Signs of impaired lung function may occur even in very early years. Because children with sickle cell disease are living 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.
Blood tests can determine whether an individual has sickle cell trait or sickle cell disease.
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 of 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.
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:
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 has experience in treating sickle cell disease.
Bone marrow transplantation is the only potential cure, but it is used in only a small number of cases because few patients are able to find donors who are suitable genetic matches. Blood transfusions are given to prevent worsening anemia and stroke.
Drug treatments for sickle cell disease include:
HbF, also called fetal hemoglobin, is the form of hemoglobin present in the fetus and young infants. (Hemoglobin is a protein in red blood cells that carries oxygen.) 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 (Hydrea/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 first-line therapy to treat adults and adolescents with moderate-to-severe recurrent pain crises (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 could benefit from this medication 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.
Hydroxyurea may be a treatment option for select children at high risk for stroke. After at least one year of transfusions, children with abnormal transcranial Doppler loss findings but no imaging evidence of vascular changes otherwise may be candidates for this medicine.
Side effects include constipation, nausea, drowsiness, hair loss, leg ulcers, and inflammation of the mouth. More severe side effects include reduction of white blood cells (neutropenia) and the cells responsible for normal blood clotting (thrombocytopenia). Hydroxyurea should not be taken by pregnant women because 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 many patients the risks of untreated sickle cell disease may outweigh the risks of hydroxyurea'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.
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 are needed in the following situations:
Chronic (on-going) transfusions are used for:
Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to blood borne microbes. 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.
Transfusions may be either simple or exchange:
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.
Bone marrow transplantations have been performed successfully in select children with sickle cell disease. Best results are obtained with matched sibling or related donors. The next best option is fully matched but unrelated donors. Unfortunately, this second option is only rarely available. However, due to a lack of available donors and the risks of potential complications, bone marrow transplantations for sickle cell disease are not routinely performed. Complications can include the immune system's rejection of the transplant (a condition called
Before a bone marrow transplant can be performed, the patient must undergo chemotherapy to completely destroy their own bone marrow. Bone marrow transplantation is considered too risky for adults with sickle cell disease, because they cannot tolerate the chemotherapy regimen as well as children and they tend to have long-term organ damage as a result of the condition.
Researchers are investigating new types of bone marrow transplants for children and adults with sickle cell disease. Several new approaches appear promising. They include giving less intense doses of chemotherapy prior to the transplant (a regimen known as "
In recent years, researchers have reported some success with "half-matched" marrow transplants (
Nitric oxide is a natural chemical in the body that relaxes smooth muscles and widens blood vessels. Patients with sickle cell disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes sickle cell pain. Some studies have indicated that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. Other studies report that nitric oxide is of no benefit. In addition, nitric oxide is difficult to administer. More studies are needed to determine if nitric oxide should have a role in sickle cell therapy. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)
Arginine is an amino acid 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.
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.
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.
Acute chest syndrome can be fatal and must be treated immediately in a hospital. Basic treatments include:
Fever in any sickle cell patient should be considered an indication of infection. Temperatures over 101°F (38.3°C) 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 (37.8°C) 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.]
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, patients who are given multiple transfusions should avoid iron supplements. Also, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12.
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.
Priapism causes prolonged and painful erections that can last from several hours to days. It is best to treat this problem within 12 hours. Relief within 36 hours is important to avoid permanent erectile dysfunction. Pain relief, oxygen, and intravenous fluids are the initial steps. Exchange transfusions have also been proposed. 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.
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.
Leg ulcers are difficult to treat. Simple treatment with a moist dressing usually provides the best results. To treat mild ulcers, gently wash the leg 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 to 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.
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. Problems that occur more often during pregnancy include, preeclampsia, HELLP syndrome, blood clots, and anemia.
To prevent or reduce the severity of long-term complications of sickle cell disease, several precautions may be helpful:
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:
Tuberculosis skin testing should be performed every year except in patients who have tested positive in the past.
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.
Good nutrition, while essential for anyone, is critical for patients with sickle cell disease. Some dietary recommendations include:
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.
Some research suggests that zinc supplements may possible help reduce the frequency sickle cell crises and infections. More research is needed.
Sickle cell disease presents great emotional challenges for patients and their families. 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 stress of not knowing when a sickle cell crisis will occur. They also have to struggle with lost time and social isolation at school and work, as well as fear of death.
Any chronic illness places stress on the patient and family, but sickle cell patients and caregivers often face particular obstacles in finding psychological support for the disease. Communities in which many sickle cell patients live may 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. The following are some measures that may help in dealing with this disease:
Anie KA, Green J. Psychological therapies for sickle cell disease and pain. Cochrane Database Syst Rev. 2015 May 8;5:CD001916. Review. PMID: 25966336 www.ncbi.nlm.nih.gov/pubmed/25966336.
Burnett AL, Anele UA, Trueheart IN, Strouse JJ, Casella JF. Randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in sickle cell disease. Am J Med. 2014 Jul;127(7):664-668. Epub 2014 Mar 25. PMID: 24680796 www.ncbi.nlm.nih.gov/pubmed/24680796.
DeBaun MR, Frei-Jones MJ, Vichinsky EP. Hemoglobinopathies. In: Kliegman RM, Stanton BMD, St. Geme J, Schor NF, eds. Nelson Textbook of Pediatrics. Philadelphia, PA: Elsevier; 2016:chap 462.
DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21;371(8):699-710. PMID: 25140956 www.ncbi.nlm.nih.gov/pubmed/25140956.
Fitzhugh CD, Abraham AA, Tisdale JF, Hsieh MM. Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. Hematol Oncol Clin North Am. 2014 Dec;28(6):1171-1185. Epub 2014 Sep 29. Review. PMID: 25459186 www.ncbi.nlm.nih.gov/pubmed/25459186.
Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305(9):893-902. PMID: 21364138 www.ncbi.nlm.nih.gov/pubmed/21364138.
Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol. 2012;59(13):1123-1133. PMID: 22440212 www.ncbi.nlm.nih.gov/pubmed/22440212,
Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2014 Nov 6;11:CD003427. Review. PMID: 25375222 www.ncbi.nlm.nih.gov/pubmed/25375222.
Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N. Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease. Cochrane Database Syst Rev. 2015 Aug 12;8:CD010849. Review. PMID: 26264938 www.ncbi.nlm.nih.gov/pubmed/26264938.
Klings ES, Machado RF, Barst RJ, An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014 Mar 15;189(6):727-740. PMID: 24628312 www.ncbi.nlm.nih.gov/pubmed/24628312.
Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006;108(3):847-852. PMID: 16861341 www.ncbi.nlm.nih.gov/pubmed/16861341.
Machado RF, Gladwin MT. Pulmonary complications of hematologic diseases. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds. Murray and Nadel's Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier; 2016:chap 94.
Martí-Carvajal AJ, Conterno LO, Knight-Madden JM. Antibiotics for treating acute chest syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2015 Mar 6;3:CD006110. Review. PMID: 25749695 www.ncbi.nlm.nih.gov/pubmed/25749695.
Rana S, Houston PE, Wang WC, et al. Hydroxyurea and growth in young children with sickle cell disease. Pediatrics. 2014 Sep;134(3):465-472. PMID: 25157002 www.ncbi.nlm.nih.gov/pubmed/25157002.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. PMID: 21131035 www.ncbi.nlm.nih.gov/pubmed/21131035.
Schatz J, Schlenz AM, McClellan CB, et al. Changes in coping, pain, and activity after cognitive-behavioral training: a randomized clinical trial for pediatric sickle cell disease using smartphones. Clin J Pain. 2015 Jun;31(6):536-547. PMID: 25503599 www.ncbi.nlm.nih.gov/pubmed/25503599.
Steinberg MH. In the clinic. Sickle cell disease. Ann Intern Med. 2011;155(5):ITC31-15. PMID: 21893620 www.ncbi.nlm.nih.gov/pubmed/21893620.
Swe KM, Abas AB, Bhardwaj A, Barua A, Nair NS. Zinc supplements for treating thalassaemia and sickle cell disease. Cochrane Database Syst Rev. 2013;6:CD009415. PMID: 23807756 www.ncbi.nlm.nih.gov/pubmed/23807756.
Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016 Feb 13;387(10019):661-670. Epub 2015 Dec 6. PMID: 26670617 www.ncbi.nlm.nih.gov/pubmed/26670617.
Ware RE, Helms RW; SWiTCH Investigators. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood. 2012;119(17):3925-3932. PMID: 22318199 www.ncbi.nlm.nih.gov/pubmed/22318199.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sicklecell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-1048. Review. PMID: 25203083 www.ncbi.nlm.nih.gov/pubmed/25203083.
Reviewed By: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.