Hematology

Sickle cell syndromes

Sickle cell syndromes

What every physician needs to know:

Sickle cell disease (SCD) is an inherited, chronic, hemolytic anemia characterized by acute episodes of vaso-occlusion and progressive organ dysfunction. The disease results from mutation in the beta globin chain, leading to production of sickle hemoglobin.

Sickle hemoglobin polymerizes and results in fragile, deformed red cells that obstruct vascular flow resulting in tissue injury.

SCD is a group of syndromes that share a common pathophysiology, with marked variation in the severity based on the genotype. All are autosomal recessive and include two beta gene mutations, with at least one being a sickle mutation.

There are three major genotypes:

  • Sickle cell anemia refers to homozygous sickle cell anemia

  • Hemoglobin SC (sickle cell) disease refers to a double heterozygote for S and C mutations

  • Sickle ß thalassemia is secondary to the sickle mutation with either a ß0 or a ß+ mutation

Sickle cell trait (SCT) results in increased survival to carriers in areas endemic for malaria.

It is this protective effect of malaria that drives the distribution of SCD and its frequency. Therefore, the disease develops in multiple ethnic groups, including Caucasians, that have their origins in malaria endemic regions.

Nationally, universal screening in newborns for SCD is standard. Newborns are not symptomatic because the sickle hemoglobin level is low at birth, gradually rises during early infancy, and is paralleled by the development of symptoms. Infants commonly present with dactylitis (swelling of the hands and feet), splenic sequestration, and serious infection. In fact, fatal infection, secondary to Streptococcus pneumoniae, was a common presentation for sickle cell anemia in infants until the universal use of prophylactic penicillin following newborn diagnosis.

Infections are common in SCD, secondary to early loss of splenic function. Acute episodes of pain are often the initial presenting symptom and are the most common cause of hospitalization. The hospitalized events for pain represent a small number of the painful events, which are often managed at home.

Pulmonary disease is a serious complication of sickling. Acute pulmonary events, called "acute chest syndrome", are a leading cause of mortality and as patients’ age increases, chronic lung disease becomes prominent. Neurologic complications are an important cause of morbidity and mortality. In sickle cell anemia, 0.8% per year of the population experienced an overt clinical stroke.

Additionally, at least 25% of the population have non-focal ischemic brain damage often associated with neurocognitive abnormalities. Neurologic injury is often associated with abnormal cerebral blood flow, which can be detected before an overt event with transcranial Doppler (TCD) screening. This non-invasive TCD screening has become standard for children and has successfully decreased progression to clinical strokes by the initiation of chronic transfusion in asymptomatic, high-risk patients.

As sickle cell patients age, they have a marked increased rate of intracranial hemorrhage that is often fatal. It commonly occurs in patients with undetected aneurysms in the circle of Willis and internal carotid arteries. Genitourinary complications vary in severity, affect most patients, and increase with age. Most patients develop hyposthenuria in early infancy that results in increased susceptibility to dehydration. Proteinuria is common and precedes the development of chronic renal failure in up to 25% of adults. The early initiation of ACE (angiotensin-converting-enzyme) inhibitors may prevent the progression of renal disease. Priapism occurs in up to two-thirds of males. It is caused by obstruction of the venous drainage of the penis and, untreated, leads to fibrosis and impotence.

Sickling within the retinal vascular bed leads to a proliferative retinopathy associated with vitreous hemorrhage and retinal detachment. Early detection may prevent its progression. Orthopedic complications are common, including bone infarction, osteomyelitis, and avascular necrosis of the femoral head. Osteonecrosis is a major cause of morbidity resulting in pain and eventual hip replacement in many patients. In warm climates, chronic leg ulcers due to sickling within the skin microvasculature is a painful problem that is often resistant to healing and requires aggressive management.

The chronic hemolytic anemia in SCD varies dramatically from a hemoglobin of 5g/dL to almost normal hemoglobin levels. The hemolytic anemia often results in gallstones and the necessity for cholecystectomy. Most patients tolerate their steady state hemoglobin without transfusion. However, acute exacerbations of their anemia secondary to aplastic episodes, splenic sequestration, and infection, often result in the need for transfusion.

The therapy for sickle cell syndromes requires a multidisciplinary team designed to prevent or detect early complications. This includes education, counseling, immunizations, prophylactic antibiotics, prompt pain management, TCD screening, and monitoring each at risk organ for early damage.

Hydroxyurea is the first and only FDA (Food and Drug Administration) approved treatment for SCD. It inhibits ribonucleotide reductase and leads to increased production of hemoglobin F. Hemoglobin F has an anti-sickling effect. Hydroxyurea decreases painful events, acute lung injury, and appears to lower mortality rate. Many patients require chronic transfusion therapy to prevent or treat complications. While transfusion therapy is efficacious, it is complicated by alloimmunization, infection, and iron overload. The progressive morbidity of the disease has led to the routine use of matched sibling donor stem cell transplantation for high risk children.

Are you sure your patient has sickle cell disease? What should you expect to find?

In the newborn period, patients are asymptomatic and have no overt or simple laboratory findings. As the patient ages, symptoms and physical findings become more prominent but are often vague and non-diagnostic. The hemolytic anemia results in hyperbilirubinemia and clinical jaundice in many patients. The anemia and an increased metabolic rate gradually induces decreased growth and weight gain. The skeletal development is often delayed, as is the onset of sexual development and puberty. In infancy, a hepatosplenomegaly may develop. However, as the patient ages, the spleen undergoes autoinfarction except in the more benign variance. Chronic anemia commonly results in a benign cardiac flow murmur, an increased pulse pressure, and a hyperactive precordium.

The expansion of marrow space may lead to facial changes and malocclusion. Pulmonary symptoms are common but not specific to the disorder. Upper airway problems, secondary to tonsillar enlargement, is common and may result in sleep apnea and upper airway obstruction. There is a marked increased incidence of bronchoreactive lung disease, possibly secondary to nitric oxide deficiency. As patients age, deteriorating lung function, often with pulmonary hypertension, results in a decreased exercise tolerance and sternal discomfort.

In warm climates, such as Jamaica, 75% of adults with SCD have experienced a leg ulceration. These ulcers are typically in the areas around the ankle and are often associated with granulation tissue. Many patients, because of the hyposthenuria (impaired concentration ability), have a history of enuresis and nocturia.

Beware of other conditions that can mimic sickle cell disease:

There are two major components of SCD that can lead to misdiagnosis. The first is the differential diagnosis of hemolytic anemia, and the second and most important, is the etiology of acute or chronic symptoms in a sickle cell patient. There are many causes of hemolytic anemia in the "at risk" population. Therefore, a sickle cell solubility test does not separate out SCT from SCD.

Sickle SCT does not cause hemolytic anemia. Following SCT, a more definitive test is required, such as hemoglobin electrophoresis. Except in the newborn period, hemoglobin electrophoresis must demonstrate that hemoglobin (Hb) S is the predominant hemoglobin. There are many other common causes of hemolytic anemia including enzyme deficiencies, membrane abnormalities, autoimmune hemolytic anemia, and other hemoglobinopathies. These disorders may share the same characteristics of anemia with markers of hemolysis.

Each of the acute and chronic manifestations of SCD are largely diagnoses of exclusion. Each should undergo an evaluation to rule out common etiologies in the general population. This includes the etiology of pain, neurologic dysfunction, cardiopulmonary disease, and renal failure.

Which individuals are most at risk for developing sickle cell disease:

SCD is a genetic disorder that results from the inheritance of two mutations of the beta globin. One or more of these mutations must be SCT.

SCT has survival protections for individuals in malaria endemic areas. The carrier state is autosomal recessive and is not linked to race or sex, but to geographic origins of population. Therefore, people from Africa, the Mediterranean, the Middle East, South America, the Caribbean, and regions in India are most at risk.

Over 300,000 infants are born with the disease annually. In the United States, there are estimated to be 104,000 to 138,000 patients with SCD. Migration has led to sickle cell disorders occurring in all populations and the establishment of universal newborn screening in the United States. In California, approximately 1 in every 120 births have SCT, with the highest incidence in African Americans and Hispanic individuals. In African Americans, 1 in 400 births will have a sickle cell disorder.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Initial laboratory tests usually include red blood cell indices, reticulocyte count, hemoglobin level, and peripheral blood smear. Most patients have a variable anemia that can range from 6 to 12g/dL depending on the SCD variant. The mean corpuscular volume (MCV) is normal, except in patients with an associated thalassemia mutation. The reticulocyte count and markers of hemolysis are elevated. Definitive diagnosis requires further testing with hemoglobin electrophoresis, isoelectric focusing, or HPLC (high-performance liquid chromatography.

The solubility test can detect SCT outside the newborn period, but cannot distinguish it from SCD. Both cellulose acetate and citrate agar are utilized together to diagnose a SCD, because of the similar electrophoretic mobility of hemoglobin variance. Prenatal diagnosis is available by obtaining fetal DNA samples at 8 to 10 week gestation. The peripheral blood smear may show target cells in Hb SC and Hb S ß-thalassemia. In sickle cell anemia, irreversible sickle cells may be noted. There are pitfalls in interpreting these results. Benign disorders such as sickle-HPFH (hereditary persistence of fetal hemoglobin) has a similar electrophoresis as SCD but is benign. It can be distinguished by family studies and DNA testing. SCT may be difficult to separate from sickle ß+ thalassemia, particularly in the newborn period. Prior transfusion will result in artificial elevation of Hb A.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of sickle cell disease?

Imaging tests are not required in order to make the initial diagnosis, but are necessary in the evaluation and monitoring of the disease manifestations and its complications.

If you decide the patient has sickle cell disease, what therapies should you initiate immediately?

The type of therapy to be initiated is determined by the age of the patient. Following prenatal diagnosis, the family must decide on the decision of pregnancy. At that time, extended family testing and genetic counseling is required. Following newborn screening and the identification of a SCD baby, education and counseling is started as soon as possible with a focus on fever, infection, sequestration crisis, and growth and development. By 2 months of age, prophylactic penicillin twice daily is required to prevent life threatening infections.

Aggressive immunizations are required including pneumococcus, meningococcus, Haemophilus influenzae, and viral influenza. Dehydration, secondary to early loss of renal concentration ability, requires immediate counseling concerning fluid intake. Urinary loss continues despite dehydration, and urine output cannot be used as a judge of hydration status. Routine treatments and evaluations include folic acid at 1mg/day, TCD screening annually to detect the risk of stroke after 2 years of age, retinal evaluation at 5 years of age, echocardiogram at 15 years of age, baseline pulmonary function studies after 5 years of age, and biannual laboratory monitoring of chemistries for renal disease and organ dysfunction.

More definitive therapies?

The morbidity of SCD increases with age, resulting in premature death, decreasing quality of life, and repeated, unexpected life threatening emergencies. This has led to the initiation of selective use of therapy that alters the disease.

Three common therapies are utilized: hydroxyurea, chronic transfusion therapy, and stem cell transplantation. Hydroxyurea is FDA approved in adults and appears equally efficacious in children. It appears to reduce by 50% the incidence of painful events, hospitalizations, and acute chest syndrome. It requires daily administration and monitoring of the laboratory side effects. Hydroxyurea is an anti-tumor drug that elevates the Hb F level within the cell, resulting in less sickling. The initial starting dose is 15mg per kg per day, escalating to a maximum of 30mg per kg per day. Studies suggest that it has a good safety margin, but may cause cytopenia and has the theoretical small risk of carcinogenesis and mutagenesis.

Chronic transfusion therapy, designed to lower the Hb S level to 30%, is the standard therapy for patients with overt CNS (central nervous system) disease. It is often used in patients with severe complications or high risk for stroke. It is affective, but complicated by iron overload, alloimmunization, and transfusion risks.

Stem cell transplantation is curative in SCD. The use of extended red cell phenotypically matched units and oral iron chelation decrease the risk of transfusion therapy. HLA (human leukocyte antigen)-matched allogeneic transplantation is considered in high risk patients under 16 years of age. Less than one quarter of patients have a matched sibling. In children, the overall and event-free survival is approximately 94% and 84% respectively. Approximately 10% of the patients develop graft rejection or a recurrence of SCD, and 5% die from transplant related complications. Indications are expanding into older patients and those with unrelated HLA matches. However, these are experimental.

What other therapies are helpful for reducing complications?

SCD is a protean illness that affects all organs. There are preventative and treatment recommendations for each potential complication.

Pain

Pain is the most common symptom SCD patients experience. It can result in sudden, acute pain requiring hospitalization, but often is characterized by moderate pain that affects patients up to 40% of the time. It can be precipitated by infection, dehydration, hypoxia, rapid temperature changes, but is often without a precipitating factor. Patients are often undertreated and mislabeled as drug-seeking, resulting in a stigma that is unwarranted. The rate of addiction in SCD is not increased compared to matched controls. Ethnic, racial, and social cultural biases are factors in the treatment.

Initial treatment should include optimal hydration and aggressive pain relief with opiates or other analgesics. Meperidine is not recommended because of its seizure potential. Nonsteroidal anti-inflammatory drugs, patient controlled analgesia devises, incentive spirometry, and pain assessment tools are a standard part of the management of a hospitalized patient. Chronic pain syndrome can develop in a subgroup of patients and requires a multidisciplinary approach with pain specialists, to address problems such as hyperalgesia syndrome.

Infection

Infection is a common, potentially life-threatening complication, particularly in young children. All patients with fever of 101.5F (38.5C) need immediate evaluation. This evaluation includes physical exam, blood culture, and blood counts. Chest x-rays are routinely done, even without pulmonary symptoms, because of the high rate of serious pulmonary events that follow fever. High risk patients are usually given a dose of ceftriaxone and hospitalized. Lower risk patients, following a dose of antibiotics, can be followed at home. These patients are at high risk for meningitis and osteomyelitis and require aggressive evaluation.

Pulmonary disease

Patients are at high risk of pulmonary disease, which is the most common cause of death. Acute pneumonia, pulmonary hypertension, asthma, and eventual and chronic lung failure are serious complications that require annual screening with pulmonary functions tests and aggressive management. Pulmonary hypertension and bronchoreactive lung disease are independent predictors of early mortality.

All patients with an abnormal chest x-ray and acute symptoms should be admitted to the hospital and receive antibiotic therapy including a macrolide antibiotic. Routine administration of bronchodilators is recommended, unless airway hyperreactivity studies are available. Patients with severe respiratory symptoms require transfusion therapy. In moderately ill patients, a simple transfusion to correct the anemia is considered. In patients with respiratory distress and hypoxia, exchange transfusion is indicated.

Cerebral vascular disease (CNS)

Sickle cell patients are at least 300 times more likely than non-sickle cell patients to experience a CNS complication. The risk varies by sickle variant.

Complications usually occur from ischemic infarction in children and hemorrhagic stroke in older adults. Often, there is occlusion of the circle of Willis on magnetic resonance angiography (MRA). At least 25% of patients have non-focal ischemic injury that results in neurocognitive abnormalities and increases the risk of an overt stroke. This has led to the routine screening of all children with TCD, followed by transfusion prophylaxis in those with an abnormality.

Once a CNS event has occurred, chronic transfusion therapy is indicated indefinitely. The management of the acute event should include an immediate exchange transfusion and close monitoring of metabolic fluid status, because there is potential for cerebral edema. Neurosurgical consultation is recommended in all patients with hemorrhage. Rehabilitation programs should be started early. Patients with moya collateral vessels are at high risk for hemorrhage and may benefit from encephaloduroarteriosynangiosis (EDAS).

Renal

Renal damage is common. It is often preceded by protenuria, which requires annual screening. Early use of ace inhibitors may be beneficial. Most patients have hyposthenuria, which leads to nocturia, polyuria, and dehydration. Under clinical stress, many patients demonstrate renal tubular acidosis. Acute, severe renal injury may complicate a severe vasoocclusive syndrome and may respond to transfusion therapy. Progressive renal failure in older patients is common secondary to glomerulosclerosis, though other causes occur, including recurrent renal infections.

Rarely, a unique renal cancer called renal medullary carcinoma may develop. This almost always occurs in people with sickle cell trait or disease. It is preceded by hematuria, which is a common problem in SCD due to papillary necrosis. If papillary necrosis is the cause, hydration and vasopressin may be beneficial. All patients should undergo a renal ultrasound if abnormalities are noted. Other causes of renal disease should be investigated. Renal transplantation is indicated and should not be delayed because of the disease.

Priapism

The sudden sustained penile erection with pain is a serious, underdiagnosed problem that may occur in 40% of males. Sensitive questioning of the problem should be included with all patients. If left untreated, it leads to severe erectile dysfunction. Acute treatment with aspiration and irrigation with adrenergic is beneficial. Prophylaxis with pseudoephedrine may be beneficial.

Bone

Acute and chronic bone disease is a major cause of pain and disability. Many patients develop avascular necrosis of the femoral heads. In addition, collapse of vertebral bodies, osteomyelitis, and osteoporosis are relatively common. Early aggressive physical therapy and decompression coring procedures of the hip may delay or prevent progression to hip replacement.

Sickle cell trait

SCT is not a disease. There are over 300 million people who are carriers. Their life span is normal. There is a small risk of some complications, including hematuria, thrombosis, and possibly sudden death from extreme heat related injuries. While the NCAA (National Collegiate Athletic Association) recommends testing for athletes, the American Society of Hematology and most other professional groups oppose this and support routine athlete conditioning.

Acute anemic events

Most patients sustain a steady state hemoglobin level, which allows them to function without transfusion therapy. However, sudden acute anemic events do occur, requiring early detection and treatment. Acute sequestration complication refers to intrasplenic trapping of red cells, resulting in an acute fall in hemoglobin that could be fatal. It usually occurs in infancy and is preceded by viral infections. It can occur in older patients who have sickle variance and do not undergo autosplenectomy. Patients and families are instructed on how to palpate the spleen and be familiar with symptoms of sudden weakness and pallor, and abdominal fullness. Transfusion therapy is often curative. Some patients require splenectomy.

Transient red cell aplasia results in a slower decline in hemoglobin and is associated with reticulocytopenia. It is often triggered by a B19 parvovirus infection. Transfusion therapy is indicated in severe cases. Occasionally, patients have a sudden hyperhemolytic event, usually associated with infection. These events may represent an undetected transfusion reaction in some cases. Close monitoring, obtaining matched red cell units, and evaluation of different etiologies are indicated.

What should you tell the patient and the family about prognosis?

The life span of SCD people has dramatically changed. In the United States, it is not a fatal pediatric disorder. It is a chronic illness with progressive deterioration of organ dysfunction and quality of life. While acute, life threatening events may happen, most patients with optimal care should have a life span of 50 years old or greater. Comprehensive care with preventative and early treatment of complications is likely to markedly improve the quality of life, as well as life span. However, patients do experience significant morbidity that is likely to affect most patients eventually.

These complications can be minimized by optimal management including hydroxyurea. Most patients have families, are employed, and live productive lives. Optimal quality of life is more likely to occur by anticipatory counseling, psychological support, and appropriate career goals. Transplantation is curative, but is not indicated in every patient. New therapy is on the horizon, including more potent fetal hemoglobin stimulating drugs, gene therapy, and other anti sickling compounds.

What if scenarios.

Diagnosis

A major pitfall is in the wrong initial diagnosis. This is corrected by performing the appropriate laboratory tests. A solubility test does not discriminate SCT from disease. Furthermore, SCT may be confused with sickle ß+ thalassemia on laboratory testing. In sickle cell disease states, the Hb S is greater than the Hb A. There may be mutations that appear like SCD, but are benign. These require a correlation with the clinical and laboratory findings.

DNA testing and family screening will uncover the definitive diagnosis. Physicians often believe significant anemia is part of the sickle cell syndrome; however, the disease syndrome does not require anemia. Sickle cell variants, such as Hb SC may have hemoglobin levels in the normal range.

Misdiagnosis of a complication

SCD can affect every organ and result in many complications. However, these patients are at risk for concurrent, unrelated events that affect the general population. Failure to search for another etiology of a symptom is a common problem that delays appropriate diagnosis and treatment.

Pain management

Pain is a complex, difficult complication to manage. Many physicians believe there are laboratory tests that indicate whether a painful event is occurring. This is not true; there is no reliable laboratory test. Pain should be assessed by history and examination, and treated. Hyperalgesia syndrome and pseudoaddiction may complicate a patient’s care and require a multidisciplinary approach with pain specialists. Tolerance and drug withdrawal symptoms are normal, biologic effects of narcotic analgesia administration. They do not indicate addiction.

Acute pulmonary events

Often the patient is evaluated for a fever with an initial chest x-ray that is stable. It is common that an acute pulmonary event then develops within 48 hours of the hospitalization. The initial normal chest x-ray does not mitigate the need to repeat the chest x-ray in patients with prolonged fever or chest pain.

Cognitive functioning

Most patients have normal and appropriate intellectual functioning. Specific learning defects and school absenteeism due to illness may alter their performance. These patients are inappropriately placed in home school or special classes, rather than receiving additional tutoring and being kept in mainstream education.

Pathophysiology

The deoxygenation of Hb S leads to the formation of hemoglobin polymers. Polymerization reduces red cell deformability, increases blood viscosity, leads to red cell membrane injury, and cell death. Membrane damage results in cell dehydration, which further increases polymerization. The membrane damage exposes phosphatidylserine, which results in red cells becoming adherent to vascular endothelium. Vascular endothelial damage occurs, resulting in increased expression of endothelial adhesion molecules.

An hemolysis induced deficiency of nitric oxide results in abnormal vascular tone, which further alters flow. Leukocytosis, inflammatory cytokines, and platelet activation accelerate endothelial adhesion and obstruction. Polymerization and the downstream abnormalities are modulated by many genes and environmental factors. Fetal hemoglobin clearly decreases polymerization. Polymerization proceeds more rapidly in Hb SS than Hb SC. Acidosis, hyperosmolar, environment, deoxygenation, and elevated levels of 23, DPG (doi-phospho glycerate) promote polymer formation. In vivo studies document these factors inducing impaired blood flow and vaso occlusion.

What other clinical manifestations may help me to diagnose sickle cell disease?

N/A

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Charache, S, Terrin, ML, Moore, RD. "Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia". N Engl J Med. vol. 332. 1995. pp. 1317-22.

(This article is the result of a randomized placebo trial of hydroxyurea in adults. It demonstrated a marked reduction in pain and hospitalizations.)

Vichinsky, EP, Neumayr, LD, Earles, AN. "Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group". N Engl J Med. vol. 342. 2000. pp. 1855-65.

(A prospective study evaluating the etiology, treatment, and outcome of acute chest syndrome in SCD.)

Tsaras, G, Owusu-Ansah, A, Boateng, FO. "Complications associated with sickle cell trait: a brief narrative review". Amer J of Med. vol. 122. 2009. pp. 507-12.

(This article summarizes the literature on morbidity of SCT.)

Rees, DC, Olujohungbe, AD, Parker, NE. "Guidelines for the management of the acute painful crisis in sickle cell disease". BJH. vol. 120. 2003. pp. 744-52.

(This article outlines the standard therapy for assessing and treating pain crises in SCD.)

Vichinsky, EP, Luban, NL, Wright, E. "Prospective RBC phenotype matching in a stroke prevention trial in sickle cell anemia: a multicenter transfusion trial". Transfusion. vol. 41. 2001. pp. 1086-92.

(The benefit of extended red cell matching in chronically transfused sickle cell patients.)

De Montalembert, M, Ferster, A, Colombatti, R. "ENERCA Clinical Recommendations for prevention and complications of SCD". Am J of Hem. vol. 86. 2011. pp. 72-5.

(This article reviews the standard recommendations of treatment for children with SCD.)

Adams, R.J.. "Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography". N Engl J Med. vol. 339. 1998. pp. 5-11.

(A landmark paper that demonstrates the benefit of TCD in detecting patients at risk of a stroke and the benefit of transfusion therapy.)

Michlitsch, J, Azimi, M, Hoppe, C. "Newborn screening for hemoglobinopathies in California". Pediatr Blood Cancer. vol. 52. 2009. pp. 486-90.

(This article reviews the methodology and results of universal newborn screening for SCD in California.)

Platt, OS, Brambilla, DJ, Rosse, WF. "Mortality in sickle cell disease. Life expectancy and risk factors for early death". N Engl J Med. vol. 330. 1994. pp. 1639-44.

(Long-term survival, mortality rate, and causes of death in SCD from a large, prospective population.)

Ohene-Frempong, K, Weiner, SJ, Sleeper, LA. "Cerebrovascular accidents in sickle cell disease: rates and risk factors". Blood. vol. 91. 1998. pp. 288-94.

(A comprehensive study on the natural history of stroke in SCD from a large cohort of patients.)

Yawn, BP, Buchanan, GR, Afenyi-Annan, AN, Ballas, SK, Hassell, KL5, James, AH, Jordan, L, Lanzkron, SM, Lottenberg, R, Savage, WJ, Tanabe, PJ, Ware, RE, Murad, MH, Goldsmith, JC, Ortiz, E, Fulwood, R, Horton, A, John-Sowah, J. "Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members". JAMA. vol. 312. 2014. pp. 1033-48.

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. vol. 28. 2014. pp. 1171-1185.

DeBaun, MR, Gordon, M, McKinstry, RC, Noetzel, MJ, White, DA, Sarnaik, SA, Meier, ER, Howard, TH, Majumdar, S, Inusa, BP, Telfer, PT, Kirby-Allen, M, McCavit, TL, Kamdem, A, Airewele, G, Woods, GM, Berman, B, Panepinto, JA, Fuh, BR, Kwiatkowski, JL, King, AA, Fixler, JM, Rhodes, MM, Thompson, AA, Heiny, ME, Redding-Lallinger, RC, Kirkham, FJ, Dixon, N, Gonzalez, CE, Kalinyak, KA, Quinn, CT, Strouse, JJ, Miller, JP, Lehmann, H, Kraut, MA, Ball, WS, Hirtz, D, Casella, JF. "Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia". N Engl J Med. vol. 371. 2014. pp. 699-710.

Klings, ES, Machado, RF, Barst, RJ, Morris, CR, Mubarak, KK, Gordeuk, VR, Kato, GJ, Ataga, KI, Gibbs, JS, Castro, O, Rosenzweig, EB, Sood, N, Hsu, L, Wilson, KC, Telen, MJ, Decastro, LM, Krishnamurti, L, Steinberg, MH, Badesch, DB, Gladwin, MT. "American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. 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. vol. 189. 2014. pp. 727-40.

Howard, J1, Malfroy, M, Llewelyn, C, Choo, L, Hodge, R, Johnson, T, Purohit, S, Rees, DC, Tillyer, L, Walker, I, Fijnvandraat, K, Kirby-Allen, M, Spackman, E, Davies, SC, Williamson, LM. "The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a Randomised, Controlled, Multicentre Clinical Trial". Lancet. vol. 381. 2013. pp. 930-8.

Wong, TE, Brandow, AM, Lim, W, Lottenberg, R. Update on the use of hydroxyurea therapy in sickle cell disease. vol. 124. 2014. pp. 3850-3857.

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