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Sickle Cell Disease

Overview

Sickle cell disease (SCD) is a group of inherited disorders that results from a genetic mutation in the beta-globin gene forming sickle hemoglobin, Hb S. Hb S polymerizes under deoxygenated conditions in red blood cells giving them an abnormal “sickle” shape.

Amino Acid Sequence Ultimately Causing Sickle Cells
Sickle Cell Coding and Blood Cells. The change in amino acid sequence. SCD is the medical abbreviation
Sickle cell disease results in chronic hemolytic anemia, systemic inflammation, small vessel vaso-occlusion, and endothelial cell dysfunction. Nearly every organ system in the body can be affected. Acute complications include painful vaso-occlusive crises, acute chest syndrome, splenic sequestration, and stroke. [Kato: 2018] Chronically, sickle cell disease affects all organs in the body and can lead to end-organ damage in the brain, heart, lungs, and kidneys (as well as other areas).

Other Names & Coding

Hb S disease
Hemoglobin S disease
SCD (medical abbreviation)
Sickle cell disorders (a broad group of conditions that includes sickle cell anemia)

The convention for indicating the composition of hemoglobin types in the red cells of an individual is to use an acronym listing the types in decreasing proportion or amount. For example, sickle cell carrier (sickle cell trait), in which the amount of HB F (fetal) is greater than that of Hb A (adult), which is greater than that of Hb S (sickle), is designated as FAS.
ICD-10 coding

D57.0x, Hb SS disease with crisis

D57.1, Sickle cell disease without crisis

D57.2xx, Sickle cell/Hb-C disease

D57.4xx, Sickle cell thalassemia

D57.8xx, Other sickle cell disorders

An "x" indicates the need or potential for additional digits to provide a more specific diagnosis. More coding details can be found at  ICD-10 for Sickle Cell Disorders (icd10data.com).

Prevalence

Sickle cell disease is the most common abnormality found in newborn screening programs. The incidence in African Americans of sickle trait is 1:14 and sickle cell disease is 1:396. [Lorey: 1996] The number of individuals with sickle cell disease in the United States may approach 100,000, even after accounting for the effect of early mortality on estimations. [Hassell: 2010]

Genetics

Normal hemoglobin is composed of 2 alpha subunits and 2 beta subunits. Abnormal sickle hemoglobin is formed from a single point mutation in the beta-globin gene, HBB, which results in substitution of valine for glutamine at position 6 on the beta helix. Sickle cell disease is inherited in an autosomal recessive manner when patients have 2 abnormal beta-globin genes and at least 1 of the beta-globin mutations is Hb S. Hb S can also be inherited with other mutations such as Hb C (Glu6Lys) or beta thalassemia, which results in a sickle phenotype. The term sickle cell anemia is reserved for patients who make only the abnormal Hb S (e.g., homozygous Hb SS disease or sickle beta zero thalassemia). Sickle Cell Disease (GeneReviews) offers additional information.

Prognosis

Several decades ago, the majority of individuals with sickle cell anemia died during childhood. However, in high resource countries with modern comprehensive care, newborn screening with early initiation of penicillin prophylaxis, improved immunizations, and use of hydroxyurea, children now live well into adulthood. The median life remains in the mid 40s. [Kato: 2018]

Practice Guidelines

Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E.
American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.
Blood Adv. 2020;4(12):2656-2701. PubMed abstract / Full Text

DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH.
American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.
Blood Adv. 2020;4(8):1554-1588. PubMed abstract / Full Text

Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA.
American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease.
Blood Adv. 2019;3(23):3867-3897. PubMed abstract / Full Text

Chou S, Alsawas M, Fasano R, Field J, Hendrickson J, Howard J, Kameka M, Kwiatkowski J, Pirenne F, Shi P, Stowell S, Thein S, Westhoff C, Wong T, Akl E.
American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support.
Blood Adv.. 2020;4(2):327-355. / Full Text

Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, 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. 2014;312(10):1033-48. PubMed abstract

Roles of the Medical Home

For the child with sickle cell disease, the medical home should manage well-child care, including standard childhood immunizations, acute illnesses unrelated to sickle cell disease and chronic comorbid conditions, such as asthma. It is very important that all children with sickle cell disease are co-managed by a sickle cell specialist throughout their lifespan. Sickle cell-specific care (e.g., transcranial Doppler (TCD) evaluation, hydroxyurea) should be managed by a pediatric hematologist with sickle cell comprehensive care experience. In locations remote from sickle cell specialty care, the medical home may also provide care for acute complications of sickle cell disease (e.g., febrile illness and mild pain crises) and laboratory monitoring for hydroxyurea in collaboration with a sickle cell specialist.

Comprehensive sickle cell care is multidisciplinary, and the medical home plays an important role in coordinating this care. With evolving medications to improve the well-being of children with sickle cell disease and possibly cure the disease (see Treatment & Management), the medical home can help families be aware of options and their pros and cons. Primary care clinicians should collaborate with sickle cell specialists and programs to facilitate access to the latest information and best care. Further, primary care can help ensure ongoing engagement and follow-up with a sickle cell specialist to ensure timely preventative assessments such as annual eye exams and stroke screening. A recent study examined the information sources and perspectives of parents and other primary caregivers of children with sickle cell disease related to new therapies.

Clinical Assessment

Overview

Sickle cell disease is a multisystem disorder that can cause acute and chronic complications in nearly every organ system. Careful history and physical examination should focus on eliciting signs and symptoms of these complications or comorbid conditions.

Pearls & Alerts for Assessment

Pulse oximetry can underestimate oxygen saturation

Pulse oximetry is an inaccurate measurement and often underestimates oxygen saturation due to increased levels of carboxyhemoglobin and methemoglobin in patients with sickle cell disease.

Assessment of pain

Children experiencing an acute vaso-occlusive pain crisis may not have changes in vital signs (tachycardia or hypertension). Assessment of pain should be based primarily on the patient’s subjective report. Patients may have a higher opioid tolerance over time.

Screening

For the Condition

Universal screening for sickle cell disease is conducted in all states as part of newborn screening programs. Hemoglobin separation techniques can identify infants with sickle trait (FAS), homozygous sickle cell anemia or sickle β0 thalassemia (FS), sickle-Hb C (FSC), or sickle β+ thalassemia (FSA). If an abnormal newborn screen is obtained, repeat newborn screening should be sent per recommendations by the appropriate state newborn screening program. If the repeat testing confirms FS, FSC, or FSA, the patient should be referred to a pediatric hematologist with expertise in managing sickle cell disease. Patients with Hb SS disease or sickle beta zero thalassemia should be started on penicillin prophylaxis. Some centers also prescribe penicillin prophylaxis for patients with other sickle genotypes. Sickle Cell Disease provides additional information for response to a positive newborn screen.

Of Family Members

Parents and partners of a child with sickle cell disease unaware of their carrier status should be screened with a hemoglobin electrophoresis for sickle trait, Hb C, or beta thalassemia (or other hemoglobin abnormalities based on ethnic risk) so that appropriate genetic counseling may be provided about risks to future offspring.

For Complications

Retinopathy: Annual to biennial screening for sickle retinopathy should be performed starting at age 10 years. Those with retinopathy should be referred to a retina specialist.

Stroke risk: Measurement of cerebral blood flow velocities by transcutaneous Doppler ultrasonography should be conducted by those trained in the technique specific for sickle cell anemia. Begin annual testing at age 2 and until age 16 to screen for elevated stroke risk requiring intervention with chronic transfusion therapy.

Silent cerebral infarcts: New guidelines recommend a baseline MRI/MRA without sedation (when tolerable) to evaluate for silent cerebral infarcts and CNS vasculopathy once in early childhood.

Pulmonary hypertension: Routine screening echocardiograms are no longer recommended in asymptomatic individuals; however, those with symptoms or signs of fatigue, exercise intolerance, chest pain, or peripheral edema should be referred for an echocardiogram.

Iron overload: Patients receiving frequent transfusions as well as those on chronic transfusion therapy are at risk for iron overload and should have screening ferritin levels to evaluate the potential for iron overload. If ferritin >1000, screening MRIs for liver iron content should be performed and monitored in conjunction with initiation of iron chelation therapy. [Coates: 2017]

Presentations

Infants are usually identified by newborn screening during the asymptomatic period. Prior to the advent of universal newborn screening, patients with the severe sickle cell genotypes would present initially with dactylitis of the hands or feet, severe illness including splenic sequestration or sepsis, or sudden death.

The presentation of complications related to sickle cell disease depends on the organ system involved. Those with stroke will usually present acutely with a focal neurologic deficit, such as hemiparesis, aphasia, or ataxia, depending on the anatomic location of the stroke. Depending on the severity or stage of sickle retinopathy, patients may present with spots in the field of vision (floaters), blurriness, decreased visual acuity, or visual field loss. Patients with pulmonary hypertension may present with exertional dyspnea or persistent hypoxia.

Diagnostic Criteria

Diagnosis is established by hemoglobin separation techniques, such as isoelectric focusing, high-performance liquid chromatography, or hemoglobin electrophoresis. For patients who have been transfused, diagnosis may also be made through genetic testing and sequencing of the beta-globin gene.

Clinical Classification

Sickle cell disease is a group of sickling disorders. There are a variety of genotypes and associated clinical phenotypes. The most common genotypes are summarized in the table below.

Common Sickle Cell Genotypes
Common Sickle Cell Genotypes

Differential Diagnosis

Differential diagnoses include:
  • Homozygous sickle cell anemia (Hb SS)
  • Sickle-Hb C disease
  • Sickle β0 thalassemia
  • Sickle β+ thalassemia
  • Sickle-Hb D disease
  • Sickle-Hb E disease
  • Other sickle syndromes
All of these are sickling syndromes that can manifest as hemolytic anemia with intermittent episodes of vaso-occlusion and/or risk of organ damage (which can occur in individuals who do not exhibit symptoms of pain). These usually can be distinguished based on the hemoglobin separation results for diagnostic testing. Homozygous sickle cell anemia is the most severe clinical phenotype with more significant anemia and increased frequency of disease complications including vaso-occlusive pain crises. Patients with sickle beta0 thalassemia are clinically similar to homozygous Hb SS patients with the addition of microcytosis on laboratory evaluation. Hemoglobin C and sickle beta+ thalassemia have milder clinical phenotypes with higher baseline hemoglobins and less frequent complications. Co-inheritance with Hb D results in a severe phenotype similar to homozygous sickle cell anemia. Sickle-Hb E disease is usually seen in patients with some Asian ancestry (where Hb E is prevalent) and results in a mild phenotype similar to sickle beta+ thalassemia.

Comorbid & Secondary Conditions

Commonly co-occurring conditions may include:
  • Asthma: Patients with uncontrolled asthma may have more frequent vaso-occlusive pain due to increased sickling with hypoxia.
  • Gall stones/hyperbilirubinemia
  • Sickle lung disease: Due to chronic sickling within the lung vasculature, patients develop obstructive, and then restrictive, changes in the lungs, which frequently leads to pulmonary hypertension and is the leading cause of death in adults with sickle cell disease.
  • Stroke: Children with prior stroke may have residual neurologic deficits.
  • Sickle nephropathy: Children with sickle cell disease can develop renal complications over time. This usually starts with urine concentrating defects (hyposthenuria) followed by glomerular hyperfiltration, proteinuria, and eventually focal segmental glomerulonephritis.
  • Retinopathy: If untreated, sickling within the retinal vessels can cause proliferative retinopathy, hemorrhage within the retina, retinal detachment, and blindness.
  • Osteonecrosis: Infarction of the bones can cause chronic severe pain and limitation in mobility.
  • Leg ulcers [Minniti: 2010]
  • Priapism

History & Examination

Current & Past Medical History

It is important to understand the history of prior complications or other comorbid conditions. Knowledge of the frequency of vaso-occlusive crises and what medications work best for controlling pain can help with planning for treatment of future episodes. Patients with a severe history of complications may need therapy with chronic transfusions or qualify for bone marrow transplant.

Family History

Birth parents will have a sickle trait, Hb C trait, or beta-thalassemia trait. Because universal newborn screening for this disease was not implemented prior to the last couple of decades, there may be a history of family members who died during childhood, had frequent pain, stroke, or gallstones.

Pregnancy/Perinatal History

Pregnancy and birth history are usually normal since the predominant form of hemoglobin present in the fetus and newborn is unaffected fetal hemoglobin. If the parents were aware of their carrier status, it is possible that chorionic villus sampling or amniocentesis was performed to establish prenatal diagnosis.

Developmental & Educational Progress

More than a quarter of children with sickle cell disease will experience a silent cerebral infarct by the age of 6 years. This number increases to 37% by 16 years of age. Silent cerebral infarcts are associated with decreased IQ and poor academic performance. [DeBaun: 2014] Referral to a sickle cell expert is recommended for those with silent infarct. Neuropsychiatric testing should be offered to at-risk patients. Efforts should be made to ensure each child has an individualized education plan in place as appropriate.

Maturational Progress

Pubertal development and growth are significantly delayed in patients with sickle cell disease. On average, puberty is delayed 1-2 years, and the median age at menarche for girls is 13.2 years. Skeletal age is delayed by 1.3 years in children between the ages of 10-15 years. [Zemel: 2007]

Social & Family Functioning

Family structure should be determined and primary caregivers identified so that they may be educated about acute complications and instructed on the correct technique for splenic palpation. Assessment of family resources should include availability of transportation for appointments and acute visits, a working phone to schedule appointments, and the ability to obtain prescribed medications.

Physical Exam

Patients experiencing acute vaso-occlusive pain crises typically appear distressed and very uncomfortable. However, some patients, especially those with frequent pain episodes or chronic pain, may be more stoic or not show the “expected” behaviors of someone with severe pain. The vital signs may be normal. Swelling does not have to be present. Further, there are no radiographic or laboratory findings/dx of a “crisis.”

Vital Signs

Abnormalities in vital signs should prompt further evaluation. Hypertension is associated with increased risk of stroke and should be managed aggressively. Pulse oximetry is an inaccurate measurement and often underestimates oxygen saturation in patients with sickle cell disease due to increased levels of carboxyhemoglobin and methemoglobin. Tachypnea or hypoxia should prompt evaluation for acute chest syndrome. Tachycardia and hypertension are not universally present in patients experiencing acute vaso-occlusive pain crises.

Growth Parameters

Children have a decreased growth velocity in proportion to the severity of their anemia.

Skin

Chronic skin ulcers in the lower extremities can develop as a result of small vessel vaso-occlusion, vasoconstriction, decreased oxygenation of skin tissue, or infections.

HEENT/Oral

Adenotonsillar hypertrophy is the most common risk factor for obstructive sleep apnea in children with sickle cell disease. [Rosen: 2014] In patients with sickle cell disease, obstructive sleep apnea is associated with increased frequency of vaso-occlusive pain crises due to more frequent deoxygenation, which triggers red cell sickling. Children and adolescents with sickle cell disease have an increased risk of retinopathy and may have neovascularization or hemorrhage on retinal exam. Many children will require orthodontia due to maxillary protrusion secondary to compensatory bone marrow expansion (Orthodontics (see MT providers [51])).

Chest

Tachypnea, retractions, decreased breath sounds, crackles, or wheezing should prompt evaluation for acute chest syndrome or reactive airway disease.

Heart

Systolic flow murmurs may be present secondary to chronic anemia. An accentuated pulmonic component of the second heart sound or gallop can indicate development of pulmonary hypertension.

Abdomen

Acute splenomegaly may indicate splenic sequestration crisis. Chronic splenomegaly may result in hypersplenism or put patients at risk for splenic rupture. Due to chronic hemolysis, there is an increased risk for cholelithiasis, which can manifest with a positive Murphy’s sign (hypersensitivity to deep palpation in the subcostal area when a patient with gallbladder disease takes a deep breath) or severe right upper quadrant tenderness.

Genitalia

Males with sickle cell disease can develop priapism, a painful and prolonged erection. Delayed pubertal maturity is not uncommon.

Extremities/Musculoskeletal

Limited range of motion with forced internal rotation of the lower extremity or painful straight leg raise may be a sign of avascular necrosis of the femoral head. Avascular necrosis in the humeral head may cause similar symptoms in the shoulder. Point tenderness or swelling with fever can occur in the setting of osteomyelitis or bone infarction.

Neurologic Exam

Any new focal neurologic deficit or weakness is a medical emergency and could be a sign of either an acute ischemic or hemorrhagic stroke.

Testing

Sensory Testing

All patients should receive dilated retinal examinations by an ophthalmologist to screen for sickle retinopathy starting at age 10 years. Any child receiving iron chelators should have ophthalmologic examinations yearly.  

Patients receiving iron chelation should have audiology screening yearly. Testing should also be offered if a patient or parent reports concerns about hearing loss as there is some newer evidence that patients with SCD may have increased risk for hearing deficits. [Schopper: 2019]

Laboratory Testing

Patients with sickle cell disease should have routine screening of kidney and liver function annually with bloodwork and urinalysis. Patients receiving hydroxyurea therapy on stable doses need complete blood counts performed every 3 months to monitor absolute neutrophil and platelet counts. A complete blood count, including reticulocyte count, should be obtained when children present with acute sickle-related complaints.

Imaging

Children with Hb SS or sickle β0 thalassemia should receive annual screening with TCD starting at age 2 and continuing through age 16. The relative risk of stroke is 44 in children with abnormal velocities on TCD. [Adams: 1992] Screening with TCD is not recommended in asymptomatic adults.

A one-time baseline MRI/MRA should be obtained for patients with the most severe types of sickle cell disease to evaluate for silent cerebral infarcts and CNS vasculopathy. This screening should occur in early childhood but should be performed when the patient does not require sedation for the imaging study. Baseline screening in adults should also be performed if no previous history of MRI/MRA.

Routine screening with echocardiograms is no longer recommended. Patients with new cardiopulmonary symptoms should receive an echocardiogram and be evaluated for asthma or other non-sickle-cell-disease conditions.

Patients receiving chronic transfusions should be screened annually with MRI for hepatic or cardiac siderosis to determine need for oral chelation therapy.

Genetic Testing

Genetic testing is available for mutations in the beta-globin gene. Mutation testing may be sent to help distinguish between Hb SS and sickle β0 thalassemia. It can also be used in unusual cases with ambiguous electrophoretic patterns.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see MT providers [14])

Refer for annual or bi-annual sickle retinopathy screening beginning at age 10.

Pediatric Pulmonology (see MT providers [7])

Refer if there is a history of acute chest syndrome, reactive airway disease, or concern for obstructive sleep apnea.

Pediatric Cardiology (see MT providers [14])

Refer for consideration of cardiac catheterization and management of pulmonary hypertension if TRV >3 m/s on echocardiogram

Pediatric Neurology (see MT providers [15])

Refer if there is a history of stroke, cerebral vasculopathy, or silent infarct.

Genetic Testing and Counseling (see MT providers [12])

Parents of childbearing age should receive genetic counseling regarding the risk of having another child with sickle cell disease.

Treatment & Management

Overview

The management of sickle cell disease focuses on primary and secondary prevention of complications as well as management of chronic comorbid conditions. The care of all patients with sickle cell disease should be directed/overseen by a clinic that specializes in that care and collaborates with primary care to ensure high-quality, comprehensive care. Distance from such a center may determine where key care components are delivered. The Sickle Cell Disease National Resource Directory (CDC) lists national agencies, specialty care centers, and community-based organizations that provide services and resources for people affected by sickle cell disease.

Pearls & Alerts for Treatment & Management

Hydroxyurea

Hydroxyurea is the mainstay of therapy for patients with Hb SS disease or sickle beta zero thalassemia. It is recommended that this therapy be offered to these patients starting at 9 months of age. Hydroxyurea can increase fetal hemoglobin levels and has been shown to decrease the frequency of vaso-occlusive complications, increase total hemoglobin levels and decrease number of transfusions needed. Hydroxyurea can cause myelosuppression and the dose should be titrated to prevent excessive neutropenia or thrombocytopenia. [Yawn: 2014]

L-glutamine for sickle cell disease treatment

The FDA approved the use of L-glutamine powder (Endari) in July 2017 for patients age 5 years and older. It is an oral medication shown to decrease rates of acute chest syndrome, as well as frequency of hospitalization and length of stay for vaso-occlusive pain crises in patients who had 2 or more episodes of pain in the preceding year. It is the first drug to gain FDA-approval for sickle cell disease treatment in more than 2 decades.

Perioperative surgical management

Undergoing general anesthesia for surgical procedures increases the risk for development of acute chest syndrome or vaso-occlusive pain crisis. Preoperative simple or exchange transfusion has been demonstrated to minimize these risks.

Newer therapies

Recent advances in therapy have resulted in dramatic reductions in symptoms and complications of sickle cell disease. Hydroxyurea was approved by the FDA for use in children in 2017; voxeletor and crizanlizumab were both approved in 2019. Hematopoietic stem cell transplantation can be curative. [Gardner: 2018] Gene therapy is currently experimental and clinical trials are ongoing to determine long term safety and efficacy. See under the Hematology/Oncology System below for more detail.

How should common problems be managed differently in children with Sickle Cell Disease?

Viral Infections

Fever of 101ºF (≥38.3ºC) in a patient with sickle cell disease is a medical emergency. Patients with sickle cell disease who test positive for influenza should be immediately evaluated for concerns for acute chest syndrome. Depending on the diagnostic window, they may also treated with a therapeutic course of oseltamivir.

Bacterial Infections

Fever of 101ºF (≥38.3ºC) in a patient with sickle cell disease is a medical emergency. The clinician should urgently evaluate the patient, obtain blood cultures, and administer broad-spectrum antibiotics (e.g., third-generation cephalosporin). Inpatient admission may be indicated if the patient is less than 1 year old, incompletely vaccinated, noncompliant with penicillin prophylaxis, toxic-appearing, or has an elevated white blood count >30k or <5k. In the event of a positive blood culture, patients without adequate outpatient follow-up (e.g., no transportation or working phone) should be observed inpatient.

Systems

Hematology/Oncology

Primary prevention
Children with sickle cell disease should be started on penicillin prophylaxis at diagnosis to prevent pneumococcal sepsis. Prophylaxis may be discontinued at age 5 if there is no history of pneumococcal bacteremia or surgical splenectomy. [Falletta: 1995] All patients should complete a normal immunization series as well as additional meningococcal and pneumococcal vaccines as recommended by the most current version of the Centers for Disease Control and Prevention's Immunization Schedules (CDC).

The 2014 National Heart, Lung, and Blood Institute recommend that hydroxyurea therapy be offered to all patients with homozygous sickle cell anemia or sickle β0 thalassemia starting at 9 months of age regardless of prior complications or baseline fetal hemoglobin percentage. [Yawn: 2014] Hydroxyurea therapy has been shown to decrease frequency of vaso-occlusive pain crises, acute chest syndrome, and lifetime transfusion requirements, as well as increase life expectancy. [Steinberg: 2010] Hydroxyurea for Sickle Cell (Hospital for Sick Children) (PDF Document 395 KB) is an information sheet for parents with children prescribed hydroxyurea (Hydrea).

Hydroxyurea can cause depression of the absolute neutrophil count. Patients treated with hydroxyurea should be monitored every 3 months with CBCs. The dose is titrated to achieve an absolute neutrophil count between 1,250 and 4,000, with a maximum dose of 35 mg/kg/day. Recommendations for initiation and monitoring of hydroxyurea therapy are summarized in [Yawn: 2014].

Patients with abnormal cerebral velocities measured by transcutaneous Doppler should be treated with chronic red cell transfusions, which has been shown to decrease stroke risk by 90%. [Adams: 1998] New data suggest that children with abnormal TCDs who have had more than 1 year of chronic transfusions AND who have been evaluated with MRI and MRA to assess for cerebral vasculopathy may be safely switched to a maximal tolerated dose of hydroxyurea for primary stroke prophylaxis. [Ware: 2016] Discussion should always be included with SCD specialist.

Voxelotor was granted FDA approval in November 2019 for use in adult and pediatric patients age 12 and older. Voxelotor increases hemoglobin levels and reduces hemolysis by directly binding and stabilizing oxygenated hemoglobin and reducing polymerization. It is taken by mouth once daily and is generally well tolerated with a side effect profile that may include diarrhea and headache. Findings from the recently published phase III trial (HOPE) demonstrated an increase in hemoglobin by >1 g/dL in a significant proportion of participants receiving the drug. A trend toward decreased pain crises was observed, but statistical significance was not achieved. Voxelotor may be taken concurrently with hydroxyurea. There is no data that voxelotor prevents stroke and should not replace chronic transfusions or hydroxyurea in primary or secondary stroke prophylaxis. [Vichinsky: 2019]

The FDA approved crizanlizumab in November 2019 for use in patients 16 and older to reduce the frequency of acute pain crises. In a recent phase II trial (SUSTAIN), crizanlizumab reduced acute pain events by 45.3% and increased the median time to first and second pain episodes. Patients may take crizanlizumab while also taking hydroxyurea. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin and likely decreases pain crises by reducing vaso-occlusion and inflammation and improving blood flow by inhibiting cellular adhesion to the endothelium. It is given intravenously every 2 weeks for 2 doses, then monthly thereafter. It is generally well-tolerated. Adverse events may include arthralgia, diarrhea, pruritus, vomiting, and chest pain. A number of clinical trials are currently open to further investigate efficacy and safety of crizanlizumab in both adult and pediatric patients. [Ataga: 2017]

Secondary prevention
Patients with prior stroke should begin a chronic transfusion regimen to prevent stroke recurrence. The goal of chronic transfusions is to maintain sickle hemoglobin percentage <30% and maximum hemoglobin <11-12 g/dL. Chronic transfusions are sometimes prescribed for patients with frequent and severe episodes of vaso-occlusive pain or acute chest syndrome.

Iron chelators are prescribed for patients receiving chronic transfusions who have evidence of iron overload. This therapy should be monitored by a sickle cell specialist familiar with this medication. Patients will need annual ophthalmology and audiology screening while taking iron chelators.

L-glutamine was approved by the FDA in July 2017 for patients age 5 years and older. This is the first drug to gain approval for sickle cell disease in more than 2 decades. It is an oral medication taken twice daily and has been shown to decrease rates of acute chest syndrome, as well as frequency of hospitalization and length of stay for vaso-occlusive pain crises in patients who had 2 or more episodes of pain in the preceding year. It is well-tolerated with a minimal side effect profile that may include constipation, nausea, abdominal pain, or headache.

Management of acute complications
Vaso-occlusive pain crisis: Patients presenting with painful crises should receive therapy with NSAIDs and opiates. Moderate to severe episodes may require treatment with parenteral opiates and hospitalization. Intravenous fluid hydration may help decrease red blood cell sickling. The Pain Rating Scale (Wong-Baker FACES Foundation) is a self-assessment that uses expressions on faces to depict pain level. The scale can be used with people ages 3 and older to facilitate communication and improve assessment so pain management can be addressed. Sickle Cell: What to Do When Your Child is Experiencing Pain (Children's Hospital Colorado) (PDF Document 304 KB) lists steps for comforting a child with sickle cell who is experiencing pain and includes medication dosing charts.

Acute chest syndrome: Patients with respiratory symptoms and a new infiltrate on chest radiography should be admitted and managed by a sickle cell specialist. Concern for pneumonia requires that individuals should be treated empirically with a third-generation cephalosporin and macrolide antibiotic. For patients with hypoxia, red cell transfusion is always indicated. Simple or red cell exchange transfusion may be required for worsening respiratory distress.

Splenic sequestration: Patients should be admitted to the hospital for serial examinations and CBCs. Red cell transfusion may be required.

Sickle Cell: When to Call The Doctor (Children's Hospital Colorado) (PDF Document 287 KB) lists possible symptoms in children with sickle cell disease that may indicate a serious problem and need immediate medical attention.

Curative therapy
Patients with sickle cell disease and severe complications may be cured by allogeneic hematopoietic stem cell transplant. The typical indications for transplant are frequent episodic vaso-occlusive pain, recurrent acute chest syndrome, or prior history of stroke. The best candidates for hematopoietic stem cell transplant have an HLA-identical related donor and are less than 16 years of age.

The absence of a suitable donor is one of the major factors limiting the availability of curative therapy for patients with severe disease. Alternative donor transplant using HLA-identical unrelated donors has been attempted but is associated with increased morbidity and mortality due to development of graft versus host disease in many patients limiting wider adoption of this technique. Clinical trials are currently in progress evaluating the use of haploidentical donors with post-transplant cyclophosphamide for graft versus host disease prophylaxis. [Kassim: 2017]

Newer (potential) curative options
Gene therapy is another strategy that may increase the number of patients eligible for curative therapy. There are currently several competing strategies (e.g., gene addition, gene editing) that either increase the concentrations of non-sickling adult hemoglobin or protective fetal hemoglobin. Currently, gene therapy is only available in the United States in clinical trials. [Olowoyeye: 2020] [Demirci: 2018]

Specialty Collaborations & Other Services

Pediatric Hematology/Oncology (see MT providers [9])

Children should be followed by a pediatric hematologist with expertise in sickle cell disease and hemoglobinopathies and who can provide comprehensive care as well as management of acute complications.

Sickle Cell Disease Centers (see MT providers [1])

The care of all patients with sickle cell disease should be directed/overseen by a clinic that specializes in that care and collaborates with primary care to assure high-quality comprehensive care. Distance from such a center may determine where key care components are delivered.

Audiology (see MT providers [50])

Children and adolescents will need annual screening while taking iron chelators.

Pediatric Ophthalmology (see MT providers [14])

Children and adolescents will need annual screening while taking iron chelators.

Neurology

Neuropsychologic testing should be offered to patients with a history of stroke, abnormal TCDs, or school underperformance. Efforts should be made to ensure each child has an individualized education plan in place as appropriate. The treatment of ischemic stroke in patients with sickle cell disease is immediate red cell exchange transfusion with a goal of decreasing sickle percentage to <30% with an end hemoglobin of 10 g/dL. This differs significantly from thrombolytic therapy used in the general population. Referral to a sickle cell expert is recommended for those with silent infarct, which are usually picked up on imaging performed to rule out acute stroke (found in an anatomic area that does not explain the acute symptoms) or cerebral vasculopathy (moyamoya).

Specialty Collaborations & Other Services

Pediatric Neurology (see MT providers [15])

Patients with a history of overt stroke or cerebral vasculopathy should be referred for annual follow-up. Neurology will continue to monitor for progression of cerebral vasculopathy, which might warrant intervention with the encephaloduroarteriosynangiosis (EDAS) procedure.

Neuropsychiatry/Neuropsychology (see MT providers [3])

Patients with impaired school performance or a history of silent cerebral infarction or overt stroke should be referred for formal neuropsychology assessment. Appropriate learning accommodations should be made within the context of an IEP or 504 plan based on these results.

General Counseling Services (see MT providers [147])

Patients and families often benefit from mental health services to help with the impacts of sickle cell disease and optimizing educational and social outcomes.

Renal

Sickling of red blood cells in the renal glomeruli causes urinary concentrating defects or hyposthenuria. This can manifest as nocturnal enuresis or nocturia in otherwise continent children. This complication may need pharmacologic intervention such as DDAVP in addition to the typical behavioral modifications approaches to enuresis recommended by primary care providers.

Specialty Collaborations & Other Services

Pediatric Nephrology (see MT providers [2])

Refer patients with significant proteinuria or abnormal kidney function for evaluation and collaborative management.

Recreation & Leisure

Child wearing safety equipment climbing a wall or obstacle
Considerations when making activity level recommendations may include:
  • Avoid handling reptiles and amphibians (turtles, lizards, frogs, etc.) due to increased risk of Salmonella infection. See Animals that May Carry Salmonella (CDC) for a more extensive list.
  • Participate in sports and other physical activities, but remain hydrated at all times.
  • Avoid environmental exposure to severe cold, which may precipitate vasoconstriction and painful crises.
  • If residing at sea level, do not travel to an altitude above 7,500 feet due to the risk for painful crises and splenic infarction secondary to hypoxia.
Depending on the temperature and humidity, swimming in an unheated outdoor pool can precipitate pain crises due to evaporative cooling.

Learning/Education/Schools

By the age of 5 years, 20% of patients with Hb SS disease have evidence of prior silent cerebral infarction. This increases to 37% by 14 years of age. Patients with silent cerebral infarcts have impaired academic achievement and commonly have decreased attention and executive functioning that can impact organizational and problem-solving skills. Individuals also have decreased IQ compared to other patients with sickle cell disease who have not had a silent cerebral infarction. Students should have an individualized education plan targeting their specific deficits identified on neuropsychology testing. Interventions may be aimed at treating inattention or impulsivity and providing accommodations, such as additional time to complete tests. [Schatz: 2001]

Transitions

Historically, sickle cell disease had been a pediatric disorder; however, with the advent of modern comprehensive sickle cell care, the majority of patients in high resource countries including the United States now survive into adulthood and require transition of care to adult providers. This transition is a vulnerable time for these adolescents. Studies have shown worse health outcomes and increased health care utilization in the young adult population as they transition out of pediatric care. Transitioning individuals have increased rates of emergency department visits and decreased access to chronic therapy, such as hydroxyurea. [Hemker: 2011] [Blinder: 2015]

For a successful transition from pediatric to adult sickle cell care, counsel the patient about the transition prior to transfer; communicate among pediatric and adult providers, and ensure that the first visit to an adult provider is before the final pediatric visit or within 1-3 months of the last pediatric visit. [Sobota: 2017] Potential indicators for successful transition are that the:
  • Individual is keeping clinic appointments and remaining adherent to treatment and medications
  • Written transfer summary has been sent to the adult provider
  • First visit to adult provider is within an appropriate interval after leaving pediatric hematology.
  • Overall quality of life is good

Issues Related to Sickle Cell Disease

School Accommodations: IEPs & 504s

Working with Insurance Companies

No Related Issues were found for this diagnosis.

Ask the Specialist

How do I interpret the newborn screening report, and what should I do if the results are consistent with possible sickle cell disease?

The newborn screening report will list the types of hemoglobin present in decreasing order of relative quantity. Because fetal hemoglobin is most common in the first several weeks of life, it is always listed first in untransfused babies. Normal infants should have a screen showing “F+A”. Patients with one of the sickling disorders may have newborn screens showing “F+S”, “F+S+A” (sickle beta plus thalassemia) or “F+S+C”. Patients with “F+A+S” have sickle cell trait.

If a child’s newborn screen results are consistent with possible sickle cell disease, the state newborn screening lab will provide instructions for sending a second newborn screen to confirm the abnormal hemoglobin pattern. If sickle cell disease is confirmed, the patient should be referred to pediatric hematology or a comprehensive sickle cell center. Penicillin prophylaxis should be prescribed by two months of age for patients with severe phenotypes (homozygous sickle cell anemia or sickle beta0 thalassemia) if there is a delay in subspecialty evaluation. Sickle Cell Disease has further Information about initial clinical response to a positive newborn screen.

What additional immunizations to patients with sickle cell disease need?

You should consult the latest version of the CDC Immunization Schedule for high-risk patients with functional or anatomic splenectomy for details as this may change annually.

Patients with sickle cell disease should receive annual influenza immunization. Because of the functional asplenia, they are at increased risk for infection with encapsulated organisms. Therefore, they should complete the normal pneumococcal series with PCV13 as well as a dose of PPSV23 after the age of 2 and at least 8 weeks after the last PCV13. A single booster of PPSV23 should be administered 5 years after the last dose of PPSV23. Primary meningococcal vaccination should occur early with two doses given 8 weeks apart starting at age 2 years. They should also receive meningococcal B vaccination with a 2-dose series starting at 10 years of age.

What counseling should I perform for a patient with sickle cell trait?

Sickle cell trait is common with a prevalence of up to 1:14 in African Americans. It is appropriate for primary care providers to provide counseling to patients regarding their sickle cell trait status. It is important that patients know they do not have sickle cell disease. Patients with sickle trait rarely have health problems. In some extreme conditions, such as severe dehydration or high altitude, there may be complications such as rhabdomyolysis or splenic infarction. Sometimes patients with sickle trait may have blood in their urine and should notify their doctor immediately if this happens.

The National Collegiate Athletic Association (NCAA) screens every collegiate student-athlete for sickle cell trait. The presence of sickle cell trait is not a contraindication to participation, but additional precautions should be taken. Precautions include paying particular attention to hydration; avoiding high-caffeine energy drinks, supplements, and stimulants; graduated activity; and stopping activity in the event of symptoms, such as muscle pain, abnormal weakness, or breathlessness. See Sickle Cell Trait – Fact Sheet for Student Athletes (NCAA) (PDF Document 1.3 MB).

Patients should also be made aware of the reproductive implications of their trait status. If their partner also has sickle trait or beta-thalassemia trait, then their offspring have a 25% chance of having sickle cell disease. We encourage patients to discuss their partner’s trait status prior to conceiving.

Do patients with sickle cell trait experience any symptoms or complications?

In general, individuals with sickle cell trait are asymptomatic and do not experience sickle-related complications like pain. Some data suggest individuals with sickle trait may be at slightly increased risk for renal complications (hematuria), venous thromboembolism (PE) in adulthood, and rarely experience splenic infarction when exposure to altitude. Testing for sickle cell trait is required by the NCAA for college athletes as there have been rare cases of exercise-related complications in individuals who carry sickle cell trait.[Naik: 2015] 

Resources for Clinicians

On the Web

Sickle Cell Disease
Information about initial clinical response to a positive newborn screen for sickle cell disease; Medical Home Portal.

Sickle Cell Information for Healthcare Providers (CDC)
A broad range of useful information, including clinician and patient education materials, clinical guidelines, data/statistics, and scientific articles; Centers for Disease Control and Prevention

Sickle Cell Disease (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for articles published in the last year about sickle cell disease in children

Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP.
Crizanlizumab for the prevention of pain crises in sickle cell disease.
N Engl J Med. 2017;376(5):429-439. PubMed abstract / Full Text

Borhade MB, Kondamudi NP.
Sickle Cell Crisis.
StatPearls [Internet] Treasure Island (FL) StatPearls Publishing. 2020. PubMed abstract / Full Text

Gardner RV.
Sickle cell disease: advances in treatment.
Ochsner J. 2018;18(4):377-389. PubMed abstract / Full Text

Piel FB, Steinberg MH, Rees DC.
Sickle Cell Disease.
N Engl J Med. 2017;376(16):1561-1573. PubMed abstract

Wang CJ, Kavanagh PL, Little AA, Holliman JB, Sprinz PG.
Quality-of-care indicators for children with sickle cell disease.
Pediatrics. 2011;128(3):484-93. PubMed abstract

Clinical Tools

Assessment Tools/Scales

Pain Rating Scale (Wong-Baker FACES Foundation)
Self-assessment that uses expressions on faces to depict pain level.

Patient Education & Instructions

Sickle Cell: What to Do When Your Child is Experiencing Pain (Children's Hospital Colorado) (PDF Document 304 KB)
Steps for comforting a child with sickle cell who is experiencing pain; includes medication dosing charts and suggestions for when to call your doctor.

Hydroxyurea for Sickle Cell Disease (American Society of Sickle Cell Disease) (PDF Document 876 KB)
Information for parents with children about side effects and instructions for how to administer hydroxyurea, what to do if a dose is missed, and safety measures to prevent infections.

Teens with Sickle Cell Disease Moving to Adult Care (St. Jude Children’s Research Hospital) (PDF Document 456 KB)
Tips for teens taking responsibility for changing from a pediatric hematologist to a hematologist who treats adults. Tips include practical suggestions for understanding how sickle cell disease affects your body, getting your full medical record, and obtaining a medical ID card, durable power of attorney for health care, and health insurance.

Resources for Patients & Families

Books

Platt AF, Eckman J, Hsu L.
Hope & Destiny: The Patient and Parent's Guide to Sickle Cell Disease and Sickle Cell Trait.
4th ed. Hilton Publishing; 2016. 098475668X https://www.amazon.com/Hope-Destiny-Patient-Parents-Disease/dp/0984756...
A 260-page book that offers in-depth information about research, treatment, pain management, and preventing complications.

Information on the Web

For Parents & Families
Information for parents to help them better care for their child with complex conditions from diagnosis through their child's transition to adult care; Medical Home Portal.

Sickle Cell Disease (MedlinePlus)
Overview of sickle cell disease plus links to many other relevant sources of information and support for patients and families; from the National Library of Medicine.

Sickle Cell Disease (CDC)
Comprehensive information about sickle cell disease for caregivers, families, and patients; Centers for Disease Control and Prevention.

Sickle cell anemia: How our red blood cells evolved to fight malaria (HealthMatch)
This web resource discusses the evolutionary role of how sickle cells help fight malaria, with a discussion of emerging therapeutics and option to search for relevant drug trials.

National & Local Support

Sickle Cell Disease Association of America
The mission of this nonprofit is to improve the quality of health, life, and services for individuals, families, and communities affected by sickle cell disease and related conditions while promoting the search for a cure.

Studies/Registries

Sickle Cell Disease (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Montana (MT)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: November 2017; last update/revision: September 2021
Current Authors and Reviewers:
Author: Christopher McKinney, MD
Reviewer: Julie Kanter, MD
Authoring history
2020: update: Susan Kuldanek, MDA; Christopher McKinney, MDA
2017: first version: Christopher McKinney, MDA; Rachelle Nuss, MDCA; Kathryn L. Hassell, MDSA
AAuthor; CAContributing Author; SASenior Author; RReviewer

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Crizanlizumab for the prevention of pain crises in sickle cell disease.
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