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Sickle Cell Disease

, MD, PhD and , MN, MPH, ARNP.

Author Information
, MD, PhD
Department of Pediatrics
University of Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington
, MN, MPH, ARNP
Odessa Brown Children’s Clinic
Seattle Children’s Hospital
Seattle, Washington

Initial Posting: ; Last Update: October 23, 2014.

Summary

Disease characteristics. Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ in the body, including the bones, lungs, liver, kidneys, brain, eyes, and joints. Dactylitis (pain and/or swelling of the hands or feet) in infants and young children is often the earliest manifestation of sickle cell disease. In children the spleen can become engorged with blood cells in a “splenic sequestration.” The spleen is particularly subject to infarction and the majority of individuals with SCD are functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but may be relatively protected from vaso-occlusive pain.

Diagnosis/testing. The term “sickle cell disease” encompasses a group of symptomatic disorders associated with pathogenic variants in HBB and defined by the presence of predominantly hemoglobin S (Hb S), or Hb S along with other Hb variants that allow for Hb S polymerization. Normal human hemoglobin is a heterotetramer composed of two α-hemoglobin chains and two β-hemoglobin chains. Hemoglobin S results from a single nucleotide variant in HBB, changing the sixth amino acid in the β-hemoglobin chain from glutamic acid to valine (Glu6Val). Sickle cell anemia (homozygous Hb SS) accounts for 60%-70% of sickle cell disease in the US. Other forms of sickle cell disease result from coinheritance of Hb S with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle β-thalassemia (Hb Sβ+-thalassemia and Hb Sβ°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab, O-Arab, and E. The diagnosis of sickle cell disease is established by demonstrating the presence of significant quantities of Hb S by isoelectric focusing (IEF), cellulose acetate electrophoresis, high-performance liquid chromatography (HPLC), or (less commonly) DNA analysis. Targeted mutation analysis is used to identify the common pathogenic variants of HBB associated with hemoglobin S, hemoglobin C, and additional rarer pathogenic variants. HBB sequence analysis may be used to detect pathogenic variants associated with β-thalassemia hemoglobin variants. Gel electrophoresis or HPLC can differentiate these disorders from heterozygous carriers of the Hb S pathogenic variant (Hb AS). In the United States, mandatory newborn screening establishes the diagnosis of sickle cell disease in neonates with the goal of assuring referral to specialty care prior to the onset of symptoms.

Management. Treatment of manifestations: The mainstays of management of pain episodes are prevention and supportive therapy: hydration (e.g., intravenous fluids), anti-inflammatory agents, and pain medication (e.g., nonsteroidal anti-inflammatory drugs and opiate analgesia). Hydroxyurea may be used to prevent pain episodes, but does require monitoring. Pain episodes are additionally managed with a multi-model approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Aggressive pulmonary toilet and prompt evaluation and treatment of underlying infections are essential. Life-threatening or severe complications (e.g., severe acute chest syndrome and stroke) are often treated with transfusion to reduce the percentage of Hb S while increasing oxygen carrying capacity. Other treatments may include joint replacement, hemodialysis, kidney transplantation, splenectomy for splenic sequestration crisis, and/or cholecystectomy for cholelithiasis. Acute treatment of stroke includes red blood cell exchange transfusion and aggressive management of increased intracranial pressure and seizures. Severe priapism may require aspiration and irrigation. Management of pulmonary hypertension can include routine treatments and specific therapies such as phosphodiesterase inhibitors or nitric oxide.

Prevention of primary manifestations: The mainstay is good hydration and avoidance of climate extremes, extreme fatigue, and activities leading to inflammation. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Chronic red blood cell transfusion is indicated in children with either a history of or risk factors for stroke and other specific complications, such as pulmonary hypertension and chronic renal failure. Stem cell transplantation may be an option in selected individuals who have severe disease.

Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; up-to-date immunizations; folic acid supplementation; and iron chelation therapy for those with iron overload.

Surveillance:

  • Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and recommendation for routine dental care.
  • Yearly for healthy affected individuals: CBC and reticulocyte count, assessment of iron status, liver and renal function tests, urinalysis, LDH, and vitamin D level; extended red cell phenotyping should be done at least once.
  • Evaluation for end-organ damage starting at age seven years: chest x-ray, ECG, pulmonary function tests, abdominal ultrasound, and ophthalmology evaluation.
  • For all individuals with Hb SS and Hb Sβ°-thalassemia: yearly transcranial Doppler to determine risk of stroke.
  • Further cardiac and pulmonary evaluations (echocardiogram to determine the tricuspid regurgitant jet; pulmonary function tests; sleep study) for older individuals or individuals of any age with cardiac or pulmonary concerns.

Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, and recreational drugs with vasoconstrictive or cardiac stimulation effects.

Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present.

Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by hematology and obstetrics; an increased risk for preterm labor, thrombosis, infectious complications, and acute painful episodes has been reported during pregnancy; hydroxyurea should be discontinued during pregnancy.

Genetic counseling. Sickle cell disease is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB Hb S pathogenic variant and the other is a carrier of any of the HBB pathogenic variants (e.g., Hb S, Hb C, β-thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of sickle cell disease is most commonly accomplished by HPLC. Prenatal diagnosis for pregnancies at increased risk for sickle cell disease is possible by molecular genetic testing if the HBB pathogenic variants have been identified in the parents.

Diagnosis

Clinical Diagnosis

The term sickle cell disease (SCD) encompasses a group of disorders characterized by the presence of at least one hemoglobin S (Hb S) allele and a second abnormal allele allowing abnormal hemoglobin polymerization leading to a symptomatic disorder.

  • Sickle cell anemia (Hb SS) accounts for 60%-70% of sickle cell disease in the US. This percentage may decrease due to the increasing number of children born to multiracial parents.
  • The other forms of sickle cell disease result from coinheritance of Hb S with other abnormal globin β chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle β-thalassemia (Hb Sβ+-thalassemia and Hb Sβ°-thalassemia).
    Note: The β-thalassemias are divided into β+-thalassemia, in which reduced levels of normal β-globin chains are produced, and β°-thalassemia, in which there is no β-globin chain synthesis.
  • Other globin β chain variants such as D-Punjab, O-Arab, and E also result in sickle cell disease when coinherited with Hb S.

Most individuals with sickle cell disease are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin (Hb F; see Beta-Thalassemia) levels decrease and hemoglobin S (Hb S) levels increase. In the United States, the diagnosis is usually determined at birth via newborn screening. In the absence of newborn screening, sickle cell disease is often suspected in infants or young children with painful swelling of the hands and feet (dactylitis or "hand-foot syndrome"), pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.

Note: Universal newborn screening (and subsequent diagnosis at birth) facilitates referral to specialty care prior to the onset of symptoms. Immigrants and those born in countries where universal newborn screening does not exist will require evaluation based on symptoms, family history, or findings on screening blood work such as a complete blood count (CBC).

Testing

Hematologic Testing

Table 1 summarizes the relative quantity of hemoglobins observed by age six weeks and typical hematologic studies by age two years for the four most common sickle cell diseases.

Table 1. Sickle Cell Disease: Diagnostic Test Results

Abnormal Globin β Chain Variants 1Hemoglobins Identified by Age Six Weeks 2 PhenotypeHematologic Studies by Age Two Years
MCV 3Hb A2(%) 4
SS (βSβS)Hb F, Hb SHemolysis and anemia by age 6-12 monthsN <3.6%
S β°-thal (βSβ°)>3.6% 5
S β+-thal (β+βS)Hb F, Hb S, Hb AMilder hemolysis and anemia N or ↓>3.6% 5
SC (βSβC)Hb F, Hb S, Hb C<3.6%

Table shows typical results; exceptions occur. Less common genotypes (e.g., SD, SOArab, SCHarlem, Lepore, and E) are not included.

thal = thalassemia

MCV = mean corpuscular volume

N = normal

↑= increased

↓= decreased

1. The β-thalassemias are divided into β+-thalassemia, in which reduced levels of normal β-globin chains are produced, and β°-thalassemia in which there is no β-globin chain synthesis.

2. Hemoglobins reported in order of quantity (e.g., F, S, A = F>S>A)

3. Normal MCV: ≥70 at 6-12 months; ≥72 at 1-2 years; ≥81 in adults

4. Hb A2 results vary somewhat depending on laboratory method.

5. Hb S with coexistent β-thalassemia causes ↓MCV and often leads to an Hb A2 >3.6%.

The diagnosis of sickle cell disease is established by demonstrating:

  • The presence of significant quantities of Hb S by high-performance liquid chromatography, isoelectric focusing, or (less commonly) cellulose acetate or citrate agar electrophoresis; and
  • The lack of a normal β-globin gene (see Molecular Genetic Testing).

A complete blood count (CBC) and measure of iron status (e.g., zinc-protoporphyrin (ZPP) or serum iron and total iron binding capacity [TIBC]) help distinguish between specific diagnostic entities.

  • High-performance liquid chromatography (HPLC)
    • Readily separates some proteins that cannot be resolved by other means;
    • Allows for accurate quantification of normal and variant hemoglobins at low concentrations, enabling differentiation of Hb Sβ+-thalassemia from sickle cell trait (Hb AS), as well as a quantitative description of compound heterozygous disorders such as Hb S-HPFH (hereditary persistence of fetal hemoglobin; see Beta-Thalassemia, Clinical Description, Genotype Phenotype Correlations) and Hb SC;
    • Does not definitively distinguish Hb Sβ°-thalassemia from Hb SS (identification requires DNA testing or additional laboratory studies).
  • Isoelectric focusing (IEF)
    • Capable of higher resolution than other hemoglobin electrophoresis
    • Routine isoelectric focusing provides an efficient platform for high-throughput screening and thus is often used for newborn screening, but is less quantitative than HPLC.
    • Capillary isoelectric focusing technology allows for separation of very small samples, quantification, and automation of sampling.
  • Cellulose acetate and citrate agar electrophoresis
    • Useful for quick screening of a small number of samples
    • Protein bands are relatively wide and many abnormal hemoglobins overlap.
    • Quantitative densitometry of abnormal hemoglobins is inaccurate at low concentrations (e.g., Hb A2 and Hb F in adults).
  • Peripheral blood smear
    • Sickle cells, nucleated red blood cells, and target cells may be seen. Other abnormal forms may be present depending on the specific genotype.
    • Presence of Howell-Jolly bodies indicates hyposplenism.
    • Neutrophils are typically increased and platelets are often increased as well.

Kleihauer-Betke test. This acid-elution test detects the presence of cells with high fetal hemoglobin content and can be used to characterize coexistent hereditary persistence of fetal hemoglobin (HPFH) with sickle cell disease.

The solubility test (i.e., Sickledex, Sickleprep, or Sicklequik) utilizes the relative insolubility of deoxygenated Hb S in solutions of high molarity. Hemoglobin S in hemolysates precipitates in the test solution while other hemoglobins remain in solution. Note: Solubility tests alone should NEVER be used for genetic counseling assessments if one partner is known to have Hb S, as this test will not detect β°-thalassemia, Hb C, or other hemoglobin variants that can lead to compound heterozygous forms of sickle cell disease.

The solubility test has no place in the definitive diagnosis of sickle cell disease because:

  • It does not differentiate sickle cell disease from sickle cell trait (Hb AS);
  • False positives have been reported [Hara 1973];
  • High levels of Hb F may cause false negative results in infants with sickle cell disease; and
  • It may miss some clinically significant forms of sickle hemoglobinopathies (e.g., Hb SC) [Fabry et al 2003].

The main uses for the solubility tests are:

  • A low-cost and rapid screen for the presence of Hb S prior to investing in definitive testing; and
  • Emergent estimation of whether a clinically significant hemoglobinopathy exists (if combined with a CBC, blood smear, and reticulocyte count).

Newborn Screening

Because of the high morbidity and mortality of sickle cell disease in undiagnosed toddlers, all 50 US states, the District of Columbia, Puerto Rico, and the Virgin Islands currently provide universal newborn screening for sickle cell disease. The vast majority of new cases are diagnosed at birth, allowing referral to specialty care prior to the onset of symptoms.

Outside the United States, screening is limited (and variable between and within countries) but is rapidly evolving. Some countries perform universal screening while other countries limit screening to populations at higher risk for sickle cell disease (targeted screening). In sub-Saharan Africa, where the incidence of the sickle mutation is very high, screening is minimal, costly, and regional [Tshilolo et al 2008]. However, there is a trend towards increasing testing in sub-Saharan Africa and India.

The majority of newborn screening programs perform isoelectric focusing of an eluate of dried blood spots. A few programs use HPLC, DNA testing, or cellulose acetate electrophoresis as the initial screening method [genes-r-us.uthscsa.edu].

Hemoglobins identified by newborn screening are generally reported in order of quantity. For example, more fetal hemoglobin (Hb F; see Beta-Thalassemia) than adult hemoglobin (Hb A) is present at birth; thus, most infants show Hb FA on newborn screening.

Specimens with abnormal screening results are retested using a second, complementary electrophoretic technique, HPLC, citrate agar, IEF, or DNA-based assay [genes-r-us.uthscsa.edu].

Infants with hemoglobins that suggest sickle cell disease or other clinically significant hemoglobinopathies (Table 1) require confirmatory testing of a separate blood sample by age six weeks.

Molecular Genetic Testing

Gene. The term sickle cell disease encompasses a group of symptomatic disorders associated with pathogenic variants in HBB and defined by the presence of hemoglobin S (Hb S; Glu6Val pathogenic variant).

  • Sickle cell anemia (also known as homozygous sickle cell disease and Hb SS) accounts for 60%-70% of sickle cell disease in the US [genes-r-us.uthscsa.edu].
  • Sickle cell disease may also result from coinheritance of the HBB Glu6Val hemoglobin S pathogenic variant with a second HBB pathogenic variant associated with another abnormal hemoglobin variant that results in a clinically significant quantity of sickled cells including:
    • Hemoglobin C (Hb C; Glu6Lys pathogenic variant): sickle-hemoglobin C disease (Hb SC)
    • β-thalassemia pathogenic variants: Sβ+-thalassemia and Sβ°-thalassemia
    • Hemoglobin D (D-Punjab; Glu121Gln pathogenic variant)
    • Hemoglobin O (O-Arab; Glu121Lys pathogenic variant)
    • Hemoglobin E (Hb E; Glu26Lys pathogenic variant)

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Sickle Cell Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
HBBSequence analysis 2See footnotes 3, 4
Deletion/duplication analysis 5See footnote 6
Targeted mutation analysis 7, 8See footnote 9

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Sequence analysis detects most, but not all, sequence variants associated with β-thalassemia; some deletions will be missed.

4. HBB sequence analysis may be used when targeted mutation analysis is uninformative or as the primary test to detect pathogenic variants associated with β-thalassemia hemoglobin variants.

5. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. While deletions or duplications will not result in a sickle mutation, gene deletions lead to a thalassemic allele which, if combined with a sickle cell mutation in trans configuration leads to S β°-thalassemia.

7. Identifies HBB pathogenic variants Glu6Val (associated with hemoglobin S), Glu6Lys (hemoglobin C), Glu121Gln (hemoglobin D), and Glu121Lys (hemoglobin O-Arab). Testing for any of the large number of β-thalassemia pathogenic variants and other HBB pathogenic variants associated with other specific hemoglobin variants is also possible (see Beta-Thalassemia).

8. Pathogenic variants included in a panel may vary by laboratory.

9. Varies depending on ethnicity of the individual. In individuals known to have SCD by hematologic studies, the hemoglobin C (Glu6Lys) mutation is more common in those of western African descent; the hemoglobin D (Glu121Gln) mutation is more common in those of Mediterranean and Indian descent but also to a lesser extent in those with Thai and Turkish backgrounds [Atalay et al 2007]; the hemoglobin O-Arab (Glu121Lys) mutation is most common in those of Middle Eastern descent as well as Greek Pomaks [Zimmerman et al 1999]; and the hemoglobin E (Glu26Lys) mutation is more common in people of Southeast Asian descent (see Molecular Genetic Testing, Gene and Table 4). These mutations have been described in a wide population distribution reflecting migration patterns of founder populations throughout the world.

Testing Strategy

To confirm/establish the diagnosis in a proband. The multiple testing strategies possible vary depending on the specific diagnosis, proband's age, family history, and availability of parents for testing. Strategies should take into account assessment of modifying factors, such as the coexistence of α-thalassemia.

  • Newborns. When initial screening detects a clinically significant hemoglobinopathy, the result should be confirmed within six weeks with the same or, preferably, a complementary method.
    • For compound heterozygotes (e.g., Hb SC, SD, SO, or SE) a repeat test is adequate.
    • Newborns with Hb F>Hb S could have homozygous sickle cell (Hb SS), Sβ°-thalassemia, or Sβ+-thalassemia with a low level of Hb A. These hemoglobinopathies can be difficult to distinguish in the newborn period when 95% of hemoglobin is Hb F. Further testing for these infants, as well as newborns diagnosed with Sβ+-thalassemia can include molecular testing and/or hematologic testing of parents. Alternatively, some diagnoses are easier to make with increased age. Timing is in part dependent on the genetic counseling needs of the parents.
  • Infants about age one year. Regardless of the outcome of testing in the newborn period, additional testing that should be done at about age one year (once Hb F levels have fallen) includes: a CBC, reticulocyte count, some type of electrophoresis or HPLC, a measure of iron status, and inclusion body preparation with BCB (brilliant cresyl blue) stain. Together these help determine if there is a coexisting thalassemia component, and if so, if it is α-thalassemia or β-thalassemia. This is important for genetic counseling and for providing insight into disease-specific outcomes.
  • Individuals over age one year. A one-time assessment as described for Infants about age one year should be done.

Clinical Description

Natural History

The clinical manifestations of sickle cell disease (SCD) result from intermittent episodes of vascular occlusion leading to tissue ischemia/reperfusion injury and variable degrees of hemolysis, both of which contribute to multi-organ dysfunction. The severity of disease manifestations varies from severe to minimal, even in individuals with the same HBB pathogenic variant status.

Previously, median survival in the US for those with SCD was estimated to be age 42 years for men and age 48 years for women [Platt et al 1994]; however, survival of a subset of individuals with SCD to over age 55 or 60 has been described, though morbidity remains high [Wierenga et al 2001, Serjeant 2013]. In addition, some evidence shows a shift towards older age at death over the last 20 years, marked by significant decreases in death rates during childhood [Hassell 2010]. The main causes of death are infection, acute chest syndrome, pulmonary artery hypertension, and cerebrovascular events [Steinberg et al 2003, Bakanay et al 2005]. Causes of death in children tend to differ from those in adults. Children have higher rates of death from infection and sequestration crises whereas adult mortality is related to chronic end-organ dysfunction, thrombotic disease, and treatment-related complications [Manci et al 2003].

Disease Complications

The hallmarks of SCD-related disease complications are the result of chronic hemolysis and intermittent vaso-occlusive episodes. In addition, immune dysregulation and hypercoagulability contribute to disease complications.

Chronic hemolysis is associated with chronic anemia as well as vascular dysfunction [Morris 2011].

  • Individuals with the highest rates of hemolysis are at increased risk of developing pulmonary artery hypertension, priapism, and leg ulcers [Morris et al 2008a, Taylor et al 2008, Kato & Taylor 2010].
  • Biologic markers for this “hemolytic phenotype” include the following:
    • Elevated plasma levels of lactate dehydrogenase (LDH)
    • A low hemoglobin level
    • A high reticulocyte count

Vaso-occlusive events (VOE) are associated with ischemia/reperfusion damage to tissues that lead to pain and acute or chronic injury affecting any organ system. The bones/marrow, spleen, liver, brain, lungs, kidneys, and joints are often affected [Vichinsky 2002].

Biologic markers associated with this “vaso-occlusive phenotype” include the following [Charache et al 1996, Darbari et al 2012, Wood et al 2012]:

  • A higher WBC count
  • A lower Hb F level
  • Older age
  • Co-existing alpha thalassemia trait
  • Iron overload
  • Vessel flow resistance related to deoxygenation

Common SCD Complications

Infection. Individuals with sickle cell disease develop splenic dysfunction as early as age three months; thus, young children with sickle cell disease are at high risk for septicemia and meningitis with pneumococci and other encapsulated bacteria including Streptococcus pneumonia, Neisseria meningiditis, and Haemophilus influenza. Historically, the single most common cause of death in children with sickle cell disease was Streptococcus pneumoniae sepsis, with the risk of death being highest in the first three years of life. Notably, the role of newborn screening, education, and access to healthcare cannot be overstated. Despite not altering infection rates, these measures do lower morbidity and mortality [Powars et al 1981, Vichinsky et al 1988]. With the further addition of vaccination programs and prophylactic penicillin the incidence of these infections has decreased significantly [Adamkiewicz et al 2003].

Individuals with sickle cell disease are also at increased risk for other infections such as osteomyelitis caused by Staphylococcus aureus or other organisms such as Salmonella species. Infectious agents implicated in acute chest syndrome include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Streptococcus pneumonia, as well as viruses. Parvovirus remains an important cause of aplastic crisis. Indwelling central venous catheters confer a high risk of bacteremia in individuals with SCD [Chulamokha et al 2006, Zarrouk et al 2006].

Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. The dorsa of the extremities are most often involved; one or all four extremities can be involved. When present, dactylitis usually occurs in infants and children. Although immediate sequelae are rare, dactylitis has been implicated as a risk factor for severe disease [Miller et al 2000].

Vaso-occlusive pain episodes are the most frequent cause of recurrent morbidity in sickle cell disease and account for the majority of sickle cell disease-related hospital admissions as well as school and work absences [Platt et al 1991, Gill et al 1995]. Vaso-occlusion occurs as a result of formation of multicellular aggregates that block blood flow in small blood vessels, depriving downstream tissues of nutrients and oxygen. The end result is tissue ischemia and tissue death in the affected vascular beds. Excruciating pain results from vaso-occlusion and ischemic tissue damage. Young children more often complain of pain in their extremities, whereas older individuals more commonly experience pain in the head, chest, abdomen, and back.

Splenic sequestration and infarction. Splenic sequestration is characterized by an acutely enlarging spleen with hemoglobin more than 2 g/dL below the affected individual's baseline value. Mild-to-moderate thrombocytopenia may also be present. Splenic sequestration occurs in 10%-30% of children with sickle cell disease, most commonly between age six months and three years, and may follow a febrile illness. Children with splenic sequestration may experience abdominal pain, nausea, vomiting, lethargy, or irritability. Blood transfusion may be required as severe splenic sequestration may progress rapidly to shock and death. Recurrent episodes, or difficult-to-manage acute episodes, may require splenectomy. Most children with Hb SS or Sβ°-thalassemia will have a dysfunctional spleen within the first year of life and complete auto-infarction and atrophy due to ischemia of the spleen by age five years. This contributes to the increased risk of sepsis and infection.

Aplastic crisis is the temporary interruption of red blood cell production, typically due to human parvovirus B12 infection in children, resulting in an acute and potentially life-threatening exacerbation of an individual’s anemia. Sickle red blood cells survive for only about seven to 12 days, compared to 100-120 days for normal red blood cells. Thus parvovirus B12 infection, which can interrupt red blood cell production for eight to ten days, can result in a drop of hemoglobin level of 1 g/dL per day, leading to life-threatening levels in individuals with SCD that may require red blood cell transfusion.

Acute chest syndrome (ACS) is a complex process that can arise from multiple diverse etiologies. ACS is a major cause of mortality [Bakanay et al 2005]. Although the definition varies in the literature, the diagnosis typically is made by the presence of a new pulmonary infiltrate on chest radiography in a person with sickle cell disease. This is often in the presence of respiratory tract symptoms, chest pain, hypoxemia, and/or fever. ACS often develops in the setting of a vaso-occlusive episode or with other acute manifestations of sickle cell disease, frequently after two to three days of severe vaso-occlusive pain. ACS can progress rapidly (over several hours to days) to requiring intubation and mechanical ventilatory support. A high index of suspicion is indicated: the presenting signs and symptoms of ACS can be highly variable and affected individuals may have an initial normal physical examination [Vichinsky et al 1997, Morris et al 1999]. Multiple etiologies (e.g., fat emboli from bone marrow infarcts, infection [particularly community-acquired pneumonia, mycoplasma pneumonia, Chlamydia pneumoniae, and viral pneumonia], pulmonary infarction, and pulmonary embolus), often at the same time, can lead to acute chest syndrome [Vichinsky et al 2000, Mekontso Dessap et al 2011].

Neurologic complications in SCD include stroke, silent cerebral infarcts, cerebral hemorrhage, cerebral blood flow abnormalities including Moyamoya disease, and cerebral microvascular disease. It is estimated that up to 50% of individuals with SCD will manifest some degree of cerebrovascular disease by age 14 [Bernaudin et al 2011].

Ischemic strokes, most often seen in children and older adults [Ohene-Frempong et al 1998], are among the most catastrophic manifestations of sickle cell disease. Common presenting signs and symptoms include: hemiparesis, monoparesis, seizures, aphasia or dysphasia, cranial nerve palsies, and mental status changes. Overt strokes occur in as many as 11% of children with sickle cell disease, with the peak occurrence between ages two and nine years. Recurring strokes occur in 50%-70% of affected individuals within three years after the first event. Transfusion therapy instituted after the initial stroke significantly reduces this risk [Serjeant 2013]. Narrowing of cerebral vessels is a risk factor for stroke, and elevated flow velocity on transcranial Doppler (TCD) has been identified as a means of distinguishing high-risk children [Adams et al 1998], allowing intervention prior to the development of stroke.

Silent cerebral infarcts (SCI) occur in approximately 22%-35% of individuals with SCD [Pegelow et al 2002, Bernaudin et al 2011]. Silent cerebral infarcts are lesions identified on cerebral imaging studies without known focal neurologic symptoms; however, such lesions may be associated with neurocognitive deficits [Schatz et al 2001] and an increased risk for overt stroke [Miller et al 2001]. Thus, a “silent infarct” should not be thought of as a clinically insignificant condition. Cerebral arterial stenosis is noted to be a risk factor for SCI but is not always reflected by increased transcranial Doppler (TCD) velocities due to multiple variables which influence individual vessel velocities. Additionally, accuracy of TCD measurements in demonstrating intracranial stenosis has not been firmly established. Utilization of methods to identify increased risk of stroke due to SCI, such as MRI/MRA, are being studied [Arkuszewski et al 2014].

Complications related to hemolysis. A hyper-hemolysis syndrome, marked by an elevated LDH, low hemoglobin level and low reticulocyte count, is associated with leg ulcers, priapism, pulmonary artery hypertension, systemic hypertension, and platelet activation [Hebbel 2011]. Other consequences of hemolysis include: chronic anemia, jaundice, predisposition to aplastic crisis, and cholelithiasis. While those with the highest rates of hemolysis may experience fewer pain episodes, the overall mortality rate for this group of individuals may be higher [Hebbel 2011].

Pulmonary hypertension. Pulmonary artery hypertension (PAH) affects approximately 6%-35% of adults with SCD and can have profound consequences [Gladwin et al 2004, Ataga et al 2006, Parent et al 2011].

Although a similar proportion of children with SCD have PAH as diagnosed by echocardiography, PAH does not appear to be associated with the same dire outcomes as in adults [Lee et al 2009, Liem et al 2009, Hebson et al 2014].

While many have defined PAH in SCD by an elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), subsequent studies using direct measurement of PAP (pulmonary arterial pressure) by right heart catheterization indicate that this may over-diagnose PAH [Parent et al 2011]. PAH in adults is associated with markedly increased mortality [Gladwin et al 2004, Ataga et al 2006, De Castro et al 2008] and significant morbidity, including exercise intolerance [Sachdev et al 2011]. Risk factors for PAH include markers of increased hemolysis, such as elevated LDH [Kato et al 2006], markers of cardiac strain, such as elevated brain natriuretic peptide (BNP) [Machado et al 2006], and the presence of obstructive sleep apnea [Hebson et al 2014]. Some individuals are relatively asymptomatic in the early stages of PAH. The relevance of these factors in children is less clear.

Priapism is very common among males with sickle cell disease, with a mean age of onset of 15 years [Mantadakis et al 1999, Adeyoju et al 2002]. These painful, unwanted erections occur spontaneously, or with nocturnal erections, or fever and dehydration. Males may have episodes of stuttering (intermittent) priapism lasting fewer than two to four hours which are often recurrent and may precede a more severe and persistent episode. “Severe priapism” episodes are persistent; those lasting more than two to four hours need rapid intervention because prolonged priapism may result in permanent erectile tissue damage and impotence [Rogers 2005].

Other complications of sickle cell disease include: avascular necrosis (typically involving the femoral head or humerous), nephropathy, restrictive lung disease, cholelithiasis, retinopathy, cardiomyopathy, and delayed growth and sexual maturation. Individuals with hemoglobin SC disease are at particularly high risk for retinopathy [Powars et al 2002]. Cardiopulmonary complications represent a major mortality risk in adults [Fitzhugh et al 2010].

Individuals who receive frequent red blood cell transfusion can develop problems with iron overload, with tissue iron deposition potentially damaging the liver, lungs, and heart [Kushner et al 2001] and alloimmunization that may interfere with the ability to obtain fully matched units of blood for transfusion [Vichinsky et al 1990].

Heterozygotes for Hb S have hemoglobins A and S (Hb AS) (also called sickle cell trait). Heterozygous individuals are not anemic and have normal red cell indices with hemoglobin S percentages typically near 40%. In regions of the world where malaria is endemic, Hb AS confers a survival advantage in childhood malaria; this is thought to be a major selective pressure for persistence of the Hb S pathogenic variant (Glu6Val).

The amount of Hb S present is insufficient to produce sickling manifestations under normal circumstances and, thus, these individuals are usually asymptomatic but are at risk for several complications [Key & Derebail 2010]:

  • Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with hemoglobin AS [Mitchell 2007]. It is recommended that individuals with known Hb AS maintain aggressive hydration during extremes of physical exertion, with no formal activity restrictions recommended. There is increased awareness of the low but significant risks for pulmonary emboli, exertional rhabdomyolysis, and sudden death with extreme exertion in individuals with Hb AS. This has led to the mandatory offering of testing to all NCAA Division I college athletes [Bonham et al 2010]. The full implications of this policy are unclear, and the role of genetic counseling in this setting is complex as there is debate about the impact and consequences of testing [Aloe et al 2011, Tarini et al 2012, Thompson 2013].
  • Splenic infarct at high altitudes, impaired renal concentrating abilities, and intermittent micro- and macroscopic hematuria can occur in some individuals with hemoglobin AS. Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with sickle cell trait [Swartz et al 2002, Hakimi et al 2007, Goldsmith et al 2012] such that a high index of suspicion for this rare diagnosis should be given for individuals with sickle cell trait who present with hematuria.
  • HB AS may be associated with an increased risk for venous thromboembolism [Austin et al 2007].
  • There has not been an association of sickle cell trait with avascular necrosis, stroke, leg ulcers, or cholelithiasis [Goldsmith et al 2012].

Genotype-Phenotype Correlations

Although a tremendous amount of individual variability occurs, individuals with Hb SS and Sβ°-thalassemia are generally more severely affected than individuals with Hb SC or Sβ+-thalassemia. Molecular and genetic factors that are responsible for this variability are being investigated [Steinberg & Adewoye 2006]. Genome-wide association studies have been used to identify regions associated with variations in Hb F levels [Thein 2013]. While several groups have identified variants associated with altered risk for specific complications, their role in clinical management has not been determined [Steinberg & Sebastiani 2012]. Examples include genetic correlates of Hb F levels [Galarneau et al 2010, Bhatnagar et al 2011], leg ulcers [Nolan et al 2006], renal nephropathy [Ashley-Koch et al 2011], stroke [Flanagan et al 2011], and disease severity [Sebastiani et al 2010].

HBB Glu6Val haplotypes correlate with disease severity, with the Sen (Senegal) haplotype being the mildest, the CAR/Bantu haplotype the most severe, and the Ben (Benin) haplotype of intermediate severity [Powars 1991]. In the US, increased disease severity likely relates to an increased prevalence of the Bantu haplotype in African Americans [Solovieff et al 2011]. In practice, these haplotypes are not routinely determined and more objective predictors of disease severity are used when available.

The presence of α-thalassemia may modify sickle cell disease severity (see Differential Diagnosis). In general, α-thalassemia improves red cell survival and decreases hemolysis in the sickle cell disease syndromes. However, the clinical effect on SCD is unclear and can be variable including possible decreased complications arising from hemolysis and potentially increased complications from vaso-occlusive events [Steinberg 2005].

In individuals with Hb SC:

  • Longer red cell life span and higher hemoglobin concentration are associated with fewer vaso-occlusive pain episodes.
  • Splenomegaly and the associated risk for splenic sequestration can persist well beyond early childhood.
  • Proliferative retinopathy and avascular necrosis are more likely to develop than in those with other sickle hemoglobinopathies.

Nomenclature

Historically in the US, the term "sickle cell anemia" was used to describe persons homozygous for Hb S. With increased awareness of the broad spectrum of clinically significant sickle hemoglobinopathies with varying degrees of anemia, the trend has been to use the umbrella term “sickle cell disease.” The term sickle cell disease should be followed by a detailed genotypic description for the individual (e.g., Hb SS, Hb SC, or Sβ°-thalassemia).

Prevalence

The Hb S allele is common in persons of African, Mediterranean, Middle Eastern, and Indian ancestry and in persons from the Caribbean and parts of Central and South America but can be found in individuals of any ethnic background.

Among African Americans, the prevalence of sickle cell trait (Hb AS) is about 10%, resulting in the birth of approximately 1100 infants with sickle cell disease (Hb SS) annually in the US. Approximately one in every 300-500 African Americans born in the US has sickle cell disease; more than 100,000 individuals are estimated to have homozygous sickle cell disease [Hassell 2010].

The prevalence of HBB alleles associated with sickle cell disease is even higher in other parts of the world. In many regions of Africa, the prevalence of the Hb S pathogenic variant (Glu6Val) is as high as 25%-35%, with an estimated 15 million Africans affected by sickle cell disease and 200-300,000 affected births per year worldwide [WHO Regional Committee for Africa 2006, World Health Organization 2006, Aliyu et al 2008, Mousa & Qari 2010]. Sickle cell disease accounts for as many as 16% of deaths of children younger than age five years in Western Africa [Neville & Panepinto 2011].

Differential Diagnosis

Once the presence of Hb S has been confirmed, the differential diagnosis is among clinically significant, less significant, and carrier states.

Clinically significant

  • Homozygous S/S (i.e., Hb SS)
  • Compound heterozygotes, including but not limited to:
    • Hb SC, Hb SD, Hb SO-Arab
    • Hb Sβ°-thalassemia
    • Some forms of Hb Sβ+-thalassemia

Less clinically significant

  • Some forms of Hb Sβ+-thalassemia
  • Hb SE

Carrier state. Sickle cell trait (Hb AS)

Alpha-thalassemia is often coinherited with the Hb S pathogenic variant (Glu6Val). Alpha-thalassemia pathogenic variants generally arise as a consequence of large deletions in one or both α-globin genes and are detected by PCR techniques. Testing for coexisting α-thalassemia is typically considered only in the presence of a low MCV in iron-replete individuals with SS disease or SC disease.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to sickle cell disease, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

If the initial diagnosis is made by newborn screening, confirmation of the diagnosis via a second newborn screen should be obtained with reassessment of the diagnosis around age one year, as the fetal hemoglobin level falls to the adult level (see Molecular Genetic Testing).

Evaluations to establish the extent of end-organ damage associated with sickle cell disease include:

  • Hematology consultation

Additional evaluations vary with the age and clinical status of the individual:

  • Infants after 12 months should have baseline laboratory studies including:
    • CBC and reticulocyte count
    • Measurement of Hb F (%)
    • Assessment of iron status
    • A thalassemia screen, which includes hemoglobin electrophoresis or HPLC and an inclusion body prep
    • Baseline vitamin D, renal and liver function tests
    • Extended red cell phenotyping so that antigen matched blood may be given if transfusion is urgently needed.
  • During childhood HLA typing should be offered for the affected individual and all full biologically matched siblings.
  • Older individuals. See Surveillance.

Treatment of Manifestations

Lifelong comprehensive care is necessary to minimize morbidity, reduce early mortality, and maximize quality of life [NHLBI 2002, Yawn et al 2014]. See Published Guidelines/Consensus Statements.

Education of parents, caregivers, and affected individuals is the cornerstone of care:

  • Families must appreciate the importance of routine health maintenance visits, prophylactic medications, and early intervention for both acute and chronic complications.
  • Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, and neurologic changes must be reviewed regularly and must incorporate the affected individual, as developmentally appropriate.
  • All families should have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome, splenic sequestration, and stroke.
  • A plan to deal with mild-to-moderate episodes of pain at home should be in place.
  • Families should be provided baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness [NHLBI 2002].

General management of specific problems [Benjamin et al 1999, Gladwin & Rodgers 2000, Walters et al 2000, NHLBI 2002, Rees et al 2003, Lottenberg & Hassell 2005, NHS 2010, Bender & Seibel 2012, Brousse et al 2014, Yawn et al 2014]:

  • Vaso-occlusive pain episodes including dactylitis
    • The initial focus should include the reversal of inciting triggers (e.g., cold or dehydration).
    • Pain episodes are optimally managed using a multi-model approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, and self-hypnosis in addition to pharmaceuticals.
    • Many uncomplicated episodes of pain can be managed at home with oral hydration and oral analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates.
    • More severe episodes of pain require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
    • Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device (PCA) or by continuous infusion.
    • NSAIDs such as ketorolac, ibuprofen, naproxen, and/or acetaminophen may be used to augment the analgesic effect of opiates and to decrease inflammation that is part of the pathophysiology.
    • Adequate but not excessive hydration with hypotonic fluids should be used to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as acute chest syndrome, splenic sequestration or opiate-induced constipation.
    • A thorough evaluation for infection, including blood culture, urine culture, and chest x-ray should be performed based on the clinical scenario.
    • Hydroxyurea should be encouraged as a treatment to prevent or lessen pain episodes over time. It is not, however, a useful treatment for acute pain episodes.
  • Infection/fever. All affected individuals with temperature greater than 38.3° C or persistent temperature elevation above baseline require rapid triage and physical assessment, urgent CBC and reticulocyte count, blood culture (and other cultures as clinically indicated), and a low threshold for chest x-ray when respiratory symptoms are present, as ACS can often present with a normal physical examination [Vichinsky et al 1997, Morris et al 1999].
  • Note: With the changing natural history of fever and sepsis in individuals with SCD in the US there is increasing evidence that empiric treatment with parenteral antibiotics without obtaining cultures may be appropriate for well-appearing, fully immunized children with fever <39 C; however this work has not yet been replicated nor has it become accepted practice [Baskin et al 2013].

    Individuals with fever should be given parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results:
    • A macrolide antibiotic should be added if pneumonia / acute chest syndrome is a concern.
    • Additional antibiotics should be added only for proven or suspected meningitis or other severe illness.
  • Acute chest syndrome (ACS). The index of suspicion for acute chest syndrome should be high when individuals with SCD have fever, chest pain, or respiratory signs or symptoms. Given the high mortality associated with ACS, an aggressive multimodal treatment strategy should be initiated [Miller 2011].
    • Because physical signs are variable (and can be absent), the threshold for obtaining a chest x-ray should be low [Vichinsky et al 1997, Morris et al 1999].
    • Those suspected of having ACS should be aggressively treated with oxygen, analgesics, and antibiotics (including a macrolide). Incentive spirometry should be encouraged. Hypoxemia can progress to need for intubation and mechanical ventilatory support.
    • Blood transfusion for those who are critically ill, have multilobar disease or have progressive disease despite conservative therapy may be necessary.
  • Aplastic crisis. Monitoring of hematocrit (both absolute and compared with the individual's baseline), reticulocyte count, and cardiovascular status are required. Transfusion support may be necessary. Most cases caused by parvovirus B19 will spontaneously resolve; however, if the reticulocyte count does not improve, intravenous gammaglobulin can be considered to assist in viral clearance. Any sibs or other close contacts with SCD should be monitored for red blood cell aplasia because the virus is easily transmissible.
  • Splenic sequestration. Severe episodes of splenic sequestration may progress rapidly to cardiovascular collapse and death; thus, emergency transfusion is indicated when signs of cardiovascular instability are present. Parents should be taught how to monitor for splenic enlargement and symptoms of sequestration. Individuals who experience multiple or severe episodes of splenic sequestration may require splenectomy.
  • Pulmonary hypertension. Diagnostic criteria, as well as when and how to intervene, are becoming increasingly controversial [Hassell et al 2014, Hebson et al 2014, Klings et al 2014a, Klings et al 2014b]. Existing consensus guidelines are not fully accepted by experts in the field. As a result, discussion with local sickle cell and pulmonary hypertension experts should be used to guide care. The following general approach is reasonable:
    • Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
    • Optimization of sickle cell disease-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, and oxygen therapy if hypoxemic)
  • Stroke. Any history of an acute neurologic symptom or event warrants emergent evaluation including a CBC with reticulocyte count and a non-contrast CT scan. Cerebral hemorrhage requires immediate neurosurgical consultation. An MRI/MRA to define injury should be obtained as soon as available, but treatment should never be delayed for these results.

    Treatment for children with acute ischemic stroke includes the following:
    • Monitor neurologic status and aggressively treat increased intracranial pressure and seizures, if present.
    • Exchange transfusion with the goal of decreasing Hb S percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease repeat risk for stroke [Wang et al 2000]. Without continued therapy as many as 60%-90% of individuals who have had a stroke have a second stroke within three years. Thus, in most cases, a preventive chronic transfusion protocol is initiated after a CNS event and continued indefinitely [Adams & Brambilla 2005] (see Prevention of Primary Manifestations).
    • Hydroxyurea has been studied as an alternative to transfusion therapy [Ware & Helms 2012]. While it does not provide the protection that transfusion therapy provides, it may be an alternative for affected individuals who are unable to receive transfusion therapy.

      No consensus regarding the management of individuals with silent infarcts exists.
  • Priapism. Episodes of severe priapism require urgent evaluation and treatment, including hydration and analgesia, and may require aspiration and irrigation by an urologist [Mantadakis et al 2000].

Prevention of Primary Manifestations

Ongoing education for all individuals with SCD is essential to help minimize morbidity and mortality. Education includes a regular review of interventions including:

  • Maintaining hydration and avoiding extremes of climate
  • Monitoring for signs and symptoms requiring acute medical intervention
  • Early detection of chronic complications
  • Updates on new therapies

Disease-modulating therapies are discussed in several reviews [Wang 2007, Vichinsky 2012, Kassim & DeBaun 2013].

Chronic red blood cell transfusion therapy. The initial goal of chronic red blood cell transfusion therapy varies depending on indication but typically is to maintain the percentage of Hb S below 30% and suppress reticulocytosis.

Chronic red blood cell transfusion therapy may be warranted for the following [Wanko & Telen 2005, Josephson et al 2007, Ware 2007, Wahl & Quirolo 2009, Wun & Hassell 2009, Smith-Whitley & Thompson 2012]:

  • Primary prevention of stroke in individuals with an abnormal transcranial Doppler
  • Prevention of stroke recurrence
  • Treatment of chronic pain refractory to other therapies
  • Pulmonary hypertension
  • Chronic renal failure
  • Recurrent episodes of ACS
  • Severe end-organ damage

Complications of chronic red blood cell transfusion therapy include: iron overload, alloimmunization, and, rarely, infection. To limit alloimmunization and transfusion reactions, extended matching of red blood cell antigens should be performed and blood products should be leuko-reduced (removal of white blood cells from the transfusion product). Red blood cells antigen matched at the full Rh locus (D, C, E) and Kell have been suggested to decrease alloimmunization rates, as well as other alleles when possible [Castro et al 2002, Lasalle-Williams et al 2011]. Approaches to decrease alloimmunization in the future include obtaining a better understanding of the process of alloimmunization as well as molecular genotyping. Defining antigens molecularly has multiple benefits including the ability to type cells when serologic reagents are not available [Anstee 2009, Silvy et al 2011, Yazdanbakhsh et al 2012, Matteocci & Pierelli 2014].

Hydroxycarbamide (hydroxyurea) is the only FDA-approved therapy for sickle cell disease; however, despite data suggesting improved morbidity (fewer acute painful episodes, less acute chest syndrome, decreased need for transfusion, decreased hospitalizations), mortality (improved survival), reduced health care costs, and strong recommendations for its use, it remains underutilized [Charache et al 1995, Brawley et al 2008, Steinberg et al 2010, Voskaridou et al 2010, McGann & Ware 2011, Smith et al 2011, Wang et al 2011, Strouse & Heeney 2012, Ware 2013]. Hydroxyurea may benefit individuals with SCD via several mechanisms [Platt 2008, Ware 2010], including:

  • Induction of Hb F synthesis resulting in decreased sickling and improved red-cell survival
  • Reduction of white blood cell (WBC), reticulocyte and platelet counts
  • Metabolism into nitric oxide, a potent vasodilator
  • Overall improvement in blood flow
  • Reduction of vascular inflammation

A NIH consensus statement on hydroxyurea noted strong evidence to support its routine use in adults [Brawley et al 2008].

While many affected individuals and providers note a vastly improved quality of life while on hydroxyurea, there are few studies addressing this [Darbari & Panepinto 2012].

It has been demonstrated that hydroxyurea therapy is safe to use in children as young as nine months, with initiation of therapy at age two years and younger on an individual basis [Ware 2010, Rogers et al 2011, Wang et al 2011, Strouse & Heeney 2012]. Every individual with SCD who is age nine months or older should be assessed for treatment with hydroxyurea.

Hydroxyurea can have potentially significant toxicity, including myelosuppression. Individuals treated with hydroxyurea must be monitored closely with routine CBCs and reticulocyte counts. In order to balance the benefits with potential toxicities of hydroxyurea, many suggest a careful titration of the drug to find a dosing for each affected person that provides an appropriate reduction in WBC count without toxicity [Ware 2010, Strouse & Heeney 2012].

Stem cell transplantation from a normal donor or one with sickle cell trait can be curative in individuals with sickle cell disease. The risks and morbidity associated with this procedure had initially limited its use to a select group of individuals with: (1) significant complications such as frequent pain, recurrent acute chest syndrome, or a history of cerebrovascular events; and (2) a matched sibling stem cell donor [Walters et al 2000]. Among these more than 90% survive; and approximately 85% survive free from sickle cell disease [Bernaudin et al 2007, Panepinto et al 2007, King & Shenoy 2014].

With the success of myeloablative transplants in children with a fully matched sibling, this therapy is increasingly recognized as an important treatment option in any person with a severe SCD phenotype [Nickel et al 2014]. While initial myeloablative regimes yielded too much toxicity for older individuals with SCD, the development of less toxic transplant regimens makes stem cell transplantation a more acceptable option for older individuals [Hsieh et al 2011, Khoury & Abboud 2011, Tisdale et al 2013]. This has led to the successful transplant of select adults, though they have required prolonged immunosuppression. Improvements in immunosuppressive regimens and management of graft-vs-host disease and other transplant-related complications are also increasing the number of individuals for whom transplantation is an option [Shenoy 2007, Bhatia & Walters 2008]. However, it is estimated that fewer than 30% of individuals with sickle cell disease have suitable matched sibling donors and fewer than 60% have suitable matched unrelated donors; thus the use of alternate donors including unrelated donors, haploidentical donors, and use of cord blood is an active area of research [Krishnamurti et al 2003, Ruggeri et al 2011, Gluckman 2013. Tisdale et al 2013].

Because the criteria, risks, and benefits of transplantation are changing rapidly, it is important for families and providers to discuss the risks and benefits with a transplantation center with expertise in sickle cell disease.

Prevention of Secondary Complications

Newborn screening has made presymptomatic diagnosis possible, allowing for early, aggressive education on management issues, such as management of fevers [Vichinsky et al 1988]. The use of prophylactic penicillin and immunization have significantly decreased morbidity and mortality in children, primarily by reducing deaths from sepsis [Powars et al 1981].

Penicillin prophylaxis prevents 84% of life-threatening episodes of childhood Streptococcus pneumoniae sepsis [Gaston et al 1986]:

  • By age two months, all infants with sickle cell disease should receive penicillin V potassium prophylaxis, 125 mg orally, twice a day.
  • At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.

Prophylaxis for those allergic to penicillin can include erythromycin or azithromycin but care should be taken to avoid medications that alter metabolism and increase the risk of prolonged QTc syndrome [Gerber et al 2009].

Immunizations. Timely administration of vaccines is essential. Updated guidelines appear yearly for pediatric [Centers for Disease Control and Prevention 2012] and adult vaccination [Centers for Disease Control and Prevention 2011]. Clinicians should follow the recommended vaccine schedule for functionally asplenic individuals, which includes additional vaccines such as the 23-valent pneumococcal polysaccharide vaccine, and an altered schedule for meningococcal vaccines. Persons with sickle cell are considered high priority for annual influenza vaccine.

Folic acid supplementation should be considered to support the increased RBC synthesis secondary to the high RBC turnover in sickle cell.

Iron overload. Individuals receiving transfusions are at risk for iron overload and should be monitored closely, initially by tracking the amount of blood transfused and monitoring serum ferritin concentration. Those with high exposures or documented iron overload should have an assessment of organ iron accumulation. With its increasing availability and safety and the ability to assess iron in multiple organs while avoiding sampling bias, quantitative radiographic evaluation such as SQUID or a T2* MRI is increasingly replacing biopsy [Vichinsky 2001, Wood 2007]. The noninvasive nature of monitoring iron overload via MRI has led to significant improvements in the outcome individuals with iron overload [Coates 2014]. Iron chelation therapy is recommended for those with evidence of excessive tissue iron deposition.

Surveillance

Surveillance should be tailored to an individual's specific diagnosis and clinical history; however, most individuals benefit from routine age-dependent screening to allow for early detection and treatment of end-organ damage [AAP 2002, NHLBI 2002, NHS 2010, Yawn et al 2014]. The following are general guidelines compiled from several sources. Recently NHLBI has released updated guidelines that readers are encouraged to review. See Published Guidelines/Consensus Statements.

Comprehensive medical and social evaluation. Affected individuals should be seen routinely for evaluation of risks, review of care plan, education, and assessment of growth and development. Social work assessment with emphasis on support, resources, and the impact of disease on lifestyle should be performed. Routine dental care is recommended.

Mental health and neurocognitive assessment. Periodic mental health screening for signs of depression, anxiety, and isolation should occur. Neurocognitve testing should be performed prior to school entry and repeated periodically to identify learning difficulties that may be related to silent cerebral infarcts as well as other factors.

Annual laboratory assessment. Yearly lab evaluation when healthy should include the following:

  • CBC with differential and reticulocyte count
  • Assessment of iron status
  • Liver function tests (LFTs), BUN, serum concentration of creatinine (Cr), and urinalysis (UA)
  • LDH as a marker of hemolysis
  • Vitamin D level; may be indicated because of the high prevalence of deficiencies in this population

Baseline values should be given to parents for comparison during times of illness.

Extended red cell phenotyping should be done once to decrease risk of alloimmunization with transfusions.

Assessment of stroke risk. For all individuals with Hb SS and Hb Sβ°-thalassemia (as well as some others), obtain yearly transcranial Doppler (TCD) by a person certified to record velocity of arterial blood flow for comparison to national studies to determine the risk of stroke. Individuals with an abnormally high arterial blood flow velocity have a high rate of stroke, which can be prevented by chronic red blood cell transfusion therapy. Children with normal velocities require yearly reevaluation as a proportion of them convert to higher risk velocities over time [Adams et al 2004]. Initial studies suggest that this approach is decreasing the incidence of overt stroke in individuals with SCD but additional measure may be of benefit as well [Mazumdar et al 2007, Jordan et al 2012, Webb & Kwiatkowski 2013].

End-organ evaluation. In addition to TCD, extended studies should be obtained starting at age seven years and including the following:

  • Chest x-ray
  • ECG
  • Pulmonary function tests (PFTs)
  • Abdominal ultrasound examination
  • Ophthalmology evaluation

Note: There is an increasing tendency in the field to obtain abdominal ultrasound and PFTs only as needed; however, there are no published recommendations advocating this practice at this time.

Further cardiac and pulmonary evaluation for older individuals or individuals of any age with cardiac or pulmonary concerns – typically:

  • Echocardiogram to determine the tricuspid regurgitant (TR) jet with consideration of right heart catheterization depending on symptoms;
  • Pulmonary function testing with six-minute walk test; and
  • Sleep study (to assess nighttime hypoxemia).

Guidelines for initiation and frequency of screening have not been established.

Other. Additional studies should be tailored to the affected individual's clinical history.

Agents/Circumstances to Avoid

Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:

  • Dehydration
  • Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
  • Physical exhaustion
  • Extremely high altitude without oxygen supplementation
  • Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects are particularly dangerous drugs in the setting of sickle cell disease.
  • The analgesic meperidine, which should be avoided as first-line therapy because of potential CNS toxicity

Evaluation of Relatives at Risk

Early diagnosis of at-risk family members may allow intervention before symptoms are present.

  • In the United States, sibs affected with sickle cell disease are diagnosed by universal newborn screening soon after birth (at which time referral to a pediatric hematologist is appropriate).
  • If newborn screening data is not available for at-risk sibs, several diagnostic approaches can be considered.
    • If the HBB pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
    • If the pathogenic variants in the family are not known, the gold standard is a combination of HPLC or isoelectric focusing combined with a CBC and reticulocyte count and measure of iron status such as a ZPP or serum iron and TIBC.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy complications in SCD can be minimized with close follow up and collaboration between hematology and obstetric teams [Naik & Lanzkron 2012]. Pregnancy in women with SCD involves increased risk for thrombosis, infectious complications, and acute painful episodes [Villers et al 2008, Naik & Lanzkron 2012, Alayed et al 2014, Costa et al 2014]. There is conflicting data as to whether the risks for preeclampsia, eclampsia, pre-term labor, and maternal death are increased [Smith et al 1996, Hassell 2005, Villers et al 2008, Naik & Lanzkron 2012, Alayed et al 2014, Costa et al 2014]. The risk of pregnancy complications increases when access to prenatal care is limited, reinforcing the importance of close hematologic and obstetric follow up in decreasing complication rates [Sun et al 2001, Naik & Lanzkron 2012]. The benefits of a chronic transfusion program versus the use of “as-needed” transfusions has not been established [Okusanya & Oladapo 2013]. As hydroxyurea is recommended for (and increasingly used in) adults, the current recommendation is that it be discontinued during pregnancy. While case reports of human infants exposed prenatally to hydroxyurea have not noted an increased risk of malformations, in experimental animal models hydroxyurea has been noted to lead to an increase in congenital anomalies. The role of chronic transfusions in lieu of hydroxyurea needs to be addressed.

More than 99% of births to women with SCD occurring after 28 weeks’ gestation are live births with normal Apgar scores [Smith et al 1996]. Several studies have reported increased rates of low birth weight and intrauterine growth retardation in babies born to women with SCD [Smith et al 1996, Hassell 2005]. Attention to postnatal opiate withdrawal in the babies of mothers treated with high-dose opiates during pregnancy is warranted.

Infants with SCD are asymptomic in the antenatal, perinatal, and immediate postnatal periods; they manifest disease symptoms when fetal hemoglobin production switches to adult hemoglobin.

Therapies Under Investigation

There is increasing promise of modulating the severity of sickle cell via a plethora of pathways. While it is impossible to be complete some examples emphasizing the diverse array of involved pathways are listed below.

  • Prevention of Hb S polymerization. 5-hydroxymethyl- 2-furfural (5-HMF), a naturally occurring compound, can inhibit polymerization and was recently used in a Phase I clinical trial [Abdulmalik et al 2005].
  • Decreasing adhesion to the endothelium. GMI-1070 is an inhibitor of E-selecting mediated binding of neutrophils and is the subject of a pending Phase III clinical trial [Chang et al 2010. Wun et al 2014]. Prasugrel, an antiplatelet agent, has shown promise in a Phase II clinical trial in adults and is being evaluated in a pediatric setting [Wun et al 2013].
  • Modifying inflammatory responses. Regadenoson is an adenosine A2A receptor agonist that modifies natural killer cell activity and has shown benefit in animal models. It has been evaluated in a Phase I study and a Phase II clinical trial is underway [Field et al 2013].
  • Antioxidants therapy. Glutamine is a key factor in determining red cell red-ox state. Glutamine level has been a marker of disease severity and a Phase III clinical trial of glutamine supplementation was concluded [Morris et al 2008b]. N-acetylcysteine can modulate markers of oxidative damage and hemolysis and is being studied in multiple clinical trials [Nur et al 2012].
  • Rejuvenation of nitric oxide (NO) stores. Arginine, the precursor of NO, has been studied in several contexts and a Phase II clinical trial has shown benefit in hospitalized people with sickle cell pain [Morris et al 2013]. As a result arginine has been featured in multiple clinical trials.
  • Induction of fetal hemoglobin. Multiple pathways and factors associated with the high level expression of the fetal hemoglobin genes (HBG1 and HBG2) have been identified and are currently targets for intervention. Representative pathways include LSD-1 inhibitors [Shi et al 2013], thalidomide inhibitors (e.g., pomolidomide) [Meiler et al 2011], nuclear factor erythroid 2-related factor 2 inhibitors (e.g., tert-butylhydroquinone) [Macari & Lowrey 2011], HDAC inhibitors (e.g., suberanilohydroxamic acid) [Bradner et al 2010, Hebbel et al 2010], short chain fatty acids (e.g., butyrate or valproic acid) and antimetabolites (e.g., 2’ deoxy 5’ azacytidine [decitabine]) [Saunthararajah et al 2008]. A promising approach to therapy is the development of inhibitors to the protein Bcl11a. Bcl11a was identified as an Hb F cell quantitative trait locus in a genome-wide association study [Menzel et al 2007]. Since then it has been shown to bind within the β-globin locus and to be critical for suppressing fetal globin gene expression in adult erythroid cells [Sankaran et al 2008, Sankaran et al 2010]. Knockdown or knockout of Bcl11a in model systems, as well as naturally occurring deletions that remove its binding site in humans, result in substantial increases in Hb F. These elevated levels of Hb F provide therapeutic benefits to individuals with both sickle cell disease and thalassemia [Sankaran et al 2011, Wilber et al 2011, Xu et al 2011]. Multiple approaches are being taken to inhibit Bcl11a function in vivo, including gene editing to disrupt the erythroid specific enhancer of Bcl11a [Bauer et al 2013].
  • Phytomedicines, including two mixtures of plants, have shown some initial promising results [Oniyangi & Cohall 2010].

Gene therapy. As sickle cell disease arises from a defined single-nucleotide substitution in the β-globin gene whose expression is restricted to erythroid cells derived from bone marrow hematopoietic stem cells, sickle cell disease is an ideal candidate for gene therapy [Payen & Leboulch 2012, Dong et al 2013, Chandrakasan & Malik 2014]. Gene therapy provides the benefit of stem cell transplantation, but without the problems associated with the use of an allogenic source of stem cells. Ideally, gene therapy would lead to an increase in non-sickle β-like chains, while lowering the number of sickle chains, for example by replacing the Hb S pathogenic variant (Glu6Val) with a normal allele.

The most progress has been made using viral vector-mediated addition of a normal β-like gene, potentially modified to have additional anti-sickling properties. This leaves the endogenous sickle allele intact. To date, reports on clinical trials using this approach have been limited to treatment of thalassemia, where transfusion independence has been achieved, but several clinical trials for treatment of SCD have opened, or are about to open [Cavazzana-Calvo et al 2010]. The status of these is changing rapidly and it is best to refer to ClinicalTrials.gov for the most up-to-date information.

Multiple gene therapy strategies that do not involve the addition of an additional, therapeutic globin gene are being pursued. A major obstacle to the above gene addition approaches is the requirement for long-term, high-level expression of the therapeutic gene, which requires the presence of large amounts of the major regulatory element, the locus control region, to be included. In contrast, these approaches involve the transduction and stable integration of therapeutic reagent for which low-level expression suffices. These include:

  • Using transactivators to stimulate the minimally expressed delta gene or the fetal or embryonic genes;
  • Inducing embryonic α-like chains that, when forming tetramers with sickle chains, are less likely to polymerize;
  • Knockdown of Bcl11a gene expression; and
  • Inducing “looping” between the locus control region and the fetal globin genes.

Some of the above approaches have the additional benefit of reducing expression of the sickle gene while increasing expression of a therapeutic gene. However, they require long-term expression, typically from a viral vector integrated into the genome, leading to the very real risk of severe sequelae, such as leukemia, stemming from insertional mutagenesis [Cavazza et al 2013]. These detriments of routine gene therapy are avoided by “gene editing.” As multiple techniques to modify the human genome with base pair accuracy are becoming increasingly easy and efficient, gene editing approaches are fervently being pursued [Scharenberg et al 2013, Kim & Kim 2014]. Gene editing typically entails the generation of a break in the DNA at or near the site of interest and the presence of a “corrective template.” Fortuitously, the cell’s endogenous DNA repair machinery inadvertently uses the therapeutic template when repairing the DNA, resulting in the incorporation of the corrective sequence. Gene editing is a “hit and run” approach, as it can be performed with the transient expression of the editing tools, thus avoiding the need for long-term expression as well as the risks of insertional mutagenesis, yet providing lifelong correction of the DNA. Two major approaches are being taken: removal of the sickle mutation and replacement with a normal sequence; and disruption of regulators of globin gene expression, such as Bcl11a, which in turn results in increased expression of the fetal genes. As this can be done in hematopoietic as well as induced pleuripotent stem cells, gene editing is the future of gene therapy.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Sickle cell disease (SCD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an individual with Hb SS are heterozygotes and therefore carry at least one Hb S allele.
  • For probands with other forms of sickle cell disease such as Hb SC or Hb Sβ°-thalassemia, each parent is usually heterozygous for a different HBB allele.
  • Heterozygotes (carriers) are generally asymptomatic, but may develop complications under extremes of physical exertion, dehydration, and/or altitude. There is increasing awareness of the risk for impaired renal concentrating abilities and microhematuria as well as an increased risk for venous thromboembolism in carriers of Hb S.
  • It is possible that a parent is homozygous (i.e., Hb SS) or is a compound heterozygote (e.g., Hb Sβ°-thalassemia) rather than a heterozygote (Hb AS).

Sibs of a proband

  • If both parents are carriers of an HBB pathogenic variant, each sib of an affected individual has, at conception, a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
    • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • If one parent is homozygous and the other parent is heterozygous for an HBB pathogenic variant, each sib of an affected individual has a 50% chance of being affected and a 50% chance of being a carrier.
    • Once an at-risk sib is known to be unaffected, he/she can be assumed to be a carrier.
  • If both parents are homozygous, all sibs of an affected individual will be affected.
  • Heterozygotes (carriers) are generally asymptomatic, but may develop complications under extremes of physical exertion, dehydration, and/or altitude. There is increasing awareness of the risk for complications such as impaired renal concentrating abilities and microhematuria, and increased risk for venous thromboembolism in carriers of Hb S as well as splenic infarcts, or sudden death associated with extreme conditions.

Offspring of a proband. The offspring of an individual with SCD are obligate heterozygotes (carriers) for a pathogenic variant in HBB. If the reproductive partner of an affected individual is heterozygous for Hb S or another sickle cell HBB pathogenic variant, each offspring will be at a 50% risk of having sickle cell disease.

Other family members. Each sib of the proband's parents is at a 50% or greater risk of being a carrier of an SCD-causing HBB variant. If one sib of a proband's parent is affected, each other (unaffected) sib of the proband's parent is at a 67% (2/3) risk of being a carrier.

Carrier Detection

If both sickle cell disease-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are carriers.

If only one (or neither) sickle cell disease-related HBB pathogenic variant in a family is known, HPLC can be used to detect common HBB pathogenic variants involving qualitative abnormalities (i.e., abnormal hemoglobins). Note that HPLC may not always detect quantitative abnormalities such as thalassemias, which, when inherited with an Hb S allele, result in a significant hemoglobinopathy; see Beta-Thalassemia for information on how to diagnose a coexisting thalassemia. Typical parental genotypes are described in Table 3.

Table 3. Sickle Cell Disease: Parent and Proband Abnormal Globin β Chain Variants

Abnormal Globin β Chain Variants of the ProbandTypical Parental Globin β Chain Variants 1
One ParentOther Parent
SSASAS
Sβ°-thalA2
↓MCV 3
N or ↑Hb A2
N or ↑Hb F 3
Sβ+-thal
SCAC

Table shows typical results; exceptions occur. Some rare globin β chain variants (e.g., SD, SOArab, SCHarlem, Lepore, SE) are not included.

SCD = sickle cell disease

thal = thalassemia

N = normal

↑= increased

↓= decreased

1. Assumes that uniparental disomy is absent and that both parents are heterozygous. In some cases, parents may be homozygous or compound heterozygous.

2. Hb A is detectable in Sβ+-thalassemia but not Sβ0-thalassemia or Hb SC.

3. Low MCV, often with high Hb A2 and/or F

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

It must be kept in mind that non-sickle β-globin disorders (e.g., β-thalassemia) can interact with the SCD-causing variant to cause clinically significant disease. As a result, family members with no Hb S can still have a child with a significant sickle hemoglobinopathy, which makes counseling difficult and leads to misconceptions in the community, and, on occasion, allegations of infidelity. For example, if one parent has sickle cell trait and the other has β-thalassemia trait, it would be correct to state that, although one parent is not a sickle cell carrier, there is still a 25% chance that each pregnancy would have a significant hemoglobinopathy. Therefore, partners of individuals who are known to carry sickle cell trait should be offered a thalassemia screening panel that includes hemoglobin electrophoresis, CBC and reticulocyte count, and a measure of iron status (e.g., ZPP or serum iron and TIBC) to screen for carrier status for sickle cell trait and other β-globin disorders.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Early testing. Building community awareness of SCD in populations at high risk is an important component in facilitating early testing and receiving genetic counseling.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Though it will not alter the diagnosis, consideration can be given to banking DNA of affected individuals as it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future (allowing better understanding of risk and modifying loci).

Cord blood banking. Given the (1) increasing safety and availability of stem cell transplantation in SCD and (2) limited number of immunologically matched donors available for individuals with SCD, it is appropriate to discuss cord blood banking with the parents of an affected individual following delivery of a sib.

Prenatal Testing

If the HBB pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Because one parent may have a non-Hb S HBB pathogenic variant that can interact with Hb S to cause a sickle hemoglobinopathy (e.g., Hb C or Hb β-thalassemia), both disease-causing HBB alleles of the carrier parents must be identified before prenatal testing can be performed. Because of the large variation in clinical course, currently it is not possible to accurately predict the severity of SCD in an individual.

When the mother is a known carrier and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the HBB pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • About Sickle Cell Disease
  • American Sickle Cell Anemia Association
    10300 Carnegie Avenue
    Cleveland OH 44106
    Phone: 216-229-8600
    Fax: 216-229-4500
    Email: irabragg@ascaa.org
  • California Sickle Cell Resources
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • Sickle Cell Adult Provider Network
  • Sickle Cell Disease Association of America, Inc. (SCDAA)
    231 East Baltimore Street
    Suite 800
    Baltimore MD 21202
    Phone: 800-421-8453 (toll-free); 410-528-1555
    Fax: 410-528-1495
    Email: scdaa@sicklecelldisease.org
  • Sickle Cell Disease Foundation of California
    5777 West Century Boulevard
    Suite 1230
    Los Angeles CA 90045
    Phone: 310-693-0247
    Fax: 310-216-0307
    Email: info@scdfc.org
  • Sickle Cell Disease National Resource Directory
  • Sickle Cell Information Center
  • National Newborn Screening and Global Resource Center
  • National Haemoglobinopathy Registry
    MDSAS NHR Administrator
    5 Union Street
    City View House
    Manchester M12 4JD
    United Kingdom
    Phone: 0161 277 7917
    Email: support@mdsas.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Sickle Cell Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Sickle Cell Disease (View All in OMIM)

141900HEMOGLOBIN--BETA LOCUS; HBB
603903SICKLE CELL ANEMIA

Molecular Genetic Pathogenesis

Hemoglobin S is produced by a substitution in the second nucleotide of the sixth codon of HBB, resulting in the changing of the glutamic acid residue to a valine. In deoxygenated sickle hemoglobin, an interaction between the Glu6Val residue and the complementary regions on adjacent molecules can result in the formation of highly ordered insoluble molecular polymers that aggregate and distort the shape of the red blood cells, making them brittle and poorly deformable, increasing adherence to the endothelium. This can lead to veno-occlusion and potentially decreased tissue perfusion and ischemia. While this is thought to be the proximate defect leading to several aspects of clinical disease, there is increasing awareness that multiple pathophysiologic pathways are involved in SCD [Kato et al 2007].

Polymerized hemoglobin is also injurious to the red cell membrane, resulting in cellular dehydration, oxidative damage, and increased adherence to endothelial cells [Gladwin & Rodgers 2000, Hebbel 2000, Nagel 2001]. There is increasing awareness of a hyper-hemolysis syndrome associated with leg ulcers, priapism, and pulmonary artery hypertension. Other consequences of hemolysis include: chronic anemia, jaundice, predisposition to aplastic crisis, and cholelithiasis.

Other factors contributing to the pathophysiology of sickle cell include: leukocytosis, resulting in increased production of injurious cytokines and altered blood flow; coagulation abnormalities; and abnormal vascular regulation. The net result of these abnormalities is shortened red cell life span or hemolysis and intermittent vascular occlusion and a state of chronic inflammation.

Gene structure. HBB, which spans 1.6 kb, contains three exons. HBB is regulated by an adjacent 5' promoter, which contains TATA, CAAT, and duplicated CACCC boxes, and an upstream regulatory element known as the locus control region (LCR). A number of transcription factors regulate the function of HBB, including the erythroid Kruppel-like factor (EKLF) which binds the proximal CACCC box and whose knockout in the mouse leads to a thalassemia-like clinical picture. Many other factors are critical, but their deletion results in milder phenotypes because of compensation by other factors. HBB is contained within the HBB gene cluster, which also includes the genes encoding the delta-globin chain, A gamma and G gamma chains, and HBBP1 (an HBB pseudogene) and epsilon. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Sickle cell disease may also result from coinheritance of the HBB Glu6Val hemoglobin S pathogenic variant with a second HBB pathogenic variant, some of which are listed in Table 4 (see also Molecular Genetic Testing).

Table 4. HBB Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change 1Protein Amino Acid Change
(Standard Nomenclature 2)
Hb Variant 3Reference Sequences
c.20A>TGlu6Val
(p.Glu7Val)
Hb SNM_000518​.4
NP_000509​.1
c.19G>AGlu6Lys
(p.Glu7Lys)
Hb C
c.79G>AGlu26Lys
(p.Glu27Lys)
Hb E
c.364G>CGlu121Gln
(p.Glu122Gln)
Hb D-Punjab
c.364G>AGlu121Lys
(p.Glu122Lys)
Hb O-Arab

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. DNA nucleotide changes follow current nomenclature guidelines where the number 1 corresponds to the first nucleotide of the initiating methionine.

2. In this column and throughout the text of the GeneReview, the protein amino acid changes (e.g., Glu6Val) follow the long-standing convention in the hemoglobin literature to begin numbering the amino acids at the second amino acid residue (Val) rather than the initiating Met. This convention was adopted many years ago because the initiating methionine is not part of the mature β-globin protein. The standard nomenclature for protein changes are given in parentheses. The Globin Gene Server (globin​.cse.psu.edu) lists variants using both numbering conventions.

3. Also see Molecular Genetic Testing

Normal gene product. HBB encodes the hemoglobin β chain. The normal heterotetrameric protein hemoglobin A (Hb A) comprises two hemoglobin α chains, two hemoglobin β chains, and four heme moieties.

Abnormal gene product. Sickle hemoglobin (Hb S) results from one single nucleotide variant in which the codon determining the amino acid at position 6 of HBB has changed from a GAG codon for glutamic acid to GTG codon for valine. Hb S is a heterotetrameric protein made up of two hemoglobin α chains, two hemoglobin sickle-β chains, and four heme moieties.

References

Published Guidelines/Consensus Statements

  1. National Health Service. NHS Sickle Cell & Thalassaemia Screening Programme. Standards and Guidelines. Available online. Accessed 10-15-14.
  2. National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report. Available online. 2014. Accessed 10-15-14.

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Chapter Notes

Author History

MA Bender, MD, PhD (2006-present)
Gabrielle Douthitt Seibel, MN, MPH, ARNP (2014-present)
William Hobbs, MD, PhD; Puget Sound Blood Center (2009-2014)
Krysta Schlis, MD; Children's Hospital Oakland (2003-2006)
Elliott Vichinsky, MD; Children's Hospital Oakland (2003-2006)

Revision History

  • 23 October 2014 (me) Comprehensive update posted live
  • 17 May 2012 (mb) Revision: clarification of information regarding risk for renal medullary carcinoma in individuals with sickle cell trait
  • 9 February 2012 (me) Comprehensive update posted live
  • 17 September 2009 (cd) Revision: corrections to testing information (Table 2)
  • 6 August 2009 (me) Comprehensive update posted live
  • 7 March 2006 (me) Comprehensive update posted to live Web site
  • 15 September 2003 (me) Review posted to live Web site
  • 21 April 2003 (ev) Original submission
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