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.
• 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 and O-Arab 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) levels decrease and hemoglobin S (Hb S) levels increase. The diagnosis of sickle cell disease is 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: With the initiation of universal testing of newborns in the US, the diagnosis is made primarily at birth with the goal of assuring referral to specialty care prior to the onset of symptoms.

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.

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) 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 identification of compound heterozygous disorders such as Hb S-HPFH (hereditary persistence of fetal hemoglobin) and Hb SC;
  • Does not identify Hb Sβ°-thalassemia (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 (i.e., Hb A2, Hb F).
• 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.
  • Neutrophil and platelet numbers are often increased.

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. Hemolysates containing Hb S precipitate in the test solution, while those without Hb S remain in solution. The solubility test has no place in the 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 neonates with sickle cell disease; and
• It may miss some clinically significant forms of sickle hemoglobinopathies (e.g., Hb SC) [Fabry et al 2003].

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.

International screening is limited: the United Kingdom and Bahrain screen regularly, while other countries such as France do limited 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].

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) 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.

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, or SO) 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.

Carrier testing for at-risk relatives is commonly accomplished by HPLC to screen for abnormal hemoglobins. Other methods such as IEF and molecular genetic testing may also be used and vary by laboratory.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing alleles in the family.

Genetically Related (Allelic) Disorders

Beta-thalassemia is defined by an imbalance of α- and β-globin synthesis. Most commonly this is caused by HBB mutations that result in decreased or absent production of β-globin (hemoglobin A), although this can also occur with excessive α-chain production, as with the presence of triplicated α-globin genes. More than 200 different β-thalassemia mutations have been described.

Alpha-thalassemia is often coinherited with the Hb S mutation (Glu6Val). Alpha-thalassemia mutations 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 homozygous SS disease or SC disease.

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 multiorgan dysfunction. The severity of disease manifestations varies from severe to minimal, even in individuals with the same HBB mutation 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 60 has been described [Wierenga et al 2001, Serjeant et al 2007]. 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].

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]. While several groups have identified variants associated with altered risk for specific complications, their role in clinical management has not been determined. Examples include genetic correlates of HbF 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. 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 accompanying risk of 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

HBB alleles associated with SCD are 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 they can be found in individuals of any ethnic background.

Among African Americans, the prevalence of sickle cell trait (Hb AS) is 8%-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.

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 mutation (Glu6Val) is as high as 25%-35%, with an estimated 15 million Africans affected by sickle cell disease [WHO Regional Committee for Africa 2006, Aliyu et al 2008].

Evaluations Following Initial Diagnosis

Evaluations to establish the extent of end-organ damage associated with sickle cell disease vary with the age and clinical status of the individual:

• Newborns. Confirmation of diagnosis. See Molecular Genetic Testing.
• Infants age 9-12 months (usually when fetal hemoglobin levels have fallen to adult levels). Reticulocyte count, CBC, measurement of Hb F (%), and assessment of iron status
• 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].

Education of parents, caregivers, and affected individuals is essential:

• 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.
• 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, and splenic sequestration.
• A plan to deal with mild-to-moderate episodes of pain 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]:

• Vaso-occlusive pain episodes including dactylitis
  • 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.
  • Optimal analgesia is generally achieved with morphine, or other opiate, given around-the-clock or by patient-controlled analgesia.
  • 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 or splenic sequestration.
  • A thorough evaluation for infection, including blood culture, urine culture, and chest x-ray should be performed based on the clinical scenario.
  • Pain episodes are additionally managed with a multi-model approach that may include warmth, massage, distraction, acupuncture, biofeedback, and self-hypnosis.
• 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 (other cultures should be obtained as clinically indicated), and chest x-ray.
  
  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 [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.
  • Simple transfusion or exchange transfusion 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 of an individual 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. Individuals who experience multiple or severe episodes of splenic sequestration may require splenectomy.
• Pulmonary hypertension. No consensus regarding the optimal management for pulmonary hypertension exists; however, the following approach is reasonable:
  • Optimization of sickle cell disease-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, and oxygen therapy if hypoxemic)
  • Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
  • Note: Sildenafil is not currently recommended in the treatment of PAH in SCD. A recent large trial of sildenafil (a phosphodiesterase inhibitor hypothesized to be therapeutic by increasing nitric oxide levels) in SCD-associated pulmonary hypertension was recently terminated early due to increased pain episodes in the treatment arm [Machado et al 2011].
• 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. CNS 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 stroke risk [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 et al 2005] (see Prevention of Primary Manifestations).
    
    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 a 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 reviewed by Vichinsky [2002] and Wang [2007].

Chronic red blood cell transfusion therapy. The initial goal of chronic red blood cell transfusion therapy 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]:

• 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 leukoreduced (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].

Hydroxyurea, the most prescribed therapy for sickle cell disease, may benefit individuals with SCD via several mechanisms [Platt 2008]:

• Induction of Hb F synthesis resulting in decreased sickling and improved red-cell survival
• Lowering the white blood cell (WBC) count and platelet count
• Metabolism into nitric oxide, a potent vasodilator
• Reducing vascular inflammation

Adults treated with hydroxyurea have significantly fewer acute painful episodes, fewer episodes of acute chest syndrome, decreased need for transfusion, and, most importantly, improved survival [Steinberg et al 2010, Voskaridou et al 2010, Smith et al 2011]. A similar benefit has been reported in children, and the use of hydroxyurea in childhood is now gaining more acceptance [Wang et al 2011]. It is not clear if hydroxyurea prevents the cerebrovascular complications of sickle cell disease; current clinical trials are underway to investigate this [Ware et al 2011].

Individuals treated with hydroxyurea must be monitored closely for significant myelosuppression by routine CBC. As noted above, while this is a potential toxicity, a decreased white blood cell (WBC) count is a major mechanism of action of the drug.

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 have limited its use to a select group of individuals with (1) significant complications, most often a history of cerebrovascular events, and (2) a matched sib stem cell donor [Walters et al 2000]. Among these individuals, more than 90% survive; and approximately 85% survive free from sickle cell disease [Bernaudin et al 2007, Panepinto et al 2007]. With the development of less toxic transplant regimens, stem cell transplant is becoming a more acceptable option for more individuals even absent severe end-organ damage [Hsieh et al 2011, Khoury & Abboud 2011]. 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 is an active area of research [Krishnamurti et al 2003, Ruggeri et al 2011].

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.

Prevention of Secondary Complications

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

Penicillin prophylaxis prevents 80% 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.

Erythromycin prophylaxis is an alternative for individuals allergic to penicillin.

Folic acid supplementation should also be considered because of increased RBC turnover.

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]. These include:

• Hemophilus influenzae type b (Hib) vaccine
• Neisseria meningitidis vaccine
• 13-valent pneumococcal conjugate vaccine (PCV13)
• 23-valent pneumococcal polysaccharide vaccine
• Annual influenza immunization is recommended.

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 is increasingly replacing biopsy [Vichinsky 2001, Wood 2007]. Iron chelation therapy is recommended for those with evidence of tissue iron deposition.

Surveillance

Surveillance should be tailored to a specific individual's clinical history; however, most individuals benefit from routine age-dependent screening to allow for early detection and treatment of end-organ damage [NHLBI 2002, NHS 2010]. The following are general guidelines:

• Routine. Developmental and/or neurocognitive assessments; social work assessments with emphasis on support, resources, and impact of the disease on lifestyle; nutritional and dental evaluations
• Yearly. A CBC and reticulocyte count, assessment of iron status, liver function tests (LFTs), BUN, serum concentration of creatinine (Cr), and urinalysis (UA)
• Yearly starting at age two to three years. For all individuals with Hb SS and Hb Sβ°-thalassemia (as well as some others), 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 convert to higher risk [Adams et al 2004]. Initial studies suggest that this approach is decreasing the incidence of overt stroke in individuals with SCD [Mazumdar et al 2007].
• Yearly starting at age seven years. Chest x-ray, pulmonary function tests (PFTs), and abdominal ultrasound examination
• For older individuals or individuals of any age with cardiac or pulmonary concerns. Typically, echocardiogram to determine the tricuspid regurgitation (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.

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

The analgesic meperidine 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.

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 attentive obstetric care. Pregnancy in women with SCD involves increased risks for thrombosis and infectious complications as well as increased acute painful episodes [Villers et al 2008]. However, the risk for preeclampsia, eclampsia, and pre-term labor is not increased above the general population risk [Smith et al 1996]. Similarly the risk for maternal death in SCD is not increased [Hassell 2005]. The risk for pregnancy complications increases with limited access to prenatal care [Sun et al 2001], reinforcing the importance of obstetric follow up in limiting complication rates. The use of chronic transfusion support has not been shown to be beneficial over intermittent simple transfusion as needed for clinical symptoms [Gilli et al 2007] with the possible exception of a small improvement in gestational age [Koshy et al 1988].

Over 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 do not manifest disease symptoms in the antenatal, perinatal, nor immediate postnatal period until fetal hemoglobin production switches to adult hemoglobin.

Therapies Under Investigation

A number of ongoing clinical studies are evaluating new therapies for sickle cell disease; several studies are ongoing to identify novel therapeutic targets.

While chronic transfusion has been used to treat many complications of SCD, it is unclear if transfusion support prevents the development of silent cerebral infarcts in children who have a history of overt stroke [Hulbert et al 2011]. A multicenter trial comparing observation vs a chronic transfusion regimen is underway.

Many factors in sickle-cell-induced ischemic injury (e.g., blood vessel tone, leukocyte and platelet activity, and endothelial adhesion) are regulated by nitric oxide (NO) [Gladwin & Rodgers 2000, Hebbel 2000]. Nitric oxide bioavailability is decreased in sickle cell disease. While pilot studies treating individuals with NO initially showed beneficial effects, larger studies have not shown similar benefit. A recent study of inhaled NO in acute pain crisis did not show significant benefit [Gladwin et al 2011], and a trial to increase nitric oxide in SCD-associated pulmonary hypertension was terminated early because of increased pain episodes in the treatment arm [Machado et al 2011].

Several studies have examined whether NO production could be increased by administering L-arginine, a precursor of NO. While it does appear that L-arginine may increase NO levels in some situations, the clinical benefit remains unknown [Morris et al 2003, Sullivan et al 2010]. A recent study to boost NO production using supplemental arginine failed to alter respiratory function [Sullivan et al 2010]. A benefit of arginine butyrate was seen in a small study of patients with leg ulcers [McMahon et al 2010], but this has not yet been validated in a larger study. In general, these approaches may provide short-term, but not sustained, benefit.

Other novel agents currently being investigated as potential therapies for sickle cell disease include:

• Drugs that increase HbF percentage including pomolidomide [Meiler et al 2011], HDAC inhibitors [Bradner et al 2010], and short chain fatty acids (i.e., butyrate or valproic acid). Both 5-azacytidine [Hagar & Vichinsky 2000, Atweh & Loukopoulos 2001] and 2’ deoxy 5’ azacytidine (decitabine) [Saunthararajah et al 2008] are being investigated as both are potent inducers of Hb F and reduce anemia in SCD.
• Drugs that block adhesive pathways such as anti-selectins [Chang et al 2010, Gutsaeva et al 2011]
• Anti-coagulants [Qari et al 2007]
• Anti-inflammatory pathway drugs [Knight-Perry et al 2009]
• Statins (because of their vascular protective effects) [Hoppe et al 2011]
• Modulators of the transport systems involved in cellular dehydration, including the Gardos channel inhibitor ICA-17043. While this drug improved RBC survival, there was minimal clinical improvement in pain episodes [Ataga et al 2011].
• Phytomedicines, including two mixtures of plants that have shown some initial promising results [Oniyangi & Cohall 2010]

While not yet in clinical trials, a promising approach to therapy is the development of inhibitors to the protein Bcl11a. Bcl11a was identified as an HbF 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 HbF. These elevated levels of HbF 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.

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. 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 mutation (Glu6Val) with a normal allele.

Previously the primary focus had been on adding a normal β-like gene, potentially modified to have additional anti-sickling properties; increasingly, however, alternate strategies are being pursued. These include (1) using trans-activators to stimulate the minimally expressed delta gene or the fetal or embryonic genes; (2) inducing embryonic α-like chains that, when forming tetramers with sickle chains, are less likely to polymerize; or (3) gene correction (see Gene therapy using iPS cell lines.).

Though the efficiency of gene transfer and obtaining high levels of stable expression are still a hurdle, successful expression of the human β-globin gene by retroviral vectors in a mouse model for sickle cell anemia has demonstrated the potential of these approaches [Levasseur et al 2003, Sadelain 2006]. New strategies for in vivo selection may be useful. Currently there are several clinical trials recruiting or poised to open.

Gene therapy using induced pleuripotent stem (iPS) cell lines. New techniques for generating human embryonic stem (hES) cell lines from peripheral tissue (IPS cells) have opened the door to promising new approaches [Hanna et al 2007, Higgs 2008]. IPS cell lines are generated by the addition of several genes to cells from a skin biopsy taken from an affected individual. These IPS cells, which have tremendous expansion potential, can undergo Hb S mutation (Glu6Val) correction by homologous recombination, and then be assayed for toxic effects prior to being used clinically. Increasingly new methods are being developed to improve the efficiency of gene correction, often making use of nucleases engineered to cleave in the region of the mutation, enhancing the incorporation of a correction template. In theory, these cells could be differentiated into hematopoietic stem cells for transplantation providing a permanent cure, or differentiated into erythroid progenitors that could be transfused intermittently, which would produce new normal red blood cells while avoiding the risk of alloimmunization and iron overload. Although preliminary, these approaches provide a new paradigm likely to lead rapidly to the availability of treatment with Hb S mutation (Glu6Val)-corrected autologous cells.

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

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 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 mutation.
• 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 HbS.
• As the carrier rate for Hb S in certain populations is high, it is possible that a parent is homozygous (i.e., Hb SS) or compound heterozygous (e.g., Hb Sβ°-thalassemia) rather than heterozygous.

Sibs of a proband

• If both parents are carriers of an HBB mutation each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic 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 mutation, each sib of an affected individual has a 50% chance of being affected and a 50% chance of being an asymptomatic 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 impaired renal concentrating abilities and microhematuria as well as an increased risk for venous thromboembolism in carriers of HbS.

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

Other family members of a proband. Each sib of the proband's parents is at a 50% or greater risk of being a carrier of an SCD-causing HBB mutation. 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

Carrier detection for common HBB mutations involving qualitative abnormalities (i.e., abnormal hemoglobins) is most commonly accomplished by HPLC. Note that HPLC may not detect quantitative abnormalities such as thalassemias, which, when inherited with an Hb S allele, result in a significant hemoglobinopathy. Other methods such as IEF and DNA-based assays may also be used. Typical parental genotypes are described in Table 3.

Related Genetic Counseling Issues

It must be kept in mind that non-sickle β-globin disorders (e.g., β-thalassemia) can interact with the SCD-causing mutation 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 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. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Because one parent may have a non-Hb S mutation 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 disease-causing mutations have been identified. In particular, implantation of embryos that lack SCD but are a full HLA match allows the progeny to be a stem cell donor for an affected sibling.

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.

Normal allelic variants. 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.

Pathologic allelic variants. Hemoglobin C results from a substitution in the second nucleotide of the sixth codon of HBB that codes for lysine instead of glutamic acid (Glu6Lys).

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

Abnormal gene product. Sickle hemoglobin (Hb S) results from a single point mutation 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.

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Suggested Reading

1. Gladwin MT, Machado RF. Pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365:1646–7. [PubMed: 22029998]
2. Hagar W, Vichinsky E. Advances in clinical research in sickle cell disease. Br J Haematol. 2008;141:346–56. [PubMed: 18341629]
3. Rahimy MC, Gangbo A, Ahouignan G, Alihonou E. Newborn screening for sickle cell disease in the Republic of Benin. J Clin Pathol. 2009;62:46–8. [PubMed: 19103860]

Author History

MA Bender, MD, PhD (2006-present)
William Hobbs, MD, PhD (2009-present)
Krysta Schlis, MD; Children's Hospital Oakland (2003-2006)
Elliott Vichinsky, MD; Children's Hospital Oakland (2003-2006)

Revision History

• 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