Author(s): Sunil K Jain, MD, James Kwok
Originally published: June 14, 2023 Last updated: June 14, 2023
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Disease/ Disorder

Definition

Sickle Cell Disease (SCD) is a group of inherited red blood cell disorder that affects hemoglobin and results in the characteristic “sickling” of red blood cells that is responsible for hemolytic anemia, pain crises, and multiorgan dysfunction.1 

Etiology

SCD is inherited in an autosomal recessive manner. The most common form of SCD occurs when there is a point mutation in both copies of a patient’s HBB gene on chromosome 11, resulting in a replacement of both beta-globin subunits of hemoglobin with hemoglobin S (HbS).2,3,4 Phenotypic expression will vary depending on the type of mutation (HbS, HbD, HbE, or HbO) and number of copies of mutated genes (sickle cell trait vs sickle cell disease).5  

Epidemiology including risk factors

Sickle cell disease is one of the most common inherited red blood cell disorders in the world, with the homozygous genotype HbSS being the most prevalent. SCD affects millions worldwide with an estimated 300,000 people born with it every year. It occurs most commonly in Sub-Saharan Africa regions where malaria is most prevalent, due to the protective effect of the sickle cell allele against malaria.6,7,8 Importantly, SCD is not exclusive to African populations, and is also quite prevalent in Eastern Mediterranean regions and South-East Asia.6,9 Per the CDC, approximately 100,000 people in the United Sates are living with SCD, including 1 in 365 African Americans and 1 in 16,300 Hispanic Americans that are born with the disease.3,8  

Risk factors that relate to increased inheritance of SCD include family history and people of African descent.

Patho-anatomy/physiology  

The pathophysiology of SCD has been studied extensively. A point mutation in position 6 in the beta-globin gene results in the substitution of glutamic acid with valine. The replacement of a hydrophilic amino acid with a hydrophobic one decreases the solubility of hemoglobin especially in its deoxygenated state.10,11 The decrease in solubility in its deoxygenated state induces polymerization of the hemoglobin, causing RBC to take on the characteristic sickle shape seen in SCD.12 The sickling of RBCs decreases membrane stability, induces membrane damage, and promotes vaso-occlusion in microcirculation which presents as hemolytic anemia and a vaso-occlusive crisis. Over time, constant reperfusion injury will eventually result in multiorgan dysfunction due to microinfarctions.13 This pathophysiology is similar in other forms of sickle cell disease where the mutation is slightly different. It is also important to note that while SCD and beta-thalassemia are genetic conditions that both affect hemoglobin, thalassemia results in the reduction of structurally normal beta globin chains while SCD is a mutation in the beta-globin gene, resulting in structurally abnormal hemoglobin.14

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

As mentioned above, SCD is not a single disorder, but rather a group of inherited red blood cell disorders with varying clinical severity. SCD Type HbSS is the most common form and the most severe, but other common types can include HbSC, and HbS beta thalassemia.1 It is usually detected at birth during newborn screening and symptoms generally will not arise until around 6 months of age because of the protective effects of fetal hemoglobin. Symptoms can include vaso-occlusive crises, acute chest syndrome, splenic sequestration, dactylitis, and priapism.15,16 SCD can also increase the risk of stroke and developmental delays. Life expectancy has steadily increased from 28 in 1979 to 43 in 2014 due to improvements in symptom management and patient education.8,17 Common causes of death in the pediatric population are infection, acute chest syndrome, acute splenic sequestration, and stroke.

Specific secondary or associated conditions and complications

Severity of symptoms and complications vary depending on the type of SCD. Conditions and complications not mentioned above can include avascular necrosis, pulmonary hypertension, leg ulcers, vision loss, and sleep apnea.6

Essentials of Assessment

History                      

Sickle cell is often diagnosed via genetic testing at birth due to mandatory SCD screening for newborns in all 50 states since 2008. However, symptoms will not present themselves until around 4-6 months. Sickle cell should be suspected if the patient or family mentions unexplained painful episodes suggestive of vaso-occlusive crises.6 Age of onset and symptoms will be key in identifying the type of SCD.

Physical Examination

Physical examination for infants and children suspected of SCD should focus on musculoskeletal, abdominal, HEENT, and skin findings.  Severe inflammation of the finger and toe joints on musculoskeletal examination may suggest dactylitis. Abdominal findings may include splenomegaly. Skin and HEENT exam may show jaundice. A complete multisystem physical exam is important to assessing all potential complications.15,16

Functional Assessment

Functional assessments are a key component when evaluating SCD patients. Functional impairment due to severe pain from vaso-occlusive crises or underlying neurological issues will vary among different types of SCD.18

Laboratory Studies

Diagnosis of SCD is vital in order to begin prophylactic treatment as soon as possible. Following the initial newborn screening, an additional blood test is required to confirm the initial findings.19 While there is no gold standard test, a combination of screening tests such as CBCs, peripheral blood smears, and sickling tests are routinely done along with confirmatory tests such as hemoglobin electrophoresis.19 Furthermore, CBCs and reticulocyte count should be performed at every visit to establish a baseline value.

Imaging

Imaging is not used in the diagnosis of SCD but can be used for the management of the disease. Transcranial Doppler or MRI is commonly used to screen patients at high risk of stroke.8 Other forms of imaging for gastrointestinal, respiratory, and musculoskeletal symptoms may be appropriate depending on patient presentation.  

Supplementary Assessment Tools

A child’s cognitive abilities must be assessed at every visit, and a drastic change in performance may suggest a “silent cerebral infarct” that warrants immediate investigation.8 Psychiatric assessment is suggested to identify possible depression.21

Early predications of outcomes

Early predictions of outcomes depend on the type of SCD. Although life expectancy has increased in the last few decades due to new treatment options, it is still shortened by more than 2 decades compared with the general population.8 The primary cause of death among patients with SCD in the United States has also shifted. A few decades ago, the primary cause was acute cardiac complications and infection whereas recent studies have shown that the current leading cause of death is chronic cardiac complications.8,21

Environmental

Environmental factors such as cold temperatures, dehydration, insufficient rest, and stress can trigger pain-crisis and should be avoided.1  

Social role and social support system

Studies have shown that complications from SCD can take a large emotional toll on a child, and approximately 25% of all SCD patients suffer from depression.8,20,22 As a child ages and begins to understand his disease, social workers, psychologists, and child life specialists may be necessary to assist the child in adjusting to school and personal life.23 Patient and family support is crucial as well and there are also numerous community support groups in many states that families may benefit from.

Professional Issues

Accommodations may be necessary for SCD patients depending on the severity of symptoms. Patients with SCD have an increased risk of cognitive impairment thought to be due to silent cerebral infarcts and may require special arrangements at school.8 On average, patients usually have 3-4 vaso-occlusive crises a year, thus further necessitating the need for school and workplace accommodations.24,25

Rehabilitation Management and Treatment

Available or current treatment guidelines

Current treatment involves a mix of symptom management, transfusion, and medications. Treatment begins at two months of age where patients are given prophylactic penicillin until the age of 5 due to splenic impairment.26 Children should receive all childhood immunizations with particular attention being paid to the pneumococcal conjugate vaccine series, Haemophilus influenzae type B series, and the meningococcal vaccine.27

Hypertransfusion is a regimen of chronic blood transfusions designed to reduce sickle hemoglobin levels and reduce the risk of sickle cell disease complications such as stroke.28,29 Over the last few decades, studies have shown that hypertransfusion therapy can minimize complications of sickle cell anemia, especially the prevalence of strokes in children with HbSS in high-income settings. In particular, a study in 2010 indicated that hypertransfusion therapy in children with abnormal transcranial Doppler ultrasound (TCD) velocities (>2m/s) resulted in a 10-fold decrease in the incidence of strokes. As a result, one of the recommendations for management of pediatric SCD is use of TCD screening with hypertransfusion therapy when indicated (Hb levels <9g/dL).30,31 Should preventative measures fail and a stroke occurs, a physiatrist’s involvement may be requested as children can develop significant residual deficits post-stroke.

Hydroxyurea is the primary medication used in the treatment of SCD. It shifts production of adult hemoglobin towards fetal hemoglobin, which is not affected by the sickle mutation, thus reducing the incidence of vaso-occlusive crises.8 Hydroxyurea therapy is offered starting at 9 months of age regardless of presence of symptoms per the recommendation of the National Heart, Lung, and Blood Institute. It can be offered as early as 6 months if the patient exhibits symptoms such as dactylitis or pain episodes.32 Hydroxyurea is considered the standard of care for children with SCD, and recent studies have suggested that hydroxyurea may improve neurocognition in children.33,34 Although hydroxyurea is generally well tolerated by children, some side effects can include headaches or GI upset and additional treatments mentioned below may be considered if hydroxyurea is not well tolerated.

Additional treatments that have been approved in the last 5 years include L-glutamine, crizanlizumab, and voxelotor that all function to reduce the incidence of vaso-occlusive crises. These medications are generally only given if hydroxyurea is not tolerated. L-glutamine is a twice daily oral medication that is thought to reduce the susceptibility of sickle RBC to oxidative damage.8 Crizanlizumab is a monthly IV injection that is a monoclonal antibody directed against P-selectin, preventing the adhesion of WBC and RBC to the vascular endothelium.8 Voxelotor is a once daily tablet that prevents the polymerization of HbS.35

Symptom management is extremely important in SCD. This may include but is not limited to chronic transfusions for anemia, opioid therapy for pain crises, diet modification, stress reduction, and adequate hydration.36

Coordination of care

Care of this complex condition requires an interdisciplinary approach that includes the following37

  • Primary physician
  • Physiatrist
  • Hematologist
  • Pediatrician
  • Geneticist
  • Neurologist
  • Cardiologist
  • Nephrologist
  • Pulmonologist
  • Social worker
  • Psychologist
  • Clinical care coordinator

Patient and family education

Families should be educated about acute and chronic symptoms of SCD in order to bring them to medical attention if necessary. Caregivers must be educated and trained in the following

  • Risk of splenic sequestration and daily palpation of the spleen16
  • Patient requires urgent medical attention if a fever is present, even if the fever has resolved without the use of antipyretics38
  • Ability to recognize pain crisis and treat appropriately38
  • Ability to recognize acute chest syndrome and to seek appropriate care
  • Stroke risk and warning signs of a stroke
  • Priapism and when to seek assistance

If family or caretakers are unable to provide the level of support a SCD patient needs, then a referral to social service is recommended.

Both patient and family should also be given genetic counseling to make informed decisions in the future. Patients should be offered preconception counseling and their planned partner should be screened.3

Families and patients should be encouraged to learn more about SCD by visiting external sources.

Oftentimes, SCD patients experiencing a vaso-occlusive crisis are treated like drug seekers and do not receive the proper care. As adolescents transition to adulthood and begin to seek care on their own, they should be further encouraged to continuously educate themselves on their own condition and look into outreach projects and support groups so they can better advocate for themselves.39

Emerging/unique interventions

Current medications approved for SCD work by reducing the number of vaso-occlusive crises. Rivipansel is a molecule that was designed to bind all members of the selectin family involved in the adhesion of RBCs to vascular endothelium to shorten the duration of acute vaso-occlusive crises. It failed to meet its primary and secondary goals in Phase 3 testing in 2019 but was granted a rare pediatric disease designation in 2020 after post-hoc analysis showed some favorable results.8,40

Numerous gene therapy trials also continue to be explored.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • SCD is a lifelong disease that requires management via a multidisciplinary team.
  • Studies have shown that medication adherence is often difficult, so provider must be ready to offer alternatives.32,40
  • No lab or clinical findings can help a provider confirm pain, therefore patient-provider communication is crucial.
  • Likelihood of depression in SCD patients are correlated with pain severity.8
  • When taking a patient’s history, it is important for a physician to remain open-minded and unbiased to avoid instinctively characterizing a patient experiencing a vaso-occlusive crisis as a drug-seeker.
  • When treating patients in the ED, it is imperative that physicians remain mindful of deeply ingrained stigmatization of drug-seeking behavior and ensure that a SCD patient is provided with the treatment they need. 

Cutting Edge/ Emerging and Unique Concepts and Practice

Numerous gene therapy and gene technologies are currently being investigated in clinical trials. Rivipansel has shown promise as the first medication that can shorten the duration of an acute vaso-occlusive crisis.41 Crizanlizumab, L-glutamine, and voxelotor has shown promise in patients where hydroxyurea is not tolerated but requires further research to establish proper dosages for combination therapy.8 However, even if gene therapy is successful, cost will remain an issue as estimates for a full treatment cycle have ranged from $1.8million- $2.75 million.42,43

Gaps In the Evidence-Based Knowledge

  • Further research is needed to establish optimal combinations of medications if hydroxyurea is not tolerated
  • Continued research on Rivipansel is needed.
  • Only way to cure SCD is via stem cell transplant or gene therapy which requires more research
  • Voxelotor’s efficacy in patients under 4 years of age is unknown and needs further investigation.

References

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Author Disclosure

Sunil K Jain, MD
Nothing to Disclose

James Kwok
Nothing to Disclose