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Special populations Top of Page

Goals
CLINICAL OVERVIEW
Disposition

Admission criteria
Sickle Cell Disease
Elsevier Point of Care (see details)
Recommendations for Updated June 22, 2023. Copyright Elsevier BV. All rights reserved.
specialist referral

Treatment Options

Drug therapy
Synopsis
Nondrug and supportive
care

Urgent Action
Special populations
Urgent evaluation and treatment is necessary for patients presenting with fever, priapism, respiratory symptoms, and
Monitoring neurologic symptoms suggesting stroke, splenic sequestration, or painful vaso-occlusive crisis

Complications and Prognosis

Complications

Prognosis
Key Points
Sickle cell disease is an inherited RBC disorder primarily affecting people of African descent and characterized by hemolytic
Screening and Prevention anemia, vaso-occlusive events, and vasculopathy leading to multiorgan damage and early mortality
Screening
Caused by autosomal recessive variant of β-globin gene resulting in production of a mutant form of hemoglobin known as
sickle hemoglobin
At-risk populations

Screening tests Sickle cell anemia is the most severe form and represents most cases; affects patients who are homozygous for the sickle
hemoglobin variant and those in whom variants responsible for β-thalassemia combine with sickle hemoglobin as a
References compound heterozygous variant

Other forms of sickle cell disease occur when variants responsible for other aberrant types of hemoglobin combine with
sickle hemoglobin as a compound heterozygous variant; these typically manifest as milder forms of sickle cell disease

Patients experience a wide variety of symptoms and complications, including hemolytic anemia, susceptibility to infections,
vaso-occlusive events causing acute and chronic pain, and organ damage that can affect any organ system (eg, eyes, bones,
spleen, liver, brain, heart, lungs, kidneys, joints)

Suspect diagnosis based on known family history, results of prenatal testing or newborn screening, or presence of clinical
manifestations in a person of sub-Saharan African, Mediterranean, Middle Eastern, Indian, Caribbean, or Central or South
American descent

Diagnosis is established by hemoglobin analysis using protein-based or molecular methods, CBC, and peripheral blood
smear demonstrating characteristic sickle cells and evidence of hemolytic anemia

Management consists of preventing invasive pneumococcal disease in childhood, hydroxyurea therapy or blood transfusion
to ameliorate or prevent manifestations of sickle cell disease, control of symptoms (eg, pain), and surveillance for chronic
organ damage

Hemopoietic stem cell transplantation can be curative in patients with sickle cell anemia

Pitfalls
A serious complication may be missed if patients who present with fever, increased or new pain, or pain that is not typical of
previous vaso-occlusive crises are not thoroughly evaluated with comprehensive history, physical examination, and focused
laboratory studies

In children and adolescents with sickle cell anemia, screening with transcranial Doppler ultrasonography (prompting
transfusions if threat of cerebral blood flow impairment is found) is crucial to prevent strokes

Terminology

Clinical Clarification
Sickle cell disease is an inherited RBC disorder primarily affecting people of African descent, characterized by hemolytic
anemia, vaso-occlusive events, and vasculopathy leading to multiorgan damage and early mortality

Caused by autosomal recessive variant of HBB (β-globin gene) resulting in production of a variant form of hemoglobin
known as HbS (hemoglobin S, also called sickle hemoglobin) 1

Patients experience varying symptoms, including vaso-occlusive episodes causing acute pain, chronic pain, and multiple end-
organ complications

Classification
Sickle cell disease encompasses a variety of different genotypes:

Sickle cell anemia 2

Refers to clinically similar disorders hemoglobin SS disease and hemoglobin S β⁰-thalassemia

Hemoglobin SS disease

2 copies of HbS sequence variant are inherited; patients are homozygous (HbSS) and have phenotypic disease 1

Considered the most severe form of sickle cell disease

Typically accounts for 70% of sickle cell disease cases 3

Hemoglobin S β⁰-thalassemia

Occurs when sequence variants responsible for β-thalassemia combine with that for HbS as a compound
heterozygous variant

One of the more severe forms and clinically very similar to hemoglobin SS disease 2

Other forms of sickle cell disease

Occur when sequence variants responsible for other aberrant types of hemoglobin (eg, C or E) or for β-thalassemia
variant combine with HbS as a compound heterozygous sequence variant 1

A variety of genotypes have been described, including: 3

Hemoglobin S β⁺-thalassemia

Hemoglobin SC disease

Hemoglobin SE disease

Considered to be milder forms of sickle cell disease

Sickle cell trait 1

People who inherit only 1 copy of the HbS variant are simple heterozygous carriers of the variant and have no clinical
sickle cell disease; however, there is evidence suggesting they may have an increased risk for chronic kidney disease or
thromboembolism 4

Diagnosis

Clinical Presentation

History
Most patients who are not diagnosed during newborn screening usually develop clinical manifestations in infancy or
childhood as fetal hemoglobin levels decline

Suspect sickle cell disease in infants or children of sub-Saharan African, Mediterranean, Middle Eastern, Indian,
Caribbean, or Central or South American descent, or those with a family history of sickle cell disease, who present with any
of the following: 1 5

Spontaneous painful swelling of hands and feet (dactylitis)

Recurrent episodes of severe pain with no other identified cause

Children typically experience pain in the extremities, whereas older patients more commonly experience pain in the
head, chest, abdomen, and back

Pallor

Jaundice

Abdominal distention (due to enlarged spleen)

Recurrent infections

Dyspnea or fatigue (due to anemia)

Fever

Poor nutritional status and growth

Delayed puberty

Sickle cell anemia is a multiorgan disease resulting in a range of symptoms and complications that vary and worsen with age;
pain is the most common presentation

May present with symptoms of acute or chronic complications including: 2

Acute pain crises; typically heralded by sudden onset of severe pain, often localized to extremities, chest, or back 6

Acute chest syndrome (manifesting with fever, cough, chest pain, dyspnea)

Splenic sequestration (abdominal pain and pallor)

Pneumococcal sepsis or meningitis (Related: Sepsis)

Stroke (especially in children) (Related: Ischemic Stroke)

Acute renal failure (Related: Acute Kidney Injury)

Priapism

Cholecystitis

Chronic pain

Cholelithiasis (Related: Cholelithiasis and Choledocholithiasis)

Chronic renal dysfunction (Related: Chronic Kidney Disease)

Retinopathy

Thromboembolic complications

Opioid dependence or tolerance (Related: Opioid Use Disorder)

Neurocognitive impairments

Osteonecrosis

Physical examination
Physical findings may include:

Pallor

Jaundice

Leg ulcers

Swelling of hands and feet

Tachycardia

Fever

Ejection murmur (midsystolic)

Hypotension

Splenomegaly

Hepatomegaly

Right upper quadrant or epigastric tenderness on palpation

Bone tenderness

May have other physical findings associated with specific complications

Causes and Risk Factors

Causes
Sickle cell disease is caused by a mutant form of hemoglobin known as HbS that arises from replacement of glutamic acid
with valine in position 6 on β-globin subunit of hemoglobin 1

Under low oxygen conditions (eg, stress, hypoxia, acidosis), the presence of HbS results in deformed and fragile RBCs with
characteristic sickle (half-moon) shape and reduced lifespan (from 120 to 10-20 days) 1

Sickle RBCs cause episodes of microvascular occlusion, leading to tissue ischemia and infarction, reperfusion damage, and
chronic hemolytic anemia 1 5

Sickle RBCs also interact abnormally with leukocytes, platelets, vascular endothelium, and clotting factors, causing chronic
inflammation and blood vessel damage 3 6

Risk factors and/or associations

Age
Clinical manifestations develop from about age 6 months; may be diagnosed beforehand via universal neonatal screening 1

Genetics
Autosomal recessive variant of HBB (β-globin gene supplying some of the subunits to the hemoglobin tetramer) results in
production of a variant form of hemoglobin known as HbS 2

Most prevalent sickle cell disease genotypes include homozygous hemoglobin SS disease and compound heterozygous
conditions hemoglobin S β⁰-thalassemia, hemoglobin S β⁺-thalassemia, and hemoglobin SC disease

Ethnicity/race
People of sub-Saharan African, Mediterranean (eg, Turkey, Greece, Italy), Middle Eastern (eg, Saudi Arabia), and Indian
ancestry and people from the Caribbean and parts of Central and South America are most commonly affected by HbS variant;
however, it can be found in people of any ethnic background 5

Most common in patients of African ancestry or those who self-identify as Black 2

Prevalence of sickle cell trait (hemoglobin A/S) is about 10% in Black populations born in the United States 5

Prevalence of homozygous sickle cell disease (denoted as HbSS) is approximately 1 in 300 to 500 in Black populations
born in the United States 5

Prevalence is significantly higher in some regions of Africa 5

Middle Eastern, Indian, Hispanic, and Southern European populations are generally affected to a lesser extent 2

Other risk factors/associations

HbS variant is thought to confer a survival advantage in malaria-endemic regions 3

Variation in clinical presentation and course of sickle cell disease may be influenced by fetal hemoglobin concentration;
higher levels persisting beyond infancy ameliorate many aspects of sickle cell disease, as does α-thalassemia coinheritance 3

Environmental factors may also contribute to phenotypic heterogeneity 3

Diagnostic Procedures

Primary diagnostic tools

Suspect diagnosis based on known family history, results of prenatal testing or newborn
screening, or presence of clinical manifestations in a person of sub-Saharan African,
Middle Eastern, Mediterranean, Indian, Caribbean, or Central or South American
descent 5

Diagnosis is established by hemoglobin analysis using protein-based methods (eg, Peripheral blood smear of a patient
with sickle cell anemia. - This blood
protein electrophoresis, high-performance liquid chromatography, isoelectric focusing)
film shows irreversibly sickled cells
or molecular methods (DNA testing) 5 (S), a nucleated red blood cell (NR),
and a Howell-Jolly Body (HJB); these
CBC and peripheral blood smear show characteristic sickle cells and evidence of last 2 features are mainly associated
hemolytic anemia 7 with hyposplenism (stained with
May-Grünwald-Giemsa).
Other routine tests after initial diagnosis include assessment of iron status, renal and
liver function tests, and extended red cell phenotyping 5

Additional laboratory tests, imaging, and other evaluations may be indicated to assess
for specific complications depending on clinical context

Laboratory

Differential Diagnosis

Most common
Most patients in the United States are identified via newborn screening; the following diagnoses may be considered in
children presenting with clinical features of sickle cell disease who did not have access to newborn screening:

Iron deficiency anemia (Related: Iron Deficiency Anemia)

Like sickle cell disease, may present with pallor, dyspnea, or fatigue

May have signs of long-standing iron deficiency (eg, glossitis, angular stomatitis, koilonychia, pica)

Differentiated based on the absence of HbS on hemoglobin assay and other laboratory findings (eg, decreased serum
iron and ferritin; increased transferrin and iron-binding capacity)

Thalassemia

Like sickle cell disease, may present with pallor, dyspnea, fatigue, splenomegaly, and evidence of hemolytic anemia

Differentiated based on the absence of HbS and findings consistent with the type of thalassemia on hemoglobin assay

β-thalassemia: absent or reduced adult hemoglobin, increased fetal hemoglobin, and variable increase in amount of
hemoglobin A₂

α-thalassemia: hemoglobin electrophoresis findings within the reference range except for the presence of
hemoglobin H in hemoglobin H disease

Legg-Calvé-Perthes disease (Related: Legg-Calvé-Perthes Disease)

Idiopathic avascular osteonecrosis of capital femoral epiphysis of femoral head

Like sickle cell disease, may present in childhood with pain in lower extremity

Differentiated based on the absence of HbS on hemoglobin assay and other clinical, laboratory, and radiologic findings

Osteomyelitis or septic arthritis (Related: Osteomyelitis in Adults)

Like sickle cell disease, may be associated with pain and swelling in affected extremity or joint, and fever

Presence of inflammation and edema in bone tissue on MRI confirms diagnosis

Differentiated based on the absence of HbS on hemoglobin assay and other clinical, laboratory, and radiologic findings

Treatment

Goals
Control symptoms

Prevent and treat complications

Disposition

Admission criteria
Patients with acute complications such as sepsis, acute chest syndrome, persistent pain, stroke, or chronic conditions requiring
inpatient management

Criteria for ICU admission

Children with suspected acute chest syndrome, risk of rapid deterioration, and respiratory failure

Recommendations for specialist referral

Refer to a hematologist or sickle cell expert for diagnostic confirmation and sickle cell disease management

Refer to relevant subspecialty providers (ie, neurologist, ophthalmologist, pulmonologist, cardiologist, nephrologist, pain
management specialist, orthopedist) for multidisciplinary management of chronic complications

Refer to a clinical geneticist and/or genetic counselor for reproductive guidance

Treatment Options
Treatment of sickle cell anemia typically consists of the following:

Invasive pneumococcal disease prevention

Without prophylaxis, young children with sickle cell anemia are at very high risk for septicemia and meningitis; risk is
much lower in infants with hemoglobin SC disease or hemoglobin S β⁺-thalassemia 2

Older children and adults with all sickle cell disease genotypes have an increased risk of invasive bacterial infections

Administer twice-daily prophylactic oral penicillin to all children with sickle cell anemia, beginning in early infancy and
continuing through at least age 5 years 2 8

Discontinue at age 5 years unless the child has had splenectomy or invasive pneumococcal disease; ensure
pneumococcal vaccination series is completed before discontinuation

Erythromycin may be used in patients allergic to penicillin 5

Consider withholding penicillin prophylaxis in children with hemoglobin S β⁺-thalassemia or hemoglobin SC disease,
except in those who have had splenectomy

Confirm all patients have been vaccinated against Streptococcus pneumoniae

Administer 13-valent conjugate pneumococcal vaccine series to all infants with sickle cell disease soon after birth,
followed by 23-valent pneumococcal polysaccharide vaccine at age 2 years and then at age 5 years 2

Children aged 6 to 18 years who have functional or anatomic asplenia should receive at least 1 dose of 13-valent
pneumococcal conjugate vaccine 2

Advise patients and caregivers regarding risk for severe bacterial infections and need to obtain immediate medical
attention for fever (temperature higher than 38.5 °C) 2

Disease-modifying therapy

Pharmacologic therapy

Hydroxyurea therapy

Decreases sickle cell disease–related complications (eg, acute chest syndrome, venoocclusive events) and reduces
mortality, need for RBC transfusions, and hospitalizations 2

Acts primarily by increasing level of fetal hemoglobin, resulting in decreased sickling and improved red cell survival 5

Suitable for all patients with sickle cell disease who are aged 9 months and older; however, less often required in those
with compound heterozygous conditions (eg, hemoglobin SC disease, hemoglobin S β⁺-thalassemia) than those with
hemoglobin SS disease 6

Offer hydroxyurea therapy to infants aged 9 months or older, children, and adolescents with sickle cell anemia,
regardless of clinical severity 2

Hydroxyurea therapy is indicated in adults with sickle cell anemia who have: 2

3 or more moderate to severe pain crises per year

Sickle cell disease–related pain that affects quality of life

Severe or recurrent acute chest syndrome

Severe symptomatic chronic anemia that affects quality of life

Obtain the following laboratory tests before starting hydroxyurea: 2

CBC with differential and reticulocyte count

Quantitative measurement of fetal hemoglobin if available (eg, hemoglobin electrophoresis, high-performance

liquid chromatography)

Comprehensive metabolic profile, including renal and liver function tests

Pregnancy test

Monitor therapy using an established prescribing and monitoring protocol 2

Measure CBC with differential and reticulocyte count at least every 4 weeks when adjusting dosage, then every 2 to 3
months once on stable dose

Aim for a target absolute neutrophil count of 2000/μL or higher (can be as low as 1250/μL in younger patients with
lower baseline counts)

Maintain platelet count of 80,000/μL or higher

Contraindicated during pregnancy and breastfeeding 5

L-Glutamine 5

FDA approved for prevention of acute complications in patients with sickle cell anemia who are aged 5 years and
older, regardless of whether they are receiving hydroxyurea

May decrease frequency of sickle cell pain–related episodes

Voxelotor 9

Small molecule that binds to the alpha chain of hemoglobin and prevents RBC sickling 10

The FDA granted accelerated approval of voxelotor for adults and pediatric patients aged 4 years and older with sickle
cell disease

Accelerated approval based on increase in hemoglobin; indicated for patients with significant morbidity due to
hemolytic anemia. Also useful in patients with leg ulcers secondary to sickle cell disease 12 11 12

Most common adverse reactions (more than 10%) are headache, diarrhea, abdominal pain, nausea, rash, fatigue, and
pyrexia

May interfere with measurement of hemoglobin subtypes (HbA, HbS, HbF) by high-performance liquid
chromatography

Crizanlizumab 10

Monoclonal antibody against the adhesion molecule P-selectin, which mediates abnormal adhesion of sickle RBCs to
the endothelium and is implicated in painful vaso-occlusive crises

Reduces number of vaso-occlusive crises 13

FDA approved for patients age 16 years and older with sickle cell disease

Blood transfusion therapy

First disease-modifying therapy used for sickle cell disease 2

Reduces percentage of circulating RBCs with HbS 3

RBC transfusion can ameliorate or prevent sickle cell disease manifestations in some circumstances; however,
transfusion is not universally beneficial as many transfusion complications, such as the risk of alloimmunization, are
increased in sickle cell disease 2

Patients receiving transfusion therapy should undergo prophylactic extended red cell antigen matching for Rh (C, E or
C/c, E/e) and K antigens 14

Symptom control, including acute and chronic pain

Screening to identify chronic organ damage and prevent further deterioration (eg, vascular disease, retinopathy, renal disease)

Curative therapies

Hemopoietic stem cell transplantation

Children with sickle cell disease receiving stem cell transplantation using a matched sibling donor demonstrated a 92%
chance of cure with an overall survival of 95% 5

Also curative in adults with sickle cell disease, but more difficult owing to increased risk of treatment-related
complications 5

Drawbacks include potential long-term risks, such as chronic graft-versus-host disease, infertility, lack of suitable matched-
sibling donors, and high cost

Guidelines suggest HLA-matched related hemopoietic stem cell transplantation over standard care in the following: 15

Patients who have experienced an overt stroke or have transcranial Doppler ultrasound abnormalities

Patients with frequent pain

Transplantation may also be considered in the following: 15

Patients who experience recurrent acute chest syndrome despite optimization of standard treatment

Patients who have not adequately responded to standard treatment, including hydroxyurea, targeted therapies, or
chronic transfusion therapy

Allogeneic transplantation should ideally be performed at an earlier rather than older age in patients who have indications
for it 1

Gene therapy 10

May be accomplished by introduction of a therapeutic antisickling coding gene (gene addition), induction of fetal
hemoglobin by silencing repressors of its production, or correcting the sickle variant via clustered regularly interspaced
short palindromic repeats (gene correction) 16 17

In the largest series of patients undergoing gene therapy for sickle cell disease published to date, 35 patients underwent
autologous transplantation of hematopoietic stem and progenitor cells containing a modified β-globin gene that produces
an antisickling hemoglobin 18

Reduction in hemolysis, increase in medium hemoglobin, and complete resolution of vaso-occlusive events was
observed at median follow-up of over 17 months

Currently experimental; various gene therapy and gene editing approaches are being investigated

Drug therapy
Penicillin antibiotic

Penicillin V Potassium Oral solution; Infants and Children 1 month to 2 years: 125 mg PO twice daily.

Penicillin V Potassium Oral solution; Children 3 to 5 years: 250 mg PO twice daily.

Macrolide antibiotic

For patients allergic to penicillin 2

Erythromycin

Erythromycin Ethylsuccinate Oral suspension; Infants and Children 1 month to 2 years: 10 mg/kg/dose (Max: 125
mg/dose) PO twice daily. Continue prophylaxis until at least age 5 years.

Erythromycin Ethylsuccinate Oral suspension; Children 3 to 5 years: 10 mg/kg/dose (Max: 250 mg/dose) PO twice daily
until at least age 5 years.

Ribonucleotide reductase inhibitor

Hydroxyurea

Hydroxyurea Oral tablet; Children and Adolescents 2 to 17 years: 20 mg/kg/dose PO once daily initially. Base dose on
actual or ideal body weight (whichever is less) and round the calculated dose to the nearest 50- or 100-mg strength.
Increase dose by 5 mg/kg/day every 8 weeks or if a painful crisis occurs as tolerated. Max: 35 mg/kg/day. Reduce dose or
interrupt or discontinue therapy in patients who develop myelosuppression.

Hydroxyurea Oral capsule; Adults: 15 mg/kg/dose PO once daily initially. Base dose on actual or ideal body weight
(whichever is less). Increase dose by 5 mg/kg/day every 12 weeks as tolerated. Max: 35 mg/kg/day. Reduce dose or
interrupt or discontinue therapy in patients who develop myelosuppression.

L-Glutamine

L-Glutamine Powder for Oral Solution; Children and Adolescents 5 to 17 years weighing less than 30 kg: 5 g PO twice daily.

L-Glutamine Powder for Oral Solution; Children and Adolescents 5 to 17 years weighing 30 to 65 kg: 10 g PO twice daily.

L-Glutamine Powder for Oral Solution; Children and Adolescents 5 to 17 years weighing more than 65 kg: 15 g PO twice
daily.

L-Glutamine Powder for Oral Solution; Adults weighing 30 to 65 kg: 10 g PO twice daily.

L-Glutamine Powder for Oral Solution; Adults weighing more than 65 kg: 15 g PO twice daily.

Voxelotor

May be given with or without hydroxyurea 9

Voxelotor Oral suspension; Children 4 to 11 years weighing 10 to 19 kg: 600 mg PO once daily. Coadministration of certain
drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Voxelotor Oral suspension; Children 4 to 11 years weighing 20 to 39 kg: 900 mg PO once daily. Coadministration of certain
drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Voxelotor Oral suspension; Children 4 to 11 years weighing 40 kg or more: 1,500 mg PO once daily. Coadministration of
certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Voxelotor Oral suspension; Children and Adolescents 12 to 17 years: 1,500 mg PO once daily. Coadministration of certain
drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Voxelotor Oral tablet; Adults: 1,500 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage
adjustments may be necessary; review drug interactions.
 Crizanlizumab

Crizanlizumab Solution for injection; Adolescents 16 to 17 years: 5 mg/kg/dose IV at Week 0, Week 2, and every 4 weeks
thereafter.

Crizanlizumab Solution for injection; Adults: 5 mg/kg/dose IV at Week 0, Week 2, and every 4 weeks thereafter.

Nondrug and supportive care

Vaccination

Ensure all infants with sickle cell disease receive complete series of 13-valent conjugate pneumococcal vaccine series
beginning shortly after birth and the 23-valent pneumococcal polysaccharide vaccine at age 2 years, with a second dose at age
5 years 2

Vaccinate infants at ages 2, 4, and 6 months, and again at age 12 to 15 months with meningococcal vaccine (HibMenCY) 2

Vaccinate patients aged 9 months to 55 years with MenACWY 2

Administer all other routine immunizations per Advisory Committee on Immunization Practices 19

Administer influenza vaccination to children at age 6 months and yearly thereafter 19

Blood transfusion

Common indications for transfusion include acute stroke, multisystem organ failure, acute chest syndrome, chronic
refractory pain, pulmonary hypertension, and chronic renal failure 2 5

Transfusions can be given episodically (eg, for an acute complication of sickle cell disease) or prophylactically (to reduce HbS
and correct anemia before anesthesia or surgery) 2

Chronic transfusion therapy is given to maintain low levels of HbS as a means of preventing sickle cell disease complications,
most commonly for primary and secondary prevention of stroke in children 20 21

Typical goal is to maintain percentage of HbS below 30% and to suppress reticulocytosis; however, goal may vary according
to specific indication 5

May be administered as simple transfusion or as exchange transfusion; automated red cell exchange is preferred over simple
transfusion or manual red cell exchange for patients receiving chronic transfusions 14 22

Common adverse effects include iron overload, hyperviscosity, alloimmunization, autoimmunization, and hemolysis (delayed
hemolytic transfusion reaction) 2

Patients receiving prophylactic or chronic transfusions are at risk for iron overload; monitor by recording amount of blood
transfused and serum ferritin level, and MRI screening for liver iron content every 1 to 2 years 5 14

Vitamin supplementation with folic acid to meet increased requirements 5

Education

Educate patients and caregivers about sickle cell disease

Stress importance of immunizations, penicillin prophylaxis, and regular follow-up 5

Instruct patients and caregivers to seek medical help in case of fever above 38.5 °C 2

Teach parents and caregivers to identify signs and symptoms that require acute medical intervention 5

Advise patients and caregivers regarding hydration, home management of pain, and avoidance of extreme temperatures 5

Provide contraceptive advice

Reproductive counseling 2

Provide education and health promotion counseling to all patients of reproductive age

Provide contraception counseling or preconception counseling as desired

Refer partner of patient with sickle cell disease for hemoglobinopathy screening if genetic status is unknown

Refer at-risk couples who desire to start a family for genetic counseling to discuss carrier detection methods and subsequent
prenatal DNA testing, if appropriate

Counsel all women with sickle cell disease and their partners about adverse pregnancy outcomes and health risks during
pregnancy

Evaluate women with sickle cell disease for RBC alloantibodies if they have received transfusion and are expecting pregnancy

Counsel couples regarding hemolytic disease of the newborn if the woman has RBC alloantibodies and her partner has
corresponding antigens

Procedures

Allogenic hematopoietic stem cell transplant

General explanation

Transfusion of healthy stem cells from an HLA-matched donor into the patient to restore hematopoietic cell lines that have
been eradicated by chemotherapy or radiation 23

Immunosuppressive medication is administered after procedure to reduce rejection risk

Indication

Sickle cell disease; represents only recognized cure 1 3

Consider for patients with stroke, abnormal transcranial doppler ultrasound, or recurrent acute complications despite
hydroxyurea therapy

Contraindications

Relative

Previous hematopoietic stem cell transplant

24 25
Complications

Acute and chronic graft-versus-host disease 1

Intolerance to immunosuppressive medications

Sinusoidal obstructive syndrome (venoocclusive disease of liver)

Infertility 1

Hypothyroidism 1

Iron overload

Late malignancy

Special populations
Pregnant patients 5

Patients with sickle cell disease who become pregnant have an increased risk for preeclampsia, preterm labor, thrombosis,
infectious complications, and acute painful episodes

Neonatal complications include low birth weight and fetal growth retardation

Close follow-up and monitoring by a hematologist and an obstetrician is required

Folic acid supplementation is essential during pregnancy

Hydroxyurea therapy is contraindicated

Monitoring
Patients with sickle cell disease require regular multidisciplinary follow-up 5

Clinically evaluate every 2 to 4 months from birth to 1 year and every 6 to 12 months thereafter 26

Obtain annual CBC and reticulocyte count, liver and renal function tests, lactate dehydrogenase and vitamin D levels,
urinalysis, and iron status 5

Maintain low threshold to evaluate for end-organ damage 5

Monitor for the following chronic complications at regular intervals: 2

Vascular disease and stroke risk

Annually screen children and adolescents with sickle cell anemia with transcranial Doppler ultrasonography, beginning
at age 2 years and continuing until at least age 16 years 27

Refer children with conditional (170-199 cm/second) or elevated (200 cm/second or higher) transcranial Doppler
ultrasonographic findings to a specialist with expertise in long-term transfusion therapy aimed at preventing stroke

Importance of this screening tool to prompt transfusions and thus prevent strokes in young people has been missed
in some patients, owing to a lack of care coordination and lack of counseling of parents, reflecting inequity in health
systems; primary care in children and adolescents with sickle cell anemia requires due appreciation of how important
this screening is to prevent future disabilities

Transcranial Doppler ultrasonographic screening is not recommended in children with sickle cell disease or
asymptomatic adults 27

MRI or magnetic resonance angiography is generally obtained following an abnormal transcranial Doppler result 28

MRI screening to detect silent cerebral infarcts is recommended to be performed at least once in early-school-age
children and is also suggested for adults 27

Ischemic retinopathy

Refer patients with sickle cell disease to an ophthalmologist for an annual dilated retinal examination beginning at age
10 years

Rescreen patients with normal dilated retinal examination findings at 1- to 2-year intervals

Renal disease

Begin annual screening for microalbuminuria and proteinuria with spot urine testing by age 10 years in patients with
sickle cell disease

Refer patients with proteinuria (greater than 300 mg/24 hours) to a nephrologist for further evaluation

Hypertension

Screen for hypertension at least annually

Blood pressure goal of 130/80 mm Hg or less is recommended 29

Iron overload 1

Patients with a lifetime transfusion history of 10 to 20 units of blood are at high risk for iron overload

Monitor by recording amount of blood transfused and monitoring serum ferritin level; further assessment with MRI
every 1 to 2 years is recommended to quantitate liver iron content

Refer patients with evidence of iron overload for chelation therapy

Pulmonary hypertension

Diagnostic echocardiography with or without NT-pro-BNP measurement and 6-minute walk distance assessment should
be considered for patients with symptoms suggestive of pulmonary hypertension 29

Guidelines recommend against routine screening echocardiography in asymptomatic patients

Repeat echocardiography every 1 to 3 years depending on tricuspid regurgitant jet velocity values 30

Patients with tricuspid regurgitant jet velocity of 3 m/second or higher should have right-sided heart catheterization to
confirm pulmonary hypertension

Also suggested for patients with peak tricuspid regurgitant jet velocity of 2.5 m/second or greater who also have a
reduced 6-minute walk distance and/or elevated NT-pro-BNP 29

Complications and Prognosis

Complications
Common complications

Vaso-occlusive pain episodes 5

Most common cause of recurrent morbidity and sickle cell disease–related hospitalization in patients with sickle cell
disease

Occlusion of microvascular circulation and ischemic tissue damage cause severe pain

Management consists of correcting precipitating factors such as cold or dehydration, oral or IV hydration, and oral or IV
analgesics including NSAIDs and opiates 31

Adjunctive treatments include application of warmth, massage, and physical therapy

Infection 5

Sickle cell disease and splenic dysfunction are associated with an increased risk of infection with encapsulated bacteria

Young children, particularly those with sickle cell anemia, are at very high risk for septicemia and meningitis caused
by Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenza

Older children and adults also have an increased risk of these invasive bacterial infections and others (eg,
osteomyelitis)

Patients presenting with fever (temperature higher than 38.5 °C) require rapid assessment, urgent CBC and reticulocyte
count, and urine and blood cultures (with other cultures as clinically indicated) 2

Immediate chest radiography is indicated when respiratory symptoms are present; undertake evaluation for
osteomyelitis if bone pain is present

Administer IV broad-spectrum empiric antibiotics, pending culture results

Add macrolide if pneumonia or acute chest syndrome is suspected; administer vancomycin in children with possible
bacterial meningitis

Guidelines have been compiled for management of COVID-19 in patients with sickle cell disease 32

Acute chest syndrome 5

Major cause of mortality in patients with sickle cell disease

Multiple causes are implicated, including pneumonia, pulmonary infarction, pulmonary embolism, and fat emboli from
bone marrow infarcts

Often develops after vaso-occlusive pain episode or another acute manifestation of sickle cell disease

Consider acute chest syndrome in patients with sickle cell disease who present with fever, chest pain, or respiratory signs
or symptoms

Diagnosed based on the presence of a new pulmonary infiltrate on chest radiograph

Treatment includes oxygen, analgesics, antibiotics (a cephalosporin and a macrolide 2 ), and incentive spirometry; may
require intubation and mechanical ventilatory support

Simple blood transfusion may have a role in patients with hemoglobin level greater than 1 g/dL below baseline; urgent
exchange transfusion is indicated in critically ill patients with rapidly progressive disease 2

Splenic sequestration 5

Occurs in 10% to 30% of children with sickle cell disease, with children aged 6 months to 3 years most commonly
affected 5

Characterized by acute splenomegaly and decline in hemoglobin level more than 2 g/dL below baseline; mild to
moderate thrombocytopenia may also be present 5

May follow febrile illness

Clinical presentation includes abdominal pain, nausea, vomiting, lethargy, or irritability; severe splenic sequestration
may progress rapidly to shock and death

Provide immediate IV fluid resuscitation in patients with hypovolemia 2

Blood transfusion may be required

Recurrent or refractory episodes may require splenectomy

Ischemic stroke 5 (Related: Ischemic Stroke)

Most common in children and older adults; up to 11% of children with sickle cell disease suffer clinically apparent
strokes, most commonly between ages 2 and 9 years 5

Common presenting signs and symptoms include seizures, hemiparesis, aphasia or dysphasia, cranial nerve palsies, and
altered mental status

Evaluate patients with neurologic symptoms (in consultation with a neurologist) using head CT, MRI, and magnetic
resonance angiography

Monitor neurologic status and treat increased intracranial pressure and seizures; perform exchange transfusion 27 2

Repeated strokes are common; however, risk can be significantly reduced by chronic blood transfusion therapy. 20

Hydroxyurea may be an alternative for affected patients who are unable to receive transfusion therapy

Elevated flow velocity on transcranial Doppler identifies children at high risk and allows intervention by means of
chronic transfusion therapy aimed at stroke prevention 33

Priapism 5

Common complication in males with sickle cell disease

Characterized by painful, unwanted erections that can occur spontaneously or nocturnally, or may be precipitated by
fever and dehydration

Prolonged priapism may result in permanent erectile tissue damage and impotence

Severe episodes lasting more than 4 hours are a urologic emergency 10

Management consists of hydration and analgesia, and may include aspiration and irrigation by a urologist

Other complications include: 5

Pulmonary hypertension (Related: Pulmonary Hypertension)

Aplastic crisis

Avascular necrosis (typically involving femoral head or humerus)

Nephropathy

Restrictive lung disease

Cholelithiasis (Related: Cholelithiasis and Choledocholithiasis)

Retinopathy

Cardiomyopathy

Delayed growth and sexual maturation

Iron overload

Chronic pain (Related: Opioid Use Disorder)

Opioid dependence

Silent cerebral infarct or neurocognitive dysfunction

Venous thromboembolism 10

Prognosis
Median lifespan in the United States for those with sickle cell disease has been estimated at 42 years for men and 48 years for
women 5

Trend toward longer survival in the past 20 years; childhood deaths have significantly decreased

Primary causes of death are infection, acute chest syndrome, stroke, and pulmonary artery hypertension 5

Children have higher mortality from infection and splenic sequestration crises

Most adult deaths are secondary to chronic end-organ damage, thrombotic disease, and treatment-related complications

α-thalassemia trait coinheritance and higher fetal hemoglobin levels are associated with improved prognosis 3

Screening and Prevention

Screening

At-risk populations
Newborns, especially of sub-Saharan African, Mediterranean, Middle Eastern, and Indian ancestry and those from the
Caribbean and parts of Central and South America

Screening tests
Universal newborn screening

All states require screening for sickle cell anemia and other hemoglobinopathies in all newborns at birth 34

Newborn screening programs test blood obtained by heel prick using isoelectric focusing or high-performance liquid
chromatography 5

Specimens with HbS present are retested using a second complementary technique (eg, high-performance liquid
chromatography, citrate agar electrophoresis, isoelectric focusing, DNA-based assay)

Prenatal diagnosis

Prenatal diagnosis by molecular genetic testing is possible if pathogenic hemoglobin variants have been identified in
parents

Non-HbS HBB sequence variants in carrier parents must also be identified before prenatal testing because these can
interact with HbS variant to cause forms of sickle cell disease (eg, sickle–hemoglobin C disease, hemoglobin S β-
thalassemia) 5

Samples for testing are usually obtained by chorionic villus sampling at 8 to 10 weeks of gestation or amniocentesis at 14 to
18 weeks of gestation

Preimplantation genetic diagnosis is also possible

References

1 Kanter J et al: Management of sickle cell disease from childhood through adulthood. Blood Rev. 27(6):279-87, 2013
View In Article | Cross Reference

2 National Heart, Lung, and Blood Institute: Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. NHLBI website.
Published 2014. Accessed April 22, 2022. https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease
View In Article | Cross Reference

3 Rees DC et al: Sickle-cell disease. Lancet. 376(9757):2018-31, 2010

View In Article | Cross Reference

4 Bucknor MD et al: The risk of potential thromboembolic, renal and cardiac complications of sickle cell trait. Hemoglobin. 38(1):28-32, 2014
View In Article | Cross Reference

5 Bender MA: Sickle cell disease. In: Adam MP et al, eds: GeneReviews [internet]. University of Washington; 1993-2022
View In Article | Cross Reference

6 Yawn BP et al: Management of sickle cell disease: recommendations from the 2014 expert panel report. Am Fam Physician. 92(12):1069-76,
2015
View In Article | Cross Reference

7 Saunthararajah Y et al: Sickle cell disease: clinical features and management. In: Hoffman R et al, eds: Hematology: Basic Principles and
Practice. 7th ed. Elsevier; 2018:584-607
View In Article

8 Rankine-Mullings AE et al: Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane
Database Syst Rev. 3:CD003427, 2021
View In Article | Cross Reference

9 US Food and Drug Administration: FDA Approves Voxelotor for Sickle Cell Disease. FDA website. Updated November 25, 2019. Accessed
April 22, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-voxelotor-sickle-cell-disease
View In Article | Cross Reference

10 Ogu UO et al: Management of sickle cell disease complications beyond acute chest syndrome. J Blood Med. 12:101-14, 2021
View In Article | Cross Reference

11 Howard J et al: Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international,
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 8(5):e323-33, 2021
View In Article | Cross Reference

12 Minniti CP et al: The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease. Am J Hematol. 96(4):E126-8, 2021
View In Article | Cross Reference

13 Kutlar A et al: Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J
Hematol. 94(1):55-61, 2019
View In Article | Cross Reference

14 Chou ST et al: American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 4(2):327-55, 2020
View In Article | Cross Reference

15 Kanter J et al: American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 5(18):3668-89,
2021
View In Article | Cross Reference

16 Esrick EB et al: Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 384(3):205-15, 2021
View In Article | Cross Reference

17 Frati G et al: Genome editing for β-hemoglobinopathies: advances and challenges. J Clin Med. 10(3):482, 2021
View In Article | Cross Reference

18 Kanter J et al: Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 386(7):617-28, 2022
View In Article | Cross Reference

19 CDC: Immunization Schedules. CDC website. Reviewed February 17, 2022. Accessed April 22, 2022. https://www.cdc.gov/vaccines/schedules/
View In Article | Cross Reference

20 Estcourt LJ et al: Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst
Rev. 7:CD003146, 2020
View In Article | Cross Reference

21 Estcourt LJ et al: Interventions for preventing silent cerebral infarcts in people with sickle cell disease. Cochrane Database Syst Rev.
4:CD012389, 2020
View In Article | Cross Reference

22 Tsitsikas DA et al: Automated red cell exchange in the management of sickle cell disease. J Clin Med. 10(4), 2021
View In Article | Cross Reference

23 Mandelli F et al: Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute
myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 27 (32):5397-403, 2009
View In Article | Cross Reference

24 Arnaout K et al: Complications of allogeneic hematopoietic stem cell transplantation. Cancer Invest. 32(7):349-62, 2014
View In Article | Cross Reference

25 Mohty B et al: Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update. Blood Cancer J.
1(4):e16, 2011
View In Article | Cross Reference

26 Section on Hematology/Oncology Committee on Genetics et al: Health supervision for children with sickle cell disease. Pediatrics.
109(3):526-35, 2002
View In Article | Cross Reference

27 DeBaun MR et al: American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of
cerebrovascular disease in children and adults. Blood Adv. 4(8):1554-88, 2020
View In Article | Cross Reference

28 Phillips S et al: Practice patterns for neuroimaging and transfusion therapy for management of neurologic complications in sickle cell
anemia: DISPLACE Consortium. Pediatr Blood Cancer. 67(11):e28569, 2020
View In Article | Cross Reference

29 Liem RI et al: American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv.
3(23):3867-97, 2019
View In Article | Cross Reference

30 Klings ES et al: An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of
pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 189(6):727-40, 2014
View In Article | Cross Reference

31 Brandow AM et al: American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood
Adv. 4(12):2656-701, 2020
View In Article | Cross Reference

32 Sickle Cell Disease Association of America (SCDAA). Sickle cell disease and COVID-19: an outline to decrease burden and minimize
morbidity. Published 2020. Accessed April 22, 2022. https://www.sicklecelldisease.org/2020/03/18/sickle-cell-disease-and-covid-19-provider-
directory/
View In Article | Cross Reference

33 Schlenz AM et al: Practice patterns for stroke prevention using transcranial Doppler in sickle cell anemia: DISPLACE Consortium. Pediatr
Blood Cancer. 67(4):e28172, 2020
View In Article | Cross Reference

34 Berry SA: Newborn screening. Clin Perinatol. 42(2):441-53, x, 2015

View In Article | Cross Reference

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