Sickle cell disease is caused by hereditary hemoglobinopathy, which includes sickle cell anemias (i.e., HbSS and HbSβ0thal) and other compound heterozygous genotypes (e.g., HbSC, Hbβ+thal). Mutations in the hemoglobin β chain lead to the formation of hemoglobin S, which polymerizes when deoxygenated. Deoxygenated HbS results in sickle-shaped erythrocytes that can occlude blood vessels and cause ischemia. Homozygous sickle cell anemia (HbSS) is the most common variant of sickle cell disease and occurs predominantly in individuals of African and Eastern Mediterranean descent, although people of any ethnicity can develop sickle cell disease. Screening for sickle cell disease is routinely recommended for all infants born in the United States. Hemoglobin separation studies (e.g., hemoglobin electrophoresis, ) and genetic studies are used to confirm the diagnosis. Complications can begin in early infancy and childhood and continue for the rest of the affected individual's lifetime. Acute complications include vascular occlusion events (e.g., vasoocclusive pain crisis, stroke, acute chest syndrome), severe anemia (e.g., sequestration, aplastic anemia), and invasive infections from encapsulated organisms (e.g., bacteremia, pneumonia, meningitis, osteomyelitis). Infants with confirmed sickle cell disease should receive antibiotic prophylaxis against invasive pneumococcal infection and all age-appropriate immunizations, and hydroxyurea therapy. Transfusion therapy (e.g., for vasoocclusive events, secondary prevention of stroke) and hydroxyurea are key aspects of decreasing morbidity and mortality. Screening for (including annual transcranial doppler to screen for stroke risk from 2 months till 16 years of age) should occur at regular intervals. Long-term complications include progressive loss of organ function (e.g., functional asplenia, cognitive decline, avascular osteonecrosis) secondary to repeated infarctions. Allogeneic bone marrow transplantation is currently the only curative treatment option.
Sickle cell trait, which occurs in heterozygous carriers (HbSA), is not considered a form of sickle cell disease, but affected individuals can experience acute complications due to sickling under certain conditions, for example during high-intensity exercise or at high altitude.
- Sickle cell disease
- Sickle cell anemia 
- Sickle cell trait 
- Predominantly affects individuals of African and Eastern Mediterranean descent 
- Africa has the highest prevalence of the disease (30% heterozygote prevalence).
- HbS gene is carried by 8% of the African American population. 
- Sickle cell anemia is the most common form of intrinsic hemolytic anemia worldwide.
Epidemiological data refers to the US, unless otherwise specified.
- Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).
- Glutamic acid can also be replaced with a lysine, creating hemoglobin C
For details on hemoglobin and its variants, see “ ” and “ ” in the article “ .”
|Hemoglobin||Globin chains||Sickle cells||Hemoglobin C|
|Sickle cell trait||Sickle cell disease||Hemoglobin SC disease (HbSC)||Hb C carrier||Hb C disease|
HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”). This can be triggered by any event associated with reduced oxygen tension.
- Hypoxia (e.g., at high altitudes)
- Sudden changes in temperature
- Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction.
- ; and anemia are common and result in .
- Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency.
- The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease.
- Often asymptomatic
- Painless gross hematuria due to renal papillary necrosis: often the only symptom
- Hyposthenuria: nocturia, enuresis
- Recurrent urinary tract infections
- Renal medullary carcinoma
- Symptoms of sickle cell disease may manifest due to severe oxygen deficiency.
- Exertional collapse and sudden death can occur during or after extreme physical exertion (e.g., during sports, military training). 
Sickle cell disease
- ∼ 30% develop symptoms in the first year of life; > 90% by age 6 years
- Typically manifests after 3–6 months of age as the production of HbF decreases and HbS levels increase 
Dactylitis in children < 5 years of age ; 
- Typically the earliest manifestation of sickle cell disease
- Most common in children between 6 months and 2 years of age; uncommon in older children and adults
- Vasoocclusive crises (sickle cell pain crisis) 
- Stroke (common in children)
- Organ infarctions (any organ; particularly the spleen)
- Avascular necrosis
- Dactylitis in children < 5 years of age ; 
- Acute hemolytic crisis
- Chronic hemolytic anemia: fatigue, weakness, pallor; usually well-tolerated
- Chronic pain
- Cholelithiasis (pigmented stones)
|Screening for sickle cell disease |
|Prenatal screening |
|Neonatal screening |
|Older infants/ children/adult screening|
sickle cell disease as they cannot distinguish between sickle cell trait and sickle cell disease, nor can they detect other abnormal hemoglobinopathies  and solubility tests should not be used to screen patients for
As adult hemoglobin levels may be very low or absent in extremely premature infants, premature neonates with sickle cell trait may have a false-positive screening result for sickle cell disease. 
- Sickle cell trait and/or disease is most commonly diagnosed on routine neonatal screening.
- Confirmatory studies should be performed for all individuals with a positive or inconclusive result on initial screening.
- Additional laboratory studies (CBC with MCV and reticulocyte count) and imaging are not required to confirm the diagnosis but may show characteristic changes.
Confirmatory studies 
- Use a different modality than the initial screening test. 
- Perform confirmatory studies within the first 2 months of age for infants with a positive or inconclusive result on sickle cell disease screening. 
|Quantitative analysis of hemoglobin types|
|Hemoglobin||Normal||Sickle cell trait||Sickle cell disease|
|HbF||< 2%||< 2%||5–25%|
- Consider (in consultation with specialists) when Hb electrophoresis and/or chromatography cannot differentiate between hemoglobinopathies (e.g., HbSS and HbSβ0thal).
- For further information on hemoglobin composition and genetics of sickle cell disease, see “Pathophysiology.”
Additional studies 
- Peripheral blood smear findings may include:
- : frequently positive
- May show hair-on-end (“crew cut”) sign
- Caused by periosteal reaction to erythropoietic bone marrow hyperplasia
Patients with sickle cell disease should ideally be managed in comprehensive sickle cell disease centers. Management of patients who do not have easy access to such specialized centers should be done in frequent consultation with hematologists or sickle cell experts. 
Infants and children
- Antibiotic prophylaxis against invasive pneumococcal disease until 5 years of age
- Hydroxyurea therapy regardless of clinical severity to minimize disease-related complications
- Annual transcranial doppler to screen for stroke risk from 2 months till 16 years of age
- Regular monitoring for other common complications of sickle cell disease
- Hydroxyurea therapy if clinically indicated
- Reproduction counselling and contraception
- Regular monitoring for complications of sickle cell disease
- Educate all patients or caregivers on: 
Infection prevention 
- Patients should receive all vaccines recommended for their age.
- ; and are particularly important; earlier/additional doses may be required. 
Antibiotic prophylaxis against invasive pneumococcal disease
- Daily prophylactic penicillin 
- Erythromycin prophylaxis is suitable for children with penicillin allergy. 
- Educate patients/caregivers to seek immediate medical attention if fever > 38.5°C (101.3°F) occurs.
Prevention of vasoocclusive crises and anemia 
- First-line agent: hydroxyurea 
- Hydroxyurea reduces the incidence of acute painful episodes and improves survival.
- All infants > 9 months, children, and adolescents with sickle cell anemia regardless of symptom severity
- Adults with any of the following:
Mechanism of action
- Monitor CBC and reticulocytes every 4 weeks during dose titration.
- Once on a stable dose, monitor HbF concentration, CBC, reticulocyte count every 3 months.
Possible adverse effects
Important considerations 
- The safety of hydroxyurea therapy during pregnancy and breastfeeding has not been established. 
- Clinical response to hydroxyurea may be seen only after 3–6 months of therapy.
Novel disease modifying agents for sickle cell disease 
- Oral L-glutamine: for children ≥ 5 years of age 
- Voxelotor: for adults and children ≥ 12 years 
- Crinzanlizumab: for patients ≥ 16 years of age with a history of vasoocclusive crises 
- Donor choice: HLA-matched related donors are preferred over nonrelated donors.
Screening for complications
|Screening for complications of sickle cell disease |
|Studies and further management|
|Stroke risk || |
|Impaired renal function |
|Hepatobiliary disease |
|Pulmonary hypertension and diastolic dysfunction || |
|Respiratory disease || |
|Retinopathy || |
|Bone disease |
Transfusional iron overload
Management of chronic pain 
- Pain lasting > 3 months is considered chronic.
- Etiology is often nonspecific; maybe due to avascular necrosis or neuropathy
- Tailor management to the individual.
- Analgesic options include NSAIDs, opioids, adjuvant analgesics (e.g., antidepressants, anticonvulsants), and adjunctive nonpharmacological therapies (e.g., acupuncture, massage therapy, cognitive interventions).
General principles 
- Mechanism of action
- Main indications
- Important pre-transfusion considerations to minimize risk of alloimmunization and transfusion reactions:
Transfusions of uncrossmatched or type-specific blood can be given to patients with severe anemia causing hemodynamic compromise or shock. Do not delay transfusion in these patients while awaiting results of recommended pRBC matching criteria. 
Simple transfusions and exchange transfusions 
|Simple transfusions versus exchange transfusions |
|Simple transfusions||Exchange transfusions|
|Target Hb levels|| || |
Unless directed by a sickle cell expert, avoid transfusing to Hb > 10 g/dL (unless HbS percentage is already low) because doing so increases the risk of hyperviscosity and vasoocclusive events. 
Indications for transfusion in sickle cell disease
|Conditions necessitating pRBC transfusion in sickle cell disease |
|Indications for transfusion||Preferred type of transfusion |
| Acute indications |
(Acute transfusion therapy)
|Long-term prevention |
(Chronic transfusion therapy)
Management of acute complications
Sickle cell disease is associated with multiple acute complications, which require timely recognition and management to decrease morbidity and mortality. The most common categories of complications are vasoocclusive crises, other vasoocclusive events, infection, and severe anemia. 
- ABCDE approach
- Start supplemental O2 if SpO2 is < 95%.
- Administer analgesics.
- Order diagnostics as needed (e.g., CBC, reticulocyte count, CMP, liver chemistries, chest x-ray, blood cultures).
- Use IV fluids judiciously; overhydration can trigger or worsen . 
- Consult hematology urgently.
- Assess the need for transfusion; see “Indications for transfusion in sickle cell disease.”
- Manage the underlying event; see “Acute complications of sickle cell disease” for possible etiologies.
- Provide prompt and proactive .
- Address modifiable causes of erythrocyte sickling (e.g., dehydration, hypoxia).
- Ensure adequate hydration.
- Administer supplemental oxygen if SpO2 on room air is < 95%. 
- Consider diagnostics for:
- Evaluation of known triggers (e.g., dehydration, infection) or complications (e.g., end-organ damage)
- Exclusion of differential diagnoses in patients with atypical features:
- Patients requiring admission
- Consult hematology.
- Reassess pain levels every 30–60 minutes and titrate analgesic dose as needed.
Patients with sickle cell disease often face bias when seeking emergent medical management for pain. Believe the patient's pain and remember that sickle cell disease can occur in patients of all ethnicities. 
Symptoms of vasoocclusive crisis can overlap with other complications (e.g., acute chest syndrome, stroke, infection). If there is clinical uncertainty, initiate a diagnostic workup and seek specialist advice immediately. 
Pain management 
- Management should be guided by patient-reported pain severity.
- Consider alternative diagnoses (e.g., acute chest syndrome, acute MI, septic arthritis) if pain is atypical.
- Use individualized (preferred) or sickle cell-specific pain management protocols.
- Parenteral opioids (morphine or hydromorphone) are preferred for moderate to severe pain crises.
- Administer first dose within 30–60 minutes of arrival.
- If an IV cannot be established quickly, administer subcutaneously or intranasally.
- Opioid-tolerant patients
- Opioid-naive patients: Follow doses recommended in “Parenteral analgesia.”
- Consider adjunctive NSAIDs for 5–7 days if there are no contraindications to NSAIDs. 
Reassessment and disposition
- Titrate medications to effect.
- Reevaluate pain every 15–30 minutes until well controlled.
- Consider incremental dose escalations of 25% for uncontrolled pain. 
- Consider adjunctive nonpharmacological modalities 
- Uncontrolled pain after 6–8 hours 
If possible, consider starting PCA dosing in the emergency room to prevent delays in pain control. 
Further management 
- Encourage incentive spirometry every 2–4 hours while awake and early ambulation to prevent atelectasis and acute chest syndrome. 
- Encourage fluid and recommended fiber intake and consider stool softeners or laxatives to prevent opioid-induced constipation.
- Manage opioid-induced pruritus with oral antihistamines every 4–6 hours e.g., diphenhydramine. 
An acute drop in hemoglobin concentration may indicate the development of acute chest syndrome and/or multisystem organ failure (MSOF), which can affect the lungs, liver, and/or kidneys. MSOF most commonly manifests when the pain crisis begins to improve. 
- Clinical presentation
- Diagnostics: See “Diagnosis of stroke.”
- Acute management (of patients with acute neurological deficits, including TIA)
- Long-term management: See “Secondary stroke prevention in sickle cell disease” for details.
- Clinical features and diagnosis: See “Diagnostic criteria for acute chest syndrome.”
- Management: See “Management of acute chest syndrome.”
Acute chest syndrome is the most common cause of mortality in patients with sickle cell disease. It may be preceded or accompanied by a vasoocclusive pain crisis. The presence of a new pulmonary infiltrate on imaging is diagnostic of acute chest syndrome. 
Splenic sequestration 
- Pathophysiology: splenic vasoocclusion and entrapment and pooling of large amounts of blood in the spleen
- Clinical presentation
- Supportive findings
- Acute management
- Long-term management
Splenic sequestration is uncommon in older patients with HbSS due to splenic atrophy from repeated splenic infarctions. Patients with HbSC and HbSβ+thal may have splenic sequestration into adulthood. 
Acute sickle cell hepatopathy 
- Acute sickle hepatic crisis: hepatic ischemia during a vasoocclusive crisis
- Acute hepatic sequestration: hepatic ischemia and sequestration of blood during a vasoocclusive crisis
- Acute intrahepatic cholestasis: a life-threatening form of sickle cell hepatopathy
- Stabilize the patient and provide , if needed.
- Send an urgent and .
- Administer transfusion indications in sickle cell disease. according to
- Identify and treat the underlying cause.
Possible etiologies of acute anemia include aplastic crisis, splenic sequestration, acute hepatic sequestration, acute chest syndrome, delayed hemolytic transfusion reaction, infection, sepsis, and acute blood loss (not necessarily linked to sickle cell disease). 
Aplastic crisis 
- Clinical presentation
- Supportive findings
General principles 
- Patients with sickle cell disease are at high risk of infection most commonly by encapsulated bacteria due to functional asplenia.
- Risk of infection, septicemia, and meningitis is highest during infancy and early childhood.
- Immunizations and antibiotic prophylaxis are important aspects of sickle cell disease management: See “Infection prevention” in “Long-term management of sickle cell disease.”
- Patients with symptoms of infection should receive aggressive antibiotic therapy.
Fever (≥ 38.5°C, ≥ 101.3°F) in sickle cell disease may be due to vasoocclusive crisis, life-threatening complications (e.g., acute chest syndrome), or infection (which can rapidly progress to septicemia) and requires urgent management. 
Routine diagnostics 
- Reticulocyte count
- Blood cultures
- Liver chemistries and renal function test
- Chest x-ray if there is chest pain, cough, or tachypnea
- Consider urinalysis, urine culture, CSF analysis, or synovial fluid analysis depending on underlying symptoms.
- Start as needed; avoid overhydration.
- Start empiric antibiotic therapy (see below) parenterally while awaiting diagnostic results. 
- While patients are receiving broad-spectrum antibiotics, hold prophylactic penicillin.
- Evaluate for and treat any underlying conditions; see relevant articles for details, e.g.:
- Admit patients for IV antibiotics if any of the following conditions are met:
- Age < 12 months
- Laboratory results concerning for serious bacterial infection
- New hypoxia or saturation < 3% from baseline
- Temperature 39.5°C (≥ 103.1°F)
- Not tolerating enteral feeds
- Social factors affecting ability to seek care
- Coverage: typically against S. pneumoniae and gram-negative enteric organisms 
- First-line: IV third-generation cephalosporin (e.g., ceftriaxone: ) 
- Second-line (e.g., due to allergy): clindamycin 
- Suspected acute chest syndrome: Add azithromycin. 
- Severe illness or suspected meningitis 
Special patient groups
Contraception and reproductive counseling 
- Educate both men and women with sickle cell disease or trait on contraceptive information; see “Family planning and emergency contraception” for details.
Contraception options for patients with sickle cell disease:
- Counsel patients and their partners that pregnancy in women with sickle cell disease is considered high risk.
- Screen reproductive partners of patients with sickle cell disease or trait for hemoglobinopathy.
- Patients desiring to have children should be offered and .
Sickle cell disease in pregnancy 
- Maternal complications 
- Fetal complications: increased risk of fetal growth restriction, low birth weight, preterm delivery, and stillbirth 
- Close maternal and fetal surveillance by experienced health care personnel (e.g., maternal-fetal specialists, sickle cell experts, and experienced obstetricians)
- Hemoglobin levels should be measured monthly.
- Evaluate the need for VTE prophylaxis and transfusion therapy in consultation with a sickle cell expert.
- Management of vasoocclusive crises and events
Recurrent vascular occlusion and disseminated infarctions lead to progressive organ damage and loss of function. In homozygotes, this progress is associated with high morbidity and mortality. In heterozygotes, organ damage is very rare.
|Acute complications of sickle cell disease |
|Hypotension and/or tachycardia|
|Acute anemia |
|Renal symptoms|| |
|Chronic complications of sickle cell disease |
We list the most important complications. The selection is not exhaustive.
Sickle cell disease and malaria
- Individuals with sickle cell trait are less likely to develop severe forms of malaria and have reduced parasite prevalence. 
- The exact mechanism of malaria resistance is unknown; presumably, the plasmodia responsible for malaria are unable to multiply sufficiently within the erythrocytes and some studies suggest increased sickling in infected RBCs.
- CRISPR-Cas miracle? Report on two successful attempts at treatment : A
Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.