Sickle cell disease

Last updated: September 8, 2022

Summarytoggle arrow icon

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, high-performance liquid chromatography) 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 complications of sickle cell disease (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 anemia genotypes (i.e., HbSS and HbSβ0thal) have the most severe clinical presentations and have almost identical clinical manifestations. [1]

Epidemiological data refers to the US, unless otherwise specified.

Genetics

Hemoglobin composition

For details on hemoglobin and its variants, see “Hemoglobin synthesis” and “Hemoglobin variants” in the article “Erythrocyte morphology and hemoglobin.”

Hemoglobin Globin chains Sickle cells Hemoglobin C
Sickle cell trait Sickle cell disease Hemoglobin SC disease (HbSC) Hb C carrier Hb C disease
HbA ααββ Absent Absent Absent
HbA2 ααδδ Absent Absent
HbF ααγγ Normal Normal Normal Absent
HbH ββββ Absent Absent Absent Absent Absent
Hb Bart γγγγ Absent Absent Absent Absent Absent
HbS ααββ ↑↑ Absent Absent
HbC ααββ Absent Absent ↑↑

Pathophysiology

Sickle cell trait

Sickle cell disease

Onset

  • ∼ 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 [6]

Acute manifestations

Chronic manifestations

Symptoms of other forms of sickle cell syndrome (HbSC disease and HbS/beta-thalassemia) are similar to sickle cell disease but less severe.

Screening for sickle cell disease [8][9][10]
Indications Recommended test
Prenatal screening [1]
Neonatal screening [11]
Older infants/ children/adult screening

Sickling tests and solubility tests should not be used to screen patients for sickle cell disease as they cannot distinguish between sickle cell trait and sickle cell disease, nor can they detect other abnormal hemoglobinopathies [12]

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. [11][13]

General principles

Confirmatory studies [9][11]

  • Use a different modality than the initial screening test. [6][10]
  • Perform confirmatory studies within the first 2 months of age for infants with a positive or inconclusive result on sickle cell disease screening. [1][11]

Qualitative analysis

On hemoglobin electrophoresis, HbA migrates the fastest (the greatest distance) towards the anode, followed by HbF, HbS, and HbC (i.e., HbA > HbF > HbS > HbC).

Quantitative analysis

Quantitative analysis of hemoglobin types
Hemoglobin Normal Sickle cell trait Sickle cell disease
HbA 95–98% 60% 0%
HbS 0% 40% 75–95%
HbF < 2% < 2% 5–25%

DNA studies

Additional studies [8]

Laboratory studies

Skull x-ray [14]

Hair-on-end appearance on skull x-ray may also be present in patients with thalassemia.

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. [15]

Overview [1][16]

Infection prevention [1]

Initiate early antibiotic prophylaxis and ensure appropriate immunizations in all infants confirmed to have sickle cell disease to minimize the risk of serious infections. [1][11]

Prevention of vasoocclusive crises and anemia [1][16]

The following pharmacologic interventions and avoidance of known triggers (e.g., dehydration, high altitudes) are the main aspects of preventing complications of sickle cell disease.

Hydroxyurea therapy

Indications [1][16]

Mechanism of action

Stimulation of erythropoiesis and increased fetal hemoglobin → proportional reduction of sickled hemoglobin → decreased red blood cell polymerization → fewer vasoocclusive episodes

Monitoring [1]

Possible adverse effects

Important considerations [1][16]

Novel disease modifying agents for sickle cell disease [16]

Hydroxyurea and chronic blood transfusions are the most established disease-modifying therapies for sickle cell disease. Recently approved agents include the following.

  • Oral L-glutamine: for children ≥ 5 years of age [16][20]
  • Voxelotor: for adults and children ≥ 12 years [16][21]
  • Crinzanlizumab: for patients ≥ 16 years of age with a history of vasoocclusive crises [22][23]

Allogeneic bone marrow transplantation (allogeneic HSCT) [24]

  • Overview
    • Currently the only potentially curative option
    • Associated with better outcomes if performed at a younger age (< 16 years)
    • However, there is a paucity of evidence on the overall benefit of allogeneic HSCT in patients with sickle cell disease.
  • Indications
  • Donor choice: HLA-matched related donors are preferred over nonrelated donors.

Screening for complications

Individuals with sickle cell disease are at risk for hemolysis due to shortened RBC lifespans and end-organ damage from repeated infarcts secondary to sickling.

Screening for complications of sickle cell disease [1][16]
Studies and further management
Stroke risk [1][16][25][26]
  • Asymptomatic children (2–16 years old) : annual transcranial doppler ultrasound (TCD) to screen for increased risk of stroke [1][25]
  • Asymptomatic patients with HbSS or HbSβ0thal: Screen for silent cerebral infarcts. [27]
    • Early-school age children (e.g., age 10 years): MRI/MRA brain (without sedation) once
    • Adult: Consider one-time screening MRI brain.
  • All children and adults: Screen for developmental delay and cognitive impairment at each visit.
  • Secondary stroke prevention in sickle cell disease: recommended in patients with evidence of previous stroke (including silent infarcts) or abnormal TCD velocities
Hemolysis [16]
Impaired renal function [1][16]
Hepatobiliary disease [1]
Pulmonary hypertension and diastolic dysfunction [16]
  • Screening echocardiogram at 10 years of age
    • Abnormal: Refer to cardiology for further management.
    • Normal: Repeat every 2–5 years.
Respiratory disease [1][16]
Retinopathy [1]
  • Age ≥ 10: Perform annual dilated ophthalmologic exams.
Bone disease [16]
  • Monitor vitamin D levels; start supplementation if < 30 IU.
  • At age 10, assess bone mineral density.
  • Refer to a dietitian and repeat screening if abnormal.

Transfusional iron overload

Management of chronic pain [1]

General principles [1][29]

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. [31]

Patients with sickle cell disease should ideally receive pRBC transfusions that are matched for C, E, and K antigens. Perform extended RBC phenotype matching when possible. [1][29]

Simple transfusions and exchange transfusions [1][29]

Both simple transfusion and exchange transfusion are used in the management of sickle cell disease depending on availability and indication.

Simple transfusions versus exchange transfusions [1][29]
Simple transfusions Exchange transfusions
Definition
Advantages
  • Readily available
  • Easy to perform
Disadvantages
  • Expensive
  • Necessitates specialized equipment and expertise
  • Increased risk of alloimmunization due to increased RBC exposure [29]
  • Often requires central access
Target Hb levels
  • Usually Hb ∼10 g/dL [1][16]
  • Variable, based on the patient's baseline Hb levels and the indication

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. [1][16]

Indications for transfusion in sickle cell disease

Conditions necessitating pRBC transfusion in sickle cell disease [1][29][32]
Indications for transfusion Preferred type of transfusion [1]
Acute indications
(Acute transfusion therapy)

Vasoocclusive events
Anemia
Long-term prevention
(Chronic transfusion therapy)
  • Stroke prevention
    • Children with abnormal transcranial doppler results
    • Adults and children with a history of stroke

Prophylactic transfusion

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. [1][7][33]

Approach [1][33]

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. [33]

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. [1]

Overhydration can trigger acute chest syndrome; administer IV fluids judiciously. [34]

Pain management [1][33][35]

Analgesics [1][33]

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. [1]
  • Consider adjunctive nonpharmacological modalities [33]
  • Uncontrolled pain after 6–8 hours [1]

If possible, consider starting PCA dosing in the emergency room to prevent delays in pain control. [1]

Avoid steroids for pain crisis (unless indicated for another condition, e.g., asthma) because steroid use is associated with complications, including rebound pain. [33]

Further management [1][33]

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. [1][34]

Patients who require > 3 hospitalizations for vasoocclusive crises in a year have an increased risk of mortality. Consider starting this group of patients on hydroxyurea therapy. [1]

Stroke [1][25]

Stroke (silent or overt) is a common complication of sickle cell disease. Early detection and management are essential to prevent or minimize cognitive decline. [1][25]

Acute chest syndrome [1][34]

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. [1]

Splenic sequestration [1]

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. [1]

Acute sickle cell hepatopathy [1][38]

Suspect life-threatening acute intrahepatic cholestasis when laboratory studies suggest a cholestatic jaundice picture but imaging does not identify common bile duct obstruction or cholangitis. [1]

Venoocclusive priapism [1]

Acute anemia in sickle cell disease is defined as a drop in hemoglobin of ≥ 2.0 g/dL from baseline, or a hemoglobin value < 6 g/dL (if baseline is unknown). [1]

Baseline hemoglobin values are typically 6–8 g/dL for HbSS, 9–12 g/dL for HbSβ+ thal, and 10–15 g/dL for HbSC. [1]

Approach

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). [1]

Aplastic crisis [1]

General principles [1]

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. [1]

Routine diagnostics [1]

Do not delay empiric antibiotic therapy while awaiting laboratory results (e.g., CBC, blood culture). [1]

Management [1][39][40]

Disposition [1][41]

  • Admit patients for IV antibiotics if any of the following conditions are met:
    • Age < 12 months
    • Ill-appearing
    • 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

Empiric antibiotic therapy

Contraception and reproductive counseling [1]

Preconception counseling [1]

Sickle cell disease in pregnancy [45]

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

Acute complications of sickle cell disease [1]
Possible complications
Hypotension and/or tachycardia
Neurologic changes
Severe pain
Abdominal pain
Respiratory symptoms
Acute anemia [1]
Fever
Renal symptoms
Ocular symptoms

Patients with sickle cell disease have increased renal tubular secretion of creatinine, so acute renal failure may be present even if creatinine is in the normal range. [1]

Chronic complications

Chronic complications of sickle cell disease [1]
Organ system Complications
Spleen
Kidney
Skeletal
CNS
Lungs
Heart

Liver

Treatment-related complications

As a result of repeated infarction of the spleen in sickle cell patients, the spleen is often atrophied rather than enlarged!

We list the most important complications. The selection is not exhaustive.

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