- Clinical science
Sickle cell syndromes are hereditary hemoglobinopathies. Homozygous sickle cell anemia (HbSS, autosomal recessive) is the most common variant of the sickle cell syndromes and occurs predominantly in individuals of African and East Mediterranean descent. Sickle cell trait occurs in heterozygous carriers (HbSA). Other rare variants of sickle cell syndrome occur in individuals with one HbS allele and one other allele (HbC or Hb-β thalassemia). A point mutation in the beta chain of hemoglobin leads to substitution of glutamic acid by valine, thus changing the structure (and properties) of hemoglobin. Abnormal hemoglobin polymerizes when deoxygenated, resulting in sickle-shaped erythrocytes, which cause vascular occlusion and ischemia. Sickle cell anemia manifests in early childhood with symptoms associated with vascular occlusion and hemolytic anemia. Infarctions in the spleen, kidneys, bone, CNS, and other organs are common and cause progressive loss of organ function and acute and chronic pain in affected parts of the body. Acute, painful vaso-occlusive crises are provoked by conditions associated with reduced oxygen tension. Neonatal screening for sickle cell anemia has been implemented across the U.S., allowing the diagnosis to be made before the first manifestation of the disease. In older children and adults, hemoglobin quantification tests are used to diagnose the condition. The cornerstones of treatment involve the management of painful vaso-occlusive crises, hemolytic anemia, and disease complications as well as prevention of infection. Allogeneic bone marrow transplantation is the only curative treatment option.
See also acute chest syndrome.
- Predominantly affects individuals of African and East 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.
- Heterozygotes (HbSA): carry one sickle allele and one other (usually normal) → sickle cell trait
- Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia
- 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.
Hemoglobin composition in sickle cell disease
|Hemoglobin||Normal||Sickle cell trait||Sickle cell disease|
|HbF||< 2%||< 2%||5–25%|
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
- Very rarely, symptoms of sickle cell disease may occur as a result of severe oxygen deficiency.
Sickle cell disease
Acute hemolytic crisis (severe anemia)
- Splenic sequestration crisis
- Aplastic crisis
- Hyperhemolysis: intravascular and extravascular hemolysis triggered by mild oxygen deficiency (rare)
- Vaso-occlusive crises (painful episodes, painful crisis): recurrent episodes of severe deep bone pain and dactylitis → most common symptom in children and adolescents
- Stroke (common in children)
- Infarctions of virtually any organ (particularly spleen) and avascular necrosis with corresponding symptoms (see “Complications” below)
- Acute hemolytic crisis (severe anemia)
- Chronic symptoms
- Symptoms of other forms of sickle cell syndrome (HbSC disease and HbS/beta-thalassemia) are similar to sickle cell anemia but less severe.
- Prenatal testing: may be conducted in select cases: chorionic villus sampling and DNA analysis at 8–12 weeks of gestation
- Neonatal screening (mandatory in all states)
Older children and adults
- Liquid chromatography and isoelectric focusing to quantify hemoglobin subtypes (best tests)
- Sickle cell test: detects sickle cells in a blood smear under anaerobic conditions.
- Peripheral blood smear
- Imaging: X-ray of the skull shows hair-on-end (“crew cut”) sign due to periosteal reaction to erythropoietic bone marrow hyperplasia (also present in ).
|Hemoglobin||Globin chains||Sickle cells||Hemoglobin C|
|Sickle cell trait||Sickle cell disease||Hemoglobin SC disease (HbSC)||HbC carrier||HbC disease|
- Laboratory analysis
- Pulmonary function tests
- Transcranial Doppler ultrasound is used to identify and monitor children with a high risk of stroke.
- Pneumococcal vaccines
- Meningococcal vaccines
- Daily penicillin prophylaxis ; (at least until the age of 5 years)
- If sepsis is suspected, treat with IV third-generation cephalosporin (e.g., ceftriaxone)
Prevent vaso-occlusive crises and manage anemia
- Avoid triggers
Hydroxyurea: first-line treatment
- Frequent, acute painful episodes or other vaso-occlusive events
- Severe symptomatic anemia
- Effect: stimulates erythropoiesis and increases fetal hemoglobin → sickled hemoglobin is proportionally reduced → red blood cell polymerization decreases → fewer vaso-occlusive episodes
Possible adverse effects: myelosuppression (beneficial in patients with myeloproliferative disease, e.g., polycythemia vera)
- Can cause an atypical form of ()
- If the response to hydroxyurea alone is not adequate
- Folic acid supplementation
- Cholecystectomy to treat cholelithiasis
Management of acute sickle cell crisis
- Prompt and adequate supportive treatment
- Blood transfusions
- Exchange transfusions (erythrocytapheresis): automated removal of erythrocytes containing HbS and simultaneous replacement with HbS free erythrocytes
Allogeneic bone marrow transplantation
- Indications: homozygotes, children < 16 years with severe disease
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.
We list the most important complications. The selection is not exhaustive.
- 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.