- 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.
- Predominantly affects individuals of African and East Mediterranean descent.
- Africa has the highest prevalence of the disease (30% heterozygote prevalence).
- Sickle cell anemia is the most common form of corpuscular anemia worldwide.
Epidemiological data refers to the US, unless otherwise specified.
- Heterozygotes; : carry one sickle allele and one other (usually normal) → sickle cell trait
- Homozygotes; : carry two sickle alleles → sickle cell anemia
Point mutation in the β-globin gene (chromosome 11)→ glutamic acid replaced with valine → 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 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.
- Sudden changes in temperature
- Sickle cells lack elasticity and adhere to vascular endothelium, disrupting microcirculation and causing vascular occlusion and subsequent tissue infarction.
- and are common.
- Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency.
Sickle cell trait
- 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 (E.g., anemia or acute chest syndrome. However, these patients typically have a concurrent inherited hemoglobinopathy) as a result of severe oxygen deficiency.
Sickle cell disease and other forms of sickle cell syndrome
- Onset: ∼ 30% develop symptoms in the first year of life; > 90% by age 6 years
Severe anemia (acute hemolytic crisis)
- Splenic sequestration crisis
- Aplastic crisis: with an acute, severe drop in hemoglobin and associated reticulocytopenia due to an infection with parvovirus B19
- Hyperhemolysis (rare!)
- Vaso-occlusive crises (painful episodes, painful crisis): recurrent episodes of severe deep bone pain and dactylitis → most common symptom in children and adolescents!
- Acute chest syndrome: chest pain, respiratory distress
- Stroke (common in children)
- Infarctions of virtually any organ with corresponding symptoms (see “Complications” below)
- Severe anemia (acute hemolytic crisis)
- 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
- Laboratory analysis
- Pulmonary function tests
- Transcranial Doppler ultrasound is used to identify and monitor children with a high risk of stroke.
- Pneumococcal vaccines: conjugate vaccine according to the immunization schedule, polysaccharide vaccine at age > 2 years, and a booster dose at age 5 years
- Meningococcal vaccines (serogroups ACWY) at age > 2 years
- 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 (10–30 mg/kg per day, WBC should be maintained between 5000–8000/μl)
- 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
- Goal: maintain hematocrit > 30% or arterial saturation > 90%)
- Iron chelation treatment may be required to treat iron overload due to continued transfusion
- 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.