Sickle cell anemia

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 ^[1]
• Africa has the highest prevalence of the disease (30% heterozygote prevalence).
• HbS gene is carried by 8% of the African American population. ^[2]
• Sickle cell anemia is the most common form of intrinsic hemolytic anemia worldwide.

Epidemiological data refers to the US, unless otherwise specified.

Genetics

• 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 SC disease
    • Heterozygosity for hemoglobin S and hemoglobin C
    • Results in a phenotype more severe than sickle cell trait but not as severe as sickle cell disease (e.g., fewer acute sickling events)

Hemoglobin composition in sickle cell disease

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

Pathomechanism

• 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)
    • In homozygotes, up to 100% of the hemoglobin molecules are affected, leading to sickle cell formation under minimally decreased oxygen tension.
    • In heterozygotes, sickling only occurs due to severe reduction in oxygen tension.
  • Infections
  • Dehydration
  • Acidosis
  • Sudden changes in temperature
  • Stress
  • Pregnancy
• Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction.
• Extravascular hemolysis and intravascular hemolysis are common and result in anemia.
• 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.

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 as a result of severe oxygen deficiency.

Sickle cell disease

• Onset
  • ∼ 30% develop symptoms in the first year of life; > 90% by age 6 years
  • Manifests after 6 months of age as the production of HbF decreases and HbS levels increase
• Acute symptoms
  • Acute hemolytic crisis (severe anemia)
    • Splenic sequestration crisis
      • Splenic vaso-occlusion → entrapment and pooling of large amounts of blood in the spleen → acute left upper quadrant pain, anemia, reticulocytosis, and signs of intravascular volume depletion (e.g., hypotension)
    • Aplastic crisis
      • Red blood cell aplasia with an acute, severe drop in hemoglobin and associated reticulocytopenia due to an infection with parvovirus B19
      • Dysmorphic erythrocytes in sickle cell disease and hereditary spherocytosis are susceptible to parvovirus B19 infection, which can temporarily suppress bone marrow erythropoiesis.
    • Hyperhemolysis: intravascular and extravascular hemolysis triggered by mild oxygen deficiency (rare)
  • Infection
    • Pneumonia
    • Meningitis
    • Osteomyelitis (most common cause: Salmonella spp., Staphylococcus aureus)
    • Sepsis (most common cause: Streptococcus pneumoniae)
  • Vaso-occlusive events
    • 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
    • Priapism
    • Stroke (common in children)
    • Acute sickle hepatic crisis (manifests with RUQ pain, jaundice, nausea, fever, hepatomegaly, and elevated transaminase levels) ^[3]
    • Infarctions of virtually any organ (particularly spleen) and avascular necrosis with corresponding symptoms (see “Complications” below)

• Chronic symptoms
  • Chronic hemolytic anemia: fatigue, weakness, pallor; usually well-tolerated
  • Chronic pain
  • Cholelithiasis (pigmented stones)
• Symptoms of other forms of sickle cell syndrome (HbSC disease and HbS/beta-thalassemia) are similar to sickle cell anemia but less severe.

Diagnosis

• 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)
  • If positive: Repeat hemoglobin electrophoresis (gold standard) confirms the diagnosis and distinguishes between heterozygotes and homozygotes and other forms of sickle cell syndrome (e.g., HbSC disease)
    • Migration towards the anode: HbA > HbF > HbS > HbC
• 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
    • Sickle cells (drepanocytes): crescent-shaped RBCs
    • Target cells
    • Possibly Howell-Jolly bodies
    • Reticulocytosis
  • 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 thalassemia).

Disease monitoring

• Laboratory analysis
  • See “Laboratory signs of hemolysis” in hemolytic anemia.
  • Liver and kidney function tests
• Pulmonary function tests
• Transcranial Doppler ultrasound is used to identify and monitor children with a high risk of stroke.

Organ damage

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.

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.

• Individuals with sickle cell trait are less likely to develop severe forms of malaria and have reduced parasite prevalence. ^[4]
• 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.

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Long term management

Prevent infections

• 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)
  • If meningitis is also suspected: add vancomycin
  • Second-line therapy (e.g., due to allergy): levofloxacin, clindamycin

Prevent vaso-occlusive crises and manage anemia

• Avoid triggers
• Hydroxyurea: first-line treatment
  • Indications
    • 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 macrocytosis (nonmegaloblastic anemia)
• If the response to hydroxyurea alone is not adequate
  • Combine with erythropoietin
  • Blood transfusions
• L-glutamine: first approved treatment for pediatric sickle cell anemia
  • Indications: recurrent, acute complications of sickle cell disease
  • Effect: ↑ free glutamine → ↑ anti-oxidant capacities → ↓ sickling of red blood cells
  • Possible adverse effects: constipation, nausea, headache, cough, pain (e.g., abdominal, back, chest)
• Folic acid supplementation
• Cholecystectomy to treat cholelithiasis
• Splenectomy or partial splenectomy to prevent recurrent splenic sequestration

Management of acute sickle cell crisis

• Prompt and adequate supportive treatment
  • Hydration
  • Pain management with nonsteroidal anti-inflammatory agents and opioids
  • Thromboembolic prophylaxis
  • Nasal oxygen
  • Bed rest
• Blood transfusions
  • Indications
    • Acute, severely symptomatic anemia (e.g., aplastic crisis)
    • Secondary prophylaxis of acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure)
    • Surgery (preoperative transfusions)
    • Pregnancy
• Exchange transfusions (erythrocytapheresis): automated removal of erythrocytes containing HbS and simultaneous replacement with HbS free erythrocytes
  • Indication: acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure), splenic sequestration crisis
  • Advantages
    • Rapid effect
    • Allows precise control of HbS levels and iron accumulation
  • Disadvantages
    • Expensive and equipment not readily available
    • Requires experienced practitioner

Curative therapy

• Allogeneic bone marrow transplantation
  • Indications: homozygotes, children < 16 years with severe disease

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