Epidemiology

Etiology

Pathophysiology

• 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).
  • Heterozygotes (HbAS): carry one sickle allele and one other (usually normal) → sickle cell trait
  • Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia
• HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”). This can be triggered by any event associated with reduced oxygen tension.

  Formation of a hydrophobic pocket on the beta globin surface that interacts with a complementary nonpolar residue on another hemoglobin molecule. The hydrophobic interaction causes polymerization of HbS molecules and subsequent erythrocyte sickling, leading to membrane damage and permanent distortion of red blood cells.

  • 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
• Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction.
• Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency.
  • Can present as macrocytic anemia
• Extravascular hemolysis and intravascular hemolysis are common and result in anemia.

Clinical features

Typically manifests after 3–6 months of age as the production of HbF decreases and HbS levels increase

Acute manifestations

• Vaso-occlusive events
  • 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
    • Swelling, tenderness, and warmth
  • Vasoocclusive crises (sickle cell pain crisis)
    • Most common acute complication of sickle cell disease
    • Characterized by recurrent episodes of severe throbbing or sharp pain
    • Typically affects the limbs, chest, and back and lasts for ∼ 7 days
    • Often associated with other vasoocclusive events (especially dactylitis in children)
  • Acute chest syndrome
  • Priapism
  • Stroke (common in children)
  • Sickle cell hepatopathy
  • Organ infarctions (any organ; particularly the spleen)
  • Avascular necrosis

Diagnostics

• Normal RBC indices (e.g. MCV)
  • Not all red blood cells are sickled

Treatment

Overview

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 (First-line)
• Annual transcranial doppler to screen for stroke risk from 2 months till 16 years of age

Hydroxyurea therapy

Indications

• All infants > 9 months, children, and adolescents with sickle cell anemia regardless of symptom severity
• Adults with any of the following:
  • Frequent (≥ 3 episodes/year) acute pain episodes or other vasoocclusive events
  • Severe symptomatic anemia
  • History of severe and/or recurrent acute chest syndrome

Mechanism of action

Stimulation of erythropoiesis and increased fetal hemoglobin

Complications

Splenic sequestration

• Pathophysiology: splenic vasoocclusion and entrapment and pooling of large amounts of blood in the spleen
• Clinical presentation
  • Most commonly affects children < 5 years of age
  • Acute left upper quadrant pain, splenomegaly
  • Hypotension and/or hypovolemic shock, especially in infants
    • Due to the trapping of blood in the spleen
  • Symptoms of anemia (e.g., pallor, fatigue)
  • Functional asplenia: Increased risk of infection with encapsulated bacteria (Streptococcus pneumoniae (most common), Neisseria meningitis, Haemophilus influenzae type b
• Supportive findings
  • Anemia (Hb drop of ≥ 2 g/dL) with reticulocytosis
  • Thrombocytopenia
• Acute management
  • Immediate IV fluid resuscitation for hypovolemia
  • Simple RBC transfusion in consultation with a sickle cell expert (avoid raising hemoglobin > 8 g/dL)