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- Hemolytic anemia with shortened RBC survival due to selective destruction of RBCs in the spleen secondary to an inherent defect of the RBC membrane.
- Pathophysiologically related to hereditary elliptocytosis and hereditary ovalocytosis
- Membrane loss is gradual; it results in spherocytosis, which results in increased osmotic fragility.
- Severity related to degree of membrane loss
- Mild (20% of patients)
- Hemoglobin near normal
- Slight reticulocytosis (<6%)
- Compensated hemolysis, mild splenomegaly
- Often not diagnosed until adulthood due to gallstones
- Moderate (60% of patients)
- Hemoglobin 8–10 mg/dL
- Reticulocytes generally >8%
- >50% patients have splenomegaly.
- Moderately severe (10%)
- Hemoglobin 6–8 mg/dL
- Reticulocytes >15%
- Intermittent transfusions
- Severe (3–5%)
- Life-threatening anemia requiring regular transfusions
- Almost always recessive
- Mild (20% of patients)
Most common in people of Northern European extraction (∼1:3,000)
- ∼75% of cases are inherited in an autosomal dominant pattern.
- The other 25% are autosomal recessive forms, dominant disease with reduced penetrance, or new mutations.
- The most common abnormality is a deficiency of ankyrin and subsequent decrease in spectrin, 2 major proteins of the erythrocyte membrane skeleton (50–60% Northern European decent; 5–10% Japan).
- Spectrin deficiency alone accounts for 20% of HS.
- Mutations in other erythrocyte surface proteins also occur, including the following:
- Beta-spectrin (typically mild to moderately severe), alpha-spectrin (severe HS)
- Band 3 (15–20% generally mild to moderately severe)
- Protein 4.2 (<5% HS, recessive and results in almost complete absence)
- Rh antigen (<10% mild to moderate hemolytic anemia)
- The membrane skeletal defect causes RBC membrane fragility, resulting in membrane loss.
- The sequelae are as follows:
- Loss of cell surface area relative to volume (spherocytosis) causes a decrease in cellular deformability.
- The spleen detains and “conditions” the nondeformable spherocytic RBC.
- Conditioning of cells involves depletion of adenosine 5′-triphosphate (ATP), increased glycolysis, increased influx and efflux of sodium, and loss of membrane lipid.
- Ultimately, these events lead to premature RBC destruction.