What is hereditary spherocytosis? pathogenesis, morphology, and clinical features.

Hereditary Spherocytosis

This disorder stems from inherited (intrinsic) defects in the red cell membrane.
Leads to formation of spherocytes — non-deformable cells that are highly vulnerable to sequestration and destruction in the spleen.
Usually transmitted as an autosomal dominant trait.
A more severe autosomal recessive form affects a small minority of patients.

Caused by inherited defects in the membrane skeleton, a network of proteins stabilizing the lipid bilayer of red cells.
Major membrane skeleton protein: spectrin — a long, flexible heterodimer that:
- Self-associates at one end.
- Binds short actin filaments at the other.
These interactions form a two-dimensional meshwork, connected to transmembrane proteins (band 3 and glycophorin) via linker proteins:
- ankyrin
- band 4.2
- band 4.1
Most common mutations involve:
- ankyrin
- band 3
- spectrin
Pathogenic mutations:
- Weaken vertical interactions between the membrane skeleton and red cell membrane proteins.
- Lead to membrane instability and vesicle shedding.
- Result: decreased surface area-to-volume ratio, forming spherical cells.
Key spleen role:
- Despite persistence of spherocytes post-splenectomy, anemia improves.
- Normal red cells are flexible; spherocytes are not — they get trapped and destroyed in the splenic cords.

On blood smear:
- Spherocytes appear dark red and lack central pallor.
Excessive destruction of red cells → anemia → reticulocytosis due to marrow compensation.
Splenomegaly:
- More common and pronounced than in other hemolytic anemias.
- Weight: 500–1000 g.
- Results from:
  - Congestion of splenic cords.
  - Increased macrophage activity.
  - Phagocytosed red cells seen inside macrophages.
Common complication: Cholelithiasis (in 40–50% of patients).

Triad of symptoms:
- Anemia
- Splenomegaly
- Jaundice
Severity of anemia varies (subclinical to profound, typically moderate).
Diagnostic clue: Red cells show increased osmotic fragility in hypotonic salt solutions.

Aplastic crises:
- Most severe complication.
- Triggered by Parvovirus B19.
- Virus infects erythroblasts → apoptosis.
- Leads to temporary cessation of red cell production.
- Red cell production usually resumes in 10–14 days.
- May require blood transfusion during the aplastic phase.

No specific cure.
Splenectomy:
- Removes main site of red cell destruction → improves anemia.
- Risks: Increased susceptibility to serious bacterial infections, especially in children.
Partial splenectomy:
- Gaining popularity in children.
- Balances hematologic benefit and preservation of immune function.
- Limitation: Regrowth of spleen may require second surgery later.
- Goal: Delay second surgery until adulthood, when sepsis risk is lower.