Intravascular vs. Extravascular Hemolysis

Hemolytic anemia may be classified according to where the hemolysis is taking place: inside the circulation (intravascular) or in macrophages of the reticuloendothelial system, especially in spleen and liver (extravascular).

Intravascular hemolysis:

  • Causes:
    • Complement fixation, typically via IgM and direct lysis:
      • Cold autoimmune hemolytic anemia
      • ABO antibody-mediated alloimmune hemolytic anemia following transfusion
      • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Mechanical, shear-force-associated red blood cell (RBC) lysis:
      • Thrombotic microangiopathy (TMA)
      • Valve hemolysis
    • RBC lysis secondary to membrane disorders, enzymopathies or hemoglobinopathies (i.e., non-immune-mediated intravascular hemolysis):
      • Hereditary spherocytosis
      • G6PD deficiency
      • PK deficiency
      • Sickle cell anemia
      • Thalassemia
  • Red cells are lysed in the blood, internal contents are leaked into the vascular space:
    • LDH is released directly into the circulation.
    • AST is released directly into the circulation.
    • Hemoglobin (Hb) is released directly into the circulation:
      • Hb binds haptoglobin.
      • Hb-haptoglobin complex taken up by macrophages.
      • Hb metabolized to bilirubin, with the latter being released into the circulation.
    • (Thousands of other proteins are also released into the plasma!)

Extravascular hemolysis

  • Causes – majority of cases of extravascular hemolysis are attributable to an immune-mediated cause.
  • Red cells are engulphed by macrophages in organs such as the spleen and liver:
    • Hemoglobin is degraded by macrophages, resulting in increased bilirubin production and release.
    • Presumably macrophages release some LDH, AST and free hemoglobin.
    • An alternative explanation for the changes in serum LDH, AST and haptoglobin is that most cases of extravascular hemolysis are also accompanied by some degree of intravascular lysis.
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