• The breakdown of heme from hemoglobin liberates iron for recirculation via plasma transferrin mainly to marrow erythroblasts, and protoporphyrin, which is broken down to bilirubin. Bilirubin circulates to the liver where it is conjugated to glucuronides, which are excreted into the gut via bile and converted to stercobilinogen and stercobilin (excreted in feces).

• Stercobilinogen and stercobilin are partly reabsorbed and excreted in urine as urobilinogen and urobilin. Globin chains are broken down to amino acids which are reutilized for general protein synthesis in the body.
• Haptoglobins are proteins in normal plasma which bind hemoglobin. The hemoglobin–haptoglobin complex is removed by the RE system. Intravascular hemolysis (breakdown of red cells within blood vessels) plays little or no part in normal red cell destruction.

Extravascular vs. Intravascular Hemolysis

Coombs’ Test

• Hemolytic anemias are defined as anemias that result from an increase in the rate of red cell destruction.
• Because of erythropoietic hyperplasia and anatomical extension of bone marrow, red cell destruction may be increased several‐fold before the patient becomes anemic – compensated hemolytic disease.
• The normal adult marrow, after full expansion, is able to produce red cells at 6–8 times the normal rate provided this is ‘effective’. It leads to a marked reticulocytosis.
• Therefore, anaemia due to hemolysis may not be seen until the red cell lifespan is less than 30 days.

• Features of increased red cell breakdown:
  • Serum bilirubin raised, unconjugated and bound to albumin;
  • Urine urinobilinogen increased;
  • Serum haptoglobins absent.
• Features of increased red cell production:
  • Reticulocytosis;
  • Bone marrow erythroid hyperplasia; the normal marrow myeloid:erythoid ratio of 2:1 to 12:1 is reduced to 1:1 or reversed.
• Damaged red cells:
  • Morphology (e.g. microspherocytes, elliptocytes, fragments);
  • Osmotic fragility;
  • Specific enzyme, protein or DNA tests.

Intravascular Hemolysis

• Free hemoglobin is released which rapidly saturates plasma haptoglobins and the excess free hemoglobin is filtered by the glomerulus → hemoglobinemia.
• If the rate of hemolysis saturates the renal tubular reabsorptive capacity, free hemoglobin enters urine → hemoglobinuria.
• Iron released from hemoglobin in the renal tubules is seen as hemosiderin in a urinary deposit → hemosiderinuria.
• Methaemalbumin is also formed from the process of intravascular hemolysis → methemalbuminemia (detected spectrophotometrically)

Hereditary Hemolytic Anemia

Hereditary Spherocytosis (HS)

• The most common hereditary hemolytic anemia in Northern Europeans.
• Autosomal dominant with variable expression; rarely it may be autosomal recessive.
• Caused by defects in the proteins involved in the vertical interactions between the membrane skeleton and the lipid bilayer of the red cell.
• The marrow produces red cells of normal biconcave shape but these lose membrane and become increasingly spherical (loss of surface area relative to volume) as they circulate through the spleen and the rest of the RE system.

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Ultimately, the spherocytes are unable to pass through the microcirculation, especially in the spleen, and die prematurely.

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• Reticulocytes are usually 5–20%.
• Jaundice is typically fluctuating and is particularly marked if the hemolytic anaemia is associated with Gilbert’s disease (a defect of hepatic conjugation of bilirubin); splenomegaly occurs in most patients.