INCREASED DESTRUCTION OF RBC

• Hemolysis


  Increased rate of destruction (lysis) of red blood cells, shortening their life span
• Hemolytic disorder


  Increased rate of destruction of red blood cells
• Hemolytic anemia


  Reduced number of red blood cells resulting in reduced tissue oxygenation and increased erythropoietin production by the kidney
• Healthy bone marrow can increase its production of red blood cells by four to eight times normal
• Significant red blood cell destruction must occur before an anemia develops during hemolysis
• Classification of hemolytic anemias

  • Acute vs chronic
  • Inherited vs acquired
  • Intrinsic vs extrinsic
  • Intravascular vs extravascular
  • Fragmentation vs macrophage-mediated
• Acute hemolysis


  Rapid onset, isolated, episodic, or paroxysmal
• Chronic hemolysis


  May not be evident if bone marrow is able to compensate, but may be punctuated over time with hemolytic crises that cause anemia
• Intrinsic hemolytic disorders


  Abnormalities of the red blood cell membrane, enzymatic pathways, or the hemoglobin molecule
• Extrinsic hemolytic conditions


  Arise from outside the red blood cell, typically substances in plasma or conditions affecting the anatomy of the circulatory system
• Intravascular hemolysis


  Occurs by fragmentation, most often within the bloodstream
• Macrophage-mediated hemolysis


  Red blood cells are engulfed by macrophages and lysed inside the phagocyte by their digestive enzymes
• Normal macrophage-mediated hemolysis and bilirubin metabolism


  1. Macrophages of the mononuclear phagocyte system recognize changes in aged red blood cells and phagocytize them

  2. Hemoglobin is hydrolyzed into heme and globin

  3. Iron is released from heme, returned to plasma via ferroportin, bound to transferrin, and recycled

  4. Protoporphyrin component is catabolized and the products are processed in the liver, move to the intestines, and are excreted mostly in the stool

  5. Bilirubin and urobilinogen are the excretory products derived from the protoporphyrin component of heme
• Protoporphyrin catabolism


  1. Heme oxygenase acts on protoporphyrin, breaking the ring to yield biliverdin

  2. Lungs excrete carbon monoxide as a byproduct

  3. Biliverdin is reduced to bilirubin

  4. Bilirubin is conjugated in the liver and excreted in bile
• The majority of red blood cell degradation occurs inside macrophages as enzymes of the macrophage phagolysosome rupture phagocytized erythrocytes and salvage or metabolize the contents
• Virtually all red blood cell iron is recycled
• Bilirubin and urobilinogen are the excretory products derived from the protoporphyrin component of heme
• Macrophage phagolysosome rupture


  1. Phagocytized erythrocytes

  2. Salvage or metabolize the contents
• Hemoglobin


  Hydrolyzed into heme and globin
• Hemoglobin degradation


  1. Heme

  2. Iron released from heme

  3. Returned to plasma via ferroportin

  4. Bound to transferrin

  5. Recycled to needy cells

  6. Protoporphyrin catabolized

  7. Bilirubin and urobilinogen excreted
• Protoporphyrin catabolism
• Protoporphyrin catabolism


  1. Heme oxygenase acts on protoporphyrin

  2. Yields biliverdin

  3. Biliverdin reduced to bilirubin
• Bilirubin is a nonpolar yellow molecule secreted into the blood
• Unconjugated bilirubin must bind to albumin for transport in blood to the liver
• Blood circulation in the liver

  • Blood enters the liver lobule via hepatic artery and portal vein
  • Blood percolates through sinusoids around hepatocytes towards central vein
• Bilirubin metabolism in the liver

  1. Bilirubin enters liver sinusoid

  2. Dissociates from albumin

  3. Carried into hepatocyte by OAT proteins

  4. Bound to ligandin

  5. Conjugated with glucuronic acid by UGT1A1

  6. Conjugated bilirubin excreted into bile canaliculi by MRP2
• Conjugated bilirubin assists with emulsification of fats for absorption from the diet
• Hepatocytes at the exterior of the lobule receive the highest concentration of unconjugated bilirubin
• Conjugated bilirubin recycling


  1. Exported into sinusoidal blood via MRP3

  2. Absorbed downstream by hepatocytes via OATP1B1

  3. Exported into canaliculi
• Intestinal metabolism of conjugated bilirubin

  1. Oxidized by gut bacteria into urobilinogen

  2. Urobilinogen absorbed into portal circulation

  3. Recycled into bile
• Urobilinogen excretion


  1. Filtered at renal glomerulus

  2. Excreted in urine
• Urobilinogen, not urobilin, causes the yellow color of urine
• Fragmentation hemolysis


  Trauma to RBC membrane causes contents to spill into plasma
• Approximately 10-20% of normal RBC destruction is via fragmentation
• Haptoglobin-hemopexin-methemalbumin system


  • Salvages hemoglobin iron and prevents oxidation reactions
• Hemoglobin salvage


  1. Hemoglobin binds to haptoglobin

  2. Avoids filtration at glomerulus

  3. Iron saved from urinary loss
• Haptoglobin-hemopexin-methemalbumin system


  Mechanism to salvage hemoglobin iron and prevent oxidation reactions
• Haptoglobin


  Liver-produced plasma protein that binds to hemoglobin dimers, preventing filtration at the glomerulus and saving the iron from urinary loss
• Hemopexin


  Liver-produced plasma protein that binds to free heme (metheme), saving the iron from urinary loss and preventing oxidant injury to cells and tissues
• Metheme-albumin system


  Albumin acts as a temporary carrier for metheme, which is then rapidly transferred to hemopexin