Causes of disorders extrinsic to the RBC include

Infectious organisms may cause hemolytic anemia through the direct action of toxins (eg, from Clostridium perfringens, alpha- or beta-hemolytic streptococci, meningococci), by invasion and destruction of the RBC by the organism (eg, Plasmodium sp, Bartonella sp), or by antibody production (Epstein-Barr virus, mycoplasma).

Defects intrinsic to the RBC that can cause hemolysis involve abnormalities of the RBC membrane, cell metabolism, or hemoglobin structure. Abnormalities include hereditary and acquired cell membrane disorders (eg, spherocytosis), disorders of RBC metabolism (eg, G6PD deficiency), and hemoglobinopathies (eg, sickle cell diseases, thalassemias). Quantitative and functional abnormalities of certain RBC membrane proteins (alpha- and beta-spectrin, protein 4.1, F-actin, ankyrin) cause hemolytic anemias.

Senescent RBCs lose membrane and are cleared from the circulation largely by the phagocytic cells of the spleen, liver, bone marrow, and reticuloendothelial system. Hemoglobin is broken down in these cells primarily by the heme oxygenase system. The iron is conserved and reutilized, and heme is degraded to bilirubin, which is conjugated in the liver to bilirubin glucuronide and excreted in the bile.

Most pathologic hemolysis is extravascular and occurs when damaged or abnormal RBCs are cleared from the circulation by the spleen and liver. The spleen usually contributes to hemolysis by destroying mildly abnormal RBCs or cells coated with warm antibodies. An enlarged spleen may sequester even normal RBCs. Severely abnormal RBCs or RBCs coated with cold antibodies or complement (C3) are destroyed within the circulation and in the liver, which (because of its large blood flow) can remove damaged cells efficiently. In extravascular hemolysis, the peripheral smear may show microspherocytes.

Intravascular hemolysis is an important reason for premature RBC destruction and usually occurs when the cell membrane has been severely damaged by any of a number of different mechanisms, including autoimmune phenomena, direct trauma (eg, march hemoglobinuria), shear stress (eg, defective mechanical heart valves), and toxins (eg, clostridial toxins, venomous snake bite). The peripheral smear may show schistocytes or other fragmented red cells.

Intravascular hemolysis results in hemoglobinemia when the amount of Hb released into plasma exceeds the Hb-binding capacity of the plasma-binding protein haptoglobin, a protein normally present in concentrations of about 100 mg/dL (1.0 g/L) in plasma. Unbound plasma haptoglobin levels will be low. With hemoglobinemia, unbound Hb dimers are filtered into the urine and reabsorbed by renal tubular cells; hemoglobinuria results when reabsorptive capacity is exceeded. Iron is embedded in hemosiderin within the tubular cells; some of the iron is assimilated for reutilization and some reaches the urine when the tubular cells slough.

Unconjugated (indirect) hyperbilirubinemia and jaundice occur when the conversion of hemoglobin to bilirubin exceeds the liver’s capacity to conjugate and excrete bilirubin (see Overview of Biliary Function). Bilirubin catabolism causes increased stercobilin in the stool and urobilinogen in the urine and sometimes cholelithiasis.

The bone marrow responds to the excess loss of RBCs by accelerating production and release of RBCs, resulting in a reticulocytosis.