In intravascular hemolysis RBCs lyse in the circulation releasing hemoglobin into the plasma. The fragmented RBCs are called schistocytes. In extravascular hemolysis RBCs are phagocytized by macrophages in the spleen and liver. Causes include RBC membrane abnormalities such as bound immunoglobulin, or physical abnormalities restricting RBC deformability that prevent egress from the spleen. Extravascular hemolysis is characterized by spherocytes.
Intravascular hemolysis releases hemoglobin which is immediately bound by haptoglobin.
Hemoglobin-haptoglobin is cleared almost immediately from the plasma by hepatic reticuloendothelial cells. As intravascular hemolysis with binding to haptoglobin generally overwhelms the rate of haptoglobin synthesis, haptoglobin levels decrease. After haptoglobin is saturated, excess hemoglobin is filtered in the kidney and reabsorbed in the proximal tubules where the iron is recovered and converted into ferritin or hemosiderin. Hemoglobinuria indicates severe intravascular hemolysis overwhelming the absorptive capacity of the renal tubular cells. Urine hemosiderin is another indicator that intravascular free hemoglobin is being filtered by the kidneys.