Shortening of the normal red cell life span, that is . premature destruction of red cells



Accumulation of the products of hemoglobin catabolism.

A marked increase in erythropoiesis within the bone marrow, in an attempt to compensate for the loss of red cells.

The psysiologic destruction of senescent red cells takes place within the mononuclear phagocytic cells of the spleen. In hemolytic anemias, too the premature destruction of red cells occurs predominantly, within the mononuclear phagocyte system (extravascular hemolysis). In only a few cases does lysis of red cells within the vascular compartment (intravascular hemolysis predominate.

Intravascular hemolysis occurs when normal erythrocytes are damaged by mechanical injury complement fixation to red cells, or exogenous toxic factors. Trauma to red cells may be caused by mechanical cardiac valves or by thrombi within the microcirculation. Complement fixation may occur on antibody coated cells during transfusion of mismatched blood. Toxic injury is exemplified by falciparummalaria and clostridial sepsis.

Whatever the mechanism, intravascular hemolysis I smanifested by (1) hemoglobinemia, (2) hemoglobinuria, (3) methemalbuminemia, (4) jandice and (5) hemosiderinuria. When hemoglobin escapes into the plasma it is promptly bound by an ?2-globulin (haptoglobin) to produce a complex that prevents excretion into the urine, since the complexes are rapidly cleared by the reticuloendothelial system. A decrease in serum haptoglobin level is characteristically seen in all cases of intravascular hemolysis. When the haptoglobin is deleted, unbound or free hemoglobin is in part rapidly oxidized to methemoglobin and both hemoglobin and methemoglobin are excreted through the kidneys imparting a red brown color to the urine- hemoglobinuria and methemoglobinuria. The renal proximal tubular cells may reabsorb and catabolize much of this filtered hemoglobin, but some passes out with the urine. Within the tubular cells, iron released from the hemoglobin may accumulate giving rise to hemosiderosis of the renal tubular epithelium. Concomitantly, the heme groups derived from the complexes are catabolized within the mononuclear phagocyte system, leading ultimately to jaundice. In hemolytic anemias, the serum bilirubin is unconjugated and the level of hyperbilirubinemia depends on hemolysis. With a normal liver the jaundice is rarely severe. Excessive bilirubin excreted by the liver into the gastrointerstinal tract leads eventually to increased formation and fecal excretion of urobilin.

Extravascular hemolysis takes place whenever red cells are injured are rendered foreigh or become less deformable. For example in hereditary spherocytosis an abnormal membrane cytoskeleton decreases the deformability of the red cell. Analogously, in sickle cell anemia the abnormal hemoglobin gels or crystallizes within the erythrocyte deforming it and reducing its plasticity. Since extreme alterations in shape are required for red cells to navigate the splenic sinusoids successfully, reduced deformability makes the passage difficult and leads to sequestration within the cords, followed by phagocytosis. This is believed to be an important pathogenetic mechanism of extravascular hemolysis in a variety of hemolytic anemias. With extravascular hemolysis, it is obvious that hemoglobinemia, hemoglobinuria, and the related intravascular changes do not appear. However, the catabolism of erythrocytes in the phagocytic cells induces anemia and jaundice that are otherwise indistinguishable from those caused by intravascular hemolysis. Furthermore, since some hemoglobin manages to escape from the phagocytic cells plasma haptoglobin levels are invariably reduced. The morphologic changes that follow are identical to those in intravascular hemolysis except that the erythrophagocytosis generally causes hypertrophy of the mononuclear phagocyte system of cells, and this may lead to splenomegaly.

The hemolytic anemias can be classified in a variety of ways. One has already been suggested, namely division into intravascular and extravascular hemolytic disorders. However, since the number of disorders with predominantly intravascular hemolysis is limited, this classification is not entirely satisfactory. A pathogenetic classification could be based on whether the underlying cause of red cell destruction is extrinsic (extracorpuscelar mechanism) or a defect inherent in the red cell (intracorpuscular defect). These anemias can also be divided into hereditary and acquired disorders. In general , hereditary disorders are due to intracorpuscular defects and the acquired disorders to extrinsic factors such as sutoantibodies.