Varying degrees of splenomegaly due to “work hyperplasia” of phagocytes in the spleen
If long-standing, formation of bilirubin-rich gallstones (pigment stones) and an increased risk of cholelithiasis
Intravascular hemolysis, by contrast, is characterized by injuries so severe that red cells literally burst within the circulation. Intravascular hemolysis may result from mechanical forces (e.g., turbulence created by a defective heart valve) or biochemical or physical agents that severely damage the red cell membrane (e.g., fixation of complement, or exposure to clostridial toxins or heat). Findings that distinguish intravascular hemolysis from extravascular hemolysis include the presence of the following:
Hemoglobinemia, hemoglobinuria, and hemosiderinuria. Hemoglobin released into the circulation is small enough to pass into the urinary space. Here, it is partially resorbed by renal tubular cells and processed into hemosiderin, which is then lost in the urine when renal tubular cells are sloughed.
Loss of iron, which may lead to iron deficiency if hemolysis is persistent. By contrast, iron recycling by phagocytes is very efficient, and so iron deficiency is not a feature of extravascular hemolytic anemias.
A final feature of both intravascular and extravascular hemolysis is decreased serum levels of haptoglobin, a plasma protein that binds free hemoglobin and is then removed from the circulation. Apparently macrophages “regurgitate” sufficient hemoglobin during consumption of red cells to cause haptoglobin levels to fall, even when hemolysis is entirely extravascular.
We now turn to some of the common hemolytic anemias.
This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to the formation of spherocytes, nondeformable cells that are highly vulnerable to sequestration and destruction in the spleen. Hereditary spherocytosis is usually transmitted as an autosomal dominant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients.
Hereditary spherocytosis is caused by inherited defects in the membrane skeleton, a network of proteins that stabilizes the lipid bilayer of the red cell (
Fig. 12.1 ). The major membrane skeleton protein is spectrin, a long, flexible heterodimer that self-associates at one end and binds short actin filaments at its other end. These contacts create a two-dimensional meshwork that is connected to the transmembrane proteins band 3 and glycophorin via the linker proteins ankyrin, band 4.2, and band 4.1.
Mutations that cause hereditary spherocytosis most frequently involve ankyrin, band 3, or spectrin. The common feature of the pathogenic mutations is that they weaken vertical interactions between the membrane skeleton and intrinsic red cell membrane proteins. This defect destabilizes the lipid bilayer of red cells, which shed membrane vesicles into the circulation as they age. Little cytoplasm is lost in the process and as a result the surface area-tovolume ratio decreases progressively with time until the cells become spherical (
Fig. 12.1
The critical role of the spleen in hereditary spherocytosis is illustrated by the beneficial effect of splenectomy; although the red cell defect and spherocytes persist, the anemia is corrected. Red cells must undergo extreme degrees of deformation to pass through the splenic cords. The floppy discoid shape of normal red cells allows considerable latitude for shape changes. By contrast, spherocytes have limited deformability and are sequestered in the splenic cords, where they are destroyed by the plentiful resident macrophages.
On smears, spherocytes are dark red and lack central pallor