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498 Part VI: The Erythrocyte Chapter 33: Erythrocyte Turnover 499

disorders, for example, ABO-incompatible transfusions (Chap. 138) glycoprotein, each molecule of haptoglobin can bind two hemoglobin
and paroxysmal nocturnal hemoglobinuria (Chap. 40), where the sur- dimers. The binding of hemoglobin not only protects against its poten-
face complement complex creates pores in the red cell membrane, and tial toxicity, it also triggers the second step of the scavenging process,
in cardiac valve hemolysis (Chap. 51) and microangiopathic hemolytic that is, recognition by macrophage receptor CD163, and subsequent
anemia (Chaps. 51 and 132), where the shear stress may be so strong as clearance of the entire complex by receptor-mediated endocytosis.
96
to break open the membrane. CD163 belongs to the scavenger receptor cysteine-rich family of pro-
teins and the haptoglobin–hemoglobin complex is cleared from the
EXTRAVASCULAR DESTRUCTION plasma with a T of 10 to 30 minutes. The heme of the hemoglobin is
1/2
Most commonly, the life of the red cell comes to an end when it is converted to iron and biliverdin by heme oxygenase and the biliverdin is
further catabolized to bilirubin. CO is released (see “Indirect Methods,”
ingested by a macrophage. Clearly, signals that allow the macrophage to above, on measuring red cell life span) in the course of cleavage of heme
distinguish the younger normal red cell from a damaged or senescent by heme oxygenase. 97
cell must exist. Such signals may consist of decreased deformability and/
or altered surface properties.
Haptoglobin
Decreased Deformability Free haptoglobin, in contrast to the hemoglobin–haptoglobin complex,
The red cell does not circulate as the biconcave disc customarily has a T of 5 days, and when large amounts of the rapidly turned over
1/2
observed under the microscope. Instead, it is normally greatly distorted haptoglobin–hemoglobin complex are formed, the haptoglobin con-
by the shear stresses in the circulation and such distortion is an abso- tent of the plasma is depleted. The haptoglobin content of the plasma is
lute requirement for the red cell to be able to negotiate the narrow slits diminished not only in the plasma of patients undergoing frank intra-
that separate the splenic pulp from the sinuses (Chaps. 6 and 56). The vascular hemolysis, but also from the plasma of patients who, like those
deformability of the erythrocyte can be measured clinically using the with sickle cell disease, have accelerated red cell destruction occurring
ektacytometer, an instrument that displays the diffraction pattern of primarily within macrophages. Presumably there is either enough intra-
a red cell suspension under shear stress. 90,91 The red cell membrane, a vascular hemolysis in such hemolytic disorders to lower the plasma
lipid bilayer, bends readily but has very little capacity to stretch. Thus, haptoglobin level or sufficient leakage from the phagocytic cells into the
deformability is largely a function of the excess red cell membrane plasma to bind to haptoglobin. Thus the measurement of plasma hap-
intrinsic to the biconcave disc shape of the cell, membrane composition, toglobin levels has usefulness in diagnosing the presence of hemolysis,
and to some extent, of the viscosity of the hemoglobin solution within although it cannot, as previously suggested, serve to clearly distinguish
the cell. As the red cell loses membrane it assumes a spherical shape extravascular from intravascular hemolysis.
and loses its ability to deform. Hereditary spherocytosis and hereditary
elliptocytosis are prototypic of hemolytic anemias in which decreased Heme
deformability as a result of a decreased surface-to-volume ratio plays a Free heme that is released into the circulation is bound in a 1:1 ratio to
98
key role in red cell destruction (Chap. 46). However, loss of membrane the plasma glycoprotein hemopexin, which is cleared from the plasma
plays a role in many types of pathologic hemolysis, including autoim- with a T of 7 to 8 hours. 99,100 The heme–hemopexin complex is taken
1/2
101
mune hemolytic anemia (Chap. 54). In sickle cell disease and hemoglo- up by a low-density lipoprotein-related receptor, CD91. Figure 33–3
bin C disease (Chap. 49), the internal viscosity of the cell is increased. illustrates the parallel functions of hemopexin and haptoglobin. When
Loss of water from the red cell, as may occur when the membrane is the capacity of hemopexin to bind heme is saturated, excess heme may
102
damaged and leaks potassium as in hereditary xerocytosis (Chap. 46), bind to albumin to form methemalbumin. Excess heme is toxic to
also markedly impairs the deformability of the cell. cells because of the ability of heme to catalyze the so-called Fenton reac-
tion, generating hydroxyl radicals, a highly reactive oxygen species. To
Altered Surface Properties avoid the phenomenon and complement the negative feedback regu-
The surface of the red cell membrane can be altered by binding of anti- lation of heme synthesis, the expression of heme oxygenase (HO)-1 is
bodies to surface antigens, by binding of complement components, and induced in response to an increased level of heme, which subsequently
by chemical alterations, particularly oxidation of membrane compo- results in the degradation of excess heme not bound to proteins. In con-
nents. Immunoglobulin (Ig) G–coated red cells and red cells coated by trast to HO-1, HO-2 is constitutively expressed and participates in the
92
the third component of complement (C ) 93,94 are bound by Fc receptors regulation of a basal heme level.
3
on macrophages and undergo partial phagocytosis. This results in the
formation of a spherocyte. EXTRAVASCULAR DESTRUCTION
In vitro oxidation of red cells with phenylhydrazine or adenosine
diphosphate (ADP) plus iron causes clustering of band 3 protein in the Red cells that are engulfed by phagocytic cells are degraded within lys-
membrane. Although the physiologic significance of this is far from osomes into lipids, protein, and heme. The proteins and lipids are repro-
clear, it has been suggested that the clustered protein serves as a recog- cessed in their respective catabolic pathways and the heme is cleaved by
103
nition site for the binding of IgG. Oxidative damage to the membrane a microsomal HO. HO catalyzes the oxygen-dependent degradation
9,95
may play a role in the removal of sickle cells (Chap. 49) and thalassemic of heme to biliverdin with the release of CO and “free” iron. Biliverdin
cells from the circulation (Chap. 48). is converted into bilirubin by biliverdin reductase α (BVRα), which is
expressed ubiquitously in all tissues under basal conditions with high
levels in macrophages in the spleen and liver. The overall reduction of
104
FATE OF DESTROYED RED CELLS biliverdin to bilirubin is very efficient, and under physiologic circum-
stances, the concentration of serum biliverdin is low.
INTRAVASCULAR DESTRUCTION
Hemoglobin Bilirubin Excretion
When red cells are destroyed in the vascular compartment the hemo- Regardless of the site of destruction of hemoglobin, one of the final
globin escaping into the plasma is bound to haptoglobin. A dimeric products is bilirubin. Bilirubin is very insoluble and transported in

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