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

only minimally enriched with old cells, and biotinylated aged cells exposure is greatest in young erythrocytes, and does not increase with
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of rabbits have been found to have only a modestly decreased surface aging. It is not yet clear whether phosphatidylserine exposure is the
area, volume, cell water, and density, and therefore slightly decreased only or even the primary signal that indicates that a cell has reached the
deformability. 51,63 end of its life span, but it is the only major difference between senescent
As they circulate red cells lose a substantial portion of their mem- and nonsenescent erythrocytes that has been documented clearly. 72
brane and hemoglobin in the form of vesicles (reviewed in Ref. 64). The Several proteins were described that bind to phosphatidylserine-
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loss of membrane material in hemoglobin vesicles may play a role in the expressing apoptotic cells including lactadherin, gas-6, Del-1, and
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aging process. In normal blood, a small number of red cell vesicles, several complement components. These proteins act as opsonins in
approximately 190/μL blood, can be harvested. During storage of RBCs, promoting the clearance of phosphatidylserine-expressing cells by
the aggregates of vesicles are formed and may contribute to acute lung macrophages. Angiogenic endothelial cells also express several integrin
injury by interacting with neutrophils. 66 associated with phagocytosis in macrophages and can engulf phosphat-
idylserine expressing “aged” erythrocytes and may play a role in clear-
MECHANISM OF DESTRUCTION OF ance of senescent cells. 80
Eryptosis is defined as cell shrinkage and exposure of phosphat-
NORMAL, AGED CELLS idylserine caused by entry of calcium ions followed by activation of
Several different mechanisms of senescent red cell destruction have been a scramblase, an enzyme capable of randomizing the distribution of
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proposed. Determining the actual mechanism(s) is especially difficult phospholipid in both membrane bilayers. It may contribute to red cell
because the cells that are marked for removal are bound to be present clearance in diseased states, but its role in senescence associated clear-
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at very low concentrations or not at all in the circulating blood—they ance is not clear. 82
have been removed. Many of the earlier data are predicated upon the Another model that has been proposed is based upon a slight
isolation of dense cells and the consideration that they are “old”; we now increase in green autofluorescence, believed to represent the result of oxi-
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recognize that they are not (see “Methodologic Considerations” above). dative damage, which has been observed in aging murine erythrocytes.
Moreover, it is likely that there is more than one mechanism that serves Interaction of erythrocyte cell surface antigen CD44 with hyaluronic
to remove effete red cells from the circulation; there is no known muta- acid may play a role in the clearance of aged erythrocytes from the circu-
tion that lengthens red cell life span. lation, but such clearance seems limited to primates, and a patient with
CD44 deficiency manifested congenital dyserythropoietic anemia. 84
Band 3 Clustering Models
It has been proposed that an altered membrane band 3 serves as a recep- NEOCYTOLYSIS
tor for antibodies directed against a neoantigen, designated senescent-
cell antigen, and that possibly after-binding complement marks the Hypoxia increases RBCs by enhancing hypoxia-inducible factors (HIFs).
senescent cell for destruction. It is not known how clustering of band Upon return to normoxia, the secondary polycythemia is overcorrected,
3 occurs in vivo and recent work suggests peroxidation of cytoplasmic as the accumulated, newly formed RBCs undergo preferential destruc-
aspect of band 3 results in carbonylation. Methemoglobin binds to the tion, a process termed neocytolysis; however, its mechanism is unclear.
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cytoplasmic peroxidized domain of band 3 and induces cluster forma- Neocytolysis was originally observed during space travel at zero grav-
tion. But much, if not all, of the evidence for these models depends ity wherein the mechanism is even less clear. It has been suggested that
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upon the assumption that dense cells are old, and the uptake of cells on return to normoxia, there is excessive generation of reactive oxygen
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by monocytes as a surrogate for their being marked for destruction. species from increased mitochondrial mass correlating with decreased
However, immunoglobulin levels on aged, biotinylated rabbit cells hypoxia controlled gene BNIP3L transcripts, 85,86 as BNIP3L mediates
are not increased, and the fact that red cell life span has never been removal of reticulocyte mitochondria accompanied by reduced catalase
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demonstrated to be prolonged in agammaglobulinemic patients casts activity. Rapid changes in hematocrit in human newborns also suggest
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serious doubt upon the concept that immunoglobulins mediate removal that neocytolysis also occurs after birth when a hypoxic fetus is poly-
of senescent red cells. cythemic at birth, but the neonate rapidly overcorrects its increased red
cell mass and becomes anemic in first 2 weeks of life. 88,89
Phosphatidylserine Exposure Models
In RBCs, as in most other cells, the anionic phospholipid phosphati-
dylserine is present exclusively in the inner cytoplasmic leaflet of the MECHANISMS OF DESTRUCTION
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membrane bilayer. The exposure of phosphatidylserine on the outer “Senescence of Normal Erythrocytes,” above, enumerated some mecha-
leaflet of the cell membrane is one of the signals that allows macro- nisms that may be involved in normally terminating the life of the effete
phages to recognize apoptotic cells. It is likely that this is, indeed, at erythrocyte. It has sometimes been assumed that the mechanisms by
least one of the signals by which macrophages recognize senescent ery- which red cells are destroyed prematurely in disease states reflect these
throcytes. 5,71,72 Data from a biotinylated rabbit erythrocyte model sug- normal mechanisms. Although there may well be some overlap, the
gests that the average time during which phosphatidylserine is exposed mechanisms of red cell destruction in disease states are likely differ-
is only 0.3 to 0.5 days, so that few cells with increased exposure of ent. The assumption that the mechanisms that bring around hemolytic
the phospholipid are in the circulation at any time. An increase of anemia represent premature aging of the erythrocyte is no more logical
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phosphatidylserine exposure has also been documented in humans than to suggest that an animal’s death through pneumonia, renal failure,
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descending from high altitudes. The exposure of phosphatidylser- or cancer represents premature aging.
ine on the outer leaflet of the cell membrane is one of the signals. A
proposed model for the destruction of newly formed cells was that
endothelial cells might respond to changes in circulating erythropoi- INTRAVASCULAR DESTRUCTION
etin by influencing the interaction of phagocytes with young red cells, If the red cell membrane is breached in the circulation the red cell is
targeting the cells by surface adhesion molecules. A study in mice, destroyed. This mode of erythrocyte demise occurs at a low frequency,
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using somewhat different methods, suggested that phosphatidylserine but may be the predominant mode of destruction in some hemolytic

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