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496 Part VI: The Erythrocyte Chapter 33: Erythrocyte Turnover 497

Hypersplenism SURFACE COUNTING FOR CHROMIUM-51
Normal (Hereditary Spherocytosis)
Surface counting for Cr-labeled red cells provides a characteristic
51
organ distribution of radioactivity and has been used to demonstrate
Marrow the degree of red cell sequestration and destruction in an enlarged
2 2 Marrow Spleen spleen (see Fig. 33–2). This approach has been used to predict the
46
results of elective splenectomy, but the utility of this method has been
Liver challenged. The in situ localization of red cell sequestration or destruc-
47
1 1
tion can also be determined by following the tissue distribution of
Spleen Blood Liver 59 Fe-labeled red cells, especially if the red cell life span is very short.
Blood
0 0
0 2 4 6 8 10 0 2 4 6 8 10 SENESCENCE OF NORMAL ERYTHROCYTES
Methodologic Considerations
59
Labeling a cohort of human erythrocytes with Fe and centrifuging the
cells in a density gradient demonstrates that reticulocytes and young red
59 Fe Ineffective Erythroid cells are less dense than mature red cells. 48,49 However, at the end of the
Ratio Erythropoiesis Hypoplasia life span of the labeled cohort, radioactivity is fairly evenly distributed
(Pernicious Anemia) (Aplastic Anemia) throughout red cells of all densities, with only a slight tendency of the
radioactivity to be concentrated in the more dense cells. Unfortunately,
Liver
Marrow many studies of the properties of senescent cells in the past have been
2 Spleen 2 based upon the characteristics of the most dense fraction of erythro-
cytes, using various fractionating techniques. In fact, the most dense
Spleen fraction of red cells is only slightly enriched with old erythrocytes. 50,51
1 Liver 1 A combination of density separation and elutriation seemed to provide
results superior to density separation alone using hemoglobin A con-
1C
Blood Marrow tent as a marker, but the degree of enrichment with older cells has not
Blood
0 0 been documented using actual old red cells as separated by biotinyla-
0 2 4 6 8 10 0 2 4 6 810 tion or by the mouse hypertransfusion technique. 52
Days Days There are two animal models and one human disease model that
provide cells that are truly aged. In mice, in vivo aged cells have been
59
Figure 33–2. Tissue distribution of Fe in normal subjects, hyper- produced by serially transfusing mice, maintaining polycythemia to
splenic patients, and anemic patients with ineffective and effective 53
erythropoiesis. The radioactivity is expressed on the ordinate as a ratio suppress virtually all erythropoiesis. In other species, particularly the
relative to the radioactivity measured in the same organ 15 minutes rabbit, red cells have been labeled with traces of biotin, which allows
54
after the intravenous administration of the isotope. (Redrawn with them to be recovered from the circulation. The human model is tran-
permission from Hillman RS and Finch CA: Erythropoiesis: Normal and sient erythroblastopenia of childhood (Chaps. 36 and 55), a disorder
abnormal. Semin Hematol (4):327–336, 1967.) in which there is cessation of all erythropoiesis for several months;
however, the density and deformability of the aged cells in erythroblas-
50
topenia of childhood is normal. The use of the latter model has been
59
In a normal subject, Fe injected intravenously is cleared rap- criticized because this disorder is not fully understood and the red cells
idly from the plasma, and within 24 hours approximately 85 percent in the circulation may not be entirely normal. However, the results that
55
of the radioactivity can be accounted for in the marrow. The liver and have been obtained are consistent with those obtained in animal models
the spleen divide the remaining 15 percent. Over the next 10 days the and are probably reliable (see “Properties of Aged Cells” below).
marrow radioactivity decreases gradually as a result of the release into
circulating blood of red cells labeled with radioactive hemoglobin. Pat-
terns showing different uptake and distribution of the radioactive iron PROPERTIES OF AGED CELLS
have been found for various hematologic disorders. In hypersplenism, Although the activities of a large number of enzymes, including hex-
44
the trapping and destruction of iron-labeled cells in the spleen increases okinase, glucose-6-phosphate dehydrogenase (G6PD), and pyruvate
splenic radioactivity rapidly, and in patients with erythroid hypopla- kinase (PK), are higher in reticulocytes than in mature erythrocytes,
sia the distribution of radioactive iron between liver and marrow is the activities of these enzymes do not normally continue to decline dur-
reversed (Fig. 33–2). ing the aging of the erythrocyte. 54,56 Pyrimidine-5′-nucleotidase 57,58 and
adenosine monophosphate (AMP)-deaminase 59–61 appear to be excep-
tions to this rule in that there is continuing decline of enzyme activity
IMAGING MACROPHAGES IN THE MARROW, throughout the life span of the red cell. The decrease in the activity of
these enzymes is not linear with age but exponential. This stability of
3
LIVER, AND SPLEEN many of the red cell enzymes during the aging of normal erythrocytes
More effective methods demonstrating in situ erythropoiesis involve contrasts to the circumstances that are brought about by mutations
imaging the macrophages in the marrow, liver, and spleen with a in enzymes such as G6PD and PK, where instability of the abnormal
99m
technetium-99m ( Tc) sulfur colloid or indium-111 ( In). Although enzyme leads to accelerated decay in the amount of enzyme protein,
45
111
these isotopes label primarily the monocyte-macrophage system, their a factor that surely plays an important role in the ultimate demise of
uptake is similar to that of Fe and they can be used as surrogate mark- the cell (Chap. 47). Fluorescent sorting of blood type NN erythro-
59
ers to estimate the distribution of erythroid tissue. cytes transfused into humans shows that the most dense fractions are

Kaushansky_chapter 33_p0495-0502.indd 497 9/17/15 6:10 PM