DOWNSIZING OF THE RED CELL MASS IN CIRCUMSTANCES OF AN
OF RED BLOOD CELLS
Clarence P. Alfrey and Lawrence Rice*
Section of Hernatology - Oncology, Baylor College of Medicine, Houston, Texas, USA
In contrast to the augmentatíon in red cell production resultant froni anemia or hypoxia,
the down regulation resultant from an excess of red cells has been litúe studied. In this
review, we have cited studies from altitude medicine and spaceflight which illustrate the
kinetics and mechanisms involved in both processes. Downregulation occurs quickly and is
associated with destruction of recently produced red celis (neocytolysis). The
significance of neocytolysis to anemia of spaceffight, deadaptation to altitude, athletic
training and anemia of renal disease have been noted.
The mechanism by which the number of circulating red cells is ínereased as a consequence
of anenúa or hypoxia has been defined. In contrast, the responses which cause down
regulation of the erythron have been less well documented.
AUGMENTATION OF ERYTHROPOIESIS
Anemia or hypoxia causes the oxygen content of blood perfusing the kidneys to have a
decrease in oxygen content which results in augmentation of erythropoietin production
relative to baseline values. The increase in blood leveís of erythropoietin causes an
increase in the number of progenitor celis committed to become erythrocytes, an increase
in the number of divisions of primitive red cell precursors and a decrease in the rate of
apoptosis of colony forming units erythroid (CFU-E). The rate of maturation of committed
red cells (as manifest by hemoglobín synthesis) is litúe changed and the effects to
increase reticulocytes or augment the number of circulating red cells is not observed for
one week or more. When the increase in erythropoiesis causes the red cell mass to
increase, then serum ferritin decreases reflecting a transfer of the ¡ron in stores to
hemoglobin in circulating red cells. The decrease in serum ferñtin is therefore observed
when pernicious anemia is treated with B12 injections, astronauts return from spaceflight
with a decreased red cell mass, persons go to high altitude or normal persons receive
As noted above, augmentation of red blood cell mass cannot be appreciated for at least a
week following an increase in serum erythropoietin, reflecting the time required for
transit of an individual cell through the process of maturation including heme synthesis.
This period has been defined by observing the time required for intravenotisly injected
radioiron to appear in circulatíng red blood cells.
DOWNSIZING OF THE RED CELL MASS
A decrease in erythropoietin concentration results in a decrease in the number of
committed red cells, decreased rate of division of primítive cells or increase in the
rate of apoptosis, but cannot ínfluence the number of circulating red cells for a week or
more because those cells already in the pipeline would be expected to mature. After one
week of persisting erythropoietin suppression, the rate of change in red cells would be
expected to be less than one percent per day reflecting the survival of normal red cells.
Observations of Merino (Merino, 1950) and others (Pace et al., 1956) on long time
residents of high altitude who go to sea level indicate that their hemoglobin levels
decrease by ten percent or more during the first week. A rate which is more than can be
explained by the mechanisms described above. Astronauts who enter microgravity have a
decrease in red cell mass as a consequence of a decrease in blood contained in capacitance
blood vessels and thus "relative plethora." A decrease of twelve to fifteen
percent oceurs in less than ten days (Alfrey et al., 1996). In both high altitude dwellers
going to sea level (Rice et al., 200 1) and astronauts entering n*rogravity (Alfrey et
al., 1996; Udden et al., 1995) the decrease in red cell mass follows a decrease in
erythropoietin concentration in blood.
Merino (Merino 1950) found that fóllowing descent to sea level of high altitude residents
that serum indirect bilirubin and fecal urobilinogen increased consistent with an
increased rate of destruction of red cells. Huff (Huff 195 1) perfórmed ferrokinetic
studies on high altitude residents at sea level. He found erythropoiesis as reflected by
uptake of intravenously injected radioiron remained at baseline levels for one week and
then decreased to low levels consistent with a decrease in new red cell production. We
made similar observations in astronauts who were injected with radioiron after twenty four
(Udden et al, 1995) or seventy two hours (Alfrey et al., 1996) in spaceflight. In both
instances red cell production continued for one week at the same rate as had been observed
on earth one month earlier. Thus in neither case could the decrease in red cell mass be
attributed to change in production of red cells.
RED CELL SURVIVAL
The life span of circulating red cells was measured in each of six astronauts befóre and
during spaceflight (Alfrey et al., 1996; Udden et al., 1995) . The survival of red cells
labeled with chromium twelve days before launch was the same inflight as preflight. In the
fust four to six days of weightlessness there was selective loss of red cells which had
been in the circulation for twelve days or less (¡ron labeled red cells) on launch day.
The selective destruction of young red cells accounts for the decrease in red cell mass
during spaceflight and has been termed neocytolysis (Alfrey et al., 1997).
The mechanisms through which selective destruction of red cells occurs has not been
defined although it is well known that red cells recently released from bone marrow are
captured in the spleen where DNA particles (Howell Jolly bodies) are removed and the
membrane remodeled. In a circumstance in which the erythropoietin leve¡ is below a
threshold value, destruction of the captured red cells might occur. Trial (Trial et al.,
2001) has shown that splenic endothelial cells have erythropoietin receptors and that the
porosity of an endothelial membrane is increased when erythropoietin levels fall.
ROLE OF ADAPTATION
Neocytolysis effects rapid adaptation to a new environment in which fewer red cells are
required. Once the neocytolysis has occurred, the red cell mass may be near optimal to the
new environment and erythropoietin production would be expected to return to near baseline
levels. This was observed during the second week of spaceflight (Udden et al., 1995). This
process may not be desirable for the long time resident at high altitude that makes a
short visit to lower altitude causing rapid deadaptation to his place of residence.
Similarly neocytolysis may limit the duration of improved performance by athletes who
train at high altitude.
SIGNIFICANCE OF NEOCYTOLYSIS
In a previous study of renal failure (Rice et al., 1999), we showed that decrease in
erythropoietin levels were associated with neocytolysis. In addition, neocytolysis likely
explains why subcutaneous adnínistration of erythropoietin which avoids subthreshold
nadirs is more efficient than intravenous administration. Thus, the implications of
neocytolysis extend broadly beyond altitude and spaceflight adaptation. The
pathophysiologic implications should extend to neonatal horneostasis,
"b1ood?doping" by endurance athletes, hemolytic anemias and polycythernic
autbor address: Professor Clarence P. Alfrey, Baylor College of Medicine and The Methodist
Hospital, 6565 Fannin, MS 902, Room 930, Houston, Texas, 77030 USA, telephone:
713.441?2127, fax: 713.790.0828, e-mail: firstname.lastname@example.org