Vol.4, No 1, 1997 pp. 1 - 2
UC 616.15
ERYTHROPOIETIN CONSUMPTION BY ERYTHROID
PROGENITOR AND PRECURSOR CELLS - AN OLD DILEMMA
Vera Pavlović-Kentera
Institute for Medical Research, Belgrade, Yugoslavia
Hormone erythropoietin (Epo) is hematopoietic growth factor produced primarily
in the kidney and also to a small extent in the liver. The physiological
role of this hormone is to adjust the red cell mass to the actual oxygen
demand (1). This obligatory factor for erythoid cells interacts with erythroid
progenitor cells in the bone marrow stimulating them into a cell cycle,
supporting their survival and permitting their terminal differentation.
Epo exerts its effect on erythroid progenitors after binding to specific
receptors that are expressed on respective target cells. The stimulation
of the Epo production depends on the relationship between oxygen need and
oxygen supply (2), oxygen regulated feedback being the major control mechanism
of Epo production. However other factors may play a role too.
In the early days of Epo studies, in 1959, Stohlman (3) have suggested
that the size of erythron might influence the clearance of Epo through
the consumption of the hormone by erythropoietin target cells. However,
recent animal studies provided no evidence that such an effect is quantitatively
significant (4). Still, some of our and other authors' data are in consensus
with the Stohlman's suggestion (3).
In 1979 we have indirectly determined serum Epo levels in 25 aplastic
anemia patients by measuring Fe59 incorporation into red blood cells polycythemic
mice (5). When the Epo levels were compared to the serum Epo levels in
patients with anemia due to iron deficiency it was observed that patients
with aplastic anemia have higher levels of Epo at any given hemoglobin
concentration than do patients with hyperactive erythroid marrows. The
data were quoted in an Editorial by Nathan and Sytkowsky (6) as demonstrating
the inverse correlation of Epo levels with marrow activity. The finding
that patients with aplastic anemia have high Epo levels was confirmed by
Jelkmann and Wiedemann (7) but not confirmed by others (8). Similar results
to what we have found by mouse bioassay were obtained by Schrezenmeier
et al (9) in 1994 by means an ELISA serum Epo concentration measurement
in a much larger group of aplastic anemia patients. Significant negative
correlation of log Epo on hematocrit was found both in aplastic anemia
and iron deficiency or hemolytic anemia patients. However, for the same
degree of anemia log Epo levels were significantly higher than in patients
with two other anemias. Authors have suggested the possibility that the
high serum Epo levels in aplastic anemia patients might be due to a diminished
number of Epo receptor bearing erythropoietic progenitor cells. In conclusion
they have stated that results argue against the model of simple feedback
regulation via hypoxic anemia.
In 1992 we have published the paper dealing with serum Epo levels in
hemodialysed patients with anemia due to renal failure after administration
of recombinant human Epo (rHuEpo) (10). In this and the next work of ours
Epo was measured using the radioimmunoassay procedure by Dr Gisela Clemons
at Lawrence Berkeley Laboratories. Monitoring serum Epo concentrations
after the first i.v. rHuEpo injection and following another regular injection
after two months of rHuEpo therapy, at the time expansion of the cell pool
of erythroid progenitors and precursors was found in the bone marrow, demonstrated
that Epo elimination half life was reduced from 7.48h to 4.68h. Futhermore,
number of CFU-E derived colonies from the bone marrow of rHuEpo treated
patients correlated significantly with Epo elimination half life after
one bolus i.v. injection of rHuEpo. In that paper we suggested that the
expansion of erythroid progenitors and precursor cells bearing Epo receptors
and faster Epo elimination after two months of Epo therapy in the
patients studied is in line with Epo catabolism by utilization as first
proposed by Stohlman.
In consensus with our findings are the data of Kendall et al (11) showing
that in patients with megaloblastic anemia Epo levels fall immediately
after initiation of therapy, preceding the rise in the reticulocyte count.
An immediate reduction in serum Epo has been noted following therapy of
patients with iron deficiency anemia too. Kendall has suggested that the
explanation of these observations is that proliferating pool of erythroid
progenitor cells consumes available Epo.
In the same line are our results obtained by following Epo levels and
erythroid progenitors in rats exposed to chronic hypoxia. High Epo levels
after 24 hours of hypoxia were declining but were higher than in controls
after one week of hypoxia. A pronounced fall of Epo concentration was found
after two weeks of hypoxia.
The frequency of erythroid progenitors in the bone marrow and spleen
increased during the hypoxic treatment. As the most pronounced increase
in CFU-E number was found after two weeks of hypoxia, at the time of the
greatest decrease of Epo levels, it is possible that the levels of Epo
could be to some extent the consequence of an increased consumption of
Epo by enlarged CFU-E population (12).
Oxygen regulated feedback is the major control mechanism of Epo production,
but potential role of erythroid progenitor cell consumption in the regulation
Epo should not be neglected.
