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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2139-2145
Red Blood Cell Precursor Mass as an Independent
Determinant of Serum Erythropoietin Level
By
Mario Cazzola,
Roberta Guarnone,
Paola Cerani,
Esther Centenara,
Andrea Rovati, and
Yves Beguin
From the Department of Internal Medicine and Medical Therapy, Section
of Internal Medicine and Medical Oncology, and the Department of
Medicine, Division of Hematology, University of Liège,
Liège, Belgium.
 |
ABSTRACT |
Serum erythropoietin (sEpo) concentration is primarily related to
the rate of renal production and, under the stimulus of hypoxia,
increases exponentially as hemoglobin (Hb) decreases. Additional
factors, however, appear to influence sEpo, and in this work, we
performed studies to evaluate the role of the red blood cell precursor
mass. We first compared the relationship of sEpo with Hb in patients
with low versus high erythroid activity. The first group included 27 patients with erythroid aplasia or hypoplasia having serum transferrin
receptor (sTfR) levels < 3 mg/L (erythroid activity < 0.6 times
normal), while the second one included 28 patients with  -thalassemia
intermedia having sTfR levels > 10 mg/L (erythroid activity > 2 times normal). There was no difference between the two groups with
respect to Hb (8.3 ± 1.6 v 8.0 ± 1.3 g/dL, P > .05), but sEpo levels were notably higher in patients with low
erythroid activity (1,601 ± 1,542 v 235 ± 143 mU/mL,
P < .001). In fact, multivariate analysis of variance
(ANOVA) showed that, at any given Hb level, sEpo was higher in patients with low erythroid activity (P < .0001).
Twenty patients undergoing allogeneic or autologous bone marrow
transplantation (BMT) were then investigated. A marked increase in sEpo
was seen in all cases at the time of marrow aplasia, disproportionately high when compared with the small decrease in Hb level. Sequential studies were also performed in five patients with iron deficiency anemia undergoing intravenous (IV) iron therapy. Within 24 to 72 hours after starting iron treatment, marked decreases in sEpo (up
to one log magnitude) were found before any change in Hb level. Similar
observations were made in patients with megaloblastic anemia and in a
case of pure red blood cell aplasia. These findings point to an inverse
relationship between red blood cell precursor mass and sEpo: at any
given Hb level, the higher the number of red blood cell precursors, the
lower the sEpo concentration. The most likely explanation for this is
that sEpo levels are regulated not only by the rate of renal
production, but also by the rate of utilization by erythroid cells.
| |
INTRODUCTION |
IN ADULT HUMANS, erythropoietin (Epo) is
primarily made by a single organ, the kidney, outside the bone marrow
(BM) and participates in a classic negative feedback control
system.1,2 Hypoxia is the fundamental physiologic stimulus
that causes a rapid increase in renal production of erythropoietin
through an exponential increase in the number of
erythropoietin-producing cells. It is generally accepted that serum Epo
(sEpo) concentration is directly related to the rate of renal
production. Serum erythropoietin levels are in the range of 5 to 30 mU/mL in normal individuals and increase exponentially as hemoglobin
(Hb) or hematocrit (Hct) decreases, unless there is a blunted renal
production.3
With the availability of commercial immunoassays for sEpo, assessment
of endogenous Epo production has become a routine diagnostic procedure.
Serum Epo is evaluated in relation to the degree of anemia, and the
definition of defective Epo production relies on a low sEpo in
comparison to reference patients with similar Hct (or Hb).3
In the individual patient, the adequacy of endogenous Epo production
can be easily assessed through the observed/predicted log (sEpo) ratio
(O/P ratio).4 The O/P ratio is below 1 if the observed
value is lower than the predicted one; in reference subjects, the 95%
confidence interval ranged from 0.80 to 1.22.4
With the only exceptions of prematurity and renal failure,
determination of sEpo is mandatory in all anemic patients for deciding treatment with recombinant human Epo (rHuEpo).5 In fact, it is mainly in patients in whom endogenous Epo levels are inappropriately low for the degree of anemia that administration of rHuEpo can be
effective in increasing red blood cell production. In particular, several reports point to the use of a sEpo threshold of  100 mU/mL
for predicting response to rHuEpo in patients with Hb levels < 10 g/dL.6,7
Although tissue hypoxia is the fundamental physiologic stimulus that
increases renal secretion, a number of clinical observations suggest
that other factors might be involved in the regulation of Epo
production and/or may influence serum concentration. Abnormally high Epo levels have been reported in patients with aplastic
anemia,8,9 and dramatic changes in serum levels have been
described after chemotherapy10,11 and during vitamin B12 or
iron replacement therapy.12,13 These findings point to an
inverse relationship between red blood cell precursor mass and sEpo
levels.14 In this study, we performed studies to evaluate
whether the red blood cell precursor mass is an independent determinant
of sEpo concentration.
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MATERIALS AND METHODS |
Patients.
This study was designed to evaluate whether the red blood cell
precursor mass can directly and independently influence sEpo levels.
Therefore, we planned to study: (1) sEpo levels in patients with low
versus high erythroid activity; (2) the time course of sEpo in patients
undergoing myeloablative therapy for bone marrow transplantation (BMT);
and (3) the time course of sEpo in anemic patients with iron deficiency
or vitamin B12 deficiency undergoing specific replacement therapy.
Anemic patients with low versus high erythroid activity.
To identify any effect of the erythroid marrow activity on sEpo
concentration, we selected two groups of anemic patients: one with
defective erythroid proliferation and decreased numbers of erythroid
precursors (hypoproliferative anemia), the second one with ineffective
erythropoiesis and elevated numbers of marrow immature red blood cells
(proliferative anemia). The degree of erythroid proliferation was
evaluated through the serum transferrin receptor (sTfR) level (see
below). Patients with severe aplastic anemia (n = 11), pure red blood
cell aplasia (PRCA, n = 7), or mild hypoplastic anemia (n = 9) having
values for erythroid proliferation below the normal range (sTfR < 3 mg/L) were included in the hypoproliferative anemia group. Twenty-eight
individuals with -thalassemia intermedia having sTfR levels > 10 mg/Ll were included in the group of anemic patients with high erythroid
activity.
Sequential studies in patients receiving myeloablative therapy or
conventional chemotherapy.
Twenty patients undergoing allogeneic (n = 14) or autologous (n = 6)
BMT were investigated immediately before undergoing myeloablative therapy and on day 0. Previous studies on evolution of erythropoiesis and Epo after BMT15 showed that sEpo had a peak value on
day 0, while sTfR decreased sharply after conditioning to a minimum on
day 14. Therefore, for the purpose of this study, we decided to assay
sEpo and sTfR before transplant and on day 0. Similar studies were
performed in five patients undergoing chemotherapy for non-Hodgkin's
lymphoma.
Sequential studies in patients with iron deficiency anemia treated
with intravenous (IV) iron saccharate.
The five patients with severe iron deficiency anemia had a mean Hb
level of 6.4 ± 1.4 g/dL (range, 4.2 to 7.4 g/dL) and a mean serum
ferritin of 5 ± 4 µg/L (range, 2 to 10 µg/L). They received IV
iron therapy (iron oxide saccharate, Ferrum Hausman, Laboratorien
Hausman, St. Gallen, Switzerland). The total amount of iron required
was calculated according to the following formula16: total
dose (mg) = [Hb deficit (g/dL) × estimated blood volume (dL) × 3.4] + 500, where Hb deficit is the difference between 15 and
the patient's Hb level, blood volume is estimated according to sex and
body surface,17 3.4 is the factor converting g Hb to mg
iron, and 500 is an arbitrary quantity to allow for restoration of the
iron reserve. The daily dose was 100 or 200 mg of iron saccharate: this
amount was diluted in 250 mL of normal saline and infused IV over 1 hour.
Case reports.
Additional studies were performed in two patients with megaloblastic
anemia due to vitamin B12 deficiency or folic acid deficiency and in
one patient with pure red blood cell aplasia after autologous BMT for
treament of non-Hodgkin's lymphoma.
In the treatment of megaloblastic anemia, vitamin B12 was administered
intramuscular (IM) as cyanocobalamin, 500 µg per day; folic acid was administered IM at a dose of 15 mg per day.
The patient with PRCA was previously reported.18 He was
given high doses of rHuEpo (150 U/kg per day subcutaneously [SC], 5 days a week) based on previous observations on the use of Epo in the
treatment of PRCA after stem cell transplantation (reviewed in our
previous report18). During treatment, sEpo was measured on
Monday morning, ie, approximately 72 hours after the last SC rHuEpo
administration. In normal individuals receiving SC rHuEpo, sEpo
increases from basal levels of 10 to 20 mU/mL to peak values of 30 to
40 mU/mL after about 12 hours and then decreases with a half-life of
about 24 hours (see review by Cazzola et al5).
Hematologic profile.
Blood counts were determined with a Coulter Counter Model S (Coulter,
Hialeah, FL). Reticulocyte counts were performed with an automated
reticulocyte analyzer Sysmex R-3000 (Toa Medical Electronics GmbH,
Hamburg, Germany). This system performs reticulocyte analysis using
flow cytometry, with an argon laser as the light source. Whole blood
specimens stained with a fluorescent dye pass through a sheath flow
cell, where fluorescently-labeled cells are irradiated with a laser
beam and thus produce forward scatter and fluorescence. The scatter and
fluorescence are detected as indicator of the relative cell size and
the RNA content, respectively. Reticulocyte count is expressed both as
an absolute number per µL and as a percentage of red
blood cells. Dividing the reticulocyte area of the scattergram into
three sections according to the fluorescent intensity, reticulocytes
can then be fractionated into maturity stages: HFR (high fluorescence
ratio, immature reticulocytes), MFR (middle fluorescence ratio,
intermediate reticulocytes), and LFR (low fluorescence ratio, mature
reticulocytes).
Serum erythropoietin assay.
Circulating Epo levels were measured by a commercially available
radioimmunoassay (Incstar Corp, Sillwater, MN) that uses rHuEpo for
tracer and standards.4 To define Epo levels as appropriate or inappropriate for a given degree of anemia, an exponential regression of sEpo versus Hct was determined in reference subjects (102 normal individuals or patients with iron deficiency anemia, hemolytic
anemia, or hypoplastic anemia), and the 95% confidence limits were
defined. For Hct values 40%, the regression equation was: log(epo) = 3.42  (0.056 × Hct). For Hct values >40%, the regression equation was: log(epo) = 1.31 (0.003 × Hct). Based on these equations, the observed/predicted
log(epo) ratio (O/P ratio) was derived for each sample. The mean O/P
ratio in reference subjects was 1.01 ± 0.11 (95% confidence
interval, 0.80 to 1.22).
Measurement of sTfR.
The amount of circulating transferrin receptor was estimated by an
enzyme-linked polyclonal antibody assay, using purified placental
receptor-transferrin complexes as a reference standard and rabbit
antibodies as described in detail elsewhere.4 The mean sTfR
level in 165 normal control subjects was 5.0 ± 1.1 mg/L, with a
normal range from 3 to 7 mg/L.
Data analysis and presentation.
Data were stored, analyzed, and reported with the packages
STATISTICA/Mac (StatSoft, Tulsa, OK), Exstatix (Select Micro Systems Inc, Yorktown Heights, NY), and DeltaGraph Pro 3 (DeltaPoint Inc, Monterey, CA), all run on a Macintosh Quadra 800 (Apple Computer Inc,
Cupertino, CA) personal computer. Results were expressed as mean ± 1 standard deviation (SD) unless otherwise stated. The Student's
t test and/or the F test (one-way analysis of variance [ANOVA]) were used to evaluate the probability of significant differences between groups. Multivariate ANOVA was used to show any
significant difference in the regression of serum sEpo to Hb level in
different groups. P values less than .05 were considered statistically significant.
As discussed below, the number of erythroid cells in the BM may
directly influence the Epo clearance: the higher the erythroid activity, the lower sEpo level. To account for this effect of erythroid
activity on sEpo levels, the following correction was made:
where
5 mg/L is the mean normal value for sTfR, taken as a measure of
erythroid activity. For several reasons, including the impossibility of
distinguishing between erythroid and nonerythroid TfR at the lowest
sTfR levels, an additional empirical correction was introduced: the
minimum value for ln sTfR was set to 0.2. Any time the calculated value
was < 0.2, it was changed to 0.2.
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RESULTS |
Serum Epo in anemic patients with low versus high erythroid activity.
As reported in Table 1, there was no
significant difference with respect to Hb level (Student's t
test = 0.97, P  .05) between the 27 patients with low
erythroid activity (hypoproliferative anemia, sTfR < 3 mg/L) and the
28 individuals with -thalassemia intermedia and high erythroid
activity (sTfR > 10 mg). By contrast, sEpo levels were about one log
higher in patients with hypoproliferative anemia (Student's t
test = 4.67, P < .001).
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Table 1.
Hb Level, sTfR, and sEpo in Anemic Patients With Low
Erythroid Activity (Hypoproliferative Anemia) Versus Anemic Patients With High Erythroid Activity (-Thalassemia Intermedia)
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Figure 1A displays the relationship of sEpo
to Hb observed in the two groups of patients. A significant inverse
relationship between Hb and sEpo was found in both patient populations
(P < .001 in both groups). However, multivariate
ANOVA showed that at any given Hb level, sEpo was higher in patients
with low versus high erythroid activity (the multivariate tests Rao's
R and Pillai-Bartlett Trace V were both significant at P < .0001).
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| Fig 1.
Relationship of sEpo to Hb observed in 27 patients with
hypoproliferative anemia having erythroid activity <0.6 times normal ( ) versus 28 patients with -thalassemia intermedia having
erythroid activity >2 times normal ( ). (A) Relationship of
measured sEpo to Hb level. Multivariate ANOVA showed that, at any given
Hb level, sEpo was higher in patients with low versus those with high
erythroid activity (P < .0001). (B) Relationship of corrected
sEpo to Hb level. Data are those of (A), but corrected sEpo levels have
been used instead of the measured ones. Multivariate ANOVA showed no significant difference between the relationship in patients with low
erythroid activity and that in subjects with high erythroid activity
(P > .05).
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Assuming that the erythroid cells in the BM directly influence the Epo
clearance rate, we made an empirical correction to remove the effect of
variation in erythroid activity on sEpo levels using the formula
reported in Materials and Methods.
As shown in Fig 1B, when we reanalyzed the data of Fig 1A using the
corrected sEpo instead of the measured sEpo levels, a substantial part
of the variation previously observed was abolished. In fact, whereas
only 15.8% of the variation in sEpo was explained by variations in Hb
level (Fig 1A), these latter variations in Hb level
explained 37.5% of the variation in corrected sEpo. In particular,
there was no difference (P > .05) between corrected sEpo
levels calculated in patients with thalassemia intermedia having high
erythroid activity and those calculated in patients with low erythroid
activity.
Sequential studies in patients receiving myeloablative therapy or
conventional chemotherapy.
Twenty patients undergoing allogeneic or autologous BMT were
investigated immediately before undergoing myeloablative therapy and on
day 0 (Table 2 and
Fig 2). Conditioning regimen markedly reduced erythroid activity as shown by the sharp decrease in sTfR (t = 10.40, P < .001). Day 0 values for the circulating receptor were comparable with those of patients with aplastica anemia or PRCA
(Table 1).
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| Fig 2.
Time course of Hb level, sEpo, and circulating
transferrin receptor in 20 patients undergoing BMT. Data are mean
values ± 1 SD. Observed values before myeloablative therapy and those
on day 0 are shown. Predicted sEpo values were calculated on the basis
of the patient's Hct using the equation derived from regression analysis as previously described.4
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There was also a mild, although significant decrease in Hb level (t = 2.93, P < .05). However, the marked increment in sEpo (t = 6.66, P < .001) appeared to be disproportionately high when compared with the mild decrease in Hb level (Fig 2). We therefore calculated for each patient the day-0 sEpo concentration expected (or
predicted) on the basis of the actual Hb level. As displayed in Fig 2,
the predicted day-0 sEpo was significantly lower than the observed one
(81 ± 45 mU/mL v 254 ± 141 mU/mL, t = 6.86, P < .001), indicating that factor(s) other than Hb level contributed to
the elevation in circulating Epo level.
Similar findings were observed in five patients with non-Hodgkin's
lymphoma undergoing conventional chemotherapy
(Fig 3). A marked increase in serum Epo was
seen in all cases after 8 days, before any significant decrease in Hb
was observed; this was associated with a parallel decrease in sTfR.
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| Fig 3.
Time course of Hb level, sEpo, and circulating
transferrin receptor in five patients with non-Hodgkin's lymphoma
undergoing conventional chemotherapy (CHOP regimen). Data are mean
values ± 1 SEM. One way ANOVA showed that Hb level did not change
significantly during the observation period (P > .05),
whereas both the decrease in circulating transferrin receptor (sTfR, F
= 6.02, P < .01) and the mirror increase in sEpo
(F = 14.54, P < .001) were found to be significant
changes.
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Sequential studies in patients with iron deficiency anemia treated
with IV iron saccharate.
Five patients with severe iron deficiency anemia (mean Hb, 6.4 ± 1.4 g/dL) were studied immediately before and during IV iron therapy.
Data of these sequential studies are despicted in
Fig 4. Within 24 to 72 hours after starting
iron treatment, marked decreases in sEpo were observed (up to one log
magnitude) before any change in Hb level.
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| Fig 4.
Time course of Hb level and sEpo in five patients with
iron deficiency anemia treated with IV iron saccharate from day 0. Data
are mean values ± SEM. Within 48 hours, sEpo fell from 1,049 ± 772 mU/mL to 485 ± 567 mU/mL (P < .01), whereas Hb level did not change significantly (6.4 ± 1.4 v 6.4 ± 1.2, P > .057).
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Because both the expression of transferrin receptors on erythroid cells
and the soluble receptor level are influenced by the body iron status,
the measurement of sTfR could not be used in these patients to evaluate
the erythroid activity. However, in one patient, we were able to
monitor the reticulocyte response to IV iron.
Figure 5 shows that the reticulocyte count
and, in particular, the percentage of immature reticulocytes (HFR),
increased sharply after starting IV iron, and this was paralleled by a
mirror decrease in sEpo.
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| Fig 5.
Time course of sEpo, reticulocyte count, and HFR in a
patient with iron deficiency anemia treated with IV iron saccharate from day 0. HFR, ie, the most immature reticulocytes, expressed as % of total reticulocytes.
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Case reports: megaloblastic anemia and PRCA.
Two patients with megaloblastic anemia were studied
(Figs 6 and 7).
In both cases, replacement therapy with vitamin B12 or folate induced a
sharp decrease in sEpo in the first few days before any change in Hb
level. Such decreases were paralleled by increases in sTfR, and in one
case (Fig 7), also of immature reticulocytes (HFR), indicating that
ineffective erythropoiesis was replaced by effective erythropoiesis
with a subsequent expansion of the red blood cell precursor mass.
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| Fig 6.
Time course of Hb level, sEpo, and sTfR in a patient with
megaloblastic anemia due to vitamin B12 deficiency treated with vitamin
B12 (IM as cyanocobalamin, 500 µg per day). A marked decrease in
serum Epo was seen after the first injection and before any increase in
Hb level. There was a parallel increase in serum transferrin receptor,
indicating a rapid expansion of the erythroid marrow during the first
days of treatment.
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| Fig 7.
Time course of Hb level and sEpo (upper panel) and of
sTfR, reticulocyte count and HFR (lower panel) in a patient with
megaloblastic anemia due to folate deficiency treated with folic acid
(15 mg per day IM). A marked decrease in serum Epo was seen after the first injection and before any increase in Hb level. There was a
parallel increase in HFR, sTfR, and reticulocyte count, indicating a
rapid expansion of the erythroid marrow during the first days of
treatment.
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Of particular interest was the patient with PRCA after peripheral stem
cell transplantation (Fig 8). His sTfR was
0.4 mg/L, indicating the complete absence of any erythroid activity:
this amount of TfR, in fact, is contributed by nonerythroid tissues. As
previously reported,18 this patient responded to rHuEpo
therapy despite the elevated sEpo (2820 mU/mL). For 4 weeks, there was no increase in Hb level: however, sTfR started to increase after 2 weeks, and there was a parallel decrease in sEpo despite exogenous Epo
administration, suggesting increased use by an expanding erythroid precursor mass.
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| Fig 8.
Time course of Hb level, sEpo, and sTfR in a patient with
PRCA responding to treatment. The patient was given rHuEpo at an initial dose of 150 U/kg per day SC, 5 days a week; dosage was reduced
to three weekly administrations when Hb level achieved 12 g/dL and
treatment was discontinued after 8 weeks. Serum Epo started to decrease
as erythroid marrow activity reappeared, before any change in Hb
level.
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DISCUSSION |
Renal Epo production is typically regulated by a transcriptional
feedback mechanism where hypoxia plays a crucial role.19,20 However, a number of additional pathophysiopathologic factors, including inflammatory cytokines21 and plasma
viscosity,22 may independently affect the renal response to
hypoxia. Epo catabolism is largely unknown and it is not clear whether
sEpo levels are determined only by the production rate or rather
reflect a balance between this and consumption by erythroid cell use.
The observation that serum Epo levels in aplastic anemia are higher
than those in iron deficiency anemia8,9 suggests that use
by erythroid precursors may be an important factor in determining serum
concentrations. Unexpectedly low sEpo levels have been previously found
in patients with refractory anemia,23 sickle cell
anemia,24 thalassemia,25 and megaloblastic
anemia26 indicating that erythroid hyperplasia may involve
a faster clearance of Epo.
In the initial part of this study, we have clearly shown that the sEpo
level in aplastic anemia (erythroid activity < 0.6 times normal) is
much higher than the level in thalassemia intermedia (erythroid
activity > 2 times normal) at the same hemoglobin concentration (Fig
1A). This may either suggest that the clearance of Epo is much faster
in thalassemia than in marrow failure, or alternatively that the renal
production is to some extent higher in the latter condition.
To establish any relationship between erythropoiesis and sEpo, several
investigators studied patients receiving myelosuppressive treatments.
Overall, patients treated with chemotherapy were found to have a
temporary, but prominent, increase in sEpo titers without a concomitant
change in Hb concentration.10,11,27-30 However, different
interpretations were provided for the observed marked sEpo increase
before the decrease in Hb after treatment with cytostatic drugs.
Possible explanations included: (1) cytotoxic therapy causes direct
injury to Epo-producing cells in the kidney in a manner that mimics
hypoxia; (2) BM inhibition triggers an unknown stimulus for Epo
production; (3) a decreased mass of erythroid precursors disrupts the
usual Epo degradation pathway, reduced Epo use resulting in prolonged
sEpo lifespan and concentration; (4) cytotoxic drugs enhance Epo mRNA
stability with a consequent increase in protein synthesis.
Our studies after myelosuppressive therapy (Figs 2 and 3) definitely
show an inverse relationship between erythroid activity (as indicated
by sTfR) and sEpo. Such relationship is further reinforced by
observations in patients with iron deficiency, megaloblastic anemia,
and PRCA (Figs 4-8). Although it has been suggested that iron
deprivation increases Epo production,31 cobalamin deficieny does not raise Epo level per se, but only to the extent that it produces anemia.32 It is not clear why the erythroid marrow of our patient with PRCA did not respond to endogenous Epo and responded to exogenous rHuEpo (Fig 8). We cannot rule out that the
erythroid response was spontaneous and unrelated to rHuEpo, but at
least three other similar cases have been reported.18 Endogenous Epo production might have been defective in this patient despite the elevated sEpo levels if one assumes that these levels essentially reflected a very low utilization rate by the few erythroid cells existing in the BM.
Overall, our findings point to an inverse relationship between red
blood cell precursor mass and sEpo level: the higher the number of red
blood cell precursors, the lower the sEpo level. There are four
possible explanations for this relationship: (1) sEpo levels are
independently regulated by the rate of hormone use by erythroid cells
through Epo receptors; (2) erythroid marrow hypoplasia triggers a
stimulus for Epo synthesis; (3) erythroid marrow expansion inhibits
renal production; and (4) Epo excretion by the kidneys is directly
influenced by erythroid activity.
Two reports argue against the model of regulation by the utilization
rate, Piroso et al33 studied Epo lifespan in rats with hypoplastic and hyperplastic BMs. They found no significant difference and concluded that it is unlikely that erythroid activity determines sEpo lifespan and catabolism. Using a mouse model, Lezón et
al34 have found an inverse relationship between the rate of
stimulated Epo production and erythropoietic marrow activity. They
concluded that decreases in sEpo levels during periods of rapidly
increasing erythropoiesis are the reflection of a decrease in the rate
of production rather than an increase in the rate of utilization by
expanding erythroid cells.
Although the above direct studies failed to show evidence for increased
utilization when the erythroid precursor mass is expanded, a large body
of evidence points to a role by the utilization rate in the regulation
of circulating levels of hematopoietic growth factors. In particular,
thrombopoietin levels appear to be primarily regulated through
absorption and metabolism by both megakaryocytes and
platelets.35 Our findings indicate that the rate of
utilization by erythroid cells acts as an independent determinant of
sEpo, this latter being a balance between the rate of renal production and the rate of erythroid consumption. This interpretation may be too
simplistic, as other factors linking erythron to renal production
likely exist. Indeed, we have previously reported elevated sEpo levels
in compensated hereditary spherocytosis, a condition defined by
decreased red blood cell lifespan without anemia.36 Products of red blood cell destruction may not only exert a distinct stimulatory effect on BM,37,38 but also influence Epo
production.
From a practical point of view, we have recently proposed that
treatment with rHuEpo should be started only after an inadequate erythropoietin production has been documented, eg, by showing sEpo
levels < 100 mU/mL in patients with Hb values < 10 g/dL.5 According to the present study, when using sEpo for
this purpose, it might be necessary to take into account the patient's
erythroid activity. For example, patients with erythroid hypoplasia may present sEpo values > 100 mU/mL due to the small erythroid cell mass
and still be responsive to rHuEpo treatment.18 We are not suggesting the adoption of the empirical correction for sEpo reported in Fig 1B, but consideration of this point in the clinical reasoning of
the patient-oriented approach to the use of rHuEpo.5 In this reasoning, it should be taken into account that apparently normal
sEpo levels in patients with hypoproliferative anemia may reflect an
inadequate production combined with reduced utilization rate and,
conversely, that inappropriately low levels in patients with
proliferative anemia can be simply due to an accelerated hormone
consumption.
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FOOTNOTES |
Submitted September 2, 1997;
accepted October 28, 1997.
Supported by grants from Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS) Policlinico S. Matteo and Fondazione Ferrata
Storti, Pavia, Italy.
Address reprint requests to Mario Cazzola, MD, Internal
Medicine and Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, 27100 Pavia, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
