Erythropoietin, iron, and erythropoiesis
Lawrence T. Goodnough, Barry Skikne, and Carlo Brugnara
Recent knowledge gained regarding the therapy can produce hematologic re- tools for clinical research, but their roles
relationship between erythropoietin, iron, sponses with serum ferritin levels up to in routine clinical practice remain unde-
and erythropoiesis in patients with blood 400 µg/L, indicating that traditional bio- ﬁned. The availability of safer intravenous
loss anemia, with or without recombinant chemical markers of storage iron in iron preparations allows for carefully con-
human erythropoietin therapy, has impli- patients with anemia caused by chronic trolled studies of their value in patients
cations for patient management. Under disease are unhelpful in the assessment undergoing erythropoietin therapy or ex-
conditions of signiﬁcant blood loss, eryth- of iron status. Newer measurements of periencing blood loss, or both. (Blood.
ropoietin therapy, or both, iron-restricted erythrocyte and reticulocyte indices us- 2000;96:823-833)
erythropoiesis is evident, even in the pres- ing automated counters show promise in
ence of storage iron and iron oral supple- the evaluation of iron-restricted erythro-
mentation. Intravenous iron therapy in renal poiesis. Assays for serum erythropoietin
dialysis patients undergoing erythropoietin and the transferrin receptor are valuable 2000 by The American Society of Hematology
Several clinical settings have served as ‘‘natural experiments’’ that Blood loss anemia through
have furthered our understanding of the relationship between autologous phlebotomy
erythropoietin, iron, and the erythropoietic response to anemia in
humans. In a review nearly 20 years ago, Finch1 summarized the
knowledge gained primarily from studies of healthy persons, Erythropoiesis mediated by endogenous erythropoietin
patients with hereditary hemolytic anemias, and patients with Patients undergoing autologous blood phlebotomy may donate
hemochromatosis. Under conditions of basal erythropoiesis in 10.5 mL/kg (450 45 mL) blood as often as twice a week until 72
normal subjects, plasma iron turnover (as an index of marrow hours before surgery.7 Under routine conditions, patients usually
erythropoietic response) is little affected, whether transferrin donate once a week.8 Oral iron supplements are routinely pre-
saturation ranges from very low to very high levels. In contrast, the
scribed. This iatrogenic blood loss is accompanied by a response in
erythropoietic response in patients with congenital hemolytic
endogenous erythropoietin levels that, though increased signiﬁ-
anemia, in whom erythropoiesis is chronically raised as much as 6
cantly over basal levels, remain within the range of normal (4-26
times over basal levels,2 is affected (and limited) by serum iron
µm/mL).9 The erythropoietic response that occurs under these
levels and by transferrin saturation.3 Patients with hemochromato-
conditions is modest.8,10 A summary of selected prospective,
sis who underwent serial phlebotomy were observed to mount
erythropoietic responses as much as 8 times over basal rates, controlled trials11-16 of patients undergoing phlebotomy is pre-
attributed to the maintenance of very high serum iron and sented in Table 1. Calculated estimates of red blood cell (RBC)
transferrin saturation levels in these patients,4 whereas healthy volume expansion (erythropoiesis in excess of basal rates) were
persons have been shown to have difficulty providing sufficient determined17; 220 to 351 mL (11% to 19% RBC expansion,11,12 or
iron to support rates of erythropoiesis more than 3 times basal the equivalent to 1 to 1.75 U blood18) are produced in excess of
rates.5 These observations led Finch6 to identify a ‘‘relative iron basal erythropoiesis, deﬁning the efficacy of this blood conserva-
deﬁciency’’ state that occurs when increased erythron iron require- tion practice.
ments exceed the available supply of iron, even in the presence of For patients subjected to more aggressive (up to 2 U a week)
storage iron. The recent practice of multiple phlebotomies through phlebotomy, the endogenous erythropoietin response is more
autologous blood donation in patients who are scheduled for substantial.13-16 In one clinical trial,14 a linear–logarithmic relation-
elective surgery is also a natural experiment in blood loss anemia. ship was demonstrated between change in hemoglobin level and
This review summarizes insight gained in the past 20 years erythropoietin response,19 predicted previously by phlebotomy
regarding the relationship between erythropoietin, iron, and eryth- experiments in normal subjects.20 Erythropoietin-mediated erythro-
ropoiesis in patients with anemia, along with implications for poiesis in this setting is 397 to 568 mL (19% to 26% RBC
patient management. expansion,13-16 or the equivalent of 2 to 3 U blood18).
From the Departments of Medicine and Pathology and Immunology, Washing- ton University School of Medicine, 660 South Euclid Avenue, Box 8118, St.
ton University School of Medicine, St. Louis, MO; the Department of Medicine, Louis, MO 63110; e-mail: firstname.lastname@example.org.
University of Kansas Medical Center, Kansas City, KS; and the Departments of
Laboratory Medicine and Pathology, Children’s Hospital, Harvard Medical The publication costs of this article were defrayed in part by page charge
School, Boston, MA. payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Submitted July 30, 1999; accepted February 24, 2000.
Reprints: Lawrence T. Goodnough, Division of Laboratory Medicine, Washing- 2000 by The American Society of Hematology
BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3 823
824 GOODNOUGH et al BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3
Table 1. Endogenous erythropoietin-mediated erythropoiesis
Blood removed Iron-restricted erythropoiesis and
(donated) Blood produced
Patients donated RBC RBC RBC Expansion Iron
(n) (U) (mL) (mL) (mL) (%) therapy Reference
Blood loss and the endogenous erythropoietin response
Standard phlebotomy Erythropoiesis in response to aggressive autologous phlebotomy
108 3 2.7 522 1884 351 19 PO 11 through endogenous erythropoietin has been estimated to increase
22 3 2.8 590 1936 220 11 None 12 by approximately 3 times.16,32 As illustrated in Figure 1, panel A, no
45 3 2.9 621 1991 331 17 PO 12 relationship exists between basal iron stores and this magnitude of
41 3 2.9 603 1918 315 16 PO IV 12
erythropoiesis, suggesting that serum iron and transferrin satura-
tion for erythron requirements are adequately maintained by
30 3 3.0 540 2075 397 19 None 13
30 3 3.1 558 2024 473 23 PO 13
storage iron.13-16 Little or no beneﬁt to oral iron supplementation
30 3 2.9 522 2057 436 21 IV 13 was found in 2 studies,13,33 whereas a third study12 found some
24 6 4.1 683 2157 568 26 PO 14, 15 beneﬁt (Table 1). Intravenous iron supplementation is of no value
23 6 4.6 757 2257 440 19 PO 16 in enhancing erythropoiesis under these conditions.12,13
Data are expressed as means.
PO, oral; IV, intravenous. Blood loss and erythropoietin therapy
Erythropoiesis mediated by erythropoietin therapy
With enhanced erythropoiesis during erythropoietin therapy, iron-
restricted erythropoiesis occurs even in patients with measurable
Clinical trials have demonstrated a dose-response relationship storage iron (Figure 1B). Despite an 8-fold increase in gastrointes-
between erythropoietin and red blood cell expansion.16 A study of tinal iron absorption,34 serum ferritin and transferrin saturation
‘‘very low’’ dose erythropoietin therapy in autologous blood donors levels decline up to 50% with erythropoietin therapy.35 A 4-fold
found that 400 U/kg administered over a 2-week interval resulted in increase in erythropoietic activity is accompanied by declining
clinically signiﬁcant erythropoiesis.21 Table 2 details red cell reticulocyte counts and the appearance of hypochromic red cells by
volume expansion in 134 patients treated with erythropoietin the second week of erythropoietin therapy.23,36 The superior
therapy during aggressive blood phlebotomy,14-16,22,23 ranging from erythropoietic response in a patient with hemochromatosis further
358 to 1764 mL (28% to 79% RBC expansion) over 25 to 35 days, suggests iron-restricted erythropoiesis in patients treated with
or the equivalent of 2 to 9 U blood.18 The range in response erythropoietin (Table 2).23
(erythropoiesis) to dose (erythropoietin) is not related to patient Basal red cell precursor mass is also a limiting factor. Half-
gender or age,24,25 suggesting that patient-speciﬁc factors such as maximal hemoglobin synthesis can be achieved by as few as 50
accompanying chronic disease, iron-restricted erythropoiesis, or molecules of erythropoietin per target cell. This means that the high
other factors that normally cause the wide distribution of the levels of serum erythropoietin present initially after parenteral
hemoglobin level account for the variability in erythropoietic injection are not entirely used for erythropoiesis.37-39 The biologic
response to erythropoietin.
Studies in patients with the anemia of chronic disease (osteoar-
thritis26-28 or rheumatoid arthritis29,30) are summarized in Table 3. Table 3. Erythropoietin and erythropoiesis in patients with anemia
of chronic disease
Red cell volume expansion ranged from 157 to 353 mL (11% to
RBC RBC Expan-
24%) for endogenous erythropoietin-mediated erythropoiesis and
Patients removed produced sion Iron Refer-
268 to 673 mL (21% to 44%) with erythropoietin therapy. These (n) (U) (mL) (%) Rx ence
erythropoietic responses are indistinguishable from those in pa-
tients with anemia from blood loss alone, noted in Tables 1 and 2. A
1. Placebo 6 2.6 157 11 PO 26
study of 17 patients with inﬂammatory bowel disease treated with Placebo 3 3.3 220 18 PO IV
erythropoietin and oral iron therapy demonstrated a similar re- EPO (1800 IV)* 10 3.7 268 21 PO
sponse, with an estimated 20% increase in red cell volume over that EPO (1800 IV) 9 5.2 560 43 PO IV
in placebo-treated patients.31 EPO (3600 IV) 8 4.0 289 22 PO
EPO (3600 IV) 12 5.0 515 40 PO IV
Table 2. Erythropoiesis during blood loss and erythropoietin therapy
2. Placebo 77 3.0 353 24 PO 27
Blood removed Blood produced
Total EPO EPO (3600 IV) 75 4.5 673 44 PO
Patients dose RBC Baseline RBC Expansion Iron
(n/sex) (U/kg) Units (mL) RBC (m) (mL) (%) therapy Reference
3. Placebo 26 None 4 0.3 PO
10/F 900 SQ 3.4 435 1285 358 28 IV 22 Placebo 26 None 18 1 IV 28†
24 900 IV 5.2 864 1949 621 32 PO 16 EPO (1200 SQ) 26 None 219 14 PO
10/F 1800 SQ 4.3 526 1293 474 37 IV 22 EPO (1200 SQ) 26 None 220 15 IV
26 1800 IV 5.5 917 2032 644 32 PO 16 Rheumatoid arthritis
11/F 3600 IV 4.9 809 1796 701 39 PO 14,15 Placebo 6 2.3 271 25 PO 29
12/M 3600 IV 5.9 1097 2296 1102 48 PO 14,15 EPO (3600 IV) 4 4.8 624 37 PO
23 3600 IV 5.4 970 2049 911 45 PO 14,15 EPO (1800 IV) 11 2.6 291 27 IV 30
18 3600 IV 5.6 972 2019 856 42 PO 16 EPO (800 SQ) 11 2.5 337 27 IV
1/M 4200 SQ 8 1600 2241 1764 79 matosis Patients had measurable storage iron. Data are expressed as means.
*EPO is total dosage of erythropoietin administered, u/kg.
Data are expressed as means. †Perisurgical therapy without autologous phlebotomy.
BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3 ERYTHROPOIETIN, IRON, AND ERYTHROPOIESIS 825
Blood loss and iron therapy
Whether iron-restricted erythropoiesis is clinically important in
patients with blood loss anemia is detailed in Table 4.27,32 No
differences in erythropoiesis stimulated by endogenous erythropoi-
etin alone were seen between patients with or without measurable
storage iron, in which the mean red blood cell expansion was 20%
and 22%, respectively, in one study32 and 23% and 24%, respec-
tively, in another study.27 When patients were administered erythro-
poietin therapy, those without measurable storage iron had reduc-
tions in erythropoiesis compared to patients with storage iron that
reached statistical signiﬁcance in one study (P .05)27 but not
another (P .07).32 These studies indicate that oral iron supplemen-
tation is sufficient for endogenous erythropoietin-mediated RBC
expansion but may not be sufficient to prevent iron-restricted
erythropoiesis during erythropoietin therapy.
Intravenous iron can allow up to a 5-fold erythropoietic
response to signiﬁcant blood loss anemia in healthy persons.3,45 A
greater rate of hemoglobin production is probably not possible
unless red marrow expands into yellow marrow space, as is seen in
hereditary anemias.2,45 One limitation to intravenous iron therapy
in patients not undergoing erythropoietin therapy may be that much
of the administered iron is transported into the reticuloendothelial
system as storage iron, where it is less readily available for
erythropoiesis.46 For iron-deﬁcient patients, 50% of intravenous
iron is incorporated into hemoglobin within 3 to 4 weeks,47
whereas for patients with anemia of chronic disease or renal failure,
intravenous iron is less rapidly mobilized from the reticuloendothe-
The value of intravenous iron administration in patients under-
Figure 1. Initial storage iron and red blood cell volume expansion. (A) going erythropoietin therapy is not established. In one clinical
Relationship between initial storage iron (mg) and red blood cell volume expansion trial,26 signiﬁcantly greater erythropoietic responses were seen with
(mL/kg) in patients undergoing aggressive phlebotomy, without erythropoietin therapy.
Based on data from reference 32. Linear regression analysis (not shown) demon- intravenous iron therapy than with oral iron supplementation only
strated no signiﬁcant correlation (r 0.06; P .67). (B) Relationship between (Table 3). However, a recent study28 found no difference in red cell
initial storage iron (mg) and red blood cell volume expansion (mL/kg) in patients production between oral iron and intravenous iron therapy in
undergoing aggressive phlebotomy, with erythropoietin therapy. Linear regression
analysis demonstrated a signiﬁcant correlation (r 0.6; P .02). Reprinted with
patients before orthopedic surgery. Another study found that
permission.32 intravenous iron supplementation was not accompanied by a
corresponding erythropoietic response to increasing doses of
erythropoietin therapy; a 2-fold increase in erythropoietin dose was
response is, therefore, maximal at lower levels than the erythropoi- associated with only a 32% increase in red cell production,22
etin concentration required to saturate all erythropoietin-binding similar to the dose-response relationship using oral iron supplemen-
sites. Consistent with this, reticulocyte responses in healthy tation.16 Intravenous iron administered to normal subjects treated
subjects peak after a single erythropoietin dose of 1800 U/kg,40 and with erythropoietin abolished the marked reduction in serum
storage iron is mobilized more effectively after multiple-dose
regimens than after single-dose regimens.41 A 72-hour interval
between erythropoietin administrations is superior to a 24-hour
interval.42 Erythropoietin therapy stimulates the gradual expansion
of erythroblast mass,43 so that acute demands for erythropoiesis are
met by an inﬂux from pre-erythroid colony forming unit (CFU-E)
pools, and chronic demands (eg, chronic hemolytic anemia) are
met by an ampliﬁed pool of later erythroid precursors. Expansion
and maturation of erythroid precursor cells are, therefore, limiting
factors in the erythropoietic response to acute blood loss anemia
and in treatment strategies using larger erythropoietin dosages. In a
study of escalating (400%) erythropoietin dose administered to
patients undergoing aggressive phlebotomy, the marrow erythropoi-
etic index increased from 2.9 times (with endogenous erythro-
poietin stimulation) to 3.6 times over basal rates of erythro- Figure 2. Erythropoietic response, as reﬂected in the bone marrow erythropoi-
poiesis, representing only a 58% increase in erythropoiesis (Figure etic index, in 4 cohorts of autologous donors treated with placebo or escalating
2). Emerging growth factors, such as novel erythropoiesis- doses of erythropoietin therapy. (U/kg, given for 6 doses over 3 weeks.)
stimulating protein,44 may have different pharmacokinetics regard- Erythropoietic response (mL/kg per day) was estimated for each treatment group,
according to the formula: bone marrow erythropoietic index [RBC expansion]
ing dose and response related to longer plasma residence time and [baseline RBC production] [baseline RBC production]. Based on data from
erythron expansion. Goodnough et al.16
826 GOODNOUGH et al BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3
Table 4. Erythropoietin and erythropoiesis in patients with iron are similar to levels in normal subjects.60 During erythropoi-
or without iron deﬁciency
etin therapy, the absorption of iron increases as much as 5 times.61
RBC Baseline RBC Expan- Nevertheless, external iron loss, including loss from hemodialysis
Patients removed RBC vol produced sion Iron Refer-
Cohorts (n) (U) (mL) (mL) (%) Rx ence and blood testing, exceed gastrointestinal iron absorption.52 Poor
compliance because of gastrointestinal symptoms is problematic,
erythropoietin and signiﬁcantly reduced iron absorption may occur with some
Iron deﬁcient 6 3.8 1937 5.4 2.8/kg 22 PO 32 newer iron formulations.62 Iron-restricted erythropoiesis is evident
Iron replete 28 3.4 1942 4.8 2.3/kg 20 PO 32 by clinical responses to ascorbate supplementation, thought to
Iron deﬁcient 10 3.0 1503 367 117 24 PO 27 facilitate the release of iron from reticuloendothelial stores and
Iron replete 77 3.0 1503 355 157 23 PO 27 increased iron use by erythrons,59 and by the success of intravenous
iron therapy in reducing erythropoietin dosage.56
Iron deﬁcient 13 4.9 1824 8.2 3.0/kg 34 PO 32
Because anemia is a determinant of life expectancy in patients
Iron replete 23 5.1 1894 10.2 4.0/kg 41 PO 32 on dialysis for chronic disease,57,63 intravenous iron administration
Iron deﬁcient 11 4.5 1535 540 308 35 PO 27 has become standard therapy for many patients receiving erythro-
Iron replete 75 4.5 1535 673 190 44 PO 27 poietin therapy.64 Dialysis patients treated with intravenous iron
Absent storage iron is deﬁned as transferrin saturation 16% or ferritin 20
(100 mg twice a week) achieved a 46% reduction in erythropoietin
µg/L. dosage, required to maintain hematocrit levels between 30% and
*Total dose administered. 34%, compared with patients supplemented with oral iron.56 In a
study of patients with chronic renal failure but not on dialysis,53
ferritin and increased the reticulocyte hemoglobin content (a two thirds of patients who were unresponsive to oral iron re-
measure in g/L of the hemoglobin contained in all reticulocytes); sponded to weekly intravenous iron therapy. Improved erythropoi-
however, the total number of reticulocytes generated in 8 days after esis occurred despite initial serum ferritin levels as high as 400
therapy was not affected.49 Finally, perisurgical exposure to µg/L,65 indicating that biochemical markers of storage iron are not
allogeneic blood is not different for autologous blood donors with helpful in evaluating iron-restricted erythropoiesis.
or without measurable storage iron, regardless of oral27,32 or The effect of intravenous iron therapy in patients with the
intravenous iron28 administration. The current status of intravenous anemia of chronic disease undergoing erythropoietin therapy is
iron therapy in patients with blood loss anemia is summarized in shown in Table 3. Patients with osteoarthritis and measurable
Table 5.50-55 storage iron doubled their red cell expansion, from a range of 21%
to 22% (with oral iron) to 40% to 43% with intravenous iron.26
Intravenous iron therapy in iron-deﬁcient patients with inﬂamma-
tory bowel disease also resulted in improved responses to erythro-
Anemia of chronic renal failure or poietin therapy55 compared with a similar patient group who
chronic disease received oral iron supplementation.31 The clinical response to
intravenous iron may be attributed to the salutary effect of
The success of erythropoietin therapy in correcting the anemia of erythropoietin on iron mobilization from the reticuloendothelial
chronic renal failure has led to substantial clinical experience and system into red cell precursors.66 The risk/beneﬁt proﬁle of
knowledge in erythropoietin, iron metabolism, and erythropoiesis
intravenous iron is controversial in anemic patients on renal
in this setting.52,56 A distinguishing characteristic of the anemia in
dialysis59,63,64,67 and in patients with anemia of chronic disease.68
patients undergoing chronic renal dialysis is the presence of a
Nevertheless, clinical settings in which the effect of intravenous
normal mean corpuscular volume (MCV) in 85% of the patients
iron therapy on erythropoiesis is beneﬁcial, not beneﬁcial, or
and hypochromia in 96% of the patients.57 Hyporesponsiveness to
undeﬁned (investigational) are summarized in Table 5.
erythropoietin therapy is a common phenomenon in these pa-
tients58,59 because of a variety of co-morbid conditions, particularly
aluminum toxicity and iron deﬁciency.
Anemic patients undergoing dialysis may have suboptimal
responses to oral iron therapy for several reasons. Under basal Laboratory evaluation
conditions, their absorption levels of food iron and therapeutic oral Iron, transferrin, and transferrin saturation
Table 5. Current status of intravenous iron therapy The diagnosis of iron deﬁciency is traditionally based on a
Beneﬁcial No beneﬁt Investigational combination of parameters, including iron metabolism and hemato-
(reference) (reference) (reference) logic indices.69-73 Technical and biologic issues limit the usefulness
Anemia of renal failure, Autologous blood donation Blood loss, iron deﬁciency, of these assays in the clinical setting,74-78 and the value of iron,
with or without erythro- in patients with or and erythropoietin transferrin, and transferrin saturation is limited to uncomplicated
poietin therapy52-54 without iron deﬁ- therapy27,32 iron deﬁciency. During repeated phlebotomy, there is little change
Patients with ongoing ciency12,13 Anemia of chronic disease
blood loss35,51 and erythropoietin in iron levels until iron stores are exhausted, after which iron
Jehovah’s Witness therapy29,31,55 declines to below 50 µg/dL.69 Once iron stores are depleted,
patients with iron deﬁ- Perisurgical anemia, with transferrin increases linearly to approximately 400 µg/L. Transfer-
ciency,50 blood loss,51 or or without erythropoietin
both therapy28,35 rin saturation, therefore, falls below 16% only when iron stores are
exhausted, in contrast to erythropoietin therapy-induced erythropoi-
Absolute iron deﬁciency is deﬁned as ferritin 200 µg/L with or without iron
esis, in which iron saturation falls even in the presence of storage
saturation 20%, or relative iron deﬁciency (ferritin 400 µg/L in dialysis patients
receiving erythropoietin therapy54 or the presence of 10% hypochromic erythro- iron.71 Hence, the detection of iron-restricted erythropoiesis during
cytes, reticulocytes, or both. erythropoietin therapy6,35,41,71-73 poses additional challenges.
BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3 ERYTHROPOIETIN, IRON, AND ERYTHROPOIESIS 827
Ferritin rocytes are observed when erythropoietin is administered to normal
Ferritin is widely used as a marker of iron storage,79-81with a log subjects undergoing multiple phlebotomies,89 but not when it is
relationship between serum ferritin and liver iron (measured with administered to a patient with hereditary hemochromatosis treated
magnetic spectrophotometry) and with a cutoff of 15 µg/L indicat- similarly.23 Erythrocyte indices are helpful for monitoring iron
ing absent iron stores in normal persons.82-84 However, 1 study status and the need for iron supplementation during erythropoietin
found that 25% of women with no stainable bone marrow iron had therapy for the anemia of chronic renal failure.103-106 Hypochromic
serum ferritin levels above the 15 µg/L cutoff.85 Ferritin levels are erythrocytes also increase in patients with increased numbers of
elevated in conditions such as hyperthyroidism, inﬂammation/ normal reticulocytes and young red cells. Therefore, the value of
infection, hepatocellular disease, malignancies, alcohol consump- this assay has been questioned.107-109
tion, and oral contraceptives.86 A cutoff level of 30 µg/L87 to 40
µg/L88 for anemic patients is desirable to provide optimal diagnos-
tic efficiency (positive predictive values of 92% to 98%, respectively), Reticulocyte parameters
even without clinical evidence of infection or inﬂammation. Because reticulocytes are normally released from the marrow 18 to
Subjects treated with erythropoietin exhibit a rapid decrease in 36 hours before their ﬁnal maturation into erythrocytes, they
ferritin to levels 50% to 75% below baseline.34,49,89 Ferritin also provide a real-time assessment of the functional state of erythropoi-
decreased rapidly after intravenous iron administration in normal esis. However, in the early phases of stimulated erythropoiesis,
subjects treated with erythropoietin.49 Under these conditions, changes in absolute reticulocyte counts reﬂect the release from
ferritin most likely reﬂects the iron content of a smaller, more labile marrow of immature reticulocytes rather than the true expansion of
pool in equilibrium with erythropoietic compartment and storage erythropoiesis.45,48,110,111 It has been suggested that a response to
iron. Many patients have underlying disorders with ‘‘inappropri- erythropoietin can be assessed by measuring hemoglobin and
ately high’’ serum ferritin levels. Two thirds of patients on renal
reticulocyte counts after 4 weeks of therapy; a change in hemoglo-
dialysis respond to intravenous iron therapy; their mean ferritin
bin level by more than 1.0 g/dL or a change in absolute reticulocyte
levels of 94 µg/L and mean transferrin saturations of 22% are no
count by more than 40 109/L could indicate that the patient is a
different from those of patients not responsive to intravenous
responder to erythropoietin therapy.93,112,113
iron.65 This has led to suggested guidelines54 and algorithms90 for
Flow cytometric analysis of reticulocytes allows precise mea-
anemic patients with renal failure, in whom ferritin levels of less
surements of reticulocyte cell volume (MCVr), hemoglobin concen-
than 200 µg/L alone or less than 400 µg/L with a transferrin
tration (CHCMr), and hemoglobin content (CHr).114,115 In normal
saturation less than 20% are used to determine the need for
subjects, erythropoietin therapy induces an increase in MCVr and a
intravenous iron therapy90; only at transferrin saturations greater
decrease in CHCMr.43 Normal subjects treated with erythropoietin
than 50% or ferritin levels in excess of 800 µg/L are these patients
with baseline serum ferritin levels greater than 100 µg/L produce
considered unlikely to beneﬁt from iron therapy.54
Among patients with the anemia of cancer who are treated with almost no hypochromic reticulocytes. Iron-restricted erythropoi-
erythropoietin, ferritin levels greater than 400 µg/L correctly esis is detected at an earlier stage if reticulocyte parameters rather
predicted lack of response in 88%, whereas levels less than 400 than red cell indices are used.89,111,116,117
µg/L correctly predicted response in 75%.91 However, several CHr has been studied in patients on dialysis. CHr demonstrated
studies have failed to show a role for ferritin in predicting response 100% sensitivity and 80% speciﬁcity and was a more accurate
to erythropoietin or in identifying functional iron deﬁciency in predictor of response to iron therapy than serum ferritin, transferrin
patients with cancer-related anemia.92-94 It is reasonable to assume saturation, or percentage hypochromic erythrocytes.107 Another
that ferritin levels lower than 200 µg/L would predict response to study showed that a baseline CHr of less than 28 pg had 78%
intravenous iron in most patients receiving erythropoietin. sensitivity and 71% speciﬁcity for detecting iron-restricted erythro-
poiesis, compared with 50% and 39% for traditional biochemical
measures.118 In dialysis patients treated with erythropoietin, CHr
Erythrocyte ferritin and zinc protoporphyrin increases during intravenous iron therapy, indicating value as an
Some studies have advocated a role for erythrocyte ferritin, rather early indicator of iron-restricted erythropoiesis,119 even with nor-
than serum ferritin, in detecting iron deﬁciency in patients with mal serum ferritin or transferrin saturation.120
anemia of chronic disorders.95-98 However, this difficult assay is Measurements of total reticulocyte hemoglobin, an integrated
insensitive to dynamic changes and becomes abnormally low only index derived from the absolute reticulocyte count and the CHr,121
after most of the red cell population has been replaced by showed that reticulocyte–hemoglobin levels are much higher in
iron-deﬁcient erythrocytes. A similar limitation of the zinc protopor- subjects treated with intravenous iron.49 Moreover, in patients
phyrin measurement is that a signiﬁcant proportion of the red cell undergoing cardiac surgery, the administration of intravenous iron
pool must contain new red blood cells produced under iron- along with erythropoietin therapy abolishes the production of
restricted conditions.99 Furthermore, the zinc protoporphyrin hypochromic reticulocytes, and CHr remains within the normal
measurement is sensitive to interference by drug and plasma range.122 A recent study123 concluded that CHr was the strongest
components.100 Zinc protoporphyrin, therefore, has little value in predictor of iron deﬁciency in children, and it should be considered
identifying iron-restricted erythropoiesis.101 an alternative to standard iron studies for the diagnosis of iron
Another reticulocyte parameter now provided by automated
analyzers is the immature reticulocyte fraction. Because it is
Erythropoietin therapy in patients on dialysis is associated with the sensitive to leukocyte interference124 and is difficult to standard-
progressive appearance of hypochromic, microcytic erythro- ize,125,126 its clinical use has been limited. The immature reticulo-
cytes.102 Values exceeding 10% (normally less than 2.5%) are cyte fraction reﬂects the degree of erythropoiesis, but it is not
compatible with iron-restricted erythropoiesis.54 Hypochromic eryth- indicative of iron-restricted erythropoiesis.127,128
828 GOODNOUGH et al BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3
A classiﬁcation of anemias has been proposed around the concept
of adequate or inadequate erythropoietin response to degree of
anemia139-141; patients with iron-deﬁciency or chronic hemolytic
anemia would comprise the reference populations.142-144 The corre-
lation between the percentage of patients showing an ‘‘inadequate’’
erythropoietin response to anemia and the percentage of patients
responding to erythropoietin therapy (according to the author’s
criteria) can be illustrated (Figure 4) for several diseases, with a
range in response to myelodysplastic syndromes,145 multiple
myeloma,146 and rheumatoid arthritis.147
There are several problems with the use of erythropoietin levels
in the management of patients. The interpretation of an erythropoi-
etin level must take into account the degree of anemia at the time of
Figure 3. Endogenous erythropoietin-mediated erythropoiesis by phlebotomy measurement. Commercial assay results do not take this into
minimally inﬂuences serum transferrin receptor (TfR) until iron-restricted consideration; hence, clinicians must have some familiarity with
erythropoiesis occurs. Serial determinations of TfR during phlebotomy in 3 subjects mathematical corrections, such as observed/predicted ratios.141 A
with initial iron stores of 107 mg ( ), 335 ( ), and 1,102 mg ( ). Reprinted with
retrospective analysis of erythropoietin therapy in anemic patients
with cancer not undergoing chemotherapy148 found that pre-
treatment erythropoietin levels of less than 200 mU/mL were
correlated with red cell response to erythropoietin therapy. Subse-
The soluble transferrin receptor (TfR) is derived primarily from red quent analyses, however, have found that erythropoietin levels are
cell precursor normoblasts129 and provides an estimate of the not predictive for response in cancer patients undergoing chemother-
erythroid compartment mass. Both enhanced erythropoiesis and apy.149,150 Because almost all anemic patients with cancer or on
iron deﬁciency elevate TfR.129,130 Endogenous erythropoietin- renal dialysis have erythropoietin levels that are inadequate for the
mediated erythropoiesis through phlebotomy minimally inﬂuences degree of anemia,141 measuring erythropoietin levels is not useful
TfR until iron-restricted erythropoiesis occurs, as illustrated in in these settings. Furthermore, guidelines recommend that erythro-
Figure 3.69 Serum ferritin is the most sensitive and speciﬁc index of poietin therapy be instituted before hemoglobin levels fall below
iron status when there are residual iron stores, whereas TfR is most 10 g/L, a level at which interpretation of erythropoietin level is not
sensitive in the presence of iron-restricted erythropoiesis.88
In a study of 43 healthy, nonanemic adult women, 17 (40%) had
signiﬁcant changes in TfR in response to oral iron therapy,
indicating the presence of subclinical iron deﬁciency.131 In another
study, 25% of patients undergoing routine ferritin tests, who were
also studied for TfR measurements, were categorized as iron
deﬁcient by TfR (more than 2.8 mg/L) but not by ferritin (more
than 12 µg/L).88 These values could represent iron-replete persons
with increased erythropoiesis or iron-deﬁcient patients with acute-
phase increases of ferritin values. The clinical usefulness of the TfR
may be limited to the subset of ill patients in whom iron deﬁciency
is suspected but whose ferritin values are normal or raised,88 seen
commonly in the anemia of chronic disease; numerous stud-
ies69,87,88,132-134 have shown TfR to be of value in differentiating
iron-deﬁciency anemia (in which TfR is usually increased) from
the anemia of chronic disease (in which TfR is usually normal).
Meaningful comparisons of studies of TFR are difficult because of
differences resulting from the reagents used.
The value of TfR in predicting the response to erythropoietin
therapy and the adequacy of iron availability is modest. Although
lower baseline or low-normal TfR levels predict the initial response
to erythropoietin therapy in patients on dialysis,135 other studies
have shown little predictive value for this assay in patients
receiving erythropoietin because serum TfR values above normal
are observed in iron deﬁciency and during erythropoietin-induced
expansion of erythropoietic activity.136 The combination of TfR
Figure 4. Correlation between the percentage of patients showing inadequate
measurements, serum ferritin, and automated reticulocyte counts erythropoietin response to anemia and the percentage responding to erythro-
may be predictive of an erythropoietic response to increased poietin therapy (according to the authors’ criteria). Numbers are derived directly
erythropoietin dosage or of the need to ensure adequate iron or are calculated from reported data. ARF, anemia of renal failure; RA, anemia of
rheumatoid arthritis; HIV, anemia in patients with human immunodeﬁciency virus;
replacement, such as by the intravenous administration of iron.137,138
MM, anemia in multiple myeloma; Cancer, anemia of cancer; MDS/MMM, anemia in
Further studies are required to delineate the clinical usefulness of myelodysplastic syndromes and myeloﬁbrosis with myeloid metaplasia. Reprinted
TfR measurements in these settings. with permission.141
BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3 ERYTHROPOIETIN, IRON, AND ERYTHROPOIESIS 829
valid.141 The erythropoietin assay may be most useful as a by defective iron supply to the erythron, along with inﬂammatory
determinant of response to therapy in certain patients, such as those cytokine-mediated suppression of the erythropoietic response to
with myelodysplasia.145 erythropoietin.157,158 To effectively evaluate erythroid activity, an
The proliferative state of bone marrow erythroid cells affects assay of TfR and mathematical correction of the erythropoietin
erythropoietin levels,151 as does iron status,152 hemolysis,153 and level would be necessary,151 but this is not practical for clinical
chemotherapy-induced endothelial damage.154 TfR has helped in evaluation and patient management.
the understanding of the relationship between hemoglobin level In summary, pre-therapy laboratory evaluation of erythropoi-
and serum erythropoietin. As illustrated in Figure 5, a patient with etin, iron, or erythropoiesis in anemic patients may no longer be
pure red cell aplasia and a markedly elevated erythropoietin level always appropriate. Rather, the epidemiology (ie, clinical setting)
was administered erythropoietin therapy for 4 weeks. Before of the anemia may suggest a therapeutic trial of iron or erythropoi-
hemoglobin level increased, the erythropoietin level decreased etin therapy, with post-therapy laboratory evaluation determining
because erythroid activity measured by TfR reappeared. The the response. One example of this approach is the empiric use of
increased plasma clearance of erythropoietin is probably related to oral iron therapy in otherwise well anemic, menstruating women,
an inﬂux of early RBC precursors into CFU-E from primitive in which a follow-up blood count may serve as the sole laboratory
erythroid burst-forming units (BFU-E). CFU-E has a higher assay. A second example is patients with chronic renal failure who
concentration of erythropoietin receptors than BFU-E,39 so late remain anemic despite erythropoietin therapy and in whom an
BFU-E through the proerythroblast stage deﬁnes the narrow empiric trial of intravenous iron is recommended despite apparent
window of erythroid cellular compartment that is erythropoietin laboratory evidence of storage iron. Follow-up transferrin satura-
responsive.151 tions, serum ferritin, and blood counts then determine when
A recent study of anemic children with systemic-onset juvenile intravenous iron therapy can be modiﬁed or withdrawn.54 Hemato-
chronic arthritis found that erythropoietin levels were appropriate logic parameters are emerging as promising alternatives to biochemi-
for the degree of anemia. Variable iron status, measured by TfR cal markers in evaluating iron-restricted erythropoiesis.
levels, accounted for variations in hemoglobin levels, and intrave-
nous iron therapy resulted in the normalization of TfR levels.155
Another study in children with cancer found that TfR levels were Clinical management: iron therapy strategies
inappropriately low for the degree of anemia, and a highly
signiﬁcant correlation between the logarithms of erythropoietin and With signiﬁcant on-going iron losses, oral iron supplementation is
hemoglobin levels was identiﬁed.156 The report concluded that not enough to correct iron-deﬁcient erythropoiesis. Patients on
anemia in children with cancer results from decreased erythropoi- renal dialysis have such blood losses, and intravenous iron therapy
etic activity, in contrast to anemia in adults with cancer.142 The allows the correction of anemia through the use of lower erythropoi-
anemia of chronic inﬂammatory disease is particularly multifacto- etin doses.54,159 Another role for intravenous iron therapy is in
rial, caused not only by impaired erythropoietin response but also bloodless medical treatment and bloodless surgery for patients who
decline blood transfusions because of religious beliefs.50 These
patients include pregnant women and patients with dysfunctional
uterine bleeding who are scheduled for hysterectomy.51
Intravenous iron therapy has been closely scrutinized for risks
and adverse events. Imferon (iron dextran BP, Merrill-Dow,
Cincinnati, OH) was previously approved for parenteral use.160
This product was associated with a 0.6% risk of anaphylactoid
reactions and a 1.7% risk of severe serum sickness-like reactions
characterized by fever, arthralgias, and myalgias.161 Delayed
reactions of up to 30% and severe reactions of 5.3% were
subsequently described. They were attributed to changes in manu-
facturing processes,162 and this product was withdrawn from use.
InFed (iron dextran USP; Schein Pharm, Florham Park, NJ) has
been approved for parenteral (intramuscular or intravenous) use in
the United States. InFed (Schein Pharm) administered intrave-
nously during dialysis is associated with signiﬁcant adverse
reactions in 4.7% of patients, of which 0.7% are serious or life
threatening and another 1.7% are characterized as anaphylactoid.163
The prevalence of these reactions does not differ among patients
receiving low-dose (100 mg) or higher-dose (250-500 mg) infu-
sions.164 A recent review reported 196 incidences of allergy/
anaphylaxis from iron dextran between 1976 and 1996, of which 31
(15.8%) were fatal.165
Safety aspects of parenteral iron dextran, ferric gluconate, and
Figure 5. Time course of hemoglobin (Hb) level, serum erythropoietin level iron saccharate have been scrutinized.166-168 Iron saccharate is
(sEpo), and serum transferrin receptor (sTfR) in a patient with pure red cell available in Europe but not in the United States. Ferric gluconate
aplasia (PRCA) responding to treatment. The patient was treated with erythropoi-
has been available in Europe for more than 20 years and was
etin at a dose of 150 U/kg per day subcutaneously, 5 days a week; dosage was
reduced to 3 weekly administrations when Hb level achieved 12 g/dL, and treatment approved for intravenous use in the United States in 1999
was discontinued after 8 weeks. Reprinted with permission.151 (Ferrlecit; Schein Pharm) in patients on renal dialysis. Dosage is
830 GOODNOUGH et al BLOOD, 1 AUGUST 2000 • VOLUME 96, NUMBER 3
limited to 125 mg infused over 1 hour at each administration. The Debated links between iron stores and morbidity or mortality rates
number of allergic reactions (3.3 episodes per million doses) is include a predisposition to infection,181,182 increased death from
lower than that from iron dextran (8.7 episodes per million doses), infection183 in dialysis patients, and detrimental coronary outcomes
and the safety proﬁle is substantially better; among 74 severe in men.184-186 An accompanying editorial187 to a U.S. study of ferric
adverse events reported from 1976 to 1996, there were no deaths.165 gluconate170 concluded that its role in the management of anemia
Adverse events associated with ferric gluconate include hypo- from renal disease was unclear until its relative efficacy, tolerabil-
tension, rash, and chest or abdominal pain, with an incidence of ity, and cost effectiveness is established. However, another edito-
1.3% for serious reactions.170,171 Intravenous iron therapy can cause rial64 accompanying the target hematocrit study63 concluded that
a clinical syndrome (nausea, facial reddening, and hypotension) for patients with anemia of chronic renal disease, intravenous iron
that may be attributed to acute iron toxicity caused by oversatura- is recommended to reach target hematocrit goals of 33% to 36%.
tion (more than 100%) of transferrin172 or nonspeciﬁc drug The current status of intravenous iron therapy for patients who are
toxicity.173 The increased erythropoietic effect (4.5 to 5.5 times unresponsive to oral iron or in whom it is malabsorbed—along with
basal) of intravenous iron dextran (with an estimated half-life of 60
opportunities for investigation—are presented in Table 5.
hours) is transient and lasts 7 to 10 days, after which the remaining
iron is sequestered in the reticuloendothelial system and erythropoi-
esis returns to basal rates.3 Iron measurements and intravenous iron
therapy are optimal at 2-week intervals. Conclusion
A dose-response relationship between erythropoietin and eryth-
The development of new laboratory methods to assess iron-
ropoiesis that is affected favorably by intravenous iron has
restricted erythropoiesis, along with clinical trials of blood phle-
important implications for erythropoietin dosage and cost.174 The
botomy and erythropoietin therapy, have furthered our understand-
current total recommended erythropoietin dose for patients sched-
ing of the relationship between erythropoietin, iron, and
uled for elective surgery175 ranges from 1800 U/kg176 to 4200
U/kg,177,178 which for a 70-kg patient would cost $1300 to $3000.179 erythropoiesis. Hematologic indices and reticulocyte parameters
However, an economic analysis of erythropoietin therapy in measured by new automated counters hold promise in the evalua-
patients undergoing orthopedic surgery concluded that even the tion of iron-restricted erythropoiesis, but more studies are needed
lower recommended dosage is not cost effective.180 Intravenous to deﬁne their role with iron and erythropoietin therapy. Erythropoi-
iron may potentiate the erythropoietic response in erythropoietin etin and transferrin receptor assays are valuable tools for clinical
therapy by improving functional iron deﬁciency. research, but their roles in routine clinical practice remain unde-
A multicenter trial in dialysis patients, designed to achieve ﬁned. The availability of a safer intravenous iron preparation
normal (more than 42%) or low (more than 30%) hematocrits with allows an opportunity to study its value in patients with blood loss
a combination of erythropoietin therapy and intravenous iron anemia, particularly those undergoing erythropoietin therapy. Given
(dextran USP) supplementation, was halted because of increased the low prevalence but potential side effects, the use of intravenous
mortality in the high hematocrit cohort.63 These patients experi- iron for patients other than those with chronic renal failure and
enced a decline in dialysis adequacy and received intravenous iron those who decline blood because of religious beliefs must be
in greater quantities than those in the low hematocrit group. deﬁned by controlled clinical trials.
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