Erythropoiesis, Erythropoietin, andIron - Blood
Transcript of Erythropoiesis, Erythropoietin, andIron - Blood
�Most of the references quoted are from the work of researchfellows over the past 30 yr. This topic was chosen in order to
acknowledge their outstanding contributions and to express mypersonal gratitude for the privilege of working with them.
Blood, Vol.60, No. 6 (December), 1982 1241
BLOOD The American
The Journal of
Society of Hematology
VOL. 60, NO. 6 DECEMBER 1982
REVIEW
Erythropoiesis, Erythropoietin, and Iron
By Clement A. Finch
The basic components of erythropoiesis are stem cellprecursors, their stimulation by erythropoietin, and anadequate supply of iron from which to make hemoglobin.
A NEMIA HAS LOST much of its mystique in the
past 40 yr as a better understanding of erythro-
poiesis and red cell destruction has made diagnosis and
management a more rational process. This brief dis-
cussion* will attempt to summarize certain physiologic
concepts useful to the clinician.
The importance of erythrocyte size as an indicator
of hemoglobin synthesis became evident with the intro-
duction of the hematocrit over 50 yr ago,1 and anemias
were classified as microcytic, normocytic, and macro-
cytic. Microcytosis could be equated with a decrease in
hemoglobin synthesis, attributable to either iron defi-
ciency, a mitochondrial abnormality affecting heme
synthesis, or impaired globin synthesis. Macrocytosis
is the result of a defect in nuclear maturation or of
“stimulated erythropoiesis.” The smear is essential in
differentiating these two causes of red cell enlarge-
ment. True macrocytes are the result of a disruption of
the usual mitotic sequence in the marrow (nuclear
maturation defect). Cells that skip a mitosis appear as
mature “red cell giants” in the circulating blood. A
second type of macrocytosis is caused by increased
erythropoietin stimulation in the presence of an ade-
quate iron supply. In this normal physiologic response,
hemoglobin synthesis within the immature cell is
increased,2 and reticulocytes are released prematurely,
appearing macrocytic, basophilic, and slightly hypo-
chromic on blood smear.3 Automated equipment has
increased the dependability of the mean corpuscular
volume, but the interpretation of macrocytosis still
rests with the smear differentiation of these two types
This article discusses the effects of each of these and thesimple tests by which they may be evaluated clinically.
of macrocytosis. Other calculations of red cell indices,
i.e., mean corpuscular hemoglobin and hemoglobin
concentration, add little.
There are limitations to this “cell size” approach.
Changes take a long time to develop due to the slow
turnover ofcirculating red cells, so that one can usually
detect maturation abnormalities only after the condi-
tion has been present for months. Also, the relationship
between iron supply and erythroid proliferation affects
the degree of macrocytosis (Fig. 1 ). However, the real
problem is that most anemias are normocytic and are
therefore not amenable to this type of analysis.
The heterogeneous group of normocytic anemias
can be best approached by measurements of produc-
tion and destruction.5 Production is most simply quan-
titated by counting circulating reticulocytes as long as
two corrections are made. The first is to convert the
percent of circulating reticulocytes into their absolute
number. The second adjusts for the effect of erythro-
poietin on the release of reticulocytes from the mar-
row.6 When plasma erythropoietin levels are increased,
the usual reticulocyte maturation period in the marrow
of about 3 days is shortened and the time in circulation
is correspondingly lengthened (Fig. 2). The reticulo-
From the Division of Hematology, Department of Medicine,
University of Washington, Seattle, Wash.
Supported in part by Research Grant HL 06242 from the
National Heart, Lung and Blood Institute. National Institutes of
Health, and Training Grant AM 07237from the National Institute
ofArthritis, Diabetes, and Digestive and Kidney Diseases, NIH.
Submitted June 14, 1982; accepted July 21, 1982.
Address reprint requests to Clement A. Finch, M.D., Division of
Hematology, Department of Medicine, University of Washington,
Seattle, Wash.
© I 982 by Grune & Stratton, Inc.
0006-4971/82/6006-0001$O1.OO/O
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. 125MeanErythrocyticVolume (f I)
100
Fig. 1 . Effect of erythropoietin stimulation and iron supply onerythrocyte size. Curves represent proposed changes in red cellvolume at transferrin iron saturations from 1 0% to 1 00%. Normalmarrow function is assumed. Increased erythropoietin stimulationin the presence of increased iron supply increases red cell hemo-globin2 and red cell size.4 As iron supply decreases. so will
hemoglobin synthesis and red cell size. This relationship is also
affected by abnormalities in hemoglobin synthesis, such as in
thalassemia and by nuclear maturation abnormalities, which exag-
gerate the increase in hemoglobin synthesis by the iron-replete,
stimulated erythroid precursor.
010 20 30
Hematocrit,40%
Fig. 2. Effect of anemia on the reticulocyte maturation time inmarrow and in blood.
1242 CLEMENT A. FINCH
75
Hematocrit (%)
4,5 30 1�
100%
0 10 100 1000
Erythropoietin (units/mI)
cyte index derived from these two corrections relates
the rate of entry into circulation of the patient’s
reticulocytes to basal production. The expected pro-
duction capacity of the challenged erythroid marrow is
about 5 times basal, an increase that can be achieved
within a week under appropriate conditions.7’8 For
practical purposes, a reticulocyte index of greater than
3 times basal is taken to indicate an adequate marrow
response, while an index of less than 2 times basal is
assumed to represent impaired production.
Production failure may be due to either inadequate
erythroid proliferation or a maturation abnormality
resulting in cell death during development (ineffective
erythropoiesis).9 Although reticulocytes are low in
each, the smear differentiates the two conditions (Fig.
3). A hypoproliferative marrow is usually associated
with a fairly normal red cell population (a “quiet”
smear), a low bilirubin, and a normal lactate dehydro-
genase. Ineffective erythropoiesis will usually be
detected by changes in mean corpuscular volume (in-
creased with nuclear and decreased with cytoplasmic
abnormalities), but is also associated with red cell
fragmentation, a normal-to-high bilirubin, and an
increased plasma lactate dehydrogenase. The ery-
throid:granulocyte (EG) ratio of the aspirated marrow
or the density of erythroid forms in marrow section
gives direct evidence of the degree of erythroid prolif-
eration. Ferrokinetic measurements provide an even
more accurate quantitation of the erythroid precursor
number’#{176} and are particularly useful when leukocyte
abnormalities invalidate the EG ratio and when there
is difficulty obtaining a representative marrow aliquot.
This separation of anemias into hypoproliferative
states, ineffective erythropoiesis, and hemolytic cate-
gories can serve as a scaffold for further differential
diagnosis (Fig. 4),5 Such cataloging makes it clear that
the vast majority of anemic patients have a hypoproli-
ferative process in which erythropoietin and iron play
prominent causative roles.
ERVTHROPOIETIN
Erythropoietin output is designed to modulate
erythropoiesis so as to optimize blood hemoglobin
concentration. This regulation is illustrated by the
changes that follow altitude exposure, where the circu-
lating hemoglobin concentration increases I g for each
3%-4% decrease in arterial oxygen concentration.”
However, regulation of oxygen supply is more complex
than this. It has been observed that the hemoglobin
concentration in patients with hemoglobinopathies
correlated closely with the affinity of the abnormal
hemoglobin for oxygen.’2 Less complicated is the
increase in hemoglobin concentration observed in
patients with stable hemoglobin mutants having
increased affinity for oxygen.’3 These various observa-
tions indicate that the combination of 02 content and
50 its availability rather than oxygen content of arterial
blood alone is the basis for erythropoietin regulation.
The erythrocyte has an intrinsic mechanism for
modifying oxygen release, based on its content of
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ERVTHROPOIESIS. ERYTHROPOIETIN, AND IRON 1243
Fig. 4. Relative frequency ofdifferent types of anemia.
Fig. 3. Erythrocyte size andshape changes. (A) A normal cell
population; (B) the shift macro-cytes of stimulated erythropoie-sis; (C) microcytosis and cell frag-mentation (D) the macrocytes ofmegaloblastic anemia.
intraerythrocytic 2,3-diphosphoglycerate 14 As
long as there is adequate phosphate substrate, the
amount of erythrocyte DPG will be altered not only by
changes in oxygen availability produced by an altered
blood pH but also according to the proportion of
oxygenated versus reduced hemoglobin in circulation.
The compensatory nature of this response to hypoxia is
shown by increases in DPG occurring in cardiac failure
and anemia, making increased amounts of oxygen
available at any given oxygen tension.’5”6 Thus, two
interlocking regulatory mechanisms involving the cry-
thron exist, designed to ensure an adequate oxygen
supply. DPG is the more rapidly responsive, acting
within hours to improve available oxygen by increasing
the amount release at any given oxygen tension. This
“available oxygen,” in turn, is monitored by the
erythropoietin-regulating apparatus, and further ad-
justments in erythropoietin and erythropoiesis over a
period of weeks are required to achieve an appropriate
concentration of circulating hemoglobin.
The response of the erythroid marrow to anemia is
initiated by the action of erythropoietin on committed
stem cells (CFU-E). While it would be often helpful to
know the level of stimulation in a patient, valid quanti-
7HYPOPROLI FERATIVE
1. Iron DefIcient Erythropolesis
a. relative (bleeding)b. iron deficiencyC. inflanvnation
2. Erythropoletin Lacka. renalb. nutritional S endocrine
C. �O2 release by Hb
3. Stem Cell Dysfunctiona. aplastic anemiab. rbc aplasia
INEFFECTIVE
1. Plegaloblastlc
a. Bl2b. folate
C. refractory
2. Microcytlca. thalassemlab. sideroblastic
3. Norliocytica. stromal dIseaseb. dins,rphic
HEMOLYTI C
1. Inununologlc
a. idiopathicb. secondary to
drug, tunor or
2. lnt9I�fl�a. metabolicb. Hb
3. ExtrInsica. mechanicalb. lytlc subst.
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Tf Fe Receptor�‘ �‘ Tissues
1244 CLEMENT A. FINCH
tative measurements of erythropoietin have been lim-
ited to the research laboratory and have been virtually
unavailable to the clinician. Recently, radioimmune
assays have been developed that have biologic signifi-
cance and may become generally available in the near
future.’7 However, a simple screen is the evaluation of
the blood smear for the presence of “shift cells,” since
the premature release of these young reticulocytes is
erythropoietin-dependent.6”9 In using this, one must be
alert to stromal disorders that produce shift not
because of increased erythropoietin, but rather
because of disruption of marrow architecture.
Altered erythropoietin regulation occurs in patho-
logic states for different reasons. Production of
erythropoietin is decreased by a variety of disorders
impairing renal function,2#{176} but differences between
excretory and endocrine function of the kidney do
occur. For example, in the hemolytic uremic syndrome,
there is active stimulation of erythropoiesis despite
nitrogen retention. A decrease in erythropoietin is seen
with certain endocrine disorders and with protein-
calorie malnutrition.2’ In these situations, the erythro-
poietin-producing apparatus is intact, but output of the
hormone is decreased, presumably because less oxygen
is required for the altered metabolic state of the body.22
If erythropoietin is considered to be the regulator of
red cell proliferation, it might seem surprising that the
plasma erythropoietin concentration per se bears little
relationship to the rate of erythropoiesis in most
anemic patients. Near-normal levels are seen despite
accelerated erythropoiesis in hereditary spherocytosis.
From this we must assume that very little increase in
erythropoietin level above basal is required to sustain
the almost complete compensation in this hemolytic
anemia. On the other hand, high levels of erythropoie-
tin are usually found when production is depressed by
some other abnormality, the highest level being present
in aplastic anemia where stem cells are reduced or
cannot proliferate.20 The usual cause of a discrepancy
between marrow stimulation and response is an made-
quate supply of iron.
IRON
Iron is distributed to body tissues by plasma trans-
ferrin. Recent studies show that the transferrin iron
pool is not homogeneous but is composed of monoferric
and diferric transferrin, the latter having a far greater
capacity to dispense iron to tissue (Fig. 5)#{149}23Since iron
loading on transferrin is random, the amount of difer-
nc iron is a function of the transferrin iron saturation.
It was shown that this was the most meaningful
expression of available iron, and further, that basal
erythropoiesis could not be sustained when the propor-
tion of diferric transferrin iron fell below 16%.24 A
Fig. 5. Transferrin-mediated iron exchange. The transferrinmolecule receives iron, one iron molecule at a time, from iron-
donating tissues. Either monoferric or diferric transferrin canreact with membrane receptors with capture of all iron by the cell
and release of apotransferrin back into the plasma.
limitation of iron supply is characterized by an
increase in the extraction of transferrin iron by the
erythroid marrow from basal values of 5%-lO% to a
maximum of about 30% and a corresponding reduction
in the 80 ± 20 mm T’/2 radioiron clearance to about 20
mm.25
There are two outstanding abnormalities that char-
acterize iron-deficient erythropoiesis. The impairment
of hemoglobin synthesis, which eventually results in a
hypochromic microcytic red cell, reflects the obliga-
tory requirement of hemoglobin for iron. An impair-
ment in viability of developing and mature red cells in
iron deficiency has been suggested by iron kinetic
studies and morphological evidence of cell fragmenta-
tion, but it is likely that the amount of cell wastage has
been overstated. Of more relevance in explaining the
anemia is the effect of iron deficiency on cellular
proliferation. Transferrin iron has been shown to be
essential for proliferation in in vitro cell cultures.26’27
Fetal tissues cannot develop in utero when maternal
iron supply becomes severely restricted.23 Similarly,
the proliferation of the erythroid marrow is restricted
to near-basal levels when iron supply fails. The degree
of disparity between plasma iron supply and erythro-
poietin-imposed demand is reflected in the degree of
microcytosis and hypochromia of circulating red cells.
For this reason, little microcytosis is seen when the
patient with renal failure is iron deficient because
erythropoietin levels are also suppressed.
Considerations of iron-deficient erythropoiesis have
usually related the effect of a decreased iron supply to
basal tissue iron requirements. The term “relative iron
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>‘
Co#{149}0
�- �0cDO>0
�0C .�
0�
‘D
E0ci’E
0 20 40 60 80 100
Transferrin saturation (%)
ERYTHROPOIESIS. ERYTHROPOIETIN. AND IRON 1245
deficiency” designates an iron supply that would be
adequate to meet the needs of basal erythropoiesis but
which is not adequate to meet the needs ofan expanded
erythroid marrow. This relationship can be accurately
monitored by measuring red cell protoporphyrin. An
increased red cell protoporphyrin is found in patients
with simple iron deficiency when transferrin saturation
drops below l6%.29 In hemolytic states, an increase in
protoporphyrin will be found at a normal transferrin
saturation of 35% or at even higher saturations because
of the increased marrow iron requirement.3#{176} Previous-
ly, reticulocytes were considered to be high in proto-
porphyrin, but it is now appreciated that any increase
observed represented a relative iron deficiency.3’ It is
not uncommon to find an inadequate iron supply (high
red cell protoporphyrin) in hemolytic anemia with
production rates greater than 5 times basal.
At these high levels of erythropoiesis, transferrin
procurement of iron becomes critical. Iron is made
available to transferrin through recycling of red cell
iron, through mobilization of iron stores, and through
absorption. Little is known of the regulation of plasma
iron supply except that the very act ofgiving up iron by
transferrin appears to enhance the procurement of iron
by transferrin.32 From existing sources, the normal
individual has difficulty providing sufficient iron to
support rates of erythropoiesis of greater than 3 times
basal.533 Clinicians have learned to interpret high
reticulocyte counts as indicating hemolysis. However,
the only reason for this association is the large amount
of iron made available in hemolytic anemia through
the catabolism of damaged red cells and the corre-
sponding increase in reticulocytes due to the effective
erythropoiesis characteristic of hemolytic states. Simi-
lar degrees of reticulocytosis can be seen when blood
loss occurs in an individual with parenchymal iron
overload34 or when a near-saturated transferrin is
maintained by large doses of oral and/or parenteral
iron.7’8
The critical nature of the plasma iron concentration
in patients with hemolytic anemia may be demon-
strated by ferrokinetic studies (Fig. 6). A decrease in
transferrin saturation from 60% to 30%, as might be
caused by inflammation, may halve the production of
red cells. This is almost certainly due to a marrow iron
flow insufficient to saturate erythroid membrane
receptors for the transferrin iron complex. In the
severely anemic patient, compensatory mechanisms
are at work to maximize iron supply. Thus, iron
absorption has been shown to be increased in thalas-
semia35 and there is an increased release of catabolized
red cell iron from, rather than storage in, the macro-
phage.36 This results in a high plasma iron concentra-
tion, leading in turn to augmented erythropoiesis.
Fig. 6. Effect of transferrin saturation on iron delivery to bodytissues. Plasma iron turnover in the normal subject is doubled astransferrin saturation increases from low to high levels. In con-trast, a sixfold increase was found in six subjects with hemolyticanemia (mean ± 1 SD plotted).
While this homeostatic mechanism may permit sur-
vival of the untransfused patient with thalassemia, it
results in parenchymal iron overload in later years.
THE ERYTHROID MARROW
The target of both erythropoietin and iron is the
committed stem cell population of the marrow. Experi-
ence with marrow transplant suggests that less than
5% of the total stem cell population is required to
establish basal erythropoiesis, so that the potential
proliferative capacity of the erythron is enormous. In
considering the limitations imposed on the response to
anemia, a major one would appear to be the bony
confinement of the medullary cavity. Some additional
space is created initially by the shift of marrow reticu-
locytes into the blood. Further increases can probably
only be achieved through the gradual extension of
active marrow into inactive medullary cavities. Such
an expanded marrow with its augmented blood supply
is seen in thalassemia, where erythroid proliferation
may reach 10- 1 5 times basal as measured by our
current ferrokinetic techniques.37 This particular dis-
order has the advantage of small red cell precursors
minimizing space problems and a decreased hemo-
globin synthesis in individual cells reducing iron re-
quirements. Nevertheless, there is evidence that so
hyperplastic a marrow may have internal difficulties
involving the disruption of sinusoidal walls with inter-
mittent release of marrow into the blood and emboliza-
tion to the lung.38 This level of marrow activity is also
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1246 CLEMENT A. FINCH
poorly tolerated by the skeleton.3739 There is severe
osteopenia, and medullary cavities expand, at times
allowing marrow to rupture through the bony encase-
ment into the mediastinum. Thus, inescapable liabili-
ties arc associated with extreme marrow proliferation.
A host of other factors are involved in the intricate
process of red cell production and maintenance, includ-
ing structural features of the marrow bed, which
permit orderly maturation and transsinusoidal migra-
tion, other aspects of stem cell activation, the provision
of nutrients such as B,2, folic acid, and pyridoxine so
essential to red cell maturation, and various determi-
nants of red cell survival in circulation. However, iron,
erythropoietin, and committed erythroid stem cells
remain a central triad in the determination of red cell
production. An appreciation of the workings of these
through relatively simply laboratory methods provides
the clinician with a physiologic basis for understanding
most anemias and for anticipating the secondary prob-
lems associated with disturbances in erythropoiesis.
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1982 60: 1241-1246
CA Finch Erythropoiesis, erythropoietin, and iron
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