Pathophysiology of Anemia
A. Gerson Greenburg,MD, PhD,Providence, Rhode Island
Inherent in any decision to treat a patient for
anemia is an appreciation of the underlying
cause of a decrease in the oxygen-carrying
capacity of blood. Equally important is an
understanding of how this acute or chronic
decrease in oxygen delivery affects individual
patients. Anemia generally results from blood
loss, decreased red blood cell (RBC) production,
poor RBC maturation, or increased RBC
destruction. This article reviews the
pathophysiology of anemia, with specific
emphasis on its physiologic consequences in the
surgical patient, and provides a contemporary
definition of anemia for use in that context.
Taking a broader, more functional view of
anemia paves the way for understanding and
appreciating the newer techniques of RBC
conservation and transfusion avoidance, as well
as of pharmacologic methods available to
counter this disorder. Am J Med.
1996; 101(suppl 2A):7S-11S.
From Brown University and The Miriam Hospital, Providence,Rhode
Island.
Requestsfor reprints should be addressedto A. Gerson Greenburg,
MD, Departmentof Surgery, Brown University/TheMiriam Hospital, 154
Summit Avenue, Providence,RhodeIsland 02906.
©1996 by Excerpta Medica, Inc.
All rights reserved.
A n e m i a , a decrease in the oxygen-carrying capac-
.£---]kity of blood, is a c o m m o n finding in surgical pa-
tients. To ensure good patient outcomes, one n m s t
appreciate the impact of a n e m i a on physiologic ho-
meostatic mechanisms, as well as on surgical stress
or r e c o v e r y f r o m an operation. One m u s t also appre-
ciate the physiology of a n e m i a in light of changes in
traditional transfusion therapy and options, that will
be available in the n e a r future. To m o s t ,~urgeons,
knowing the precise cause of a n e m i a is less impor-
tant than understanding its effects on physiologic
s y s t e m s and the p r o b l e m s p r e s e n t e d by intercurrent
diseases.
WHAT IS ANEMIA?
F r o m the perspective of the surgeon, a n e m i a is not
necessarily a diagnosis. It can be viewed as a non-
specific sign of disease associated with a low he-
moglobin concentration. Traditionally, a n e m i a is de-
fined as low values for h e m a t o c r i t and hemoglobin
(for men, <39%, < 13 g/dL, respectively; for women,
<36%, < 12 g/dL, respectively). A neoclassical defi-
nition, accounting for vascular volume effects and
fluid distribution, might be an abnormally ..small red
blood cell ( R B C ) mass. In light of o u r current un-
derstanding of oxygen delivery physiology, i.e., the
interaction of h e m o d y n a m i c s and oxygen content,
both of these definitions are s o m e w h a t flawed.
Clearly, the traditional definition fails to a c c o u n t
for vascular volume. Although m e a s u r e m e n t s of he-
moglobin and hematocrit are easy to accomplish,
these values m a y be of limited use as isolated fac-
tom; in combination with vital signs and clinical as-
sessment, however, they m a y be useful ha clinical
m a n a g e m e n t . For exanlple, in acute hemorrhagic hy-
p o v o l e m i a the hemoglobin concentration m a y re-
main elevated until equilibration of the vascular
s p a c e occurs, possibly hours later, or resuscitation
intercedes. Acute hypervolemic resuscitation, with
large v o l u m e s of balanced salt solutions, m a y dilute
the residual blood volume and thereby decrease the
hemoglobin concentration. The key point is that
acute m e a s u r e m e n t of h e m o g l o b i n concentration
m a y not be useful in assessing oxygen deliw~ry in this
situation.
Measuring RBC m a s s is conceptually a fine idea.
Unfortunately, our ability to m e a s u r e this p a r a m e t e r
is limited. Even w h e n it can be assessed, m a n y fac-
tors besides the time required and the a s s u m p t i o n of
steady-state physiology m u s t be considered in inter-
0OO2-9343/96/$15.00 2A-7S
PII SOO02-9343(96)00161-1
SYMPOSIUM ON THE TREATMENT OF ANEMIA/GREENBURG
preting the data. In absolute terms, m e a s u r e m e n t of
RBC m a s s always relates to p l a s m a volume, b e c a u s e
current techniques link the two m e a s u r e m e n t s .
When p l a s m a volume is increased, the RBC m a s s is
underestimated; this occurs in patients with conges-
tive heart failure, pregnancy, or iatrogenic fluid over-
load. Conversely, an overestimate of RBC m a s s oc-
curs w h e n a patient is dehydrated or w h e n an
overaggressive use of diuretics has d e c r e a s e d the
p l a s m a volume.
Blood volume loss is a m o r e reasonable definition
of anemia; losses of b o t h p l a s m a volume and RBC
m a s s are addressed. Unfortunately, m e a s u r e m e n t by
this definition, too, is related to such factors as rate
of blood loss, w h e t h e r the loss is acute or chronic,
and the degree of vascular refilling. More important,
blood volume loss is difficult to measure, especially
in patients in unstable condition.
A m o r e c o n t e m p o r a r y definition of anemia, one
reflecting tissue perfusion and oxygen use, is pro-
posed. Anemia is here defined as an alteration i n
the o x y g e n d e l i v e r y - o x y g e n u s e p h y s i o l o g y . In the
setting of inadequate oxygen supply or exaggerated
use, true acute and chronic physiologic conse-
quences m a y occur. With adequate oxygen delivery
and appropriate oxygen use, h o m e o s t a s i s is attained,
and all appropriate c o m p e n s a t o r y physiologic re-
s p o n s e s are possible. Obviously, this is an ideal sit-
uation. In the chronically ill patient with underlying
multiorgan c o m p r o m i s e w h o is receiving a host of
pharmacologic agents, normal physiologic re-
s p o n s e s are blunted or obliterated, limiting the re-
s p o n s e to altered oxygen delivery. Furthermore, the
effects of age on physiologic reserve have a signifi-
cant i m p a c t on the m a i n t e n a n c e of adequate oxygen
delivery. ~-3
OXYGEN DELIVERY PHYSIOLOGY
To achieve adequate tissue p e r f u s i o n - - t h e prod-
uct of flow, cardiac output, and oxygen-carrying ca-
p a c i t y - h e m o g l o b i n concentration m u s t be rela-
tively constant. Tissues deprived of oxygen are
hypoxic and incur an "oxygen debt." That debt, an
overuse of oxygen, requires a period of increased
oxygen delivery to allow repletion.
Global oxygen delivery is defined as the p r o d u c t
of cardiac output and arterial oxygen content. Car-
diac output is regulated by preload, contractility, and
afterload, w h e r e a s oxygen content is determined pri-
marily by hemoglobin concentration and, to a lesser
extent, by the degree of oxygen saturation. For prac-
tical purposes, the relationship b e t w e e n cardiac out-
put and arterial oxygen content is a s s u m e d to be lin-
ear over the usual clinical ranges; it p r o b a b l y is not
linear at the physiologic limits of survival. 4 Thus,
global oxygen delivery m a y be increased by increas-
2A-8S August26, 1996 The American Journal of Medicine® Volume 101 (suppl 2A)
ing either cardiac output or hemoglobin concentra-
tion as needed to attain an oxygen delivery of 5 0 0 -
700 mL/min/m'~.
The interaction of oxygen delivery with the lungs
is described in t e r m s of oxygen saturation. To main-
tain global oxygen delivery, a decrease; of 15% in
oxygen saturation requires a significant increase in
cardiac output. Similarly, a greater cardiac compen-
sation, i.e., increased output, is required as the he-
moglobin concentration falls. 3
Global oxygen c o n s u m p t i o n is the p r o d u c t of car-
diac output and the a r t e r i a l - v e n o u s oxygen content
difference. Usually, oxygen is c o n s u m e d at a rate of
125-175 m L / m i n / m 2, a b o u t 25% of the global oxygen
delivery. The normal oxygen extraction ratio is 0.25-
0.30. When the ratio e x c e e d s this range by 20-30%,
it usually indicates inadequate tissue oxygen delivery
and resultant tissue h y p o x i a and a switch to anaer-
obic metabolism; the consequent oxygen debt will
require replenishment to reestablish homeostasis.
ADVERSE EFFECTS OF ANEMIA
Acute blood loss d e c r e a s e s blood pressure; this
triggers release of catecholamines, which in turn
p r o d u c e vasoconstriction, increase cardiac contrac-
tility, and increase cardiac output early in the course.
This physiologic p r o c e s s normalizes oxygen delivery
by increasing blood flow. If bleeding is controlled at
its site, the m o v e m e n t of fluid b e t w e e n compart-
m e n t s will lead to blood volume equilibration. How-
ever, if blood volume loss continues, vasoconstric-
tion is prolonged, and the subsequent decrease in
cardiac output is followed by severe tissue hypoxia,
cellular failure, and eventual organ dysfunction a n d /
or failure. It is this detrimental physiologic c a s c a d e
that is p r e v e n t e d by ensuring adequate oxygen deliv-
ery to tissues. ~'6
When oxygen delivery is impaired, another detri-
mental physiologic cascade occurs at the cellular
level. M e m b r a n e instability resulting f r o m altered en-
ergy production allows sodium and w a t e r to flow
into the cell, while p o t a s s i u m flows out; cellular
e d e m a occurs. Intracellular acidosis, caused by the
switch to anaerobic metabolism, will lead to extra-
cellular acidemia due to excess lactic acid produc-
tion. Eventually, the cell loses its strnctural integrity
and dies. This p r o c e s s can be arrested and reversed
in an intact cell by an adequate supply of oxygen,
achieved by increasing cardiac output a n d / o r adding
additional oxygen-carrying capacity.
MECHANISMS OF ANEMIA
Anemia ( h e r e defined as a d e c r e a s e d RBC m a s s )
is traditionally ascribed to several p r o m i n e n t mech-
anisms ( T a b l e I ) . Whereas all of these m e c h a n i s m s
 SYMPOSIUM ON THE TREATMENT OF ANEMIA/GREENBURG

quate n u m b e r s of m a t u r e red cells, as m a y o c c u r in

TABLE I
aplastic anemia. In addition, failure to p r o d u c e an
Mechanisms of Anemia
adequate n u m b e r of m a t u r e red cells m a y o c c u r in
Mechanism Proportion (%)
conditions such as thalassemia and vitamin B12 or
Acute bleeding 25 folate deficiency, despite hyperplastic bone marrow;
Iron deficiency 25
m u c h of the erythroid activity of patients with these
Infection/inflammation 25
Hemolysis/marrow failure 15 conditions is "ineffective."
Megaloblastosis 10 I n c r e a s e d RBC destruction can also lead to a de-
crease in RBC mass. The causes of increased extra-
vascular RBC destruction include various inmmno-
lead to d e c r e a s e d oxygen-carrying capacity, s o m e hemolytic diseases, hereditary spherocytosis,
p r o d u c e acute a n e m i a and others a chronic form. associated hemoglobinopathies, and enzyme defi-
ciencies. Since surgeons often see patients with
Blood Loss these underlying illnesses, they m u s t recognize such
Acute bleeding often a c c o m p a n i e s trauma. How- disorders and use t h e m as the basis for t n m s f u s i o n
ever, it m a y also be caused by acute or chronic gas- decisions w h e n appropriate.
trointestinal h e m o r r h a g e ( s e c o n d a r y to ulcer, in- Intravascular destruction of RBCs (lysis) can re-
flammatory b o w e l disease, tumor, or infection), s u l t f r o m a hemolytic transfusion reaction (lethal in
intraoperative blood loss, and excessive p h l e b o t o m y a p p r o x i m a t e l y 1 p e r 100,000 transfusions), burns, in-
for diagnostic purposes. fection (e.g., malaria or infection with Clostridium
perfringens), or fresh-water drowning, or RBC lysis
Iron Deficiency m a y o c c u r in patients w h o are deficient in glucose-
Blood loss is the single m o s t important cause of 6-phosphate dehydrogenase and thus unable to me-
iron deficiency. When blood is lost externally, a cycle tabolize various drugs. Distinctly u n c o m m o n , the re-
of negative iron balance begins: output e x c e e d s in- sults of intravascular hemolysis can range f r o m mild
put. Eventually, the lack of iron stores b e c o m e s the reactions to severe or even lethal consequences. Car-
limiting factor in erythropoiesis. diopulmonary b y p a s s circuits and intraoperative cell
Failure of erythropoiesis is usually due to iron de- salvage techniques can also contribute to RBC de-
ficiency but is also associated with renal disease struction, but rarely to an extent requiring interven-
(erythropoietin deficiency), endocrine disorders tion. Although c a r d i o p u l m o n a r y b y p a s s circuits can
( e.g., thyroid and pituitary disease), and h e a v y metal fragment RBCs and p r o d u c e s e c o n d a r y hemolysis,
toxicity. the filters in the devices are usually sufficiently ef-
fective to obviate problems.
Chronic Illness or Inflammation These underlying m e c h a n i s m s of a n e m i a rarely re-
The a n e m i a of chronic illness and inflammation is quire surgical intervention, except for s p l e n e c t o m y
n o w a s s u m e d to be in part a defect of iron metabo- to m a n a g e spherocytosis or thalassemia. However,
lism. 7 D e c r e a s e d RBC survival, an impaired m a r r o w if an acute surgical p r o b l e m develops in a patient
response, and evidence of disturbed iron m e t a b o l i s m with one of these illnesses, an understanding of the
have b e e n d o c u m e n t e d in p e r s o n s with this type of cause of the a n e m i a and its pathophysiology will be
anemia. In addition, there is s o m e evidence of a dis- helpful in guiding management.
turbance in m o n o c y t e - m a c r o p h a g e release of iron Further exploration is needed to elucidate the role
that m a y be related to inflammatory cytokines. If this of iron deficiency ( d u e to chronic blood loss or in-
hypothesis is validated, the a n e m i a of chronic illness adequate intake) during postoperative recovery. If
or inflammation m a y be a rarity due to a state of recovery is related to the rate of restoration of RBC
functional iron deficiency. Moreover, cytokines m a y mass, intravascular volume, and normalitzation of
decrease the responsiveness of erythroid p r e c u r s o r s cardiovascular h o m e o s t a t i c mechanisms, then suffi-
to erythropoietin, as well as decrease erythropoietin cient iron stores are n e c e s s a r y to optimize erythro-
p r o d u c t i o n by the kidney or increase its rate of ca- poiesis, s
tabolism. In general, s e r u m erythropoietin levels are
inappropriately low for the degree of a n e m i a in pa-
tients with the a n e m i a of chronic disease. AVOIDING THE EFFECTS OF ANEMIA
Independently of which definition of ;~.nemia is
Hemolysis, Marrow Failure, and adopted, the i m p a c t of a decrease in oxygen-carrying
Megaloblastosis capacity on patient o u t c o m e is measurable. Whether
Anemia due to d e c r e a s e d RBC production results as an acute consequence of altered oxygen delivery
f r o m failure of the b o n e m a r r o w to p r o d u c e a d e - or as a delayed effect of impaired physiologic re-

August 26, 1996 The American Journal of Medicine® Volume 101 (suppl 2A) 2A-9S
SYMPOSIUM ON THE TREATMENT OF ANEMIA/GREENBURG
sponse, a n e m i a can adversely affect patient out-
come.
Because the association of inadequate oxygen de-
livery with detrimental effects has b e e n both per-
ceived and documented, transfusion therapy is often
used to prevent adverse outcomes. A n u m b e r of is-
sues immediately arise with r e s p e c t to the transfu-
sion decision. In effect, the decision is often b e t w e e n
transfusion avoidance a n d / o r blood conservation
techniques and the risks inherent in transfusion of
allogeneic blood. Although the literature reports the
a p p a r e n t statistical associations of adverse effects
with allogeneic transfusion, firm conclusions are not
forthcoming. Since allogeneic or autologous RBC
transfusions are the only m e t h o d s currently avail-
able to increase oxygen-carrying capacity acutely,
risk a s s e s s m e n t is particularly important. Although
transfusion therapy is not free of p r o b l e m s and com-
plications, few alternatives exist to increase the ox-
ygen-carrying capacity w h e n required. 9 le
Some p o o r surgical o u t c o m e s are associated with
anemia. The anaerobic environment of a fresh
w o u n d is ideal for the establishment of infection, and
p o o r perfusion at the operative site increases the risk
of delayed w o u n d healing and w o u n d infection, la If
the tissues around the w o u n d are adequately per-
fused, better w o u n d healing results. Decreased tis-
sue perfusion has b o t h immediate and delayed con-
sequences that remain poorly understood. In a
c o m m o n clinical scenario, an elderly patient ( w h o s e
b o d y is unable to c o m p e n s a t e for loss of hemoglobin
with an increase in cardiac o u t p u t ) is put at risk peri-
operatively and allowed to undergo h y p o v o l e m i a
and p o o r tissue perfusion. P o o r systemic perfusion
can result in cerebral vascular accident (i.e., s t r o k e )
or myocardial infarction. Preoperative use of RBC
transfusion m a y obviate this r i s k . a'14-m Furthermore,
postoperative mental confusion has b e e n associated
with hypoxemia.
The results of a recent study s h o w a clear survival
advantage in high-risk surgical patients who have
adequate oxygen delivery, especially those with in-
creased metabolic needs. This is important evidence
supporting the i m p r o v e m e n t of oxygen delivery to
effect beneficial o u t c o m e s in high-risk surgical pa-
tients; such data suggest pursuing early, aggressive
m a n a g e m e n t of an oxygen debt related to p o o r per-
fusion, iv- 19
THE "TRANSFUSION TRIGGER"
Is there an easily identified transfusion trigger? Is
it possible to identify the point at which insufficient
oxygen delivery b e c o m e s severe enough to require
increased oxygen-carrying capacity to restore ade-
quate tissue perfusion? Because invasive physiologic
monitoring is n e c e s s a r y to assess the requisite pa-
2A-10S August 26, 1996 The American Journal of Medicine® Volume 101 (suppl 2A)
rameters, the ability to define this point m a y be lim-
ited to the e n v i r o n m e n t of the intensive care unit or
operating room.
A biphasic relationship is a p p a r e n t b e t w e e n oxy-
gen c o n s u m p t i o n and oxygen delivery: a flow-inde-
p e n d e n t oxygen c o n s u m p t i o n p h a s e is followed by
a flow-dependent phase. 1 The point at which the pla-
teau b e c o m e s apparent, w h e r e the slope of the flow-
d e p e n d e n t oxygen c o n s u m p t i o n changes signifi-
cantly, is called the point of critical oxygen delivery.
Notably, this point c o r r e s p o n d s to a change in oxy-
gen extraction ratio of > 0 . 3 - 0 . 3 5 and an increase in
blood lactate levels that reflects a switch to anaero-
bic metabolism, a hallmark of p o o r tissue perfusion.
With the availability of all these m e a s u r e m e n t s , the
transfusion trigger should a p p r o x i m a t e the point of
critical oxygen delivery. In practical ten~as, the crit-
ical oxygen delivery point a p p e a r s to be a global ox-
ygen delivery of 10-12 mL/min/kg. Some patients
m a y require an intervention with red cell transfusion
before this point is reached if the goals of maintain-
ing oxygen delivery or repaying oxygen debt are to
be attained.
CONCLUSIONS
If the patient-oriented goal is to maximize oxygen
delivery, the first step is the optimization of ventila-
tion followed b y optimization of hemodynamics. In
taking these steps, the physician m u s t take into ac-
count the limitations in cardiac reserve, preexisting
disease, and pharmacologic therapy for a given pa-
tient, a'2° Should these actions fail to optimize oxygen
delivery by normalizing the oxygen extraction ratio
or inclining it toward normal, intervention in the
f o r m of transfused RBCs is p r o b a b l y indicated to
provide additional oxygen-carrying capacity.
In the future, alternative solutions will be available
to augment oxygen delivery without using allogeneic
RBCs. 2° Regardless, the minimal therapeutic objec-
tive should be normal oxygen delivery with a normal
oxygen extraction ratio and d o c u m e n t a t i o n of flow-
independent oxygen consumption.
According to the c o n t e m p o r a r y definition of ane-
mia, normalization of oxygen delivery and tissue per-
fusion will obviate the adverse effects of anemia. The
time has c o m e for us to consider global oxygen de-
livery and oxygen c o n s u m p t i o n physiology rather
than focus on static m e a s u r e s of hemoglobin or he-
matocrit in assessing the c o n s e q u e n c e s of anemia
and determining the point at which trallsfusion is
necessary. 1.21
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