Approach To The Adult Patient With Anemia - UpToDate

8/30/2017 Approach to the adult patient with anemia - UpToDate
Author: Stanley L Schrier, MD

Section Editor: William C Mentzer, MD
Deputy Editor: Jennifer S Tirnauer, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Dec 19, 2016.
INTRODUCTION Evaluation for anemia is one of the most common problems seen in clinical practice. While
the evaluation may be straightforward in an otherwise healthy individual with a single cause of anemia, in many
cases the cause is not readily apparent and multiple conditions may be contributing.
An overview of the causes of anemia and an approach to the evaluation of the adult with unexplained anemia
are presented here.
Specific causes of anemia and the evaluation of specific patient populations are discussed in more detail in
separate topic reviews:
Iron deficiency (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)
B12 and folate deficiency (See "Clinical manifestations and diagnosis of vitamin B12 and folate
deficiency".)
Chronic disease/inflammation (See "Anemia of chronic disease/inflammation".)
Hemolytic anemia (See "Diagnosis of hemolytic anemia in the adult" and "Overview of hemolytic anemias
in children".)
Drug-induced (See "Hemolytic anemia due to drugs and toxins".)
Myelodysplastic syndrome (See "Clinical manifestations and diagnosis of the myelodysplastic
syndromes".)
Hemoglobinopathies (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)
Aplastic anemia (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis".)
Microangiopathic hemolytic anemia (See "Approach to the patient with suspected TTP, HUS, or other
thrombotic microangiopathy (TMA)".)
Older adults (See "Anemia in the older adult".)
Children (See "Approach to the child with anemia".)
HOW TO USE THIS TOPIC REVIEW This topic review is presented in two semi-independent parts:
The first portion of this review is devoted to an understanding of the basic aspects of red blood cell
production and destruction along with a review of the causes and clinical consequences of anemia.
The second portion is devoted to the clinical and laboratory evaluation of the anemic patient (algorithm 1).
DEFINITIONS
Anemia Anemia can be rigorously defined as a reduced absolute number of circulating red blood cells (ie, a
reduced red blood cell mass as determined via blood volume studies). However, blood volume studies are not
practical for this purpose, cost-effective, or generally available. As a result, anemia has been defined as a
reduction in one or more of the major red blood cell (RBC) measurements obtained as a part of the complete
blood count (CBC): hemoglobin concentration, hematocrit (HCT), or RBC count. In practice, however, a low
hemoglobin concentration or a low hematocrit is most widely employed for this purpose.
https://www.uptodate.com/contents/approach-to-the-adult-patient-with-anemia?source=search_result&search=anemia&selectedTitle=1~150#H25565 1/23
Hemoglobin Hemoglobin concentration is the concentration of hemoglobin, the major oxygen-carrying

molecule in whole blood. Values may be expressed as grams of hemoglobin per 100 mL of whole blood
(g/dL) or per liter of blood (g/L). Efforts are underway to determine hemoglobin levels non-invasively,
allowing continuous monitoring of this parameter [1-3].
Hematocrit Hematocrit (HCT), also called packed cell volume, is the packed spun volume of blood that
consists of intact RBCs, expressed as a percentage. HCT can be measured directly following
centrifugation of a blood sample (picture 1 and picture 2) or calculated (HCT = [RBC x MCV]/10).
RBC count RBC count is the number of RBCs contained in a specified volume of whole blood, usually
expressed as millions of cells per microL of whole blood.
In patients with anemia, hemoglobin and HCT typically decrease in parallel. RBC also usually parallels the
hemoglobin and HCT, except in cases of extreme microcytosis such as thalassemia, in which the RBC count
may be increased despite the presence of anemia.
Normal ranges for hemoglobin/HCT One set of "normal ranges" (95 percent confidence limits) for
hemoglobin, HCT, and RBC count is shown in the table (table 1). If anemia is defined as values that are more
than two standard deviations (SD) below the mean, then, by using these ranges, a hemoglobin <13.5 g/dL
(<135 g/L) or a HCT <41.0 percent represents anemia in men, and a value <12.0 g/dL (<120 g/L) or <36.0
percent, respectively, represents anemia in women. Normal ranges other than the above have been proposed:
Other authors have proposed different lower limits of normal for the hemoglobin level, ranging from 13.0 to
14.2 g/dL for men and 11.6 to 12.3 g/dL for women [4].
World Health Organization (WHO) criteria for anemia in men and women are <13 and <12 g/dL,
respectively [5]. These criteria were meant to be used within the context of international nutrition studies,
and were not initially designed to serve as "gold standards" for the diagnosis of anemia [4].
The revised WHO/National Cancer Institute's criteria for anemia in men and women are <14 and <12 g/dL,
respectively [6]. These values were meant to be used for evaluation of anemia as a complication of
chemotherapy in patients with malignancy (table 2).
Other lower limits according to sex, age, and race, based on data from NHANES III and Scripps-Kaiser
studies, have been proposed (table 3) [4]. These values are as low as 12.7 g/dL for black men >60 years of
age and 11.5 g/dL for black women >20 years of age.
These "normal" ranges may not apply to certain populations:
Athletes Values in endurance athletes may vary significantly from those in other healthy individuals due
to a combination of factors, as discussed below. (See 'Athletes' below.)
Living at high altitude Patients living at high altitude have values higher than those living at sea level
[7]. (See "High altitude, air travel, and heart disease", section on 'Long-term altitude exposure'.)
Smokers A study of blood donors who smoke found a significant and direct correlation between the
patients' blood carboxyhemoglobin and hemoglobin values [8]. Thus, patients who smoke or have
significant exposure to secondary smoke or other sources of carbon monoxide may have HCT higher than
normal [9], occasionally masking the presence of an underlying anemia. (See "Diagnostic approach to the
patient with polycythemia", section on 'Acquired secondary polycythemia'.)
African-Americans Values for hemoglobin in African-Americans of both sexes and all ages are 0.5 to
1.0 g/dL lower than values in comparable Caucasian populations [4,10-14]. Some, but not all, of these
differences may be attributable to co-existing iron deficiency anemia and/or alpha thalassemia [15].
Presence of chronic disease Normal values for a population with a high incidence of chronic disease
may be skewed toward anemic levels. Thus, anemia may be difficult to define in countries in which
malnutrition, infection (eg, tuberculosis, malaria), and/or congenital hematologic disorders (eg,
thalassemia) are common. (See "Public health issues in the thalassemic syndromes", section on
'Introduction'.)
Older adults Anemia in older adults is discussed separately. (See "Anemia in the older adult".)
There are also a number of limitations to the use of normal values in isolation:
The above ranges may be "two-tailed" to be used for defining both anemia and polycythemia
(erythrocytosis). In such cases, 2.5 percent of normal adults will have values that are more than two
standard deviations below whatever "normal range" has been selected, and will be considered anemic. On
the other hand, some ranges are "one-tailed," such that 5 percent of normal subjects will have levels below
the stated lower limit of normal [4].
The normal range for hemoglobin and HCT is so wide that, for example, a male patient with a baseline
HCT of 49 percent may lose up to 15 percent of his RBC mass and still have a HCT within the normal
range.
Setting a lower limit of normal for hemoglobin does not imply that such levels are "optimal" in terms of
morbidity and mortality. One study has suggested that the lower limits of an optimal hemoglobin level, as
assessed by all-cause mortality data, are 13.0 and 14.0 g/dL for older adult women and men, respectively
[16]. However, in one report, older black subjects classified as anemic by WHO criteria did not appear to be
at risk for adverse events such as mortality and mobility disability [17], suggesting that alternative criteria
for anemia might be required for this group (table 3) [4]. (See "Anemia in the older adult", section on
'Defining anemia in the older adult'.)
Red blood cell indices The RBC indices describe the size, shape, and hemoglobin content of RBCs, as
well as the uniformity of the RBC population. Evaluation of these values is an integral part of determining the
cause of anemia. (See 'Morphologic approach' below.)
MCV Mean corpuscular volume (MCV) is the average volume (size) of the patient's RBCs. It can be
measured or calculated (MCV in femtoliters [fL] = 10 x HCT [in percent] RBC [in millions/microL]).
Anemia can be classified based on whether the MCV is low, normal, or elevated. (See 'Morphologic
approach' below.)
MCH Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a RBC. It is calculated
(MCH in picograms [pg]/cell = hemoglobin [in g/dL] x 10 RBC [in millions/microL]. A low MCH indicates
decreased hemoglobin content per cell, and is typically reflected in hypochromia on the peripheral blood
smear. This may be seen in iron deficiency and hemoglobinopathies like the thalassemias.
MCHC Mean corpuscular hemoglobin concentration (MCHC) is the average hemoglobin concentration
per RBC. It is calculated as (MCHC in grams [g]/dL = hemoglobin [in g/dL] X 100 HCT [in percent]). Very
low MCHC values are typical of iron deficiency anemia, and very high MCHC values typically reflect
spherocytosis or RBC agglutination. Examination of the peripheral blood smear is helpful in distinguishing
these findings. (See "Evaluation of the peripheral blood smear", section on 'Red blood cells'.)
RDW Red cell distribution width (RDW) is a measure of the variation in RBC size, which is reflected in
the degree of anisocytosis on the peripheral blood smear. A high RDW implies a large variation in RBC
sizes, and a low RDW implies a more homogeneous population of RBCs. RDW is calculated as the
coefficient of variation (CV) of the red cell volume distribution (RDW = [standard deviation/MCV] x 100). A
high RDW can be seen in a number of anemias, including iron deficiency, myelodysplastic syndrome, and
hemoglobinopathies, as well as in patients with anemia who have received transfusions. Review of the
peripheral blood smear often is helpful in identifying the cause of large variations in RBC size. (See
'Morphologic approach' below and "Evaluation of the peripheral blood smear".)
Details of how these indices are determined and potential causes of spurious results are presented separately.
(See "Automated hematology instrumentation".)
THE RED BLOOD CELL LIFE CYCLE
Overview Erythropoiesis in the adult takes place within the bone marrow under the influence of the stromal
framework, cytokines, and the erythroid specific growth factor, erythropoietin (EPO). EPO is a true endocrine
hormone produced in the kidney by cells that sense the adequacy of tissue oxygenation relative to the
individual's metabolic activity (figure 1). (See "Regulation of erythropoiesis".)
EPO enhances the growth and differentiation of the two erythroid progenitors: burst forming units-erythroid
(BFU-E) and colony forming units-erythroid (CFU-E) into normoblasts of increasing maturity. The most mature
of these, the orthochromatic normoblast, extrudes its nucleus to form a red blood cell (RBC) via mechanisms
that are still unclear [18,19]. As such, the enucleate red blood cell still has a ribosomal network that, when
stained supravitally, identifies it as a reticulocyte, a cell still capable of a limited amount of hemoglobin and
protein synthesis [20].
The reticulocyte retains its ribosomal network (and its staining characteristics) for approximately four days, of
which three days are generally spent in the bone marrow and one day in the peripheral blood (figure 2). The
resulting mature RBC circulates for 110 to 120 days, after which time it is removed from the circulation by
macrophages that detect senescent signals, primarily on the RBC membrane, through mechanisms that are
poorly understood. (See "Red blood cell survival: Normal values and measurement".)
Under steady state conditions, the rate of RBC production equals the rate of RBC loss. Assuming, for ease
of calculation, a survival of mature RBC of 100 days, 1 percent of RBCs will be removed from the
circulation each day. To achieve a constant RBC mass, RBC losses must be replaced with an equal
number of reticulocytes during the same time period.
Reticulocytes normally survive in the circulation for one day; after this time they lose their reticulum (RNA)
and become mature red blood cells. Under steady-state conditions reticulocytes will represent
approximately 1 percent of total circulating RBC (table 1). Since the normal RBC count is approximately 5
million/microL (5.0 x 1012/liter), the bone marrow must produce approximately 50,000 reticulocytes/microL
(5 x 1010/liter) of whole blood each day in order to achieve a stable RBC mass. Lesser rates of RBC
production, if persistent, lead to anemia.
The rate of red cell production increases markedly under the influence of high levels of EPO. A normal bone
marrow replete with iron, folate, and cobalamin can increase erythropoiesis in response to EPO approximately
fivefold in adults and seven- to eightfold in children. Thus, under optimal conditions, steady-state absolute
reticulocyte counts as high as 350,000/microL (3.5 x 1011/liter) are possible in the adult.
Reticulocytes Reticulocytes can be enumerated manually after supravital staining of a blood sample with
dyes such as new methylene blue (picture 3). The normal range (ie, percent of RBC with positive staining) in
adults is 0.5 to 2.0 percent (table 1). Reticulocytes can be appreciated on a standard blood smear stained with
Wright-Giemsa as RBC with a blue tint (polychromatophilia) that are larger than mature RBC, with irregular
borders and a lack of central pallor (picture 4).
Reticulocytes can be counted with more accuracy via automated blood counters after staining with a
fluorescent dye, such as thiazole orange, which binds to the RNA of reticulocytes [21]. (See "Automated
hematology instrumentation", section on 'Automated counting of reticulocytes'.)
The utility of reticulocyte counting in some settings can be improved by determination of the absolute
reticulocyte count, the corrected absolute reticulocyte count, and/or the reticulocyte production index. This
subject is discussed separately. (See "Diagnosis of hemolytic anemia in the adult", section on 'High reticulocyte
count'.)
VOLUME STATUS Hemoglobin, hematocrit (HCT), and red blood cell (RBC) count are all concentrations
and dependent on the red blood cell mass (RCM) as well as the plasma volume. As a result, values for all three
parameters will be reduced if the RCM is decreased and/or if the plasma volume is increased [22]. Similarly,
values for all three will be increased if the plasma volume is decreased (ie, hemoconcentration). Three common
clinical examples will help make this point:
Acute bleeding A 70 kg adult with a bleeding peptic ulcer who had a 750 mL hematemesis (ie, 15
percent of a normal total blood volume) within the past 30 minutes may have postural hypotension due to
acute volume depletion, but will have normal values for hemoglobin and HCT. Over the ensuing 36 to 48
hours, most of the total blood volume deficit will be repaired by the movement of fluid from the
extravascular into the intravascular space. Only at these later times will the hemoglobin and HCT reflect
blood loss. Accordingly, if the total blood volume deficit is not fully repaired and the patient remains
hypovolemic, the hemoglobin and HCT will underestimate the degree of blood loss [23].
Late pregnancy In the third trimester of pregnancy the RBC mass and plasma volume are expanded by
25 and 50 percent, respectively, resulting in reductions in hemoglobin, HCT, and RBC count, often to
anemic levels (figure 3). However, according to the RBC mass, such women are polycythemic. The terms
"physiologic" or "dilutional" anemia have been applied to this setting, although such patients are not truly
anemic.
Volume depletion Anemic patients admitted to the hospital in a volume depleted (hemoconcentrated)
state may not show abnormally low hemoglobin/HCT values on initial testing. Their underlying anemia may
become apparent only after their volume status has been corrected.
CLINICAL CONSEQUENCES The signs and symptoms induced by anemia are dependent upon the degree
of anemia and the rate at which it has evolved, as well as the oxygen demands of the patient. Symptoms are
much less likely with anemia that evolves slowly, because there is time for multiple homeostatic forces to adjust
to a reduced oxygen carrying capacity of blood.
Normal red cell function Red blood cells (RBCs) carry oxygen linked to hemoglobin from the lungs to
tissue capillaries. Oxygen is then released from hemoglobin according to the characteristics of the
oxyhemoglobin dissociation curve, with each gram of hemoglobin capable of carrying 1.3 mL of oxygen. Thus,
approximately 20 mL/dL (or 20 volumes percent) can be carried by 15 g/dL of hemoglobin at full saturation.
Approximately 5 volumes percent (25 percent of the total) is normally removed by the tissues [24]. (See
"Oxygen delivery and consumption" and "Genetic disorders of hemoglobin oxygen affinity", section on
'Mutations that decrease the affinity of hemoglobin for 2,3-BPG'.)
Symptoms Symptoms related to anemia can result from two factors: decreased oxygen delivery to tissues
and, in patients with acute and marked bleeding, the added insult of hypovolemia. There is some reduction in
blood volume but not plasma volume after acute severe hemolysis, due to the fall in RBC mass. In comparison,
total blood volume remains normal in anemia due to chronic, low-grade bleeding, since there is ample time for a
compensatory increase in the plasma volume via equilibration with the extravascular space and renal retention
of salt and water.
Symptoms of impaired oxygen delivery reflect the fall in hemoglobin concentration. The extraction of oxygen by
the tissues can increase from a baseline of 25 percent to a maximum of approximately 60 percent in the
presence of anemia or hypoperfusion. Thus, normal oxygen delivery of 5 volumes percent can be maintained
by enhanced extraction alone down to a hemoglobin concentration of 8 to 9 g/dL [25].
When the added compensation of increases in stroke volume and heart rate (and therefore cardiac output) are
included, oxygen delivery can be maintained at rest at a hemoglobin concentration as low as 5 g/dL (equivalent
to a hematocrit of 15 percent), assuming that the intravascular volume is maintained [26]. (See "Indications and
hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Role of blood in oxygen delivery'.)
Symptoms will occur when the hemoglobin concentration falls below this level at rest, at higher hemoglobin
concentrations during exertion, or when cardiac compensation is impaired because of underlying heart disease.
The primary symptoms include exertional dyspnea, dyspnea at rest, varying degrees of fatigue, and signs and
symptoms of the hyperdynamic state such as bounding pulses, palpitations, and a roaring pulsatile sound in the
ears. More severe anemia may lead to lethargy, confusion, and potentially life-threatening complications such
as congestive failure, angina, arrhythmia, and/or myocardial infarction. (See "High-output heart failure".)
Anemia induced by acute bleeding is associated with the added complication of intracellular and extracellular
volume depletion. The earliest symptoms include easy fatigability, lassitude, and muscle cramps. This can
progress to postural dizziness, lethargy, syncope, and, in severe cases, persistent hypotension, shock, and
death. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
Mortality The development of anemia is a risk factor for increased mortality in a number of clinical
settings. A few of the many examples are listed below:
Chronic kidney disease (see "Effects of anemia in chronic kidney disease", section on 'Mortality')
Malignancy (see "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with
cancer", section on 'Effect on disease control and survival')
Heart failure (see "Approach to anemia in adults with heart failure", section on 'Prognosis')
The older adult (see "Anemia in the older adult", section on 'Increased mortality')
The hospitalized adult [27] (see "Indications and hemoglobin thresholds for red blood cell transfusion in the
adult", section on 'Impact of anemia on morbidity and mortality')
Fatigue Although anemia may be associated with fatigue, this complaint is non-specific, may be present
in a number of other conditions, and may be multi-factorial. This subject is discussed in depth separately. (See
"Approach to the adult patient with fatigue" and "Cancer-related fatigue: Prevalence, screening and clinical
assessment".)
CAUSES OF ANEMIA There are two general approaches one can use to help identify the cause of anemia.
Each will be discussed below.
A kinetic approach, addressing the mechanism(s) responsible for the fall in hemoglobin concentration
A morphologic approach categorizing anemias via alterations in red blood cell (RBC) size (ie, mean
corpuscular volume) and the reticulocyte response [28]
Kinetic approach Anemia can be caused by three independent mechanisms: decreased RBC production,
increased RBC destruction, and blood loss [20]. Occasional patients may have two (or all three) of these
mechanisms operating at the same time. As examples:
A patient with autoimmune hemolytic anemia (ie, increased RBC destruction) can have a low reticulocyte
response (ie, decreased RBC production) as the result of concomitant bone marrow suppression. (See
"Warm autoimmune hemolytic anemia: Clinical features and diagnosis", section on 'Reticulocyte
response'.)
A patient with aplastic anemia (decreased RBC production) may have significant hemorrhage as the result
of concomitant severe thrombocytopenia (blood loss). (See "Aplastic anemia: Pathogenesis; clinical
manifestations; and diagnosis", section on 'Clinical manifestations'.)
A patient admitted to the hospital for acute alcoholism and gastrointestinal hemorrhage (blood loss) may be
found to have concomitant folate deficiency associated with ineffective erythropoiesis (decreased RBC
production) and shortened RBC lifespan (increased RBC destruction). It would not be unusual for this
patient to also be iron deficient. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies",
section on 'Causes of folate deficiency'.)
Decreased RBC production Anemia will ultimately result if the rate of RBC production is less than that of
RBC destruction. This can occur either due to reduced effective production of red cells, or via the destruction of
RBC precursors within the bone marrow (ineffective erythropoiesis).
Decrease in effective red cell production When the bone marrow is otherwise healthy, it will respond
to anemia by increasing the number of red cell precursors and hastening their normal progression into
reticulocytes. Thus, a reduced or absent reticulocyte response for the degree of anemia indicates reduced red
cell production. A convenient way to evaluate this is via the reticulocyte production index (calculator 1),
which will be low (<2) when the marrow response to anemia is inadequate for the degree of anemia and
increased (>3) when the marrow is responding normally to the anemia. (See "Diagnosis of hemolytic anemia in
the adult", section on 'High reticulocyte count'.)
The more common causes for reduced (effective) RBC production include:
Lack of nutrients, such as vitamin B12 and iron. This can be due to dietary lack or malabsorption (eg,
sprue), although iron deficiency is commonly due to blood loss.
Bone marrow disorders leading to a reduced number of RBC precursors (eg, aplastic anemia, pure RBC
aplasia, marrow infiltration)
Bone marrow suppression (eg, drugs, chemotherapy, irradiation) (see "Hematologic complications of
malignancy: Anemia and bleeding")
Low levels of trophic hormones, which stimulate RBC production, such as erythropoietin (EPO; eg, chronic
renal failure), thyroid hormone (eg, hypothyroidism), and androgens (eg, hypogonadism)
A rare cause of anemia due to reduced EPO production has been described in patients with
autonomic dysfunction and orthostatic hypotension [29,30]. (See "Treatment of orthostatic and
postprandial hypotension", section on 'Erythropoietin'.)
Acquired inhibitors of EPO or the EPO receptor have also been described as causes of anemia [31].
(See "Pure red cell aplasia due to anti-erythropoietin antibodies".)
The anemia of inflammation, associated with infectious, inflammatory, or malignant disorders, is

characterized by reduced availability of iron due to decreased absorption of iron from the gastrointestinal
tract and decreased release of iron from macrophages, a relative reduction in EPO levels, and a mild
reduction in RBC lifespan. (See "Anemia of chronic disease/inflammation".)
Presence of ineffective erythropoiesis The hallmark of ineffective erythropoiesis is the presence of

intense erythroid hyperplasia within the bone marrow along with a relative reduction in reticulocyte production
(eg, a reduced reticulocyte production index). In such cases, the erythroid precursors in the bone marrow are
not maturing normally and are dying within the bone marrow, usually via the process of apoptosis and/or a
block in maturation.
The more common causes for ineffective erythropoiesis include the following disorders:
Megaloblastic anemia (see "Causes and pathophysiology of vitamin B12 and folate deficiencies", section
on 'Hematopoiesis')
Alpha and beta thalassemia (see "Pathophysiology of alpha thalassemia", section on 'Ineffective
erythropoiesis' and "Pathophysiology of beta thalassemia", section on 'Ineffective erythropoiesis')
The myelodysplastic syndromes (see "Clinical manifestations and diagnosis of the myelodysplastic
syndromes", section on 'Bone marrow biopsy')
Sideroblastic anemias (see "Causes and pathophysiology of the sideroblastic anemias", section on
'Pathophysiology')
Congenital dyserythropoietic anemia in children (see "Anemia in children due to decreased red blood cell
production", section on 'Erythroid maturation disorders and ineffective erythropoiesis')
Increased destruction of circulating RBCs A RBC life span below 100 days is the operational definition
of hemolysis [32]. When hemolysis is present, laboratory studies show increased levels of lactate
dehydrogenase (LDH) along with reduced haptoglobin, often accompanied by increases in indirect bilirubin and
clinical jaundice. (See 'Evaluation for hemolysis' below and "Red blood cell survival: Normal values and
measurement" and "Diagnosis of hemolytic anemia in the adult", section on 'Diagnostic approach'.)
Anemia will ensue in the adult patient when the bone marrow is unable to keep up with the need to replace
more than approximately 5 percent of the RBC mass per day, corresponding to a RBC survival of 20 days or
less. (See 'Overview' above and "Diagnosis of hemolytic anemia in the adult".)
Examples include (table 4):
Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease, thalassemia major)
Acquired hemolytic anemias (eg, Coombs-positive autoimmune hemolytic anemia, thrombotic

thrombocytopenic purpura, malaria, paroxysmal nocturnal hemoglobinuria)
Increased destruction of normal red cells by an enlarged spleen (ie, hypersplenism). (See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism",
section on 'Extravascular nonimmune hemolysis due to hypersplenism'.)
Intravascular hemolysis In most cases, hemolysis takes place in extravascular spaces, most often in
the spleen and liver. However, in some cases, red cells are destroyed while still in the circulation, a condition
called intravascular hemolysis. Common examples of conditions associated with intravascular hemolysis
include the following (table 4). (See "Diagnosis of hemolytic anemia in the adult", section on 'Intravascular
hemolysis'.)
Microangiopathic hemolytic anemia

Clostridial sepsis
Paroxysmal nocturnal hemoglobinuria
Cold agglutinin disease
Paroxysmal cold hemoglobinuria
In such cases, as with extravascular hemolysis, laboratory studies show increased levels of lactate
dehydrogenase along with reduced haptoglobin and increases in indirect bilirubin. Because destruction of
circulating red cells may be profound, anemia and clinical jaundice may be severe, often leading to circulatory
collapse, renal damage, and, in severe cases, death.
Clinical observations suggesting the presence of intravascular hemolysis include the passing of darkly colored
urine, ranging from gold to red to black (hemoglobinuria) as well as acrocyanosis or livedo reticularis (picture 5)
on exposure to cold.
Laboratory studies that suggest that the hemolysis is intravascular, rather than extravascular include the
following (see "Diagnosis of hemolytic anemia in the adult", section on 'Diagnostic approach'):
The presence of free hemoglobin in the plasma (ie, hemoglobinemia)

The presence of red cell-free hemoglobin in the urine (ie, hemoglobinuria)
The presence of hemosiderin in a stained urine sediment (sloughed renal tubular cells) if the intravascular
hemolysis has been ongoing for at least one week
Blood loss Blood loss is the most common cause of anemia, although it is often difficult to quantitate.
Sources include severe trauma with arterial bleeding at any site, and disorders of the gastrointestinal tract,
lungs, kidneys, and uterus. The patient's history is important in this regard, as is testing of urine, sputum,
gastrointestinal fluids, surgical drains, and other excreta for the presence of blood.
There are a number of situations in which blood loss can occur and not be easily recognized. These include:
Factitious bleeding, secondary to surreptitious blood drawing by the patient (Lasthnie de Ferjol syndrome)
[33-35].
Bleeding during or after surgical procedures may be extremely difficult to quantitate, and is often
underestimated.
Bleeding into the upper thigh and/or retroperitoneal space can often be significant, but may not be clinically
obvious. Such patients may, however, have associated symptoms of abdominal pain, groin or hip pain, leg
paresis, or hypotension [36]. This complication may be more common in patients taking anticoagulants,
even when results of coagulation tests are within the therapeutic range. Computed tomography (CT)
imaging of the abdomen and thigh is often helpful if this is suspected (image 1).
Iron deficiency in the United States and Western Europe is almost always due to blood loss, which may be
obvious, occult, or underappreciated, as follows:
Obvious bleeding (eg, trauma, melena, hematemesis, severe menometrorrhagia)
Occult bleeding (eg, slowly bleeding ulcer or carcinoma) (see "Evaluation of occult gastrointestinal
bleeding")
Induced bleeding (eg, repeated diagnostic testing [37,38], hemodialysis losses, excessive blood donation)
Underappreciated menstrual blood loss (see "Approach to abnormal uterine bleeding in nonpregnant
reproductive-age women", section on 'Menstrual history')
In addition to the loss of RBCs from the body, which the bone marrow must replace, loss of the iron contained
in these cells will ultimately lead to iron deficiency once tissue stores of iron have been depleted. This usually
occurs in males and females after losses of 1200 mL and 600 mL, respectively. However, since
approximately 25 percent of menstruant females have absent iron stores, any amount of bleeding will result in
anemia in this subpopulation. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in
adults".)
Since availability of iron is normally rate-limiting for RBC production, iron deficiency associated with chronic
bleeding leads to a reduced marrow response, worsening the degree of anemia.
Morphologic approach The causes of anemia can also be classified according to measurement of RBC
size, as seen on the blood smear and as reported by automatic cell counter indices [39]. The normal RBC has a
volume of 80 to 96 femtoliters (fL, 10-15 liter) and a diameter of approximately 7 to 8 microns, equal to that of
the nucleus of a small lymphocyte. Thus, RBCs larger than the nucleus of a small lymphocyte on a peripheral
smear are considered large or macrocytic, while those that appear smaller are considered small or microcytic
(table 5 and algorithm 1). (See "Evaluation of the peripheral blood smear", section on 'Red blood cells'.)
Automatic cell counters estimate RBC volume cell by cell, sampling millions of RBCs in the process. Machine
output is a value for the mean corpuscular volume of the sample (MCV), as well as an estimate of the
dispersion of values about this mean. The latter value is usually given as the coefficient of variation of RBC
volumes or RBC distribution width (RDW). (See "Microcytosis/Microcytic anemia", section on 'RDW (size
variability)'.)
An increased RDW indicates the presence of cells of widely differing sizes, but it is not diagnostic of any
particular disorder. However, some automatic cell counters have computer programs that "flag" for the presence
of abnormalities such as anisocytosis (cells of varying size), microcytosis, macrocytosis, and hypochromia
(reduced hemoglobin content per cell) [40]. (See "Automated hematology instrumentation", section on 'Red cell
distribution width'.)
Macrocytic anemia Anemia is considered "macrocytic" when the MCV exceeds 100 fL (femtoliters) (table
6). Causes include the following (see "Macrocytosis/Macrocytic anemia"):
An increased MCV is a normal characteristic of reticulocytes (picture 4). Any condition causing marked
reticulocytosis will be associated with an increased MCV.
Abnormal nucleic acid metabolism of erythroid precursors (eg, folate or cobalamin deficiency and drugs
interfering with nucleic acid synthesis, such as zidovudine and hydroxyurea) may lead to macrocytosis and
anemia.
Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, large granular lymphocyte
[LGL] leukemia).
Other common causes include alcohol abuse, liver disease, and hypothyroidism.
A report from a family practice group found macrocytosis in 2 to 4 percent of patients [41], while a study of 1784
randomly selected older adults living at home found macrocytosis in 6.3 percent of men and 3.3 percent of
women [42]. The most common causes were alcoholism, liver disease, hypothyroidism, and the megaloblastic
anemias (eg, B12 deficiency).
Microcytic anemia Anemia is considered "microcytic" when the MCV is less than 80 fL. Microcytosis is
usually accompanied by a decreased hemoglobin content within the RBC (mean corpuscular hemoglobin,
MCH), with a parallel reduction in MCV, producing a hypochromic (low MCH) as well as a microcytic (low MCV)
appearance on the blood smear (picture 6 and table 5). (See "Microcytosis/Microcytic anemia", section on
'Causes of microcytosis'.)
The following pathologic processes lead to the production of hypochromic microcytic red cells:
Reduced iron availability Severe iron deficiency, the anemia of inflammation, copper deficiency
Acquired disorders of heme synthesis Lead poisoning, acquired sideroblastic anemias
Reduced globin production Thalassemic disorders, other hemoglobinopathies
Rare congenital disorders including sideroblastic anemias, porphyria, and defects in iron absorption,
transport, utilization, and recycling [43,44]
The three most common causes of microcytosis in clinical practice are iron deficiency, alpha or beta
thalassemia minor, and (less often) the anemia of inflammation (anemia of chronic disease). Since all may have
hypochromic and microcytic RBCs, other tests must be used to establish the diagnosis.
Iron deficiency anemia Important discriminating features are a low serum ferritin concentration, an
increased total iron binding capacity (transferrin), and low serum iron concentration (table 7), resulting in a
low transferrin saturation. For clinicians making this diagnosis, it is mandatory to determine the cause of
the iron deficient state (eg, occult colonic carcinoma, excessive menstrual losses). (See "Causes and
diagnosis of iron deficiency and iron deficiency anemia in adults".)
Alpha or beta thalassemia minor Adults with thalassemia are most often heterozygotes for the alpha or
beta forms of this syndrome, and may be only minimally anemic. A family history is therefore often
negative. Physical examination may reveal splenomegaly; the peripheral smear shows varying degrees of
hypochromia, microcytosis, target cells (picture 7), tear-drop forms, and basophilic stippling (picture 8). The
RBC count may actually be increased; uncomplicated patients have normal or increased iron stores. (See
"Clinical manifestations and diagnosis of the thalassemias".)
The diagnosis of beta thalassemia trait can often be made by demonstrating increased levels of
hemoglobin A2 on hemoglobin electrophoresis or liquid chromatography (HPLC), while molecular methods
are usually required for the diagnosis of the alpha thalassemia variants [45]. (See "Methods for hemoglobin
analysis and hemoglobinopathy testing".)
Anemia of inflammation The hallmarks of this condition include a low serum iron, low total iron binding
capacity (transferrin), and a normal to increased serum ferritin concentration. Although hypochromic and
microcytic red cells can be found in these patients, a low MCV is most frequently seen only in those
patients with hepatoma or renal cell carcinoma. (See "Anemia of chronic disease/inflammation".)
Normocytic anemia By definition, the mean RBC volume is normal (ie, MCV between 80 and 100 fL) in
patients with normocytic anemia (table 5). Approach to this extremely large category of patients can be
narrowed somewhat by examination of the blood smear to determine if there is a subpopulation of RBCs with
distinctive size or shape abnormalities, which would place the patient in one of the above categories (ie, early
microcytic or macrocytic anemia), or by use of the kinetic approach to determine the mechanism(s) underlying
the anemia (see 'Kinetic approach' above and 'Systemic disorders' below).
Systemic disorders Anemia may be the first manifestation of a systemic disorder, along with other
nonspecific complaints such as fever, weight loss, anorexia, and malaise. Simple laboratory tests may give
additional clues toward the underlying disease process. These include abnormalities on the urinalysis or routine
chest x-ray, liver or renal function tests, erythrocyte sedimentation rate, C-reactive protein, serum protein
electrophoresis, WBC count and differential, and reduced (or increased) platelet counts. Anemia in older adults,
which may be difficult to categorize, is discussed separately. (See "Anemia in the older adult".)
Anemia of chronic renal disease Anemia is a common complication of renal disease, and may be
multifactorial. This subject is discussed in detail separately. (See "Overview of the management of chronic
kidney disease in adults", section on 'Anemia'.)
Cardiorenal anemia syndrome Cardiorenal anemia syndrome refers to the simultaneous presence
of anemia, heart failure, and chronic renal disease [46]. This disorder complex is discussed separately. (See
"Effects of anemia in chronic kidney disease" and "Approach to anemia in adults with heart failure".)
Cancer-associated anemia Anemia in patients with malignancy is often multi-factorial and related
to the underlying malignancy as well as its treatment. (See "Hematologic complications of malignancy: Anemia
and bleeding".)
Acquired anemia in hospitalized patients The development of anemia in a previously non-

anemic patient subsequent to hospitalization (hospital-acquired anemia, HAA) is usually multifactorial and
includes causes such as bleeding following an invasive procedure or surgery, large volumes of blood drawn for
diagnostic studies, occult bleeding, hemodilution from intravenous fluid administration, as well as a blunted
erythropoietic response associated with critical illness [38,47,48]. As examples:
In one population study, among 188,447 hospitalizations, 74 percent developed HAA, which correlated with
increases in length of stay, hospital charges, and mortality [27].
In a separate study in patients with myocardial infarction, the risk of development of moderate to severe
HAA was increased by 18 percent for every 50 mL of blood drawn for diagnostic purposes [37].
EVALUATION OF THE PATIENT
Initial approach Anemia is one of the major signs of disease. It is never normal and its cause(s) should
always be sought. The history, physical examination, and simple laboratory testing are all useful in evaluating
the anemic patient (algorithm 1). The workup should be directed towards answering the following questions
concerning whether one or more of the major processes leading to anemia may be operative:
Is the patient bleeding (now or in the past)?

Is there evidence for increased red blood cell (RBC) destruction (either intravascular or extravascular)?
Is the bone marrow suppressed? If so, why?
Is the patient iron deficient? If so, why?
Is the patient deficient in folate or vitamin B12? If so, why?
History There are a number of important components to the history in the setting of anemia:
Is there a recent history of loss of appetite, weight loss, fever, and/or night sweats that might indicate the
presence of infection or malignancy?
Is there a history of, or symptoms related to, a medical condition that is known to result in anemia (eg, tarry
stools in a patient with ulcer-type pain, significant blood loss from other sites, rheumatoid arthritis, renal
failure)?
Is the anemia of recent origin, subacute, or lifelong? Recent anemia is almost always an acquired disorder,
while lifelong anemia, particularly if accompanied by a positive family history, is likely to be inherited (eg,
the hemoglobinopathies, thalassemia, hereditary spherocytosis).
The electronic medical record is very useful in this analysis because one can document quite precisely when
the hemoglobin began to fall, as well as when the RBC indices changed and in what direction. One can use this
information to determine what, if anything, was occurring prior to the present illness.
The patient's ethnicity and country of origin may be helpful, as the thalassemias and other hemoglobinopathies
are particularly common in patients from the Mediterranean littoral, Middle East, sub-Saharan Africa, and
Southeast Asia [49]. (See "Introduction to hemoglobin mutations" and "Public health issues in the thalassemic
syndromes".)
The use of medications, both prescribed and over-the-counter, should be examined in some detail. Specific
questions should be asked about the use of alcohol, aspirin, and nonsteroidal antiinflammatory drugs. (See
"NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)
A past history of blood transfusions, liver disease, treatment of the patient (or other family members) with iron
or other hematinics, herbal preparations, and exposure to toxic chemicals in the workplace or environment
should also be obtained. An assessment of nutritional status is especially important in older adults and
alcoholics.
Physical examination The major aim of physical examination is to find signs of organ or multisystem
involvement and to assess the severity of the patient's condition. Thus, the presence or absence of tachycardia,
dyspnea, fever, or postural hypotension should be noted. While evaluation for jaundice and pallor is a standard
part of the physical examination, such signs may be misinterpreted and are not as reliable indicators of anemia
as once thought.
Pallor The sensitivity and specificity for pallor in the palms, nail beds, face, or conjunctivae as a predictor
for anemia varies from 19 to 70 percent and 70 to 100 percent, respectively [50-53], with wide interobserver
differences and widely differing conclusions as to the clinical value of the presence or absence of this finding.
Jaundice Jaundice may be difficult to detect under artificial (nonfluorescent) lighting conditions [52]. Even
under optimal conditions, it may be missed. As an example, in a double blind study involving 62 medical
observers at various levels of training, the presence of scleral icterus was detected by 58 percent at a total
serum bilirubin concentration of 2.5 mg/dL (42.8 micromol/L) and by only 68 percent at a bilirubin concentration
of 3.1 mg/dL (53.0 micromol/L) [54]. False positives were mostly attributable to medical students, while false
negatives were not related to the level of training.
Other physical findings Other items to search for on physical examination include the presence or
absence of lymphadenopathy, hepatosplenomegaly, and bone tenderness, especially over the sternum. Bone
pain may signify expansion of the marrow space due to infiltrative disease, as in chronic myeloid leukemia, or
lytic lesions, as in multiple myeloma or metastatic cancer.
It is also important to look for signs of other hematologic abnormalities, including petechiae due to
thrombocytopenia, ecchymoses, and other signs of bleeding due to abnormalities of coagulation. (See
"Approach to the adult patient with a bleeding diathesis", section on 'Disorders of platelets or blood
vessels'.)
One should also look for signs and symptoms of recurrent infections secondary to neutropenia or immune
deficiency states. Stool obtained during the examination should always be tested for the presence of occult
blood. (See "Evaluation of occult gastrointestinal bleeding".)
LABORATORY EVALUATION Initial testing of the anemic patient should include a "complete" blood count
(CBC). This routinely includes hemoglobin, hematocrit (HCT), red blood cell (RBC) count, RBC indices, and
white blood cell (WBC) count. A WBC differential, platelet count, and reticulocyte count are not part of the
routine CBC in some medical centers; these may have to be ordered separately. Thus, to avoid confusion, the
clinician should specifically request a CBC with platelets, WBC differential, and reticulocytes.
Many automated blood counters report a RBC distribution width (RDW), a measure of the degree of variation in
red cell size (red cell volume) (see 'Morphologic approach' above). However, the RDW alone does not indicate
why the RBC size varies (anisocytosis) or the RBC shapes (poikilocytosis). Some counters will "flag" for the
presence of specific RBC changes, such as hypochromia or microcytosis, which can be confirmed by
examination of the peripheral smear. (See "Automated hematology instrumentation".)
Accordingly, the blood smear should always be reviewed by an experienced examiner since many important
changes may be missed by the inexperienced observer and may not be detected by automated blood counters
[55]. (See 'Blood smear' below and "Evaluation of the peripheral blood smear".)
Red blood cell indices Three RBC indices are usually measured by automated blood counters: mean
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin
concentration (MCHC) (table 1). The values for MCH and MCHC generally parallel the information obtained
from the MCV (ie, larger or smaller RBCs tend to have higher or lower values for MCH, respectively).
Mean corpuscular volume The normal range for the MCV is 80 to 100 femtoliters (fL). The causes of
anemia associated with a low (microcytosis) or high (macrocytosis) MCV are discussed above (table 5) (see
'Morphologic approach' above).
Values of the MCV in excess of 115 fL are almost exclusively seen in vitamin B12 or folate deficiency.
Even higher values can occur as an artifact when cold agglutinins are present, which causes RBCs to go
through the counting aperture in automated instruments in doublets or triplets [56]. Warming the specimen
(and reagents) to body temperature prior to a repeat count should return the MCV to normal and confirm
the presence of a cold agglutinin. (See "Microcytosis/Microcytic anemia".)
Mean corpuscular hemoglobin The normal MCH ranges from 27.5 to 33.2 picograms of hemoglobin per
RBC. Low values are seen in iron deficiency and thalassemia, while increased values occur in macrocytosis of
any cause.
Mean corpuscular hemoglobin concentration The mean normal value for the MCHC is 34 grams of
hemoglobin per dL of RBCs (340 g/L of RBCs). The 95 percent confidence limits for the MCHC have been
variably given (table 1), with lower and upper limits of 31 to 33 and 35 to 36, respectively. Low values occur in
the same conditions that generate low values for MCV and MCH, while increased values occur almost
exclusively in the presence of congenital or acquired spherocytosis or in other congenital hemolytic anemias in
which red cells are abnormally desiccated (eg, sickle cell anemia, hemoglobin C disease, xerocytosis). (See
"Hereditary spherocytosis: Clinical features, diagnosis, and treatment" and "Stomatocytosis and xerocytosis".)
Reticulocyte count The reticulocyte count, either as a percentage of all RBCs, the absolute reticulocyte
count, the corrected absolute reticulocyte count, or as the reticulocyte production index, helps to distinguish
among the different types of anemia:
Anemia with a high reticulocyte count reflects an increased erythropoietic response to continued hemolysis
or blood loss (see 'Reticulocytes' above).
A stable anemia with a low reticulocyte count is strong evidence for deficient production of RBCs (ie, a
reduced bone marrow erythropoietic response to the anemia). (See "Anemia in adults due to decreased
red blood cell production".)
Hemolysis or blood loss can be associated with a low reticulocyte count if there is a concurrent disorder
that impairs RBC production (eg, infection, prior chemotherapy, other causes for bone marrow
suppression) (see 'Multiple causes of anemia' below).
White blood cell count and differential A low total WBC count (leukopenia) in a patient with anemia
should lead to consideration of aplastic anemia, bone marrow suppression or replacement, hypersplenism, or
deficiencies of cobalamin. In comparison, a high total WBC count (leukocytosis) may reflect the presence of
infection, inflammation, or a hematologic malignancy.
Clues to the specific abnormality present may be obtained from the WBC differential, which, in conjunction with
the total WBC count may show increased or decreased absolute numbers of the various cell types in the
circulation. Examples include:
An increased absolute neutrophil count in infection

An increased absolute monocyte count in myelodysplasia
An increased absolute eosinophil count in certain infections
A decreased absolute neutrophil count following chemotherapy
A decreased absolute lymphocyte count in HIV infection or following treatment with glucocorticoids
Neutrophil hypersegmentation Neutrophil hypersegmentation (NH) is defined as the presence of >5

percent of neutrophils with five or more lobes and/or the presence of one or more neutrophils with six or more
lobes (picture 9). This peripheral smear finding, along with macroovalocytic red cells (picture 10), is classically
associated with impaired DNA synthesis, as seen in disorders of vitamins B12 and folate. NH can also be seen
following the use of drugs interfering with nucleic acid synthesis (eg, hydroxyurea) [57].
However, in one study of 100 subjects with normal values for red cell folate and serum cobalamin, NH (as
defined above) was seen in 62 and 4 percent of 50 iron deficient and 50 normal subjects, respectively [58]. The
mechanism for NH in iron deficiency is unknown.
Circulating nucleated red blood cells Nucleated RBCs (NRBCs) are not normally found in the circulation.
They may be present in patients with known hematologic disease (eg, sickle cell disease, thalassemia major,
various hemolytic anemias after splenectomy), or as a part of the leukoerythroblastic pattern seen in patients
with bone marrow fibrosis or replacement with tumor cells (picture 11).
In patients without an underlying hematologic disease, NRBCs may reflect the presence of a life-threatening
disease, such as sepsis or severe heart failure. In one study of 4173 patients seen at a university clinic, NRBCs
were seen at least once in 7.5 percent of all patients; the highest incidence (20 percent) occurred in patients
from the general surgery and trauma intensive care unit [59]. In-hospital mortality was 1.2 and 21.1 percent in
those without or with NRBCs, respectively, and increased with increasing concentration of NRBCs. In patients
who died, nucleated RBCs were detected for the first time at a median of 13 days before death.
Platelet count Abnormalities in the platelet count often provide important diagnostic information.
Thrombocytopenia occurs in a variety of disorders associated with anemia, including aplastic anemia,
hypersplenism, marrow involvement with malignancy, autoimmune platelet destruction (either idiopathic or
drug-related), sepsis, or folate or cobalamin deficiency.
High platelet counts, in comparison, may reflect the presence of a myeloproliferative neoplasm, chronic iron
deficiency, and inflammatory, infectious, or neoplastic disorders. (See "Approach to the patient with
thrombocytosis".) Changes in platelet morphology (giant platelets, degranulated platelets) also may be
important, suggesting myeloproliferative or myelodysplastic disease.
Pancytopenia The combination of anemia, thrombocytopenia, and neutropenia is termed pancytopenia. The
causes and evaluation of pancytopenia are discussed separately. (See "Approach to the adult with unexplained
pancytopenia" and "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis", section on
'Differential diagnosis' and "Inherited aplastic anemia in children and adolescents" and "Acquired aplastic
anemia in children and adolescents".)
Blood smear Many clinicians rely on the above RBC parameters and the RDW in evaluating a patient with
anemia. However, the RDW is, as noted above, of limited utility, and examination of the peripheral blood smear
provides information not otherwise available. (See "Evaluation of the peripheral blood smear".)
As examples, the automated counter may miss the red cell fragmentation ("helmet cells," schistocytes) of
microangiopathic hemolysis (picture 12), microspherocytes in autoimmune hemolytic anemia, teardrop RBCs in
myelofibrosis (picture 13), a leukoerythroblastic pattern with bone marrow replacement (picture 11), the "bite
cells" in oxidative hemolysis (picture 14), or RBC parasites such as malaria or babesiosis (picture 15). (See
"Evaluation of the peripheral blood smear".)
Serial evaluation of hemoglobin and hematocrit Measuring the rate of fall of the patient's hemoglobin or
HCT often provides helpful diagnostic information. Suppose the hemoglobin concentration has fallen from 15 to
10 g/dL in one week. If this were due to total cessation of RBC production (ie, a reticulocyte count of zero) and
if the rate of RBC destruction were normal (1 percent/day), the hemoglobin concentration would have fallen by
7 percent over seven days, resulting in a decline of 1.05 g/dL (0.07 x 15). The greater fall in hemoglobin in this
patient (5 g/dL) indicates that marrow suppression cannot be the sole cause of the anemia and that blood loss
and/or increased RBC destruction must be present.
Evaluation for iron deficiency More complete evaluation for iron deficiency is indicated when the history
(menometrorrhagia, symptoms of peptic ulcer disease) and preliminary laboratory data (low MCV, low MCH,
high RDW, increased platelet count) support this diagnosis. In this setting, the plasma levels of iron, iron
binding capacity (transferrin), transferrin saturation, and ferritin should be measured (table 7). (See "Causes
and diagnosis of iron deficiency and iron deficiency anemia in adults".)
Evaluation for hemolysis Hemolysis should be considered if the patient has experienced a rapid fall in
hemoglobin concentration, reticulocytosis, and/or abnormally shaped RBC (especially spherocytes or
fragmented RBCs) on the peripheral smear (table 4) in the absence of blood loss. The usual ancillary findings
of hemolysis are an increase in the serum lactate dehydrogenase (LDH) and indirect bilirubin concentrations
and a reduction in the serum haptoglobin concentration. (See "Diagnosis of hemolytic anemia in the adult".)
The combination of an increased LDH and reduced haptoglobin is 90 percent specific for diagnosing hemolysis,
while the combination of a normal LDH and a serum haptoglobin greater than 25 mg/dL is 92 percent sensitive
for ruling out hemolysis [60,61].
Intravascular hemolysis Plasma and urinary hemoglobin and urinary hemosiderin should be measured
if intravascular hemolysis is a consideration, as with paroxysmal nocturnal hemoglobinuria. (See "Diagnosis of
hemolytic anemia in the adult", section on 'Diagnostic approach'.)
Bone marrow examination Examination of the bone marrow generally offers little additional diagnostic
information in the more common forms of anemia. If erythropoiesis is increased in response to the anemia, as
evidenced by an increased reticulocyte production index (calculator 1), the bone marrow will show erythroid
hyperplasia, a nonspecific finding. However, if the reticulocyte response is inadequate and the bone marrow
shows erythroid hyperplasia, this suggests the presence of ineffective erythropoiesis. (See 'Presence of
ineffective erythropoiesis' above.)
Although the absence of stainable iron in the bone marrow had previously been considered the "gold standard"
for the diagnosis of iron deficiency, this diagnosis is usually established by laboratory tests alone (table 7). (See
"Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic
evaluation'.)
Indications for examination of the bone marrow in anemic patients include pancytopenia or the presence of
abnormal cells in the circulation, such as blast forms. Such patients may have aplastic anemia, myelodysplasia,
marrow replacement with malignancy, or a myeloproliferative neoplasm. Other findings that may be seen in the
marrow in anemic patients include megaloblastic erythropoiesis (folate or cobalamin deficiency), absence of
recognizable RBC precursors (pure RBC aplasia), vacuolization of RBC precursors (alcohol or drug-induced
anemia), and increased iron-laden RBC precursors (the sideroblastic anemias). (See "Evaluation of bone
marrow aspirate smears".)
Multiple causes of anemia It is common in pediatric practice for anemia to be caused by a single
identifiable disorder. In comparison, multiple causes are frequently present in adults, particularly hospitalized
and/or older adults. Common examples include the following (see 'Kinetic approach' above):
A patient with gastrointestinal bleeding secondary to colon cancer may also have the anemia of
inflammation (anemia of chronic disease), leading to a blunted reticulocyte response. (See "Anemia of
chronic disease/inflammation".)
A patient with a chronic hemolytic anemia (eg, sickle cell anemia, hereditary spherocytosis) may develop
worsening anemia following acute infection, particularly with parvovirus B19, which may blunt or
temporarily ablate erythropoiesis and the reticulocyte response [62]. (See "Acquired pure red cell aplasia in
the adult", section on 'Etiology and pathogenesis'.)
A patient with autoimmune hemolytic anemia may develop worsening anemia from gastrointestinal blood
loss following treatment with glucocorticoids.
Anemia, renal failure, and congestive failure are often found together, a condition that has been termed
"cardio-renal anemia syndrome." Treatment of the anemia may improve both the renal failure and heart
failure [63]. (See "Effects of anemia in chronic kidney disease".)
Algorithms for diagnosing anemia in either children or adults (algorithm 2 and algorithm 1) generally fail in the
presence of more than one cause. Under such circumstances, the clinician is advised to obtain answers
separately to each of the questions outlined above (see 'Initial approach' above), to examine the peripheral
blood smear for abnormal red blood cell populations (eg, microcytes, macrocytes, spherocytes, schistocytes)
and proceed from that point.
Athletes Athletes have been reported to have anemia from a number of causes [64-73]:
Dilutional anemia from increased plasma volume

Exercise-induced acute phase response with production of inflammatory cytokines
Gastrointestinal bleeding and iron deficiency
Intravascular hemolysis from "march" hemoglobinuria
Performance-enhancing agents including androgens and erythropoietin may cause polycythemia that could
mask some of these causes of anemia [68,70].
These issues are discussed in more detail in separate topic reviews. (See "Exercise-related gastrointestinal
disorders", section on 'Gastrointestinal bleeding' and "Extrinsic nonimmune hemolytic anemia due to
mechanical damage: Fragmentation hemolysis and hypersplenism", section on 'Mechanical trauma' and "Use
of androgens and other hormones by athletes", section on 'Androgens'.)
There is evidence for an exercise-induced acute phase response in athletes, with the production of
inflammatory cytokines capable of inducing increased levels of hepcidin, consistent with a component of the
anemia of inflammation [73]. (See "Anemia of chronic disease/inflammation", section on 'The role of cytokines'.)
SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Anemia in
adults".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles
are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
Basics topics (see "Patient education: Anemia of chronic disease (The Basics)")
Beyond the Basics topics (see "Patient education: Anemia caused by low iron in adults (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS The initial approach to the patient with anemia is to perform a
complete history and physical examination along with a review of the results of a complete blood count (CBC)
with white blood cell (WBC) differential, platelet count, reticulocyte count, and an examination of the peripheral
blood smear (table 1). (See 'Evaluation of the patient' above.)
A hemoglobin concentration <13.5 g/dL (<135 g/L) or a hematocrit (HCT) <41.0 percent represents anemia
in men; a value <12.0 g/dL (<120 g/L) or <36.0 percent, respectively, represents anemia in women.
Differences may also exist between races, in older adults, and in athletes. (See 'Definitions' above.)
Most cases of anemia can be diagnosed by employing the morphologic approach, in which the anemia is
first classified via the red cell size (ie, mean corpuscular volume [MCV]), which is part of the CBC
(algorithm 1). (See 'Morphologic approach' above.)
Microcytic anemias are associated with an MCV below 80 fL. The most commonly seen causes are
iron deficiency (table 5 and table 7), thalassemia, and the anemia of (chronic) inflammation (see
'Microcytic anemia' above and 'Evaluation for iron deficiency' above).
Macrocytic anemias are characterized by an MCV above 100 fL (table 5 and table 6). The most
common causes include alcoholism, liver disease, folate and vitamin B12 deficiency, and
myelodysplasia. (See "Macrocytosis/Macrocytic anemia", section on 'Evaluation'.)
The MCV is between 80 and 100 fL in patients with normocytic anemia (table 5). Examination of the
blood smear is important in order to determine if there is a small population of red cells with distinctive
size or shape abnormalities which would place the patient in one of the above categories (ie, early
microcytic or macrocytic anemia), or would raise suspicion of an acute or chronic hemolytic state (eg,
spherocytes, sickle forms, ovalocytes).
- Hemolysis may have been suspected from the patient's history, physical examination, or
examination of the peripheral blood smear (eg, sudden onset of anemia, jaundice, splenomegaly,
presence of spherocytes or schistocytes or other red cell shape changes) (see 'Evaluation of the
patient' above). It is confirmed by the finding of increased levels of indirect bilirubin and lactate
dehydrogenase, and low levels of haptoglobin (table 4). (See 'Evaluation for hemolysis' above and
"Diagnosis of hemolytic anemia in the adult", section on 'Diagnostic approach'.)
- The presence of abnormal cells in the circulation (eg, nucleated red blood cells [RBCs], blasts,
atypical mononuclear cells) and/or abnormal increases or decreases in absolute counts for
granulocytes, lymphocytes, monocytes, or platelets suggests that the anemia is part of a more
complex hematologic disorder (eg, leukemia, aplastic anemia, myelodysplastic syndrome,
myeloproliferative neoplasm). Consultation with a hematologist would be appropriate at this point.
- Anemia may be the first manifestation of a systemic disorder (table 5), along with other
nonspecific complaints such as fever, weight loss, anorexia, and malaise. Simple laboratory tests
may give additional clues toward the underlying disease process. These include abnormalities on
the urinalysis or routine chest x-ray, elevated serum creatinine, abnormal liver function tests, and
increased erythrocyte sedimentation rate or C-reactive protein.
More complicated patients may require use of the kinetic approach, in which the following three questions
are asked in order to determine the mechanism(s) causing the anemia (see 'Kinetic approach' above):
Is there evidence for decreased red cell production? (See 'Decreased RBC production' above.)
Is there evidence for increased red cell destruction (hemolysis)? (See 'Increased destruction of
circulating RBCs' above.)
Is there a history of bleeding? (See 'Blood loss' above.)
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systematic review and meta-analysis. Anesth Analg 2014; 119:332.
4. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin
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Topic 7133 Version 45.0

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8/30/2017 Approach to the adult patient with anemia - UpToDate

Author: Stanley L Schrier, MD

Hemoglobin Hemoglobin concentration is the concentration of hemoglobin, the major oxygen-carrying

These "normal" ranges may not apply to certain populations:

THE RED BLOOD CELL LIFE CYCLE

The anemia of inflammation, associated with infectious, inflammatory, or malignant disorders, is

Presence of ineffective erythropoiesis The hallmark of ineffective erythropoiesis is the presence of

Examples include (table 4):

Acquired hemolytic anemias (eg, Coombs-positive autoimmune hemolytic anemia, thrombotic

Microangiopathic hemolytic anemia

The presence of free hemoglobin in the plasma (ie, hemoglobinemia)

Obvious bleeding (eg, trauma, melena, hematemesis, severe menometrorrhagia)

Acquired anemia in hospitalized patients The development of anemia in a previously non-

EVALUATION OF THE PATIENT

Is the patient bleeding (now or in the past)?

An increased absolute neutrophil count in infection

Neutrophil hypersegmentation Neutrophil hypersegmentation (NH) is defined as the presence of >5

Dilutional anemia from increased plasma volume

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Topic 7133 Version 45.0

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