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Approach to the adult patient with

anemia

Author Section Editor Deputy Editor   

Stanley L Schrier, MD William C Mentzer, MD Stephen A Landaw,
MD, PhD

Last literature review version 17.1: January 2009 | This topic last updated: December 31,
2008  (More)

INTRODUCTION — Although anemia can be defined as a reduced absolute number of

circulating red blood cells (ie, a reduced red blood cell mass as determined by a blood
volume study), such studies are not practical, 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: hemoglobin concentration, hematocrit, or RBC count:

Hemoglobin concentration (HGB) measures the concentration of the major

oxygen-carrying pigment 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)

Hematocrit (HCT) is the percent of a sample of whole blood occupied by intact red
blood cells ( show picture 1 ).

RBC count is the number of red blood cells contained in a specified volume of whole
blood, usually expressed as millions of red blood cells per microL of whole blood.
This topic review will provide an approach to the anemic patient. The first portion is
devoted to an understanding of the basic aspects of erythropoiesis and 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. An approach to the child with anemia is
presented separately. ( See "Approach to the child with anemia" ).

An introduction to the phenomenon of RBC destruction (hemolysis) and tests which may
be used to provide a diagnosis of hemolytic anemia is presented separately. ( See
"Approach to the diagnosis of hemolytic anemia in the adult" ).

DEFINITIONS

Normal range — One set of "normal ranges" (95 percent confidence limits) for HGB, HCT,
and RBC count is shown in the table ( show table 1 ). If anemia is defined as values which
are more than two standard deviations (SD) below the mean, then, by using these
ranges, a HGB <13.5 g/dL or a HCT <41.0 percent represents anemia in men and a value
<12.0 g/dL 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, ranging from 13.0 to
14.2 g/dL for men and 11.6 to 12.3 g/dL for women [ 1] .

WHO criteria for anemia in men and women are <13 and <12 g/dL, respectively [ 2]
. 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 [ 1] .
 diagnosis of anemia [ 1] .

The revised WHO/National Cancer Institute's criteria for anemia in men and women
are <14 and <12 g/dL, respectively [ 3] . These values are meant to be used for
evaluation of anemia in patients with malignancy.

Other lower limits according to sex, age, and race, based on data from NHANES III
and Scripps-Kaiser studies, have been proposed ( show table 2 ) [ 1] . 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.
There are a number of immediate limitations to this approach:

The above ranges may be "two-tailed" to be used for defining both anemia and
polycythemia. In such cases, 2.5 percent of normal adults will have values which are
more than 2 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 [ 1] .

The normal range for HGB 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.

"Normal" ranges may not apply to special populations (eg, high altitude living,
smokers, athletes, elderly, use of ACE inhibitors). ( See "Special populations" below
and see "Impact of anemia in patients with heart failure" , section on Etiology).

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 elderly women and men, respectively [ 4] .
However, in one study, 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
[5] , suggesting that alternative criteria for anemia are indeed required for this
group ( show table 2 ) [ 1] .

Volume status — HGB, HCT, and RBC count are all concentrations and dependent on the
red blood cell mass (RCM) as well as the plasma volume. As a result, values will be
reduced if the RCM is decreased and/or if the plasma volume is increased [ 6] . Three
common clinical examples will help make this point:

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
HGB 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 HGB and HCT reflect blood
loss. However, if the total blood volume deficit is not fully repaired and the patient
remains hypovolemic, the HGB and HCT will underestimate the degree of blood loss
[7] .

In the third trimester of pregnancy the RBC mass and plasma volume are
expanded by 25 and 50 percent, respectively, resulting in reductions in HGB, HCT,
and RBC count, often to anemic levels ( show figure 1 ). However, according to the
RBC mass, such women are polycythemic. The terms "physiologic" or "dilutional"
anemia have been applied to this setting.
 Patients admitted to the hospital in a volume depleted state may not show
abnormally low HGB/HCT values on initial testing. An underlying anemia may
become apparent only after the volume depletion has been corrected.
Special populations — Normal ranges ( show table 1 ) may not be appropriate for all
populations:

Patients living at high altitude have values higher than those living at sea level [ 8]
. ( See "High altitude and heart disease" , section on Long-term altitude exposure).

A study of blood donors who smoke found a significant and direct correlation
between the patients' blood carboxyhemoglobin and HGB values [ 9] . The same
study also found a significant relationship, although of lesser magnitude, between
HGB values and the degree of environmental air pollution with carbon monoxide in
nonsmoking blood donors. Thus, patients who smoke or have significant exposure
to secondary smoke or other sources of carbon monoxide may have hematocrits
higher than normal [ 10 ] , occasionally reaching polycythemic levels. ( See
"Diagnostic approach to the patient with polycythemia" , section on Acquired
secondary erythrocytosis).

Values for HGB in African-Americans of both sexes and all ages are 0.5 to 1.0 g/dL
lower than values in comparable Caucasian populations [ 1,11-15 ] . Some, but not
all, of these differences may be attributable to co-existing iron deficiency anemia
and/or alpha thalassemia [ 16 ] .

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 "Community public
health issues and the thalassemic syndromes: Lessons from other countries" ,
section on Introduction).
The elderly — Values for HGB and HCT in apparently healthy older adults are generally
lower than those in younger adults, and differences between males and females in HGB
and HCT that are seen in younger adults are lessened with aging [ 17-19 ] . The
prevalence of anemia in adults >65 and ≥ 85 years of age has been estimated at 10 and
>20 percent, respectively [ 20,21 ] . As an example, anemia as defined by the WHO
criteria, was present in 26 percent of a cohort of 85 year old adults [ 22 ] .

Although low hemoglobin concentrations are common in older adults, it has been
suggested that the elderly should NOT be presumed to have a lower "normal" range, for
fear of missing a serious underlying disorder [ 20,23-28 ] . A number of large studies have
shown the adverse effects (eg, decline in physical performance, morbidity, mortality) of
anemia in elderly patients [ 4,14,25,26,29-31 ] . Three of these are outlined below:

In 686 community-dwelling women ≥ 65 with self-reported disabilities, HGB levels
progressively lower than 11.0 g/dL were associated with increasingly higher risks for
all-cause mortality than levels of 12.0 g/dL, whereas HGB levels of 13.0 and 14.0
g/dL were associated with a lower risk of death [ 29 ] .

A study of 755 subjects >85 years of age showed that a HGB <13.0 g/dL in males
and <12.0 g/dL in females was associated with an increased relative risk of
mortality of 1.6 in males (95% CI 1.2-2.1) and 2.3 in females (95% CI 1.6-3.3)
[26 ] . Disorders such as malignancy, peptic ulcer, and infection were more common
in the anemic patients. However, the mortality risk in elderly anemic patients
without obvious clinical disease was also increased to more than twice that of
nonanemic patients.
 nonanemic patients.
It was concluded that anemia in older patients is due to disease and not aging, and that
further investigation is warranted if an older person's HGB is below normal, even if no
clinical disease is immediately apparent.

A study in community dwelling elderly adults (age 71 to 82 years) confirmed the

adverse effect of anemia, as defined by the WHO criteria, on mortality and mobility
disability in white men and women [ 30 ] . Older blacks classified as anemic by WHO
criteria were not at risk for adverse events, indicating, as noted above, that
alternative criteria for anemia may be warranted for blacks ( show table 2 and see
"Normal range" above ).
The causes of anemia in the elderly were evaluated in a study of the noninstitutionalized
United States population in the third National Health and Nutrition Examination Survey
(NHANES III) [ 20 ] . Overall, 10 to 11 percent of men and women ≥ 65 years of age were
anemic, with a higher rate (28 percent) in non-Hispanic blacks. The anemia was generally
mild, with only 2 to 3 percent of men and women having a hemoglobin level <11.0 g/dL.

The causes for anemia were estimated as follows:

One-third were related to presence of a nutritional deficiency (eg, iron, folate, B12).
Iron deficiency, alone or in combination with folate or B12 deficiency, constituted
more than one-half of this group.

One-third were related to chronic kidney disease and/or other chronic disorders (eg,
arthritis, diabetes, increased serum C-reactive protein, or a positive rheumatoid
factor). ( See "Anemia of chronic disease (anemia of chronic inflammation)" ).

Anemia in the remaining one-third was unexplained, although 17 percent of these

patients (6 percent of the entire patient population) satisfied one or more criteria
for the diagnosis of the myelodysplastic syndrome (eg, macrocytosis,
thrombocytopenia, neutropenia). ( See "Clinical manifestations and diagnosis of the
myelodysplastic syndromes" , section on Making the diagnosis).
In this and other studies in elderly anemic patients, 23 to 45 percent had anemia that
remained unexplained [ 17,20,28 ] . The mechanism(s) underlying "unexplained" anemia
in the elderly may include age-related decline in renal function [ 32 ] , altered
erythropoietin sensing and response, loss of hematopoietic stem cell reserve with
increasing age [ 33 ] , low testosterone levels, as well as undiagnosed myelodysplastic
syndrome [ 20,34-38 ] .

Despite these uncertainties, the most reasonable approach to the anemic elderly patient
consists of ruling out the major identifiable causes, such as bleeding disorders, nutritional
deficiencies, renal disease, inflammatory disorders, and the myelodysplastic syndrome
[37 ] .

The value of erythropoietin for the treatment of chronic unexplained (undiagnosed)

anemia in the elderly patient is unclear [ 39 ] . One small exploratory, randomized,
placebo-controlled, crossover study indicated that such treatment was associated with an
increase in hemoglobin level of >2 g/dL in two-thirds of the patients, along with
improvements in fatigue and quality of life [ 40 ] .

Athletes —  Values in male and female endurance athletes may vary significantly from
those in otherwise normal people [ 41-46 ] . Dilutional anemia secondary to an increased
plasma volume [ 42,47 ] , gastrointestinal bleeding [ 43 ] , intravascular hemolysis (eg,
march hemoglobinuria) [ 44 ] , iron deficiency [ 48,49 ] , as well as polycythemia [ 45,47 ]
have all been reported as a consequence of strenuous sports, or the use of
performance-enhancing agents, such as androgens and erythropoietin . ( See "Extrinsic
performance-enhancing agents, such as androgens and erythropoietin . ( See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and
hypersplenism" , section on Mechanical trauma and see "Use of androgens and other
drugs by athletes" , section on Androgens and section on Erythropoietin).

THE RBC 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 ( show figure 2 ). ( 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. When the normoblast extrudes its nucleus to form a
red blood cell, it still has a ribosomal network which, when stained supravitally, identifies
it as a reticulocyte, a cell still capable of a limited amount of hemoglobin and protein
synthesis [ 50 ] .

The reticulocyte retains its ribosomal network (and its staining characteristics) for about
four days, of which three days are generally spent in the marrow and one day in the
peripheral blood ( show figure 3 ). The resulting mature RBC circulates for 110 to 120 days,
after which it is removed from the circulation by macrophages that detect senescent
signals, through mechanisms that are poorly understood.

Under steady state conditions, the rate of RBC production equals the rate of RBC loss.
Assuming, as a first approximation, survival of mature RBC of 100 days, 1 percent of
RBCs are 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 ( show table 1 ).
Since the normal RBC count is approximately 5 million/microL, the bone marrow must
produce approximately 50,000 reticulocytes/microL 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
erythropoietin (EPO). A normal bone marrow replete with iron, folate, and cobalamin can
increase erythropoiesis in response to EPO about 5-fold in adults and 7- to 8-fold in
children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as
high as 250,000/microL 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 (show blood smear 1 ). The normal
range (ie, percent of RBC with positive staining) in adults is 0.5 to 1.5 percent ( show 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 ( show blood smear 2 ).

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 [ 51 ] . ( 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 "Approach to the
reticulocyte production index. This subject is discussed separately. ( See "Approach to the
diagnosis of hemolytic anemia in the adult" , section on Reticulocyte response).

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. Before discussing these issues, it is helpful to first review the
normal function of red cells.

Normal red cell function — 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
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 five volumes
percent (25 percent of the total) is normally removed by the tissues [ 52 ] . ( See "Oxygen
delivery and consumption" and see "Genetic disorders of hemoglobin oxygen affinity" ,
section on Mutations that decrease the affinity of hemoglobin for 2,3-DPG).

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 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 about 60 percent in the presence of anemia or hypoperfusion. Thus, normal
oxygen delivery of five volumes percent can be maintained by enhanced extraction alone
down to a hemoglobin concentration of 8 to 9 g/dL [ 53 ] .

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 [ 54 ] . ( See "Indications for red cell
transfusion in the adult" , section on Physiology of anemia).

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 "roaring in the ears".
More severe anemia may lead to lethargy and 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
fatiguability, lassitude, and muscle cramps. This can progress to postural dizziness,
lethargy, syncope, and, in severe cases, to persistent hypotension, shock, and death.
(See "Clinical manifestations and diagnosis of volume depletion in adults" ).

Fatigue — Although anemia may be associated with complaints of 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 see "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:

A kinetic approach, addressing the mechanism(s) responsible for the fall in

hemoglobin concentration

A morphologic approach categorizing anemias via alterations in RBC size (ie, mean
corpuscular volume) and the reticulocyte response [ 55 ] .
Kinetic approach — Anemia can be caused by one or more of three independent
mechanisms: decreased RBC production, increased RBC destruction, and blood loss [ 50 ] .

Decreased RBC production — Anemia will ultimately result if the rate of RBC production
is less than that of RBC destruction. ( See "Anemias due to decreased red cell
production" ). The more common causes for reduced (effective) RBC production include:

Lack of nutrients, such as iron, B12, or folate. This can be due to dietary lack,
malabsorption (eg, pernicious anemia, sprue), or blood loss (iron deficiency)

Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia,
tumor infiltration)

Bone marrow suppression (eg, drugs, chemotherapy, irradiation). ( See

"Hematologic consequences of malignancy: Anemia" ).

Low levels of trophic hormones which stimulate RBC production, such as 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
[56,57 ] . ( See "Treatment of orthostatic and postprandial hypotension" , section on
Erythropoietin ).

The anemia of chronic disease/inflammation, associated with infectious,

inflammatory, or malignant disorders, is characterized by reduced availability of iron
due to decreased absorption from the gastrointestinal tract and decreased release
from macrophages, a relative reduction in erythropoietin levels, and a mild
reduction in RBC lifespan. ( See "Anemia of chronic disease (anemia of chronic
inflammation)" ).

Increased RBC destruction — A RBC life span below 100 days is the operational
definition of hemolysis [ 58 ] . ( See "Red blood cell survival: Normal values and
measurement" ). Hemolytic anemia will ensue when the bone marrow is unable to keep up
with the need to replace more than about 5 percent of the RBC mass per day,
corresponding to a RBC survival of about 20 days. ( See "Approach to the diagnosis of
hemolytic anemia in the adult" ).

Examples include ( show table 3 ):

Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease,

thalassemia major)

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

thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, malaria)
Blood loss — Iron deficiency in the United States and Western Europe is almost always
due to blood loss. Blood loss is the most common cause of anemia and may take any
one of a number of forms:

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

 Occult bleeding (eg, slowly bleeding ulcer or carcinoma). ( See "Evaluation of occult
gastrointestinal bleeding" ).

Induced bleeding (eg, repeated diagnostic testing, hemodialysis losses, excessive

blood donation)
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

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 or mass, groin or hip pain, leg paresis, or
hypotension [ 59 ] . This complication may be more common in patients taking
anticoagulants, even when results of coagulation tests are within the therapeutic
range. CT imaging of the abdomen and thigh is often helpful if this is suspected.

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 about 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 anemia due to iron deficiency" ).

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 [ 60 ] . 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 ( show table 4 ). ( 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. ( See "Mean corpuscular volume" ). 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).

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 which "flag" for the presence of abnormalities such as anisocytosis
(cells of varying size), microcytosis, macrocytosis, and hypochromia (reduced hemoglobin
content per cell) [ 61 ] . ( See "Automated hematology instrumentation" , section on Red
cell distribution width).

Macrocytic anemia — Macrocytic anemias are characterized by an MCV above 100 fL

(femtoliters) ( show table 5 ). ( See "Macrocytosis" ).

An increased MCV is a normal characteristic of reticulocytes ( show blood smear 2 ).

Any condition causing marked reticulocytosis will be associated with an increased
 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 ).

Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, 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 [ 62 ]
, while a study of 1,784 randomly selected elderly people living at home found
macrocytosis in 6.3 percent of men and 3.3 percent of women [ 63 ] . The most common
causes were alcoholism, liver disease, hypothyroidism, and the megaloblastic anemias.

Microcytic anemia — Microcytic anemias are characterized by the presence of "small"

RBCs (ie, MCV below 80 fL). Microcytosis is usually accompanied by a decreased
hemoglobin content within the RBC, with parallel reductions in MCV and MCH, producing a
hypochromic (low MCH) as well as a microcytic (low MCV) appearance on the blood smear
(show blood smear 3 , show table 4 ). ( See "Mean corpuscular volume" , 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 chronic disease,
copper deficiency

Reduced heme synthesis — lead poisoning, congenital or acquired sideroblastic

anemia

Reduced globin production — thalassemic states, other hemoglobinopathies

The three most common causes of microcytosis in clinical practice are iron deficiency,
alpha or beta thalassemia minor, and (less often) the anemia of chronic disease (anemia
of chronic inflammation). 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 ( show table 6 ). For some physicians, proof of this diagnosis
requires a clinical response (ie, increase in HGB or HCT) to treatment with iron.
For physicians 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 anemia due to iron deficiency" ).

Alpha or beta thalassemia minor — Adults with thalassemia are most often
heterozygotes for the alpha or beta forms of this syndrome, and may not be
anemic. A family history is therefore often negative. Physical examination may
reveal splenomegaly; the peripheral smear shows varying degrees of hypochromia,
microcytosis, target cells ( show blood smear 4 ), tear-drop forms, and basophilic
stippling ( show blood smear 5 ). The RBC count may actually be increased and
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 mild alpha thalassemia
variants [ 64 ] . ( See "Molecular diagnosis of inherited hemoglobin disorders" ).
variants [ 64 ] . ( See "Molecular diagnosis of inherited hemoglobin disorders" ).

Anemia of chronic disease (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
patients with hepatoma or renal cell carcinoma. ( See "Anemia of chronic disease
(Anemia of chronic inflammation)" ).
Normocytic anemia — By definition, the mean RBC volume is normal (MCV between 80
and 100 fL) in patients with normocytic anemia ( show table 4 ). Approach to this extremely
large and amorphous category 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 ).

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, serum protein electrophoresis, WBC count and
differential, and reduced (or increased) platelet counts. Anemia in the elderly is discussed
separately ( see "The elderly" above ).

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 and see
"Anemia and left ventricular hypertrophy in chronic kidney disease" ).

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. 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 RBC destruction (hemolysis)?
Is the bone marrow suppressed?
Is the patient iron deficient? If so, why?
Is the patient deficient in folic acid 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 history of, or symptoms related to, a medical condition which is known to
result in anemia (eg, tarry stools in a patient with ulcer-type pain, 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,
hereditary spherocytosis).
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 South East Asia [ 65 ] . ( See "Introduction to
littoral, Middle East, sub-Saharan Africa, and South East Asia [ 65 ] . ( See "Introduction to
hemoglobin mutations" and see "Community public health issues and the thalassemic
syndromes: Lessons from other countries" ).

The use of medications, both prescribed as well as 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 the elderly and
alcoholics.

Physical examination — The major aim on 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 [ 66-69 ] , 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 [ 68 ] . 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 and by only 68 percent at a bilirubin concentration of 3.1
mg/dL [ 70 ] . False positives were mostly attributable to medical students, while false
negatives were not related to the level of training.

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 myelogenous 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 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 HGB, HCT, 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 what
the RBC shapes are (poikilocytosis). Some counters will "flag" for the presence of specific
RBC changes, such as hypochromia or microcytosis, which can be confirmed by
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 [ 71 ] . ( See "Blood smear" below and see
"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) ( show 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 MCV is from 80 to 100 femtoliters
(fL). The causes of anemia associated with a low (microcytosis) or high (macrocytosis)
MCV are discussed above ( show table 4 , see "Morphologic approach" above ). Values in
excess of 115 fL are almost exclusively seen in vitamin B12 or folic acid deficiency. Even
higher values can occur as an artifact when cold agglutinins are present, which causes
RBCs to go through the counting aperture in doublets or triplets [ 72 ] . 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 "Mean corpuscular
volume" ).

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. The 95 percent confidence limits for the
MCHC have been variably given ( show 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 dessicated (eg, sickle cell anemia, hemoglobin C disease,
xerocytosis). ( See "Hereditary spherocytosis: Clinical features; diagnosis; and treatment"
and see "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 marrow response to the anemia). ( See "Anemias
due to decreased red 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;
see "Multiple causes of anemia" below ).

A low reticulocyte percentage accompanied by pancytopenia is suggestive of aplastic

anemia, while a reticulocyte percentage of zero with normal white blood cell and
platelet counts suggests a diagnosis of pure red cell aplasia. ( See "Aplastic
anemia: Pathogenesis; clinical manifestations; and diagnosis" and see "Acquired
pure red cell aplasia" ).
White blood cell count and differential — A low total white blood cell (WBC) count
(leukopenia) in a patient with anemia should lead to consideration of bone marrow
suppression or replacement, hypersplenism, or deficiencies of cobalamin or folate. 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 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
corticosteroids
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 ( show blood smear 6 ). This peripheral smear
finding, along with macroovalocytic red cells ( show blood smear 7 ), is classically
associated with impaired DNA synthesis, as seen in disorders of vitamins B12 and folic
acid . ( See "Etiology and clinical manifestations of vitamin B12 and folic acid deficiency" ,
section on Clinical manifestations).

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 [ 73 ] . 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
replacement ( show blood smear 8 ).

In patients without known hematologic disease, NRBCs may reflect the presence of a
life-threatening disease, such as sepsis or severe heart failure. In one study of 4,173
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 [ 74 ] . 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 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 myeloproliferative disease, 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 presence of severe pancytopenia narrows the differential
termed pancytopenia. The presence of severe pancytopenia narrows the differential
diagnosis to disorders such as aplastic anemia, folate or cobalamin deficiency, or
hematologic malignancy (eg, acute myelogenous leukemia). ( See "Approach to the adult
patient with thrombocytopenia" ).

Mild degrees of pancytopenia may be seen in patients with splenomegaly and splenic
trapping of circulating cellular elements. ( See "Extrinsic nonimmune hemolytic anemia
due to mechanical damage: Fragmentation hemolysis and hypersplenism" , section on
Extravascular nonimmune hemolysis due to hypersplenism).

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 ( show blood smear 9 ),
microspherocytes in autoimmune hemolytic anemia, teardrop RBCs in myeloid metaplasia
(show blood smear 10 ), a leukoerythroblastic pattern with bone marrow replacement
(show blood smear 8 ), the "bite cells" in oxidative hemolysis ( show blood smear 11 ), or
RBC parasites such as malaria or babesiosis ( show blood smear 12 ). ( See "Evaluation of
the peripheral blood smear" ).

Serial evaluation of hemoglobin and hematocrit — Measuring the rate of fall of the
patient's HGB or HCT often provides helpful diagnostic information. Suppose the HGB
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 HGB concentration would have fallen by 7
percent over seven days, resulting a decline of 1.05 g/dL (0.07 x 15). The greater fall in
HGB 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 ( show table 6 ). ( See "Causes and
diagnosis of anemia due to iron deficiency" ).

Evaluation for hemolysis — Hemolysis should be considered if the patient has a rapid fall
in hemoglobin concentration, reticulocytosis, and/or abnormally shaped RBC (especially
spherocytes or fragmented RBCs) on the peripheral smear ( show table 3 ). 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 "Approach to the 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 [ 75,76 ] .

Intravascular hemolysis — Serum or plasma hemoglobin and urinary hemosiderin

should be measured if intravascular hemolysis is a consideration, as with paroxysmal
nocturnal hemoglobinuria. ( See "Approach to the diagnosis of hemolytic anemia in the
adult" , section on Testing for intravascular hemolysis).

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, the bone marrow will show erythroid hyperplasia,
a nonspecific finding. Similarly, although the absence of stainable iron in the bone
a nonspecific finding. Similarly, 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 ( show table 6 ).
(See "Causes and diagnosis of anemia due to iron deficiency" , section on Diagnosis).

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 disease. 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 the elderly. Common examples are:

A patient with gastrointestinal bleeding secondary to colon cancer may also have
the anemia of chronic disease, leading to a blunted reticulocyte response. ( See
"Anemia of chronic disease (Anemia of chronic 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 [ 77 ] . ( See "Acquired pure red cell aplasia" , section on
Etiology and pathogenesis).

A patient with autoimmune hemolytic anemia may develop worsening anemia from
gastrointestinal blood loss following treatment with corticosteroids .

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 [ 78 ] . ( See "Anemia and left
ventricular hypertrophy in chronic kidney disease" ).
Algorithms for diagnosing anemia ( show 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.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for
patients. ( See "Patient information: Iron deficiency anemia" ). We encourage you to print
or e-mail this topic review, or to refer patients to our public web site,
www.uptodate.com/patients , which includes this and other topics.

RECOMMENDATION — The initial approach to the diagnosis of anemia is to review the

results of a complete blood count (CBC) with WBC differential, platelet count, and
reticulocyte count ( show table 1 ). A HGB <13.5 g/dL or a HCT <41.0 percent represents
anemia in men; a value <12.0 g/dL or <36.0 percent, respectively, represents anemia in
women. It is also critical to obtain values for prior CBCs in order to detect trends, disease
progression, and to establish the date of disease onset.

The anemia is first classified via the mean corpuscular volume (MCV), which is part of the
CBC ( show algorithm 1 ):

Microcytic anemias are associated with an MCV below 80 fL. The most commonly
seen causes are iron deficiency ( show table 4 and show table 6 ), thalassemia, and
 seen causes are iron deficiency ( show table 4 and show table 6 ), thalassemia, and
the anemia of chronic disease ( see "Microcytic anemia" above and see "Evaluation
for iron deficiency" above ).

Macrocytic anemias are characterized by an MCV above 100 fL ( show table 4 and
show table 5 ). The most common causes include alcoholism, liver disease, folic acid
and vitamin B12 deficiency, and myelodysplasia. ( See "Macrocytosis" , section on
Evaluation).

The MCV is between 80 and 100 fL in patients with normocytic anemia ( show table
4). This is an extremely large and amorphous category, which can be narrowed
somewhat by examination of the blood smear 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 and physical
examination (eg, sudden onset of anemia, jaundice, splenomegaly; 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 ( show
table 3 ). ( See "Evaluation for hemolysis" above and see "Approach to the diagnosis
of hemolytic anemia in the adult" , section on Diagnostic approach).

The presence of abnormal cells in the circulation (eg, nucleated RBCs, blasts,
atypical mononuclear cells) and/or abnormal increases or decreases in absolute
counts for granulocytes, lymphocytes, monocytes, or platelets ( show algorithm 1 )
suggests that the anemia is part of a more complex hematologic disorder (eg,
leukemia, aplastic anemia, myelodysplastic syndrome, myeloproliferative disorder).
Consultation with a hematologist would be appropriate at this point.
Anemia may be the first manifestation of a systemic disorder ( show table 4 ), 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.

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26:296.

GRAPHICS
Manual hematocrit

This photo shows two anticoagulated blood-filled Wintrobe

hematocrit tubes following high speed centrifugation. The tube
on the left is from a normal subject, with a hematocrit of 38
percent (blue arrow). The tube on the right is from a
19-year-old female with essential thrombocytosis and a
platelet count of 5,000,000/ L. The extreme degree of
thrombocytosis can be appreciated by the presence of a
marked increase in the size of the "buffy coat" (white arrow).
When the Wintrobe tube is filled to near capacity (upper
arrows), the platelet count can be estimated by the thickness
of this layer, with each mm being equivalent to one million
platelets/ L. In normal subjects, the buffy coat, which is
comprised of white blood cells and platelets, is only minimally
visible. Courtesy of Stephen A Landaw, MD, PhD.
visible. Courtesy of Stephen A Landaw, MD, PhD.

Normal values for red blood cell parameters in men and women

Adult Adult
Red cell parameter men   women
Hemoglobin, g/dL 15.7 ± 1.7 13.8 ± 1.5

Hematocrit, percent 46.0 ± 4.0 40.0 ± 4.0

 
RBC count, million/µL 5.2 ± 0.7 4.6 ± 0.5

Reticulocytes, percent 1.6 ± 0.5 1.4 ± 0.5

88.0 ±
Mean corpuscular volume, fL
8.0

30.4 ±
Mean cell hemoglobin, pg/RBC
2.8
   
Mean cell hemoglobin concentration, g/dL 34.4 ±
of RBC 1.1

Red cell volume distribution width, percent 13.1 ±

(RDW) 1.4

Values are mean ± 2 standard deviations.

Adapted from Williams' Hematology, 6th ed, Beutler, E, Lichtman, MA, Coller, BS, et
al (Eds), McGraw-Hill, New York, 2001.

Proposed lower limits of normal for hemoglobin concentration of the blood

for white and black adults

Group Hemoglobin, g/dL

White men, y

20-59 13.7

60+ 13.2

White women, y

20-49 12.2

50+ 12.2

Black men, y

20-59 12.9

60+ 12.7
Black women, y

20-49 11.5

50+ 11.5

Based on Scripps-Kaiser data for the 5th percentiles given in Table 2. NHANES data
are considered to be confirmatory. To convert hemoglobin from grams per deciliter
to grams per liter, multiply grams per deciliter by 10. Reproduced from: Beutler, E,
Waalen, J. The definition of anemia: what is the lower limit of normal of the blood
hemoglobin concentration? Blood 2006; 107:1747. Copyright ©2006 The American
Society of Hematology.

Physiologic anemia of pregnancy

Schematic representations of the increases in intravascular

volume that occur during pregnancy. Plasma volume increases
more than the total red cell volume (50 versus 25 percent),
resulting in a 40 percent rise in blood volume and a dilutional
fall in the hematocrit.
Serum erythropoietin levels in anemia

This graph indicates the exponential relationship between

serum erythropoietin levels (EPO, milliUnits/mL) and venous
hematocrit (percent) in normal and anemic subjects without
renal or chronic diseases. EPO was assayed either by bioassay
or radioimmunoassay. Data from Erslev, AJ, et al. J Lab Clin
Med 1987; 109:429.
Reticulocyte shift with anemia

With worsening anemia and increasing erythropoietin

stimulation, bone marrow reticulocytes (left) leave the marrow
at an earlier stage in their maturation. This prolongs the
maturation time in the circulation from one day to as long as
2.5 days (right). Adapted from Hillman, RS, Ault, KA (Eds).
Normal erythropoiesis, in: Hematology in Clinical Practice,
McGraw-Hill, New York, p. 29.

Reticulocytosis in peripheral blood

Supravital stain of a peripheral blood smear shows

blue-stained residual reticulin (ribosomal RNA) in reticulocytes.
Courtesy of Stanley L Schrier, MD.

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Polychromatophilia

Peripheral blood smear taken from a patient with increased

reticulocytes. Unlike mature red cells (thin black arrows),
which have central pallor and are the same size as the nucleus
of a small lymphocyte (thick arrow), reticulocytes (blue
arrows) are larger, have a blue tint, and lack central pallor
because they are not biconcave discs. (Wright-Giemsa stain).
Courtesy of Stanley Schrier, MD.
Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Common causes of hemolytic anemia in the adult

Extravascular destruction of red blood cells

Intrinsic red blood cell defects

Enzyme deficiencies (eg, G6PD or pyruvate kinase deficiencies)

Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable hemoglobins)

Membrane defects (eg, hereditary spherocytosis, elliptocytosis)

Extrinsic red blood cell defects

Liver disease

Hypersplenism

Infections (eg, bartonella, babesia, malaria)

Oxidant agents (eg, dapsone, nitrites, aniline dyes)

Other agents (eg, lead, snake and spider bites)

Microangiopathic (eg, DIC, TTP-HUS)

Autoimmune hemolytic anemia (warm- or cold-reacting, drugs)

 Intravenous immune globulin infusion

Large granular lymphocyte leukemia

Intravascular destruction of red blood cells

Microangiopathy (eg, aortic stenosis, prosthetic valve leak)

Transfusion reactions (eg, ABO incompatibility)

Infection (eg, clostridial sepsis, severe malaria)

Paroxysmal cold hemoglobinuria

Paroxysmal nocturnal hemoglobinuria

Following intravenous infusion of Rho(D) immune globulin

Following intravenous infusion with hypotonic solutions

Snake bites

Differential diagnosis of the anemic adult

Low mean corpuscular volume (microcytic anemia: MCV <80 fL)

Iron deficiency anemia

Thalassemic disorders

Anemia of chronic disease (late; uncommon)

Sideroblastic anemia (eg, congenital, lead, alcohol, drugs; uncommon)

Copper deficiency, zinc poisoning (rare)

Normal mean corpuscular volume (normocytic anemia: MCV 80 to 100

fL)
Acute blood loss

Iron deficiency anemia (early)

Anemia of chronic disease (eg, infection, inflammation, malignancy)

Bone marrow suppression (may also be macrocytic)

Bone marrow invasion (eg, leukoerythroblastic blood picture)

Acquired pure red blood cell aplasia

Aplastic anemia

Chronic renal insufficiency

Endocrine dysfunction
 Hypothyroidism

Hypopituitarism

Increased mean corpuscular volume (macrocytic anemia: MCV >100 fL)

Ethanol abuse

Folic acid deficiency

Vitamin B12 deficiency

Myelodysplastic syndromes

Acute myeloid leukemias (eg, erythroleukemia)

Reticulocytosis
Hemolytic anemia

Response to blood loss

Response to appropriate hematinic (eg, iron, B12, folate)

Drug-induced anemia (eg, Hydroxyurea, AZT, chemotherapeutic agents)

Liver disease

This list is not meant to be exhaustive; only the most common causes are
mentioned. In addition, two or more of these conditions may be present (eg,
combined iron and folic acid deficiencies), resulting in a misleadingly normal mean
corpuscular volume.

Causes and mechanisms of macrocytosis

Abnormalities of DNA metabolism

Vitamin B12 (cobalamin) deficiency

Folate deficiency

Drugs
Hydroxyurea

Zidovudine

Cytosine arabinoside

Methotrexate

Azathioprine or 6-mercaptopurine

Cladribine

Capecitabine

Imatinib, sunitinib

Shift to immature or stressed red cells

 Reticulocytosis

Action of erythropoietin - skip macrocytes, stress erythrocytosis

Aplastic anemia/Fanconi anemia

Pure red cell aplasia

Primary bone marrow disorders

Myelodysplastic syndromes

Congenital dyserythropoietic anemias

Large granular lymphocyte leukemia

Lipid abnormalities
Liver disease

Hypothyroidism

Hyperlipidemia

Mechanism unknown
Alcohol abuse

Multiple myeloma and other plasma cell disorders

Microcytic hypochromic red cells

Peripheral smear from a patient with iron deficiency shows

pale small red cells with just a scant rim of pink hemoglobin;
occasional "pencil" shaped cells are also present. Normal red
cells are similar in size to the nucleus of a small lymphocyte
cells are similar in size to the nucleus of a small lymphocyte
(arrow); thus, many microcytic cells are present in this smear.
Thalassemia can produce similar findings. Courtesy of Carola
von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Laboratory tests in iron deficiency of increasing severity

Fe Fe Severe Fe
deficiency deficiency deficiency
without with mild with severe
   Normal anemia anemia anemia
Marrow reticulo-
2+ to 3+ None None None
endothelial iron

Serum iron, µg/dL 60 to 150 60 to 150 <60 <40

Iron binding
capacity 300 to
300 to 390 350 to 400 >410
(transferrin), 360
µg/dL

Saturation
20 to 50 30 <15 <10
(SI/TIBC), percent
Hemoglobin, g/dL Normal Normal 9 to 12 6 to 7

Normal or
Red cell Hypochromia
Normal Normal slight
morphology and microcytosis
hypochromia

Plasma or serum
40 to 200 <40 <20 <10
ferritin, ng/mL

Erythrocyte
protoporphyrin, 30 to 70 30 to 70 >100 100 to 200
ng/mL RBC

Nail and
Other tissue
None None None epithelial
changes
changes

Note: Test results outlined in bold type are the ones most likely to define the various
stages of iron deficiency. Thus, the presence or absence of iron stores (marrow
reticuloendothelial iron) in a non-anemic patient serves to distinguish normal subjects
from those with iron deficiency without anemia, respectively.

Beta thalassemia trait

Peripheral smear from a patient with beta thalassemia trait.

The field shows numerous hypochromic and microcytic red
cells (thin arrows), some of which are also target cells (blue
arrows). Courtesy of Stanley Schrier, MD

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Basophilic stippling

Peripheral blood smear shows basophilic stippling in several

red cells from a patient with lead poisoning. The granules
represent ribosomal precipitates. A similar picture can be seen
in a number of other conditions including thalassemia,
megaloblastic anemia, sickle cell anemia, and sideroblastic
anemia. Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Hypersegmented neutrophil

Blood smear from a patient with megaloblastic anemia,

showing a neutrophil with an increased number of nuclear
lobes. At least six discrete lobes are present; normal
neutrophils have five lobes or less. Courtesy of Stephen A.
Landaw, MD, PhD.

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Megaloblastic blood picture

Peripheral blood smear showing a hypersegmented neutrophil

(7 lobes) and macroovalocytes, a pattern that can be seen with
cobalamin or folate deficiency. Courtesy of Stanley L Schrier,
MD.

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Leukoerythroblastic smear

Leukoerythroblastic peripheral blood smear showing the

presence of nucleated red cells and immature white cells. This
pattern occurs with marrow replacement, usually due to
fibrosis that may be idiopathic (eg, myelofibrosis with
agnogenic myeloid metaplasia) or reactive to conditions such
as metastatic cancer. Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Microangiopathic smear

Peripheral blood smear from a patient with a microangiopathic

hemolytic anemia with marked red cell fragmentation. The
smear shows multiple helmet cells (small black arrows), other
fragmented red cells (large black arrow); microspherocytes
are also seen (blue arrows). The platelet number is reduced;
the large platelet in the center (red arrow) suggests that the
thrombocytopenia is due to enhanced destruction. Courtesy of
Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Teardrop cells

This peripheral smear from a patient with bone marrow fibrosis

shows numerous teardrop-shaped red cells (arrows). Note that
the teardrops are pointed in several different directions, ruling
out an artifact due to preparation of the smear. Courtesy of
Carola von Kapff, SH (ASCP).
Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Heinz body hemolytic anemia

Split screen view of a peripheral smear from a patient with

Heinz body hemolytic anemia. Left panel: red cells with
characteristic bite-like deformity (arrows). Right panel: Heinz
body preparation which reveals the denatured hemoglobin
precipitates. Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several

platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).

Malaria

Peripheral smear from a patient with malaria shows

intraerythrocytic ring forms (trophozoites) (arrows). Courtesy
of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow)
can also be seen. The red cells are of relatively uniform size
and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte;
central pallor (red arrow) should equal one-third of its
diameter. Courtesy of Carola von Kapff, SH (ASCP).
 Anemia algorithm

Adapted from Nathan, DG, Oski, FA. Hematology of Infancy and Childhood, 4th ed,
WB Saunders, Philadelphia, PA 1993. p. 352.

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