Approach to the adult patient with anemia

Author
Stanley L Schrier, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Disclosures: Stanley L Schrier, MD Nothing to disclose. William C Mentzer, MD Equity Ownership/Stock Options:
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Literature review current through: Mar 2014. | This topic last updated: Mar 26, 2014.
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 obtained as a part of
the complete blood count: hemoglobin concentration, hematocrit, or RBC count:
Hemoglobin concentration (HGB) this is the concentration of hemoglobin, 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). Efforts are underway to determine
HGB levels non-invasively, allowing continuous monitoring of this parameter [1,2].
Hematocrit (HCT) is the percent of a sample of whole blood occupied by intact red blood
cells (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 or liter 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 introduction to the phenomenon of RBC destruction (hemolysis) and tests that may be used to
provide a diagnosis of hemolytic anemia is presented separately. (See"Approach to the diagnosis of
hemolytic anemia in the adult".)
Approaches to the older adult or child with anemia are presented separately. (See "Anemia in the
older adult" and "Approach to the child with anemia".)
DEFINITIONS
Normal range One set of "normal ranges" (95 percent confidence limits) for HGB, 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 HGB
<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, ranging from 13.0 to
14.2 g/dL for men and 11.6 to 12.3 g/dL for women [3].
WHO criteria for anemia in men and women are <13 and <12 g/dL, respectively [4]. 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 [3].
The revised WHO/National Cancer Institute's criteria for anemia in men and women are <14
and <12 g/dL, respectively [5]. 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 (table 2) [3]. 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 that 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 [3].
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, older adults). (See 'Special populations' below and "Approach to anemia in adults
with heart failure", section on 'Evaluation'.)
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 [6]. 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 [7], suggesting that alternative criteria for anemia might be required for this
group (table 2) [3]. (See "Anemia in the older adult", section on 'Defining anemia in the older
adult'.)
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 for all three will be
reduced if the RCM is decreased and/or if the plasma volume is increased [8]. 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 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 [9].
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 HGB, HCT, and RBC
count, often to anemic levels (figure 1). However, according to the RBC mass, such women
are polycythemic. The terms "physiologic" or "dilutional" anemia have been applied to this
setting.
Volume depletion 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 (table 1) may not be appropriate for all populations:
Patients living at high altitude have values higher than those living at sea level [10].
(See "High altitude, air travel, 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 [11]. 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 [12], occasionally reaching polycythemic
levels. (See "Diagnostic approach to the patient with polycythemia", section on 'Acquired
secondary polycythemia'.)
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 [3,13-17]. Some, but not all, of these
differences may be attributable to co-existing iron deficiency anemia and/or alpha thalassemia
[18].
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'.)
Older adults Anemia in older adults is discussed separately. (See "Anemia in the older adult".)
Athletes Values in male and female endurance athletes may vary significantly from those in
otherwise normal people [19-24]. Dilutional anemia secondary to an increased plasma volume
[20,25], gastrointestinal bleeding [21], intravascular hemolysis (eg, march hemoglobinuria) [22], iron
deficiency [26,27], as well as polycythemia [23,25] have all been reported as a consequence of
strenuous sports, or the use of 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 "Use of
androgens and other hormones to enhance athletic performance", section on 'Androgens'.)
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 (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 [28].
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 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, 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 10
12
/liter), 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 approximately fivefold in adults and seven- to eight-fold in
children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as high
as 250,000/microL (2.5 x 10
11
/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 2). 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 3).
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 [29].
(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/orthe 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.
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 5 volumes percent (25 percent of the total) is normally removed by the
tissues [30]. (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 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 5 volumes
percent can be maintained by enhanced extraction alone down to a hemoglobin concentration of 8
to 9 g/dL [31].
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 [32]. (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 "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 fatigability, lassitude, and
muscle cramps. This can progress to postural dizziness, lethargy, syncope, and, in severe cases, to
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 "Anemia and left ventricular hypertrophy in chronic kidney
disease", section on 'General cardiovascular outcomes')
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 [33] (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:
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 [34].
Kinetic approach Anemia can be caused by one or more of three independent mechanisms:
decreased RBC production, increased RBC destruction, and blood loss [28].
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, myelodysplastic syndromes,
tumor infiltration)
Bone marrow suppression (eg, drugs, chemotherapy, irradiation) (see "Hematologic
consequences of malignancy: Anemia and bleeding")
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 [35,36]. (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 [37]. (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 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 [38]. (See "Red blood cell survival: Normal values and measurement".)
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 (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, malaria, paroxysmal nocturnal hemoglobinuria)
Blood loss 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 [39,40], hemodialysis losses, excessive
blood donation)
Underappreciated menstrual blood loss. (See "Approach to abnormal uterine bleeding in
nonpregnant reproductive-age women", section on 'Menstrual history'.)
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) [41-43]
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 [44]. 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 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 anemia in the adult".)
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 [45].
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 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.
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 "Mean corpuscular
volume", section on 'Red blood cell distribution width'.)
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) [46]. (See "Automated
hematology instrumentation", section on 'Red cell distribution width'.)
Macrocytic anemia Anemia is considered "macrocytic" when the MCV exceeds 100 fL
(femtoliters) (table 5) Causes include the following. (See "Macrocytosis".)
An increased MCV is a normal characteristic of reticulocytes (picture 3). 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 andhydroxyurea) may
lead to macrocytosis and anemia
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 [47], 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 [48]. The most common causes were alcoholism, liver disease,
hypothyroidism, and the megaloblastic anemias (eg, folate or 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 4 and 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 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 [49,50]
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 6). 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 anemia in the adult".)
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 5),
tear-drop forms, and basophilic stippling (picture 6). 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
[51]. (See "Laboratory diagnosis of the hemoglobinopathies".)
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 (anemia of [chronic] inflammation)".)
Normocytic anemia By definition, the mean RBC volume is normal (ie, MCV between 80 and
100 fL) in patients with normocytic anemia (table 4). 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 [52]. This disorder complex is
discussed separately. (See "Anemia and left ventricular hypertrophy 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 consequences 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
[40,53,54]. As examples:
In one population study, among 188,447 hospitalizations, 74 percent developed HAA, which
was correlated with increases in length of stay, hospital charges, and mortality [33].
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 [39].
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 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 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, 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 [55]. (See "Introduction to hemoglobin
mutations" and "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 older adult 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 [56-59], 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
[58]. 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) [60]. 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 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 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 [61]. (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 mean corpuscular volume (MCV) is 80 to
100 femtoliters (fL). The causes of anemia associated with a low (microcytosis) or high
(macrocytosis) MCV are discussed above (table 4) (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 [62].
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 mean corpuscular hemoglobin (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 "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, other
causes for bone marrow suppression) (see 'Multiple causes of anemia' below).
A low reticulocyte percentage accompanied by pancytopenia (ie, the combination of anemia,
thrombocytopenia, and neutropenia) is suggestive of aplastic anemia, while an extremely low
or zero reticulocyte percentage 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 "Acquired pure red cell aplasia in the adult".)
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
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 7). This peripheral smear finding, along with macroovalocytic red
cells (picture 8), is classically associated with impaired DNA synthesis, as seen in disorders of
vitamins B12 and folate. (See "Etiology and clinical manifestations of vitamin B12 and folate
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 [63]. 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 9).
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 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 [64]. 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 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 presence of severe pancytopenia narrows the differential diagnosis
considerably, and includes disorders such as aplastic anemia, folate or cobalamin deficiency,
hematologic malignancy (eg, acute myeloid leukemia, myelodysplasia), and marrow ablation from
chemotherapy or radiation or replacement with fibrosis or tumor. Rare causes include anorexia
nervosa and panhypopituitarism. (See "Anemias due to decreased red cell production", section on
'Normocytic anemia with pancytopenia' and "Approach to the adult with unexplained
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 (picture 10), microspherocytes in autoimmune
hemolytic anemia, teardrop RBCs in myelofibrosis (picture 11), a leukoerythroblastic pattern with
bone marrow replacement (picture 9), the "bite cells" in oxidative hemolysis (picture 12), or RBC
parasites such as malaria or babesiosis (picture 13). (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 (table 6). (See "Causes and diagnosis of iron deficiency anemia in the adult".)
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 3) 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 "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 [65,66].
Intravascular hemolysis Plasma and urinary 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 marrow had previously been
considered the "gold standard" for the diagnosis of iron deficiency, this diagnosis is usually
established by laboratory tests alone (table 6). (See "Causes and diagnosis of iron deficiency
anemia in the adult", section on 'Estimation of iron stores'.)
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 older adults. Common examples are:
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 (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 [67].
(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 [68]. (See "Anemia and left ventricular hypertrophy in chronic
kidney disease".)
Algorithms for diagnosing anemia (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.
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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 information: Anemia of chronic disease (The Basics)")
Beyond the Basics topics (see "Patient information: Anemia caused by low iron (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 differential, platelet count, reticulocyte count, and
an examination of the peripheral blood smear (table 1). (See 'Evaluation of the patient' above.)
A HGB <13.5 g/dL (<135 g/L) or a 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 and 'Special
populations' above.)
Diagnostic approach: morphology According to the morphologic approach, the anemia is first
classified via the red cell size (ie, mean corpuscular volume, MCV), which is part of the CBC
(algorithm 1):
Microcytic anemias are associated with an MCV below 80 fL. The most commonly seen
causes are iron deficiency (table 4 and table 6), 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 4 and table 5). The
most common causes include alcoholism, liver disease, folate and vitamin B12 deficiency, and
myelodysplasia. (See "Macrocytosis", section on 'Evaluation'.)
The MCV is between 80 and 100 fL in patients with normocytic anemia (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, 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 3).
(See 'Evaluation for hemolysis' above and "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 (algorithm 1) 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 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 or C-reactive protein.
Diagnostic approach: kinetics According to the kinetic approach, the following three questions
are asked in order to determine the mechanism(s) causing the anemia. (See 'Causes of
anemia' 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 RBC
destruction' above.)
Is there a history of bleeding? (See 'Blood loss' above.)
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