Approach To The Adult With Anemia

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Approach to the adult with anemia

Author: Stanley L Schrier, MD
Section Editor: William C Mentzer, MD
Deputy Editors: Jennifer S Tirnauer, MD, Lisa Kunins, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2019. | This topic last updated: Feb 15, 2018.
INTRODUCTION
Evaluation for anemia is one of the most common problems seen in clinical practice.
While the evaluation may be straightforward in an otherwise healthy individual with a
single cause of anemia, in many cases the cause is not readily apparent and multiple
conditions may be contributing.
An overview of the causes of anemia and an approach to the evaluation of the adult with
unexplained anemia are presented here.
Specific causes of anemia and the evaluation of specific patient populations are
discussed in more detail in separate topic reviews:
● Iron deficiency – (See "Causes and diagnosis of iron deficiency and iron deficiency
anemia in adults".)
● B12 and folate deficiency – (See "Clinical manifestations and diagnosis of vitamin
B12 and folate deficiency".)
● Chronic disease/inflammation – (See "Anemia of chronic disease/inflammation".)
● Hemolytic anemia – (See "Diagnosis of hemolytic anemia in the adult" and
"Overview of hemolytic anemias in children".)
● Drug-induced – (See "Hemolytic anemia due to drugs and toxins".)
● Myelodysplastic syndrome – (See "Clinical manifestations and diagnosis of the
myelodysplastic syndromes".)
● Hemoglobinopathies – (See "Methods for hemoglobin analysis and
hemoglobinopathy testing".)
● Aplastic anemia – (See "Aplastic anemia: Pathogenesis, clinical manifestations, and
diagnosis".)
● Microangiopathic hemolytic anemia – (See "Approach to the patient with suspected
TTP, HUS, or other thrombotic microangiopathy (TMA)".)
● Older adults – (See "Anemia in the older adult".)
● Individuals with heart failure – (See "Approach to anemia in adults with heart
failure".)
● Children – (See "Approach to the child with anemia".)
HOW TO USE THIS TOPIC REVIEW
This topic review is presented in two semi-independent parts:
● The first portion of this review is devoted to an understanding of the basic aspects of
red blood cell production and destruction along with a review of the causes and
clinical consequences of anemia.
● The second portion is devoted to the clinical and laboratory evaluation of the anemic
patient (algorithm 1).
DEFINITIONS
Anemia — Anemia can be rigorously defined as a reduced absolute number of

circulating red blood cells (ie, a reduced red blood cell mass as determined via blood
volume studies). However, blood volume studies are not practical for this purpose, cost-
effective, or generally available. As a result, anemia has been defined as a reduction in
one or more of the major red blood cell (RBC) measurements obtained as a part of the
complete blood count (CBC): hemoglobin concentration, hematocrit (HCT), or RBC
count. In practice, however, a low hemoglobin concentration or a low hematocrit is most
widely employed for this purpose.
● Hemoglobin – Hemoglobin concentration is the concentration of hemoglobin, the
major oxygen-carrying molecule in whole blood. Values may be expressed as grams
of hemoglobin per 100 mL of whole blood (g/dL) or per liter of blood (g/L). Efforts are
underway to determine hemoglobin levels non-invasively, allowing continuous
monitoring of this parameter [1-3].
● Hematocrit – Hematocrit (HCT), also called packed cell volume, is the packed spun
volume of blood that consists of intact RBCs, expressed as a percentage. HCT can
be measured directly following centrifugation of a blood sample (picture 1 and picture
2) or calculated (HCT = [RBC x MCV]/10).
● RBC count – RBC count is the number of RBCs contained in a specified volume of
whole blood, usually expressed as millions of cells per microL of whole blood.
In patients with anemia, hemoglobin and HCT typically decrease in parallel. RBC also
usually parallels the hemoglobin and HCT, except in cases of extreme microcytosis such
as thalassemia, in which the RBC count may be increased despite the presence of
anemia.
Normal ranges for hemoglobin/HCT — One set of "normal ranges" (95 percent
confidence limits) for hemoglobin, HCT, and RBC count is shown in the table (table 1). If
anemia is defined as values that are more than two standard deviations (SD) below the
mean, then, by using these ranges, a hemoglobin <13.5 g/dL (<135 g/L) or a HCT <41.0
percent represents anemia in men, and a value <12.0 g/dL (<120 g/L) or <36.0 percent,
respectively, represents anemia in women. Normal ranges other than the above have
been proposed:
● Other authors have proposed different lower limits of normal for the hemoglobin
level, ranging from 13.0 to 14.2 g/dL for men and 11.6 to 12.3 g/dL for women [4].
● World Health Organization (WHO) criteria for anemia in men and women are <13
and <12 g/dL, respectively [5]. These criteria were meant to be used within the
context of international nutrition studies, and were not initially designed to serve as
"gold standards" for the diagnosis of anemia [4].
● The revised WHO/National Cancer Institute's criteria for anemia in men and women
are <14 and <12 g/dL, respectively [6]. These values were meant to be used for
evaluation of anemia as a complication of chemotherapy in patients with malignancy
(table 2).
● Other lower limits according to sex, age, and race, based on data from NHANES III
and Scripps-Kaiser studies, have been proposed (table 3) [4]. These values are as
low as 12.7 g/dL for black men >60 years of age and 11.5 g/dL for black women >20
years of age.
These "normal" ranges may not apply to certain populations:
● Athletes – Values in endurance athletes may vary significantly from those in other
healthy individuals due to a combination of factors, as discussed below. (See
'Athletes' below.)
● Living at high altitude – Patients living at high altitude have values higher than
those living at sea level [7]. (See "High altitude, air travel, and heart disease", section
on 'Long-term altitude exposure'.)
● Smokers – A study of blood donors who smoke found a significant and direct
correlation between the patients' blood carboxyhemoglobin and hemoglobin values
[8]. Thus, patients who smoke or have significant exposure to secondary smoke or
other sources of carbon monoxide may have HCT higher than normal [9],
occasionally masking the presence of an underlying anemia.
● African-Americans – Values for hemoglobin in African-Americans of both sexes and

all ages are 0.5 to 1.0 g/dL lower than values in comparable Caucasian populations
[4,10-14]. Some, but not all, of these differences may be attributable to co-existing
iron deficiency anemia and/or alpha thalassemia [15].
● Presence of chronic disease – Normal values for a population with a high

incidence of chronic disease may be skewed toward anemic levels. Thus, anemia
may be difficult to define in countries in which malnutrition, infection (eg,
tuberculosis, malaria), and/or congenital hematologic disorders (eg, thalassemia) are
common. (See "Public health issues in the thalassemic syndromes", section on
'Introduction'.)
● Older adults – Anemia in older adults is discussed separately. (See "Anemia in the
older adult".)
There are also a number of limitations to the use of normal values in isolation:
● The above ranges may be "two-tailed" to be used for defining both anemia and
polycythemia (erythrocytosis). In such cases, 2.5 percent of normal adults will have
values that are more than two standard deviations below whatever "normal range"
has been selected, and will be considered anemic. On the other hand, some ranges
are "one-tailed," such that 5 percent of normal subjects will have levels below the
stated lower limit of normal [4].
● The normal range for hemoglobin and HCT is so wide that, for example, a male
patient with a baseline HCT of 49 percent may lose up to 15 percent of his RBC
mass and still have a HCT within the normal range.
● Setting a lower limit of normal for hemoglobin does not imply that such levels are
"optimal" in terms of morbidity and mortality. One study has suggested that the lower
limits of an optimal hemoglobin level, as assessed by all-cause mortality data, are
13.0 and 14.0 g/dL for older adult women and men, respectively [16]. However, in
one report, older black subjects classified as anemic by WHO criteria did not appear
to be at risk for adverse events such as mortality and mobility disability [17],
suggesting that alternative criteria for anemia might be required for this group (table
3) [4]. (See "Anemia in the older adult", section on 'Defining anemia in the older
adult'.)
Red blood cell indices — The RBC indices describe the size, shape, and hemoglobin
content of RBCs, as well as the uniformity of the RBC population. Evaluation of these
values is an integral part of determining the cause of anemia. (See 'Morphologic
approach' below.)
● MCV – Mean corpuscular volume (MCV) is the average volume (size) of the patient's
RBCs. It can be measured or calculated (MCV in femtoliters [fL] = 10 x HCT [in
percent] ÷ RBC [in millions/microL]). Anemia can be classified based on whether the
MCV is low, normal, or elevated. (See 'Morphologic approach' below.)
● MCH – Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a

RBC. It is calculated (MCH in picograms [pg]/cell = hemoglobin [in g/dL] x 10 ÷ RBC
[in millions/microL]. A low MCH indicates decreased hemoglobin content per cell,
and is typically reflected in hypochromia on the peripheral blood smear. This may be
seen in iron deficiency and hemoglobinopathies like the thalassemias.
● MCHC – Mean corpuscular hemoglobin concentration (MCHC) is the average

hemoglobin concentration per RBC. It is calculated as (MCHC in grams [g]/dL =
hemoglobin [in g/dL] X 100 ÷ HCT [in percent]). Very low MCHC values are typical of
iron deficiency anemia, and very high MCHC values typically reflect spherocytosis or
RBC agglutination. Examination of the peripheral blood smear is helpful in
distinguishing these findings. (See "Evaluation of the peripheral blood smear",
section on 'Red blood cells'.)
● RDW – Red cell distribution width (RDW) is a measure of the variation in RBC size,
which is reflected in the degree of anisocytosis on the peripheral blood smear. A high
RDW implies a large variation in RBC sizes, and a low RDW implies a more
homogeneous population of RBCs. RDW is calculated as the coefficient of variation
(CV) of the red cell volume distribution (RDW = [standard deviation/MCV] x 100). A
high RDW can be seen in a number of anemias, including iron deficiency,
myelodysplastic syndrome, and hemoglobinopathies, as well as in patients with
anemia who have received transfusions. Review of the peripheral blood smear often
is helpful in identifying the cause of large variations in RBC size. (See 'Morphologic
approach' below and "Evaluation of the peripheral blood smear".)
Details of how these indices are determined and potential causes of spurious results are
presented separately. (See "Automated hematology instrumentation".)
THE RED BLOOD CELL LIFE CYCLE
Overview — Erythropoiesis in the adult takes place within the bone marrow under the
influence of the stromal framework, cytokines, and the erythroid specific growth factor,
erythropoietin (EPO). EPO is a true endocrine hormone produced in the kidney by cells
that sense the adequacy of tissue oxygenation relative to the individual's metabolic
activity (figure 1). (See "Regulation of erythropoiesis".)
EPO enhances the growth and differentiation of the two erythroid progenitors: burst
forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) into
normoblasts of increasing maturity. The most mature of these, the orthochromatic
normoblast, extrudes its nucleus to form a red blood cell (RBC) via mechanisms that are
still unclear [18,19]. As such, the enucleate red blood cell still has a ribosomal network
that, when stained supravitally, identifies it as a reticulocyte, a cell still capable of a limited
amount of hemoglobin and protein synthesis [20].
The reticulocyte retains its ribosomal network (and its staining characteristics) for
approximately four days, of which three days are generally spent in the bone marrow and
one day in the peripheral blood (figure 2). The resulting mature RBC circulates for 110 to
120 days, after which time it is removed from the circulation by macrophages that detect
senescent signals, primarily on the RBC membrane, through mechanisms that are poorly
understood. (See "Red blood cell survival: Normal values and measurement".)
● Under steady state conditions, the rate of RBC production equals the rate of RBC
loss. Assuming, for ease of calculation, a survival of mature RBC of 100 days, 1
percent of RBCs will be removed from the circulation each day. To achieve a
constant RBC mass, RBC losses must be replaced with an equal number of
reticulocytes during the same time period.
● Reticulocytes normally survive in the circulation for one day; after this time they lose
their reticulum (RNA) and become mature red blood cells. Under steady-state
conditions reticulocytes will represent approximately 1 percent of total circulating
RBC (table 1). Since the normal RBC count is approximately 5 million/microL (5.0 x
1012/liter), the bone marrow must produce approximately 50,000 reticulocytes/microL
(5 x 1010/liter) of whole blood each day in order to achieve a stable RBC mass.
Lesser rates of RBC production, if persistent, lead to anemia.
The rate of red cell production increases markedly under the influence of high levels of
EPO. A normal bone marrow replete with iron, folate, and cobalamin can increase
erythropoiesis in response to EPO approximately fivefold in adults and seven- to eightfold
in children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as
high as 350,000/microL (3.5 x 1011/liter) are possible in the adult.
Reticulocytes — Reticulocytes can be enumerated manually after supravital staining of

a blood sample with dyes such as new methylene blue (picture 3). The normal range (ie,
percent of RBC with positive staining) in adults is 0.5 to 2.0 percent (table 1).
Reticulocytes can be appreciated on a standard blood smear stained with Wright-Giemsa
as RBC with a blue tint (polychromatophilia) that are larger than mature RBC, with
irregular borders and a lack of central pallor (picture 4).
Reticulocytes can be counted with more accuracy via automated blood counters after
staining with a fluorescent dye, such as thiazole orange, which binds to the RNA of
reticulocytes [21]. (See "Automated hematology instrumentation", section on 'Automated
counting of reticulocytes'.)
The utility of reticulocyte counting in some settings can be improved by determination of

the absolute reticulocyte count, the corrected absolute reticulocyte count, and/or the
reticulocyte production index. This subject is discussed separately. (See "Diagnosis of
hemolytic anemia in the adult", section on 'High reticulocyte count'.)
VOLUME STATUS
Hemoglobin, hematocrit (HCT), and red blood cell (RBC) count are all concentrations and
dependent on the red blood cell mass (RCM) as well as the plasma volume. As a result,
values for all three parameters will be reduced if the RCM is decreased and/or if the
plasma volume is increased [22]. Similarly, values for all three will be increased if the
plasma volume is decreased (ie, hemoconcentration). Three common clinical examples
will help make this point:
● Acute bleeding – A 70 kg adult with a bleeding peptic ulcer who had a 750 mL
hematemesis (ie, 15 percent of a normal total blood volume) within the past 30
minutes may have postural hypotension due to acute volume depletion, but will have
normal values for hemoglobin and HCT. Over the ensuing 36 to 48 hours, most of
the total blood volume deficit will be repaired by the movement of fluid from the
extravascular into the intravascular space. Only at these later times will the
hemoglobin and HCT reflect blood loss. Accordingly, if the total blood volume deficit
is not fully repaired and the patient remains hypovolemic, the hemoglobin and HCT
will underestimate the degree of blood loss [23].
● Late pregnancy – In the third trimester of pregnancy the RBC mass and plasma
volume are expanded by 25 and 50 percent, respectively, resulting in reductions in
hemoglobin, HCT, and RBC count, often to anemic levels (figure 3). However,
according to the RBC mass, such women are polycythemic. The terms "physiologic"
or "dilutional" anemia have been applied to this setting, although such patients are
not truly anemic.
● Volume depletion – Anemic patients admitted to the hospital in a volume depleted

(hemoconcentrated) state may not show abnormally low hemoglobin/HCT values on
initial testing. Their underlying anemia may become apparent only after their volume
status has been corrected.
CLINICAL CONSEQUENCES
Signs and symptoms of anemia — 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.
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.
● Decreased oxygen delivery – Red blood cells (RBCs) carry oxygen linked to
hemoglobin from the lungs to tissue capillaries. Oxygen is then released from
hemoglobin according to the characteristics of the oxyhemoglobin dissociation curve,
with each gram of hemoglobin capable of carrying 1.3 mL of oxygen. Thus,
approximately 20 mL/dL (or 20 volumes percent) can be carried by 15 g/dL of
hemoglobin at full saturation. Approximately 5 volumes percent (25 percent of the
total) is normally removed by the tissues [24]. (See "Oxygen delivery and
consumption" and "Genetic disorders of hemoglobin oxygen affinity", section on
'Mutations that decrease the affinity of hemoglobin for 2,3-BPG'.)
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 [25]. (See
"Indications and hemoglobin thresholds for red blood cell transfusion in the adult",
section on 'Role of blood in oxygen delivery'.)
Symptoms of impaired oxygen delivery reflect the fall in hemoglobin concentration.
The extraction of oxygen by the tissues can increase from a baseline of 25 percent
to a maximum of approximately 60 percent in the presence of anemia or
hypoperfusion. Thus, normal oxygen delivery of 5 volumes percent can be
maintained by enhanced extraction alone down to a hemoglobin concentration of 8
to 9 g/dL [26].
Symptoms will occur when the hemoglobin concentration falls below this level at
rest, at higher hemoglobin concentrations during exertion, or when cardiac
compensation is impaired because of underlying heart disease. The primary
symptoms include exertional dyspnea, dyspnea at rest, varying degrees of fatigue,
and signs and symptoms of the hyperdynamic state such as bounding pulses,
palpitations, and a roaring pulsatile sound in the ears. More severe anemia may lead
to lethargy, confusion, and potentially life-threatening complications such as
congestive failure, angina, arrhythmia, and/or myocardial infarction. (See "Causes
and pathophysiology of high-output heart failure".)
● Hypovolemia – Anemia induced by acute bleeding is associated with the added

complication of intracellular and extracellular volume depletion. The earliest
symptoms include easy fatigability, lassitude, and muscle cramps. This can progress
to postural dizziness, lethargy, syncope, and, in severe cases, persistent
hypotension, shock, and death. (See "Etiology, clinical manifestations, and diagnosis
of volume depletion in adults".)
There is some reduction in blood volume but not plasma volume after acute severe
hemolysis, due to the fall in RBC mass. In comparison, total blood volume remains
normal in anemia due to chronic, low-grade bleeding since there is ample time for a
compensatory increase in the plasma volume via equilibration with the extravascular
space and renal retention of salt and water.
Although anemia (with or without volume depletion) may be associated with fatigue, this
complaint is nonspecific, may be present in a number of other conditions, and may be
multifactorial. This subject is discussed in depth separately. (See "Approach to the adult
patient with fatigue" and "Cancer-related fatigue: Prevalence, screening, and clinical
assessment".)
Exacerbation of thrombocytopenic bleeding — In a trial involving platelet transfusion
for severe thrombocytopenia due to chemotherapy or hematopoietic cell transplantation
(the PLADO trial), a correlation was observed between severe anemia and increased
bleeding risk [27]. This effect was modest and only reached statistical significance at
hematocrits ≤25 percent (odds ratio [OR] 1.29; 95% CI 1.11-1.49). It is not clear whether
association between anemia and bleeding was due to causation or was merely an
association. Transfusion of RBCs did not appear to improve bleeding outcomes.
Mortality — The development of anemia is a risk factor for increased mortality in a

number of clinical settings. For the most part, these are associations rather than causal
relationships. A few of the many examples are listed below:
● Chronic kidney disease (see "Cardiovascular and renal effects of anemia in chronic
kidney disease", section on 'Mortality')
● Malignancy (see "Role of erythropoiesis-stimulating agents in the treatment of

anemia in patients with cancer", section on 'Effect on disease control and survival')
● Heart failure (see "Approach to anemia in adults with heart failure", section on
'Prognosis')
● The older adult (see "Anemia in the older adult", section on 'Increased mortality')
● The hospitalized adult [28] (see "Indications and hemoglobin thresholds for red blood
cell transfusion in the adult", section on 'Impact of anemia on morbidity and
mortality')
CAUSES OF ANEMIA
There are two general approaches one can use to help identify the cause of anemia.
Each will be discussed below.
● A kinetic approach, addressing the mechanism(s) responsible for the fall in

hemoglobin concentration
● A morphologic approach categorizing anemias via alterations in red blood cell

(RBC) size (ie, mean corpuscular volume) and the reticulocyte response [29]
Kinetic approach — Anemia can be caused by three independent mechanisms:
decreased RBC production, increased RBC destruction, and blood loss [20]. Occasional
patients may have two (or all three) of these mechanisms operating at the same time. As
examples:
● A patient with autoimmune hemolytic anemia (ie, increased RBC destruction) can
have a low reticulocyte response (ie, decreased RBC production) as the result of
concomitant bone marrow suppression. (See "Warm autoimmune hemolytic anemia:
Clinical features and diagnosis", section on 'Reticulocyte response'.)
● A patient with aplastic anemia (decreased RBC production) may have significant
hemorrhage as the result of concomitant severe thrombocytopenia (blood loss). (See
"Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on
'Clinical manifestations'.)
● A patient admitted to the hospital for acute alcoholism and gastrointestinal

hemorrhage (blood loss) may be found to have concomitant folate deficiency
associated with ineffective erythropoiesis (decreased RBC production) and
shortened RBC lifespan (increased RBC destruction). It would not be unusual for this
patient to also be iron deficient. (See "Causes and pathophysiology of vitamin B12
and folate deficiencies", section on 'Causes of folate deficiency'.)
Decreased RBC production — Anemia will ultimately result if the rate of RBC
production is less than that of RBC destruction. This can occur either due to reduced
effective production of red cells, or via the destruction of RBC precursors within the bone
marrow (ineffective erythropoiesis).
Decrease in effective red cell production — When the bone marrow is otherwise
healthy, it will respond to anemia by increasing the number of red cell precursors and
hastening their normal progression into reticulocytes. Thus, a reduced or absent
reticulocyte response for the degree of anemia indicates reduced red cell production. A
convenient way to evaluate this is via the reticulocyte production index (calculator 1),
which will be low (<2) when the marrow response to anemia is inadequate for the degree
of anemia and increased (>3) when the marrow is responding normally to the anemia.
(See "Diagnosis of hemolytic anemia in the adult", section on 'High reticulocyte count'.)
The more common causes for reduced (effective) RBC production include:
● Lack of nutrients, such as vitamin B12 and iron. This can be due to dietary lack or
malabsorption (eg, sprue), although iron deficiency is commonly due to blood loss.
● Bone marrow disorders leading to a reduced number of RBC precursors (eg, aplastic
anemia, pure RBC aplasia, marrow infiltration)
● Bone marrow suppression (eg, drugs, chemotherapy, irradiation) (see "Hematologic

complications of malignancy: Anemia and bleeding")
● Low levels of trophic hormones, which stimulate RBC production, such as

erythropoietin (EPO; eg, chronic renal failure), thyroid hormone (eg, hypothyroidism),
and androgens (eg, hypogonadism)
• A rare cause of anemia due to reduced EPO production has been described in
patients with autonomic dysfunction and orthostatic hypotension [30,31]. (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 [32]. (See "Pure red cell aplasia due to anti-erythropoietin
antibodies".)
● The anemia of inflammation, associated with infectious, inflammatory, or malignant

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

erythropoiesis is the presence of intense erythroid hyperplasia within the bone marrow
along with a relative reduction in reticulocyte production (eg, a reduced reticulocyte
production index). In such cases, the erythroid precursors in the bone marrow are not
maturing normally and are dying within the bone marrow, usually via the process of
apoptosis and/or a block in maturation.
The more common causes for ineffective erythropoiesis include the following disorders:
● Megaloblastic anemia (see "Causes and pathophysiology of vitamin B12 and folate
deficiencies", section on 'Hematopoiesis')
● Alpha and beta thalassemia (see "Pathophysiology of beta thalassemia", section on

'Ineffective erythropoiesis')
● The myelodysplastic syndromes (see "Clinical manifestations and diagnosis of the

myelodysplastic syndromes", section on 'Bone marrow biopsy')
● Sideroblastic anemias (see "Causes and pathophysiology of the sideroblastic

anemias", section on 'Pathophysiology')
● Congenital dyserythropoietic anemia in children (see "Anemia in children due to

decreased red blood cell production", section on 'Erythroid maturation disorders and
ineffective erythropoiesis')
Increased destruction of circulating RBCs — A RBC life span below 100 days is
the operational definition of hemolysis [33]. When hemolysis is present, laboratory
studies show increased levels of lactate dehydrogenase (LDH) along with reduced
haptoglobin, often accompanied by increases in indirect bilirubin and clinical jaundice.
(See 'Evaluation for hemolysis' below and "Red blood cell survival: Normal values and
measurement" and "Diagnosis of hemolytic anemia in the adult", section on 'Diagnostic
approach'.)
Anemia will ensue in the adult patient when the bone marrow is unable to keep up with
the need to replace more than approximately 5 percent of the RBC mass per day,
corresponding to a RBC survival of 20 days or less. (See 'Overview' above and
"Diagnosis of hemolytic anemia in the adult".)
Examples include (table 4):
● Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease,

pyruvate kinase deficiency, thalassemia major)
● Acquired hemolytic anemias (eg, Coombs-positive autoimmune hemolytic anemia,

thrombotic thrombocytopenic purpura, malaria, paroxysmal nocturnal
hemoglobinuria)
● Increased destruction of normal red cells by an enlarged spleen (ie, hypersplenism).

(See "Extracorpuscular non-immune hemolytic anemia: Fragmentation hemolysis
and hypersplenism", section on 'Extravascular nonimmune hemolysis due to
hypersplenism'.)
Intravascular hemolysis — In most cases, hemolysis takes place in extravascular

spaces, most often in the spleen and liver. However, in some cases, red cells are
destroyed while still in the circulation, a condition called intravascular hemolysis.
Common examples of conditions associated with intravascular hemolysis include the
following (table 4). (See "Diagnosis of hemolytic anemia in the adult", section on
'Intravascular hemolysis'.)
● Microangiopathic hemolytic anemia

● Clostridial sepsis
● Paroxysmal nocturnal hemoglobinuria
● Cold agglutinin disease
● Paroxysmal cold hemoglobinuria
In such cases, as with extravascular hemolysis, laboratory studies show increased levels
of lactate dehydrogenase along with reduced haptoglobin and increases in indirect
bilirubin. Because destruction of circulating red cells may be profound, anemia and
clinical jaundice may be severe, often leading to circulatory collapse, renal damage, and,
in severe cases, death.
Clinical observations suggesting the presence of intravascular hemolysis include the

passing of darkly colored urine, ranging from gold to red to black (hemoglobinuria) as well
as acrocyanosis or livedo reticularis (picture 5) on exposure to cold.
Laboratory studies that suggest that the hemolysis is intravascular, rather than
extravascular include the following (see "Diagnosis of hemolytic anemia in the adult",
section on 'Diagnostic approach'):
● The presence of free hemoglobin in the plasma (ie, hemoglobinemia)

● The presence of red cell-free hemoglobin in the urine (ie, hemoglobinuria)
● The presence of hemosiderin in a stained urine sediment (sloughed renal tubular
cells) if the intravascular hemolysis has been ongoing for at least one week
Blood loss — Blood loss is the most common cause of anemia, although it is often
difficult to quantitate. Sources include severe trauma with arterial bleeding at any site,
and disorders of the gastrointestinal tract, lungs, kidneys, and uterus. The patient's
history is important in this regard, as is testing of urine, sputum, gastrointestinal fluids,
stool, surgical drains, and other bodily fluids for the presence of blood.
There are a number of situations in which blood loss can occur and not be easily
recognized. These include:
● Factitious bleeding, secondary to surreptitious blood drawing by the patient

(Lasthénie de Ferjol syndrome) [34-36].
● Bleeding during or after surgical procedures may be extremely difficult to quantitate,

and is often underestimated.
● Bleeding into the upper thigh and/or retroperitoneal space can often be significant,
but may not be clinically obvious. Such patients may, however, have associated
symptoms of abdominal pain, groin or hip pain, leg paresis, or hypotension [37]. This
complication may be more common in patients taking anticoagulants, even when
results of coagulation tests are within the therapeutic range. Computed tomography
(CT) imaging of the abdomen and thigh is often helpful if this is suspected (image 1).
Iron deficiency in the United States and Western Europe is almost always due to blood
loss, which may be obvious, occult, or underappreciated, as follows:
● Obvious bleeding (eg, trauma, melena, hematemesis, severe menometrorrhagia)
● Occult bleeding (eg, slowly bleeding ulcer or carcinoma) (see "Evaluation of occult
gastrointestinal bleeding")
● Induced bleeding (eg, repeated diagnostic testing [38,39], hemodialysis losses,

excessive blood donation)
● Underappreciated menstrual blood loss (see "Approach to abnormal uterine bleeding

in nonpregnant reproductive-age women", section on 'Menstrual history')
In addition to the loss of RBCs from the body, which the bone marrow must replace, loss
of the iron contained in these cells will ultimately lead to iron deficiency once tissue stores
of iron have been depleted. This usually occurs in males and females after losses of
≥1200 mL and ≥600 mL, respectively. However, since approximately 25 percent of
menstruant females have absent iron stores, any amount of bleeding will result in anemia
in this subpopulation. (See "Causes and diagnosis of iron deficiency and iron deficiency
anemia in adults".)
Since availability of iron is normally rate-limiting for RBC production, iron deficiency
associated with chronic bleeding leads to a reduced marrow response, worsening the
degree of anemia.
Morphologic approach — The causes of anemia can also be classified according to

measurement of RBC size, as seen on the blood smear and as reported by automatic cell
counter indices [40]. The normal RBC has a volume of 80 to 96 femtoliters (fL, 10-15 liter)
and a diameter of approximately 7 to 8 microns, equal to that of the nucleus of a small
lymphocyte. Thus, RBCs larger than the nucleus of a small lymphocyte on a peripheral
smear are considered large or macrocytic, while those that appear smaller are
considered small or microcytic (table 5 and algorithm 1). (See "Evaluation of the
peripheral blood smear", section on 'Red blood cells'.)
Automatic cell counters estimate RBC volume cell by cell, sampling millions of RBCs in
the process. Machine output is a value for the mean corpuscular volume of the sample
(MCV), as well as an estimate of the dispersion of values about this mean. The latter
value is usually given as the coefficient of variation of RBC volumes or RBC distribution
width (RDW). (See "Microcytosis/Microcytic anemia", section on 'RDW (size variability)'.)
An increased RDW indicates the presence of cells of widely differing sizes, but it is not
diagnostic of any particular disorder. However, some automatic cell counters have
computer programs that "flag" for the presence of abnormalities such as anisocytosis
(cells of varying size), microcytosis, macrocytosis, and hypochromia (reduced
hemoglobin content per cell) [41]. (See "Automated hematology instrumentation", section
on 'Red cell distribution width'.)
Macrocytic anemia — Anemia is considered "macrocytic" when the MCV exceeds

100 fL (femtoliters) (table 6). Causes include the following (see "Macrocytosis/Macrocytic
anemia"):
● An increased MCV is a normal characteristic of reticulocytes (picture 4). Any

condition causing marked reticulocytosis will be associated with an increased MCV.
● Abnormal nucleic acid metabolism of erythroid precursors (eg, folate or cobalamin
deficiency and drugs interfering with nucleic acid synthesis, such as zidovudine and
hydroxyurea) may lead to macrocytosis and anemia.
● Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, large

granular lymphocyte [LGL] leukemia).
● Other common causes include alcohol abuse, liver disease, and hypothyroidism.
A report from a family practice group found macrocytosis in 2 to 4 percent of patients [42],
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 [43]. The most common causes were
alcoholism, liver disease, hypothyroidism, and the megaloblastic anemias (eg, B12
deficiency).
Microcytic anemia — Anemia is considered "microcytic" when the MCV is less than
80 fL. Microcytosis is usually accompanied by a decreased hemoglobin content within the
RBC (mean corpuscular hemoglobin, MCH), with a parallel reduction in MCV, producing a
hypochromic (low MCH) as well as a microcytic (low MCV) appearance on the blood
smear (picture 6 and table 5). (See "Microcytosis/Microcytic anemia", section on 'Causes
of microcytosis'.)
The following pathologic processes lead to the production of hypochromic microcytic red
cells:
● Reduced iron availability – Severe iron deficiency, the anemia of inflammation,

copper deficiency
● Acquired disorders of heme synthesis – Lead poisoning, acquired sideroblastic
anemias
● Reduced globin production – Thalassemic disorders, other hemoglobinopathies
● Rare congenital disorders including sideroblastic anemias, porphyria, and defects in
iron absorption, transport, utilization, and recycling [44,45]
The three most common causes of microcytosis in clinical practice are iron deficiency,
alpha or beta thalassemia minor, and (less often) the anemia of inflammation (anemia of
chronic disease). Since all may have hypochromic and microcytic RBCs, other tests must
be used to establish the diagnosis.
● Iron deficiency anemia – Important discriminating features are a low serum ferritin
concentration, an increased total iron binding capacity (transferrin), and low serum
iron concentration (table 7), resulting in a low transferrin saturation. For clinicians
making this diagnosis, it is mandatory to determine the cause of the iron deficient
state (eg, occult colonic carcinoma, excessive menstrual losses). (See "Causes and
diagnosis of iron deficiency and iron deficiency anemia in adults".)
● Alpha or beta thalassemia minor – Adults with thalassemia are most often
heterozygotes for the alpha or beta forms of this syndrome, and may be only
minimally anemic. A family history is therefore often negative. Physical examination
may reveal splenomegaly; the peripheral smear shows varying degrees of
hypochromia, microcytosis, target cells (picture 7), tear-drop forms, and basophilic
stippling (picture 8). The RBC count may actually be increased; uncomplicated
patients have normal or increased iron stores. (See "Clinical manifestations and
diagnosis of the thalassemias".)
The diagnosis of beta thalassemia trait can often be made by demonstrating

increased levels of hemoglobin A2 on hemoglobin electrophoresis or liquid
chromatography (HPLC), while molecular methods are usually required for the
diagnosis of the alpha thalassemia variants [46]. (See "Methods for hemoglobin
analysis and hemoglobinopathy testing".)
● Anemia of inflammation – The hallmarks of this condition include a low serum iron,
low total iron binding capacity (transferrin), and a normal to increased serum ferritin
concentration. Although hypochromic and microcytic red cells can be found in these
patients, a low MCV is most frequently seen only in those patients with hepatoma or
renal cell carcinoma. (See "Anemia of chronic disease/inflammation".)
Normocytic anemia — By definition, the mean RBC volume is normal (ie, MCV
between 80 and 100 fL) in patients with normocytic anemia (table 5). Approach to this
extremely large category of patients can be narrowed somewhat by examination of the
blood smear to determine if there is a subpopulation of RBCs with distinctive size or
shape abnormalities, which would place the patient in one of the above categories (ie,
early microcytic or macrocytic anemia), or by use of the kinetic approach to determine
the mechanism(s) underlying the anemia. (See 'Kinetic approach' above and 'Systemic
disorders' below.)
Systemic disorders — Anemia may be the first manifestation of a systemic
disorder, along with other nonspecific complaints such as fever, weight loss, anorexia,
and malaise. Simple laboratory tests may give additional clues toward the underlying
disease process. These include abnormalities on the urinalysis or routine chest x-ray,
liver or renal function tests, erythrocyte sedimentation rate, C-reactive protein, serum
protein electrophoresis, WBC count and differential, and reduced (or increased) platelet
counts. Anemia in older adults, which may be difficult to categorize, is discussed
separately. (See "Anemia in the older adult".)
Anemia of chronic renal disease — Anemia is a common complication of renal

disease, and may be multifactorial. This subject is discussed in detail separately. (See
"Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)
Cardiorenal anemia syndrome — Cardiorenal anemia syndrome refers to the

simultaneous presence of anemia, heart failure, and chronic renal disease [47]. This
disorder complex is discussed separately. (See "Cardiovascular and renal effects of
anemia in chronic kidney disease" and "Approach to anemia in adults with heart failure".)
Cancer-associated anemia — Anemia in patients with malignancy is often

multi-factorial and related to the underlying malignancy as well as its treatment. (See
"Hematologic complications of malignancy: Anemia and bleeding".)
Acquired anemia in hospitalized patients — The development of anemia in a

previously non-anemic patient subsequent to hospitalization (hospital-acquired anemia,
HAA) is usually multifactorial and includes causes such as bleeding following an invasive
procedure or surgery, large volumes of blood drawn for diagnostic studies, occult
bleeding, hemodilution from intravenous fluid administration, as well as a blunted
erythropoietic response associated with critical illness [39,48,49]. As examples:
● In one population study, among 188,447 hospitalizations, 74 percent developed

HAA, which correlated with increases in length of stay, hospital charges, and
mortality [28].
● 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 [38].
EVALUATION OF THE PATIENT
Initial approach — Anemia is one of the major signs of disease. It is never normal and
its cause(s) should always be sought. The history, physical examination, and simple
laboratory testing are all useful in evaluating the anemic patient (algorithm 1). The
workup should be directed towards answering the following questions concerning
whether one or more of the major processes leading to anemia may be operative:
● Is the patient bleeding (now or in the past)?

● Is there evidence for increased red blood cell (RBC) destruction (either intravascular
or extravascular)?
● Is the bone marrow suppressed? If so, why?
● Is the patient iron deficient? If so, why?
● Is the patient deficient in folate or vitamin B12? If so, why?
History — There are a number of important components to the history in the setting of
anemia:
● Is there a recent history of loss of appetite, weight loss, fever, and/or night sweats
that might indicate the presence of infection or malignancy?
● Is there a history of, or symptoms related to, a medical condition that is known to
result in anemia (eg, tarry stools in a patient with ulcer-type pain, significant blood
loss from other sites, rheumatoid arthritis, renal failure)?
● Is the anemia of recent origin, subacute, or lifelong? Recent anemia is almost always
an acquired disorder, while lifelong anemia, particularly if accompanied by a positive
family history, is likely to be inherited (eg, the hemoglobinopathies, thalassemia,
hereditary spherocytosis).
The electronic medical record is very useful in this analysis because one can document
quite precisely when the hemoglobin began to fall, as well as when the RBC indices
changed and in what direction. One can use this information to determine what, if
anything, was occurring prior to the present illness.
The patient's ethnicity and country of origin may be helpful, as the thalassemias and
other hemoglobinopathies are particularly common in patients from the Mediterranean
littoral, Middle East, sub-Saharan Africa, and Southeast Asia [50]. (See "Introduction to
hemoglobin mutations" and "Public health issues in the thalassemic syndromes".)
The use of medications, both prescribed and over-the-counter, should be examined in

some detail. Specific questions should be asked about the use of alcohol, aspirin, and
nonsteroidal antiinflammatory drugs. (See "NSAIDs (including aspirin): Pathogenesis of
gastroduodenal toxicity".)
A past history of blood transfusions, liver disease, treatment of the patient (or other family
members) with iron or other hematinics, herbal preparations, and exposure to toxic
chemicals in the workplace or environment should also be obtained. An assessment of
nutritional status is especially important in older adults and alcoholics.
Physical examination — The major aim of physical examination is to find signs of organ
or multisystem involvement and to assess the severity of the patient's condition. Thus,
the presence or absence of tachycardia, dyspnea, fever, or postural hypotension should
be noted. While evaluation for jaundice and pallor is a standard part of the physical
examination, such signs may be misinterpreted and are not as reliable indicators of
anemia as once thought.
Pallor — The sensitivity and specificity for pallor in the palms, nail beds, face, or
conjunctivae as a predictor for anemia varies from 19 to 70 percent and 70 to 100
percent, respectively [51-54], 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 [53]. 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) [55]. 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.
● One should also look for signs and symptoms of recurrent infections secondary to
neutropenia or immune deficiency states. Stool obtained during the examination
should always be tested for the presence of occult blood. (See "Evaluation of occult
gastrointestinal bleeding".)
LABORATORY EVALUATION
Initial testing of the anemic patient should include a "complete" blood count (CBC). This
routinely includes hemoglobin, hematocrit (HCT), red blood cell (RBC) count, RBC
indices, and white blood cell (WBC) count. A WBC differential, platelet count, and
reticulocyte count are not part of the routine CBC in some medical centers; these may
have to be ordered separately. Thus, to avoid confusion, the clinician should specifically
request a CBC with platelets, WBC differential, and reticulocytes.
Many automated blood counters report a RBC distribution width (RDW), a measure of the
degree of variation in red cell size (red cell volume) (see 'Morphologic approach' above).
However, the RDW alone does not indicate why the RBC size varies (anisocytosis) or the
RBC shapes (poikilocytosis). Some counters will "flag" for the presence of specific RBC
changes, such as hypochromia or microcytosis, which can be confirmed by examination
of the peripheral smear. (See "Automated hematology instrumentation".)
Accordingly, the blood smear should always be reviewed by an experienced examiner

since many important changes may be missed by the inexperienced observer and may
not be detected by automated blood counters [56]. (See 'Blood smear' below and
"Evaluation of the peripheral blood smear".)
Red blood cell indices — Three RBC indices are usually measured by automated blood
counters: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and
mean corpuscular hemoglobin concentration (MCHC) (table 1). The values for MCH and
MCHC generally parallel the information obtained from the MCV (ie, larger or smaller
RBCs tend to have higher or lower values for MCH, respectively).
Mean corpuscular volume — The normal range for the MCV is 80 to 100 femtoliters
(fL). The causes of anemia associated with a low (microcytosis) or high (macrocytosis)
MCV are discussed above (table 5). (See 'Morphologic approach' above.)
● Values of the MCV in excess of 115 fL are almost exclusively seen in vitamin B12 or
folate deficiency.
● Even higher values can occur as an artifact when cold agglutinins are present, which
causes RBCs to go through the counting aperture in automated instruments in
doublets or triplets [57]. Warming the specimen (and reagents) to body temperature
prior to a repeat count should return the MCV to normal and confirm the presence of
a cold agglutinin. (See "Microcytosis/Microcytic anemia".)
Mean corpuscular hemoglobin — The normal MCH ranges from 27.5 to 33.2
picograms of hemoglobin per RBC. Low values are seen in iron deficiency and
thalassemia, while increased values occur in macrocytosis of any cause.
Mean corpuscular hemoglobin concentration — The mean normal value for the
MCHC is 34 grams of hemoglobin per dL of RBCs (340 g/L of RBCs). The 95 percent
confidence limits for the MCHC have been variably given (table 1), with lower and upper
limits of 31 to 33 and 35 to 36, respectively. Low values occur in the same conditions that
generate low values for MCV and MCH, while increased values occur almost exclusively
in the presence of congenital or acquired spherocytosis or in other congenital hemolytic
anemias in which red cells are abnormally desiccated (eg, sickle cell anemia, hemoglobin
C disease, xerocytosis). (See "Hereditary spherocytosis" and "Stomatocytosis and
xerocytosis".)
Reticulocyte count — The reticulocyte count, either as a percentage of all RBCs, the
absolute reticulocyte count, the corrected absolute reticulocyte count, or as the
reticulocyte production index, helps to distinguish among the different types of anemia:
● Anemia with a high reticulocyte count reflects an increased erythropoietic response

to continued hemolysis or blood loss. (See 'Reticulocytes' above.)
● A stable anemia with a low reticulocyte count is strong evidence for deficient
production of RBCs (ie, a reduced bone marrow erythropoietic response to the
anemia). (See "Anemia in adults due to decreased red blood cell production".)
● Hemolysis or blood loss can be associated with a low reticulocyte count if there is a
concurrent disorder that impairs RBC production (eg, infection, prior chemotherapy,
other causes for bone marrow suppression). (See 'Multiple causes of anemia' below.)
White blood cell count and differential — A low total WBC count (leukopenia) in a
patient with anemia should lead to consideration of aplastic anemia, bone marrow
suppression or replacement, hypersplenism, or deficiencies of cobalamin. In comparison,
a high total WBC count (leukocytosis) may reflect the presence of infection, inflammation,
or a hematologic malignancy. Many of the automated cell counters routinely calculate and
display the absolute neutrophil count (ANC), total lymphocyte count (TLC), and absolute
monocyte count. These values are very useful because they immediately allow distinction
between leukopenia caused by a low ANC and leukopenia caused by a low TLC, and the
causes are importantly different. (See "Approach to the adult with unexplained
neutropenia" and "Approach to the adult with lymphocytosis or lymphocytopenia".)
Examples of causes of increased and decreased ANC and TLC include the following:
● An increased absolute neutrophil count in infection

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

the presence of >5 percent of neutrophils with five or more lobes and/or the presence of
one or more neutrophils with six or more lobes (picture 9). This peripheral smear finding,
along with macro-ovalocytic red cells (picture 10), is classically associated with impaired
DNA synthesis, as seen in disorders of vitamins B12 and folate. NH can also be seen
following the use of drugs interfering with nucleic acid synthesis (eg, hydroxyurea) [58].
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 [59]. The mechanism for NH in iron deficiency is
unknown.
Circulating nucleated red blood cells — Nucleated RBCs (NRBCs) are not normally
found in the circulation. The appearance of NRBCs usually signifies either stressed
erythropoiesis or extramedullary erythropoiesis. NRBCs may be present in patients with
known hematologic disease (eg, sickle cell disease, thalassemia major, various hemolytic
anemias after splenectomy), or as a part of the leukoerythroblastic pattern seen in
patients with bone marrow fibrosis or replacement with tumor cells (picture 11).
In patients without an underlying hematologic disease, NRBCs may reflect the presence
of a life-threatening disease, such as sepsis or severe heart failure. In one study of 4173
patients seen at a university clinic, NRBCs were seen at least once in 7.5 percent of all
patients; the highest incidence (20 percent) occurred in patients from the general surgery
and trauma intensive care unit [60]. In-hospital mortality was 1.2 and 21.1 percent in
those without or with NRBCs, respectively, and increased with increasing concentration of
NRBCs. In patients who died, nucleated RBCs were detected for the first time at a
median of 13 days before death.
Platelet count — Abnormalities in the platelet count often provide important diagnostic
information. Thrombocytopenia occurs in a variety of disorders associated with anemia,
including aplastic anemia, hypersplenism, marrow involvement with malignancy,
autoimmune platelet destruction (either idiopathic or drug-related), sepsis, or folate or
cobalamin deficiency.
High platelet counts, in comparison, may reflect the presence of a myeloproliferative

neoplasm, chronic iron deficiency, and inflammatory, infectious, or neoplastic disorders.
(See "Approach to the patient with thrombocytosis".) Changes in platelet morphology
(giant platelets, degranulated platelets) also may be important, suggesting
myeloproliferative or myelodysplastic disease.
Pancytopenia — The combination of anemia, thrombocytopenia, and neutropenia is

termed pancytopenia. The causes and evaluation of pancytopenia are discussed
separately. (See "Approach to the adult with unexplained pancytopenia" and "Aplastic
anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential
diagnosis' and "Inherited aplastic anemia in children and adolescents" and "Acquired
aplastic anemia in children and adolescents".)
Blood smear — Many clinicians rely on the above RBC parameters and the RDW in
evaluating a patient with anemia. However, the RDW is, as noted above, of limited utility,
and examination of the peripheral blood smear provides information not otherwise
available. (See "Evaluation of the peripheral blood smear".)
As examples, the automated counter may miss the red cell fragmentation ("helmet cells,"
schistocytes) of microangiopathic hemolysis (picture 12), microspherocytes in
autoimmune hemolytic anemia, teardrop RBCs in myelofibrosis (picture 13), a
leukoerythroblastic pattern with bone marrow replacement (picture 11), the "bite cells" in
oxidative hemolysis (picture 14), or RBC parasites such as malaria or babesiosis (picture
15). (See "Evaluation of the peripheral blood smear".)
Serial evaluation of hemoglobin and hematocrit — Measuring the rate of fall of the
patient's hemoglobin or HCT often provides helpful diagnostic information. Suppose the
hemoglobin concentration has fallen from 15 to 10 g/dL in one week. If this were due to
total cessation of RBC production (ie, a reticulocyte count of zero) and if the rate of RBC
destruction were normal (1 percent/day), the hemoglobin concentration would have fallen
by 7 percent over seven days, resulting in a decline of 1.05 g/dL (0.07 x 15). The greater
fall in hemoglobin in this patient (5 g/dL) indicates that marrow suppression cannot be the
sole cause of the anemia and that blood loss and/or increased RBC destruction must be
present.
Evaluation for iron deficiency — More complete evaluation for iron deficiency is
indicated when the history (menometrorrhagia, symptoms of peptic ulcer disease) and
preliminary laboratory data (low MCV, low MCH, high RDW, increased platelet count)
support this diagnosis. In this setting, the plasma levels of iron, iron binding capacity
(transferrin), transferrin saturation, and ferritin should be measured (table 7). (See
"Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)
Evaluation for hemolysis — Hemolysis should be considered if the patient has

experienced a rapid fall in hemoglobin concentration, reticulocytosis, and/or abnormally
shaped RBC (especially spherocytes or fragmented RBCs) on the peripheral smear
(table 4) in the absence of blood loss. The usual ancillary findings of hemolysis are an
increase in the serum lactate dehydrogenase (LDH) and indirect bilirubin concentrations
and a reduction in the serum haptoglobin concentration. (See "Diagnosis of hemolytic
anemia in the adult".)
The combination of an increased LDH and reduced haptoglobin is 90 percent specific for
diagnosing hemolysis, while the combination of a normal LDH and a serum haptoglobin
greater than 25 mg/dL is 92 percent sensitive for ruling out hemolysis [61,62].
Intravascular hemolysis — Plasma and urinary hemoglobin and urinary hemosiderin

should be measured if intravascular hemolysis is a consideration, as with paroxysmal
nocturnal hemoglobinuria. (See "Diagnosis of hemolytic anemia in the adult", section on
'Diagnostic approach'.)
Bone marrow examination — Examination of the bone marrow generally offers little
additional diagnostic information in the more common forms of anemia. If erythropoiesis
is increased in response to the anemia, as evidenced by an increased reticulocyte
production index (calculator 1), the bone marrow will show erythroid hyperplasia, a
nonspecific finding. However, if the reticulocyte response is inadequate and the bone
marrow shows erythroid hyperplasia, this suggests the presence of ineffective
erythropoiesis. (See 'Presence of ineffective erythropoiesis' above.)
Although the absence of stainable iron in the bone marrow had previously been
considered the "gold standard" for the diagnosis of iron deficiency, this diagnosis is
usually established by laboratory tests alone (table 7). (See "Causes and diagnosis of
iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
Indications for examination of the bone marrow in anemic patients include pancytopenia
or the presence of abnormal cells in the circulation, such as blast forms. Such patients
may have aplastic anemia, myelodysplasia, marrow replacement with malignancy, or a
myeloproliferative neoplasm. Other findings that may be seen in the marrow in anemic
patients include megaloblastic erythropoiesis (folate or cobalamin deficiency), absence of
recognizable RBC precursors (pure RBC aplasia), vacuolization of RBC precursors
(alcohol or drug-induced anemia), and increased iron-laden RBC precursors (the
sideroblastic anemias). (See "Evaluation of bone marrow aspirate smears".)
Multiple causes of anemia — It is common in pediatric practice for anemia to be caused

by a single identifiable disorder. In comparison, multiple causes are frequently present in
adults, particularly hospitalized and/or older adults. Common examples include the
following (see 'Kinetic approach' above):
● A patient with gastrointestinal bleeding secondary to colon cancer may also have the
anemia of inflammation (anemia of chronic disease), leading to a blunted reticulocyte
response. (See "Anemia of chronic disease/inflammation".)
● A patient with a chronic hemolytic anemia (eg, sickle cell anemia, hereditary
spherocytosis) may develop worsening anemia following acute infection, particularly
with parvovirus B19, which may blunt or temporarily ablate erythropoiesis and the
reticulocyte response [63]. (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 [64]. (See "Cardiovascular and renal
effects of anemia in chronic kidney disease".)
Algorithms for diagnosing anemia generally fail in the presence of more than one cause.
Under such circumstances, the clinician is advised to obtain answers separately to each
of the questions outlined above (see 'Initial approach' above), to examine the peripheral
blood smear for abnormal red blood cell populations (eg, microcytes, macrocytes,
spherocytes, schistocytes) and proceed from that point.
Athletes — Athletes have been reported to have anemia from a number of causes [65-
74]:
● Dilutional anemia from increased plasma volume

● Exercise-induced acute phase response with production of inflammatory cytokines
● Gastrointestinal bleeding and iron deficiency
● Intravascular hemolysis from "march" hemoglobinuria
Performance-enhancing agents including androgens and erythropoietin may cause

polycythemia that could mask some of these causes of anemia [69,71].
These issues are discussed in more detail in separate topic reviews. (See "Exercise-
related gastrointestinal disorders", section on 'Gastrointestinal bleeding' and
"Extracorpuscular non-immune hemolytic anemia: Fragmentation hemolysis and
hypersplenism", section on 'Mechanical trauma' and "Use of androgens and other
hormones by athletes", section on 'Androgens'.)
There is evidence for an exercise-induced acute phase response in athletes, with the
production of inflammatory cytokines capable of inducing increased levels of hepcidin,
consistent with a component of the anemia of inflammation [74]. (See "Anemia of chronic
disease/inflammation", section on 'The role of cytokines'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Anemia
in adults".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to
6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)
● Basics topics (see "Patient education: Anemia of chronic disease (The Basics)")
● Beyond the Basics topics (see "Patient education: Anemia caused by low iron in
adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS

The initial approach to the patient with anemia is to perform a complete history and
physical examination along with a review of the results of a complete blood count (CBC)
with white blood cell (WBC) differential, platelet count, reticulocyte count, and an
examination of the peripheral blood smear (table 1). (See 'Evaluation of the patient'
above.)
● A hemoglobin concentration <13.5 g/dL (<135 g/L) or a hematocrit (HCT) <41.0

percent represents anemia in men; a value <12.0 g/dL (<120 g/L) or <36.0 percent,
respectively, represents anemia in women. Differences may also exist between
races, in older adults, and in athletes. (See 'Definitions' above.)
● Most cases of anemia can be diagnosed by employing the morphologic approach,

in which the anemia is first classified via the red cell size (ie, mean corpuscular
volume [MCV]), which is part of the CBC (algorithm 1). (See 'Morphologic approach'
above.)
• Microcytic anemias are associated with an MCV below 80 fL. The most
commonly seen causes are iron deficiency (table 5 and table 7), thalassemia,
and the anemia of (chronic) inflammation. (See 'Microcytic anemia' above and
'Evaluation for iron deficiency' above.)
• Macrocytic anemias are characterized by an MCV above 100 fL (table 5 and

table 6). The most common causes include alcoholism, liver disease, folate and
vitamin B12 deficiency, and myelodysplasia. (See "Macrocytosis/Macrocytic
anemia", section on 'Evaluation'.)
• The MCV is between 80 and 100 fL in patients with normocytic anemia (table 5).
Examination of the blood smear is important in order to determine if there is a
small population of red cells with distinctive size or shape abnormalities which
would place the patient in one of the above categories (ie, early microcytic or
macrocytic anemia), or would raise suspicion of an acute or chronic hemolytic
state (eg, spherocytes, sickle forms, ovalocytes).
- Hemolysis may have been suspected from the patient's history, physical
examination, or examination of the peripheral blood smear (eg, sudden
onset of anemia, jaundice, splenomegaly, presence of spherocytes or
schistocytes or other red cell shape changes) (see 'Evaluation of the
patient' above). It is confirmed by the finding of increased levels of indirect
bilirubin and lactate dehydrogenase, and low levels of haptoglobin (table 4).
(See 'Evaluation for hemolysis' above and "Diagnosis of hemolytic anemia
in the adult", section on 'Diagnostic approach'.)
- The presence of abnormal cells in the circulation (eg, nucleated red blood
cells [RBCs], blasts, atypical mononuclear cells) and/or abnormal increases
or decreases in absolute counts for granulocytes, lymphocytes, monocytes,
or platelets suggests that the anemia is part of a more complex hematologic
disorder (eg, leukemia, aplastic anemia, myelodysplastic syndrome,
myeloproliferative neoplasm). Consultation with a hematologist would be
appropriate at this point.
- Anemia may be the first manifestation of a systemic disorder (table 5),

along with other nonspecific complaints such as fever, weight loss,
anorexia, and malaise. Simple laboratory tests may give additional clues
toward the underlying disease process. These include abnormalities on the
urinalysis or routine chest x-ray, elevated serum creatinine, abnormal liver
function tests, and increased erythrocyte sedimentation rate or C-reactive
protein.
● More complicated patients may require use of the kinetic approach, in which the
following three questions are asked in order to determine the mechanism(s) causing
the anemia (see 'Kinetic approach' above):
• Is there evidence for decreased red cell production? (See 'Decreased RBC
production' above.)
• Is there evidence for increased red cell destruction (hemolysis)? (See 'Increased
destruction of circulating RBCs' above.)
• Is there a history of bleeding? (See 'Blood loss' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 7133 Version 51.0

GRAPHICS
Evaluation of anemia in the adult according to the mean corpuscular volume
CBC: complete blood count; MCV: mean corpuscular volume; RBCs: red blood cells; Fe: iron; TIBC: total iron-binding cap
Graphic 99491 Version 1.0

Manual (spun) 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, a normal white
blood cell count, and a platelet count of 5,000,000/microL. 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), and the white blood cell count
is not markedly elevated, the platelet count can be estimated by the
thickness of this layer, with each mm being equivalent to one million
platelets/microL. 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.

Microhematocrit determination
The capillary tube is plugged at one end and centrifuged (left). The proportion of
blood volume occupied by red cells can be readily determined by eye in a
microhematocrit reader (right).
Courtesy of Nathaniel Duke.

Normal values for red blood cell parameters in adults
RBC parameter Men Women
Hemoglobin, g/dL 15.7 (14.0 to 13.8 (12.3 to

17.5) 15.3)
Hematocrit, percent 46 (42 to 40 (36 to

50) 45)
RBC count, million/microL 5.2 (4.5 to 4.6 (4.1 to

5.9) 5.1)
Reticulocyte count, cells/microL 20,000 to 20,000 to

110,000 110,000
Reticulocyte percentage 1.6 ± 0.5 1.4 ± 0.5
Mean corpuscular volume (MCV), femtoliters (fL) 88 (80 to 88 (80 to

96) 96)
Mean cell hemoglobin (MCH), pg/RBC 30 (28 to 30 (28 to

33) 33)
Mean cell hemoglobin concentration (MCHC), g/dL of RBC 34 (33 to 34 (33 to

36) 36)
Red cell distribution width (RDW), CV, percent 13 (12 to 13 (12 to

15) 15)
Values represent the mean and reference intervals (normal range, based on nonparametric 95%
confidence interval) for each sex. Reference ranges may vary slightly in different laboratories.
There are no sex differences in absolute reticulocyte count, MCV, MCH, MCHC, or RDW. Values for
children are presented separately in UpToDate. Refer to UpToDate topics on anemia for further
details.
RBC: red blood cell; CV: coefficient of variation method.
Adapted with permission from: Williams' Hematology, 7th ed, Lichtman MA, Beutler E, Kipps TJ, et al. (Eds),
McGraw-Hill, New York 2006, p. 12. Copyright © 2006 McGraw-Hill Education. McGraw-Hill Education makes
no representations or warranties as to the accuracy of any information contained in the McGraw-Hill
Education Material, including any warranties of merchantability or fitness for a particular purpose. In no
event shall McGraw-Hill Education have any liability to any party for special, incidental, tort, or
consequential damages arising out of or in connection with the McGraw-Hill Education Material, even if
McGraw-Hill Education has been advised of the possibility of such damages.

NCI CTCAE v5.0 hematologic toxicity
Blood
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
element
Neutrophils <LLN to 1000 to 500 to <500/microL

1500/microL 1500/microL 1000/microL
Platelets <LLN to 50,000 to 25,000 to <25,000/microL

75,000/microL 75,000/microL 50,000/microL
Hemoglobin <LLN to 10 8.0 to 10.0 <8.0 g/dL Life-threatening Death

g/dL g/dL consequences;
urgent
intervention
indicated
Lymphocytes <LLN to 500 to 200 to <200/microL

(total) 800/microL 800/microL 500/microL
CD4 count <LLN to 200 to 50 to <50/microL

500/microL 500/microL 200/microL
Febrile ANC Life-threatening Death

neutropenia <1000/microL consequences;
with a single urgent
temperature intervention
>38.3°C indicated
(100.4°F) or a
sustained
temperature
≥38°C
(100°F) for
more than one
hour
Neutropenia, thrombocytopenia, anemia, and lymphocytopenia are determined from the complete
blood count. All patients with fever in the setting of chemotherapy-induced neutropenia require
immediate medical attention regardless of the toxicity grade. Refer to UpToDate topics on febrile
neutropenia regarding the management of these patients.
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; LLN: lower limit of
normal; ANC: absolute neutrophil count. Cells/microL is equivalent to cells/mm 3 or cells x 10 9/L.
Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017,
National Institutes of Health, National Cancer Institute. Available at:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5
x11.pdf (Accessed March 27, 2018).

Proposed lower limits of normal for hemoglobin concentration in 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 for the populations in question. 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.

Serum erythropoietin levels in anemia
This graph indicates the exponential relationship between serum

erythropoietin levels (EPO, milliUnits/mL, logarithmic scale) and venous
hematocrit (percent, linear scale) in normal and anemic subjects without
renal or chronic diseases. EPO was assayed by either bioassay or
radioimmunoassay.
Data from: Erslev AJ, Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic
patients. J Lab Clin Med 1987; 109:429.

Prolongation of reticulocyte maturation time in 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: Normal erythropoiesis. In: Hematology in Clinical Practice, Hillman

RS, Ault KA (Eds), McGraw-Hill, New York. p.29.

Reticulocytes after supravital staining
Supravital stain of a peripheral blood smear shows blue-stained residual

reticulin (ribosomal RNA) in reticulocytes.
Courtesy of Stanley L Schrier, MD.

Polychromatophilia due to increased reticulocytes
Peripheral blood smear taken from a patient with increased reticulocytes.

Unlike mature red cells (arrows), which have central pallor and are the same
size as the nucleus of a small lymphocyte (arrowhead), reticulocytes (dashed
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

(arrowheads) and a normal lymphocyte (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 (dashed arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).

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%), resulting in a 40% rise in blood volume and a dilutional fall in the hematocrit.

Common causes of intravascular and extravascular hemolysis in adults
Extravascular destruction of red blood cells

Intrinsic red blood cell defects
Enzyme deficiencies (eg, deficiencies of G6PD, pyruvate kinase, glucose-phosphate isomerase, 5'
nucleotidase)
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, copper, snake and spider bites)
Large granular lymphocyte leukemia
Autoimmune hemolytic anemia (warm- or cold-reacting, drugs)
Intravenous immune globulin infusion
Intravascular destruction of red blood cells

Microangiopathic hemolytic anemia (eg, TTP, HUS, aortic stenosis, prosthetic valve leak)
Transfusion reactions (eg, ABO incompatibility)
Infection (eg, clostridial sepsis, severe malaria)
Paroxysmal cold hemoglobinuria; cold agglutinin disease (on occasion)
Paroxysmal nocturnal hemoglobinuria
Following intravenous infusion of Rho(D) immune globulin
Following intravenous infusion with hypotonic solutions
Snake bites
Exposure to compounds with high oxidant potential (eg, copper poisoning, Wilson disease)
G6PD: glucose-6-phosphate dehydrogenase; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic

uremic syndrome.

Livedo reticularis in cold agglutinin disease
This photograph demonstrates a severe degree of livedo reticularis in a patient

with cold agglutinin disease following exposure to cold. The patient's skin
changes disappear completely without residua within several minutes following
warming.
Photo courtesy of Dr. Jason Gotlib, Stanford University School of Medicine.

Retroperitoneal psoas hematoma
Coronal magnetic resonance imaging short inversion time inversion recovery

(MRI STIR) image of a left retroperitoneal psoas hematoma.
Planner AC, Donaghy M, Moore NR. Causes of lumbrosacral plexopathy. Clin Radiol
2006; 61:987. Illustration used with the permission of Elsevier Inc. All rights
reserved.

Differential diagnosis of anemia in the adult
Low mean corpuscular volume (microcytic anemia: MCV <80 fL)

Iron deficiency anemia
Thalassemic disorders
Anemia of inflammation/anemia of chronic disease (late; uncommon)
Sideroblastic anemia (eg, congenital, lead, alcohol, drugs; uncommon)
Copper deficiency, zinc poisoning (rare)
Hemolysis*
Normal mean corpuscular volume (normocytic anemia: MCV 80 to 100 fL)

Acute blood loss
Iron deficiency anemia (early)
Anemia of inflammation/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 (most commonly normocytic)
Hypopituitarism
Hemolysis*
Increased mean corpuscular volume (macrocytic anemia: MCV >100 fL)

Excessive ethanol use
Folate deficiency
Vitamin B12 deficiency
Myelodysplastic syndromes
Acute myeloid leukemias (eg, erythroleukemia)
Reticulocytosis
Response to hemolysis*
Response to blood loss
Response to appropriate hematinic (eg, iron, vitamin B12, folic acid)
Drug-induced anemia (eg, hydroxyurea, AZT, chemotherapeutic agents)
Liver disease
Hypothyroidism (less commonly macrocytic)
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 folate deficiencies),
resulting in a misleadingly normal mean corpuscular volume. Refer to UpToDate for the approach to
anemia as well as topics on specific disorders for more details.
MCV: mean corpuscular volume; fL: femtoliters; AZT: zidovudine.
* Hemolysis is typically associated with some degree of macrocytosis because reticulocytes, which are larger
than mature red blood cells, are increased in hemolysis. However, the MCV can be low, normal, or high
depending on the degree of reticulocytosis and the underlying cause of hemolysis, which determines the
MCV of the remaining cells.

Causes and mechanisms of macrocytosis
Abnormalities of DNA metabolism

Vitamin B12 (cobalamin) deficiency
Folate deficiency
Drugs
Antiretroviral therapies for HIV infection (eg, zidovudine)
Azathioprine or 6-mercaptopurine
Capecitabine
Cladribine
Cytosine arabinoside
Hydroxyurea
Imatinib, sunitinib
Methotrexate
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
Some sideroblastic anemias
Large granular lymphocyte (LGL) leukemia
Lipid abnormalities
Liver disease
Hypothyroidism
Mechanism unknown
Alcohol abuse
Multiple myeloma and other plasma cell disorders

Peripheral blood smear in iron deficiency anemia showing
microcytic, hypochromic red blood cells
The same peripheral blood smear from a patient with iron deficiency
is shown at two different magnifications. Small (microcytic) red blood cells
are shown, many of which have a thin rim of pink hemoglobin
(hypochromia). Occasional "pencil"-shaped cells are also present. A small
lymphocyte is shown for size comparison (arrow). Normal red blood cells are
similar in size to the nucleus of a small lymphocyte (arrow), and central
pallor in normal red blood cells should equal approximately one-third of the
cell diameter.
Kindly supplied by Dr. German Pihan, Department of Pathology, Beth Israel

Deaconess Medical Center, Boston, MA.


Laboratory findings during the development of iron deficiency
Iron Iron Severe iron

deficiency deficiency deficiency
Normal
without with mild with severe
anemia anemia anemia
Hemoglobin Normal range* Normal range* 9 to 12 g/dL (90 6 to 7 g/dL (60

to 120 g/L) to 70 g/L)
Red blood cell size Normal Normal Normal or slight Microcytosis

and appearance hypochromia (decrease in
(slight decrease MCV) and
in MCHC) hypochromia
(decrease in
MCHC)
Serum ferritin 40 to 200 ng/mL <40 ng/mL ¶ <20 ng/mL <10 ng/mL
(40 to 200 mcg/L; (<40 mcg/L; (<20 mcg/L; (<10 mcg/L;
89.9 to 449 <89.9 picoM/L) <45 picoM/L) <22.5 picoM/L)
picoM/L)
Serum iron 60 to 150 mcg/dL 60 to 150 mcg/dL <60 mcg/dL <40 mcg/dL
(10.7 to 26.7 (10.7 to 26.7 (<10.7 (<7.1 microM/L
microM/L) microM/L) microM/L)
Total iron-binding 300 to 360 300 to 390 350 to 400 >410 mcg/dL
capacity (TIBC; mcg/dL (53.7 to mcg/dL (53.7 to mcg/dL (62.6 to (>73.4
transferrin) 64.4 microM/L) 69.8 microM/L) 71.6 microM/L) microM/L)
Transferrin 20 to 50% 20% <15% <10%

saturation (serum
iron/TIBC)
Bone marrow iron Adequate iron Iron absent Iron absent Iron absent
stain present
Erythrocyte zinc 30 to 70 30 to 70 >100 100 to 200

protoporphyrin,
ng/mL RBC
Bold type illustrates the progression of changes and the tests most likely to define the various
stages of iron deficiency. Decreased serum ferritin and absent bone marrow iron are the earliest
changes, followed by decreases in the transferrin saturation. Serum iron may be low in anemia of
chronic disease or increased by a recent meal or normal diurnal variation and by itself cannot be
used to diagnose iron deficiency. Serum ferritin may be increased by other conditions such as acute
inflammation, liver disease, and idiopathic pulmonary hemosiderosis, making diagnosis of iron
deficiency more challenging. Testing iron studies using a fasting sample may be helpful if there is
concern that oral iron intake has affected the serum iron level, which in turn may affect the TSAT.
Bone marrow iron staining (the gold standard) and erythrocyte zinc protoporphyrin (a nonspecific
finding) are not routinely used in the evaluation or diagnosis of iron deficiency. Refer to UpToDate
for our approach to diagnostic testing.
MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; TIBC: total iron
binding capacity; RBC: red blood cell; TSAT: transferrin saturation.
* The normal range for hemoglobin varies by age and sex (adult men, 14 to 17.5 g/dL; adult women, 12.3
to 15.3 g/dL; children, refer to UpToDate topic on anemia in children).
¶ The exact value is not well established; some clinicians may use a lower value for diagnosing iron
deficiency.

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


Basophilic stippling of red cells in lead poisoning
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.


Hypersegmented neutrophil in megaloblastic anemia
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 fewer.
Courtesy of Stephen A. Landaw, MD, PhD.

Megaloblastic blood picture
Peripheral blood smear showing a hypersegmented neutrophil (seven lobes)

and macro-ovalocytes, a pattern that can be seen with cobalamin or folate
deficiency.
Courtesy of Stanley L Schrier, MD.


Leukoerythroblastic peripheral blood 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,
primary myelofibrosis) or reactive to conditions such as metastatic cancer.


Peripheral smear in microangiopathic hemolytic anemia
showing presence of schistocytes
Peripheral blood smear from a patient with a microangiopathic hemolytic

anemia with marked red cell fragmentation. The smear shows multiple
helmet cells (arrows) and other fragmented red cells (small arrowhead);
microspherocytes are also seen (large arrowheads). The platelet number is
reduced; the large platelet in the center (dashed arrow) suggests that the
thrombocytopenia is due to enhanced destruction.


Teardrop-shaped red blood cells (dacrocytes)
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.


Bite and blister cells
Examples of a bite cell (thick arrow) and blister cells (arrows) in a patient with G6PD deficiency.
Courtesy of Bertil Glader, MD, PhD, and Bessie Visco, CLS, MLS (ASCP).

Malaria: Red cell containing intraerythrocytic ring forms
(trophozoites)
Peripheral smear from a patient with malaria shows intraerythrocytic ring

forms (trophozoites) (arrows).


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HOW TO USE THIS TOPIC REVIEW

This topic review is presented in two semi-independent parts:

Anemia — Anemia can be rigorously defined as a reduced absolute number of

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

● African-Americans – Values for hemoglobin in African-Americans of both sexes and

● Presence of chronic disease – Normal values for a population with a high

● MCH – Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a

● MCHC – Mean corpuscular hemoglobin concentration (MCHC) is the average

THE RED BLOOD CELL LIFE CYCLE

Reticulocytes — Reticulocytes can be enumerated manually after supravital staining of

The utility of reticulocyte counting in some settings can be improved by determination of

● Volume depletion – Anemic patients admitted to the hospital in a volume depleted

● Hypovolemia – Anemia induced by acute bleeding is associated with the added

Mortality — The development of anemia is a risk factor for increased mortality in a

● Malignancy (see "Role of erythropoiesis-stimulating agents in the treatment of

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

● A morphologic approach categorizing anemias via alterations in red blood cell

● A patient admitted to the hospital for acute alcoholism and gastrointestinal

● Bone marrow suppression (eg, drugs, chemotherapy, irradiation) (see "Hematologic

● Low levels of trophic hormones, which stimulate RBC production, such as

● The anemia of inflammation, associated with infectious, inflammatory, or malignant

Presence of ineffective erythropoiesis — The hallmark of ineffective

● Alpha and beta thalassemia (see "Pathophysiology of beta thalassemia", section on

● The myelodysplastic syndromes (see "Clinical manifestations and diagnosis of the

● Sideroblastic anemias (see "Causes and pathophysiology of the sideroblastic

● Congenital dyserythropoietic anemia in children (see "Anemia in children due to

Examples include (table 4):

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

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

● Increased destruction of normal red cells by an enlarged spleen (ie, hypersplenism).

Intravascular hemolysis — In most cases, hemolysis takes place in extravascular

● Microangiopathic hemolytic anemia

Clinical observations suggesting the presence of intravascular hemolysis include the

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

● Factitious bleeding, secondary to surreptitious blood drawing by the patient

● Bleeding during or after surgical procedures may be extremely difficult to quantitate,

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

● Induced bleeding (eg, repeated diagnostic testing [38,39], hemodialysis losses,

● Underappreciated menstrual blood loss (see "Approach to abnormal uterine bleeding

Morphologic approach — The causes of anemia can also be classified according to

Macrocytic anemia — Anemia is considered "macrocytic" when the MCV exceeds

● An increased MCV is a normal characteristic of reticulocytes (picture 4). Any

● Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, large

● Reduced iron availability – Severe iron deficiency, the anemia of inflammation,

The diagnosis of beta thalassemia trait can often be made by demonstrating

Anemia of chronic renal disease — Anemia is a common complication of renal

Cardiorenal anemia syndrome — Cardiorenal anemia syndrome refers to the

Cancer-associated anemia — Anemia in patients with malignancy is often

Acquired anemia in hospitalized patients — The development of anemia in a

● In one population study, among 188,447 hospitalizations, 74 percent developed

● In a separate study in patients with myocardial infarction, the risk of development of

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

The use of medications, both prescribed and over-the-counter, should be examined in

Jaundice — Jaundice may be difficult to detect under artificial (nonfluorescent)

● It is also important to look for signs of other hematologic abnormalities, including

Accordingly, the blood smear should always be reviewed by an experienced examiner

● Anemia with a high reticulocyte count reflects an increased erythropoietic response

● An increased absolute neutrophil count in infection

Neutrophil hypersegmentation — Neutrophil hypersegmentation (NH) is defined as

High platelet counts, in comparison, may reflect the presence of a myeloproliferative

Pancytopenia — The combination of anemia, thrombocytopenia, and neutropenia is