C HAPTER 34 
APPROACH TO ANEMIA IN THE ADULT AND CHILD
Judith C. Lin
Anemia is the clinical state of low red cell mass and one of the most
commonly encountered laboratory findings and clinical disorders in
hematology. Anemias encompass a broad range of clinical disorders
and diseases with a spectrum of subtle to severe clinical impact on
health. The approach to anemias can be direct if the cause is a
common, singular or monogenic, easily tested and identified one; but
in challenging cases, the approach may require a careful, systematic
investigation and deduction due to the diverse span of possible pathol-
ogy and pathogenesis to the red blood cell components, erythropoiesis,
and apoptosis. The examination of the patient’s blood cell morphology
by peripheral smear supports the analysis of anemia and is an integral
skill for anemia diagnosis. Epidemiologic studies on the global burden
of anemias show that in recent decades iron deficiency accounts for
the majority of anemias, with predominance in females and the very
young (under 5 years of age) having risen and the anemias of hemo-
globinopathies, nutritional deficiency, parasitic infections, and chronic
kidney disease significantly impacting quality of life.1 When analyzing
anemia in individuals the approach should be systematic and is often
initially categorical, e.g., by relative rates of red cell production,
turnover or by characteristic indices and morphologies of red blood
cells (RBCs). Additionally, the evaluation of anemia in the adult and
child differ primarily in the changing normal ranges for red cells and
hemoglobin during childhood as well as the prevalence and onset of
congenital hematopoietic diseases and the risks and causes of acquired
anemias at different ages in the adult. As population demographics
continuously change over time, the evaluation of anemia may also
require consideration of the frequent causes of endemic origins.2
The evaluation of anemia includes the initial systematic review of
laboratory data obtained from the complete blood count (CBC),
reticulocyte count, and peripheral blood smear and consideration of
the process of RBC production, erythropoiesis.
OVERVIEW OF ERTHROPOIESIS
Erythropoiesis is the regulated process leading to the production of
mature RBCs or erythrocytes. Bone marrow (BM) stem cells stimu-
lated by the hormone erythropoietin and other factors, proliferate
and differentiate along a pathway of recognizable erythroid precursors
that ultimately leads to extrusion of the nucleus to facilitate efficient
RBC rheology after the production and accumulation of a high
concentration of hemoglobin and RBC enzymes (Fig. 34.1).1 The
early maturing RBCs lose their residual RNA under normal condi-
tions by degradation within a day. Special staining for RNA identifies
these cells, termed reticulocytes that are useful for both qualitative and
quantitative measure of the relative rate of peripheral blood erythro-
poiesis. Mature RBCs survive in blood circulation 100 to 120 days
before being removed from the circulation by macrophages in the
spleen and other cells of the reticuloendothelial system.2 At steady
state under physiologic conditions, the production and destruction
of erythrocytes is equivalent. This process is driven in large part by
the hormone erythropoietin, which is produced in a regulated fashion
by periglomerular cells in the kidney (~90%) and constitutively by
the liver (~10%).3 Because preservation of oxygen delivery to tissues
is so important, the oxygen-sensing regulatory proteins located in the
kidney respond to decreased oxygen tension from any cause such as
blood loss, high altitude, or cardiac shunts with the production of
erythropoietin (Fig. 34.2). This hormone then travels through the
458
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bloodstream and stimulates RBC production in the BM. Provided
that there are adequate nutrients, including folate, vitamin B12, and
iron, the precursors in the BM proliferate and mature and are released
into the circulation, ultimately expanding the pool of erythrocytes.4
The increase in oxygen delivery to the kidney then reduces the stimu-
lus for erythropoietin production.
DEFINITION OF ANEMIA
Anemia is defined as a reduction in the RBC mass. Because of a
variety of factors, the RBC mass normally changes during the lifespan
of an individual and may be different in males and females.5 Under-
standing the changes that occur is critical to appropriately identifying
what constitutes anemia (Table 34.1). The relatively elevated level of
hemoglobin present at birth declines over the first 1 to 2 months of
life to levels that are lower than those seen in adulthood. In later
childhood, the hemoglobin values are similar and increase modestly
over time. Around puberty, girls have reached adult levels of hemo-
globin, and androgenic steroids lead to a continued increase in
hemoglobin in boys through about age 18 years. This approximately
1.5 g/dL difference between males and females persists through much
of adult life until about age 70 years, when the hemoglobin value in
men begins to decline. Over the next two decades, the hemoglobin
value declines by about 1 g/dL in men while decreasing by only
approximately 0.2 g/dL in women.6 Thus at age 90 years, there is
only a modest difference between the mean hemoglobin values
observed in men and women (14.1 vs. 13.8 g/dL).
MECHANISMS OF ANEMIA
Although a complete review of all of the mechanisms leading to
anemia is beyond the scope of this chapter, an appreciation of some
of the mechanisms is useful before approaching the diagnosis of
anemia in adults and children. Three broad categories of anemia are
blood loss anemia, hypoproliferative anemia, and hemolytic anemia.
Blood loss may occur acutely or chronically. When blood is lost
acutely through hemorrhage, it may take several hours before a
decline in hemoglobin concentration is observed because of the time
required for restoration of the plasma volume and equilibration.
Several days may elapse before an appropriate reticulocytosis is noted.
Chronic blood loss ultimately leads to hypoproliferative anemia
because of iron deficiency.
Hypoproliferative Anemia
When used broadly, the term hypoproliferative anemia refers to entities
that manifest as an inability to produce an adequate number of
erythrocytes in response to appropriate signals. Although there are
many different causes, the hallmark of hypoproliferative anemia is a
low reticulocyte count (Table 34.2). The etiology underlying this class
of disorders may relate to the hypoproliferation of precursors within
the BM, such as may be seen when there is BM replacement (myelo-
phthisis), or to abnormal maturation of precursors in the BM, such
as that which occurs in megaloblastic anemia (folate deficiency,
vitamin B12 deficiency, myelodysplastic syndromes [MDS], and
 Chapter 34  Approach to Anemia in the Adult and Child 459

Proerythroblast Basophilic Polychromatophilic Orthochromatic Reticulocyte

erythroblast erythroblast erythroblast

Fig. 34.1  OVERVIEW OF ERYTHROPOIESIS.

Increased erythropoietin

Hypoxia

Kidney Bone marrow

Iron
Folate
Vitamin B12

Increased red blood cell production

Fig. 34.2  REGULATION OF ERYTHROPOIESIS.

others). In the latter case of megaloblastic anemia, the BM often is
packed. However, intramedullary demise of precursors prevents the
formation and release of mature RBCs.
By far the most common cause of hypoproliferative anemia glob-
ally is iron deficiency.7 It is estimated that about 2% of infants and
children may become iron deficient purely because of inadequate
dietary intake, and that 4% of women ages 20 to 49 years of age in
the United States have iron-deficiency anemia primarily because of
inadequate dietary intake in the setting of menstruation and childbirth.
Iron deficiency is also commonly encountered in older individuals
as well (~2% of individuals older than age 50 years), and it should
provoke a thorough search for its etiology, which in both men and
nonmenstruating women frequently is gastrointestinal blood loss. After
iron deficiency, acute or chronic inflammation and renal disease are
common etiologies of anemia.8,9 BM failure states and BM replacement
caused by hematologic malignancies or solid tumors are less common
causes of anemia and are often accompanied by other hematologic
manifestations, such as leukopenia and thrombocytopenia.
Hemolytic Anemia
The causes of hemolytic anemia are quite varied and may be con-
genital or acquired.10 The hallmark of hemolytic anemia is an elevated
reticulocyte count (see Table 34.2). Other features commonly associ-
ated with hemolytic anemia include an elevated lactate dehydrogenase
(LDH) level, increased unconjugated (indirect) bilirubin level, and
decreased haptoglobin level. Hemolytic anemia also may manifest
with distinctive changes on the peripheral blood smear. Congenital
causes include the hemoglobinopathies, enzymopathies (predomi-
nantly glucose-6-phosphate dehydrogenase [G6PD] deficiency), and
membrane disorders.11 Acquired conditions include autoimmune
hemolytic anemia, microangiopathic hemolytic anemia, hemolysis
related to infections, and acquired membrane disorders such as those
caused by liver disease (spur cell of anemia) and paroxysmal nocturnal
hemoglobinuria.12
COMPARISON OF ETIOLOGIES OF ANEMIA IN ADULTS
AND CHILDREN
As already noted, the designation that anemia is present relies on
comparison of the patient’s hemoglobin or hematocrit with an age-
and sex-appropriate normal range (see Table 34.1). Although many
types of anemia may occur across the age spectrum, certain types tend
to be identified more commonly in either adults or children, and
some are primarily identified in neonates. In children, the most
common causes of anemia are related to nutritional deficiency or to

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 460 Part V  Red Blood Cells

TABLE
Normal Red Blood Cell Values
34.1
Red Blood Cell
Hemoglobin (g/dL) Hematocrit (%) Count (1012/L) MCV (fL) MCH (pg) MCHC (g/dL)
Age Mean –2SD Mean –2SD Mean –2SD Mean –2SD Mean –2SD Mean –2SD
Birth (cord blood) 16.5 13.5 51 42 4.7 3.9 108 98 34 31 33 30
1–3 days (capillary) 18.5 14.5 56 45 5.2 4.0 108 95 34 31 33 29
1 week 17.5 13.5 54 42 3.1 3.9 107 88 34 28 33 28
2 weeks 16.5 12.5 51 39 4.9 3.6 105 86 34 28 33 28
1 month 14.0 10.0 43 31 4.2 3.0 104 85 34 28 33 29
2 months 11.5 9.0 35 28 3.8 2.7 96 77 30 26 33 29
3–6 months 11.5 9.5 35 29 3.8 3.1 91 74 30 25 33 30
0.5–2 years 12.0 11.0 36 33 4.5 3.7 78 70 27 23 33 30
2–6 years 12.5 11.5 37 34 4.6 3.9 81 75 27 24 34 31
6–12 years 13.5 11.5 40 35 4.6 4.0 86 77 29 25 34 31
12–18 Years
Female 14.0 12.0 41 36 4.6 4.1 90 78 30 25 34 31
Male 18–49 years 14.5 13.0 43 37 4.9 4.5 88 78 30 25 34 31
Female 14.0 12.0 41 36 4.6 4.0 90 80 30 26 34 31
Male 15.5 13.5 47 41 5.2 4.5 90 80 30 26 34 31
MCH, Mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume.
From Oski FA: Pallor. In Kaye R, Oski FA, Barness LA, editors: Core textbook of pediatrics, ed 3, Philadelphia, 1989, Lippincott, p 62.

TABLE Usefulness of the Reticulocyte Count in the Diagnosis a primary hematologic process, either hereditary or acquired. In
34.2 of Anemiaa contrast, the most common causes of anemia in adults are iron
deficiency caused by blood loss or anemia caused by systemic illness
Diagnosis Value or malignancy (Table 34.3).
Hypoproliferative Anemias Absolute Reticulocyte Count
<75,000/µL
Anemia of chronic disease
Anemia in Children
Anemia of renal disease Hypoproliferative anemia in children may be associated with either
Congenital dyserythropoietic anemias acquired or congenital etiologies. Acquired cases are most commonly
Effects of drugs or toxins
caused by nutritional deficiency but also include those caused by
acquired aplastic anemia, transient erythroblastopenia of childhood
Endocrine anemias (TEC), the anemia of acute inflammation, and marrow replacement
Iron deficiency caused by malignancy.13 Congenital causes include Diamond-Blackfan
Bone marrow replacement anemia and other rare syndromes, including refractory sideroblastic
anemia and the congenital dyserythropoietic anemias.14 Iron defi-
Maturation abnormalities Absolute reticulocyte count ciency may occur in children because of a diet that is rich in cow’s
<75,000/µL milk to the exclusion of other iron-containing foods. This is particu-
Vitamin B12 deficiency larly common during the first 2 years of life. The anemia may be
Folate deficiency quite severe and may be associated with a mean corpuscular volume
(MCV) of 50 to 65 fL. Acquired aplastic anemia, as opposed to pure
Sideroblastic anemia
RBC aplasia, is associated with bicytopenia or pancytopenia. TEC is
Appropriate response to blood loss or Absolute reticulocyte count an acquired disorder that generally occurs during the first 3 years of
nutritional supplementation ≥100,000/µL life in otherwise healthy children, although it can be seen in children
Hemolytic anemias Absolute reticulocyte count from 6 months to 10 years old. It is thought to have a viral or
≥100,000/µL immunologic cause and resolves without specific intervention. The
anemia of acute inflammation may be encountered in children who
Hemoglobinopathies
are hospitalized and is generally transient, resolving when the under-
Immune hemolytic anemias lying condition has improved. Leukemia may result in BM replace-
Infectious causes of hemolysis ment and is usually associated with abnormalities in other cell lineages
Membrane abnormalities
in addition to RBCs.
Hemolytic anemia in children is most commonly associated with
Metabolic abnormalities inherited disorders of hemoglobin or the RBC membrane.15 However,
Mechanical hemolysis acquired causes such as autoimmune hemolytic anemia and micro-
a
Note that reticulocyte counts in the range of 75,000 to 100,000/µL can angiopathic hemolytic anemia, particularly Shiga toxin–associated
sometimes be associated with appropriate response to blood loss or hemolytic hemolytic uremic syndrome (HUS), also occur.16 In older children,
anemia. many etiologies of hemolytic anemia overlap with those considered
in adults, and a similar diagnostic algorithm may be appropriate.
However, in newborns, inherited causes of hemolytic anemia must
be distinguished from more pronounced cases of the physiologic

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 Chapter 34  Approach to Anemia in the Adult and Child 461

TABLE
Comparison of the More Common Causes of Anemia in Children and Adult
34.3
Type of Anemia Children Adults
Hypoproliferative • Nutritional deficiency (most commonly iron deficiency) • Iron deficiency
• Acute inflammation • Anemia of inflammation (anemia of chronic disease)
• Transient erythroblastopenia of childhood • Anemia of renal disease
• Acquired aplastic anemia • Folate or vitamin B12 deficiency
• Marrow replacement caused by malignancy • Drugs or toxins
• Pure RBC aplasia (viral or idiopathic)
• MDS
Hemolytic • Inherited hemoglobinopathies • Inherited hemoglobinopathies with milder manifestations
• Inherited membrane disorders • Inherited membrane disorders with milder manifestations
• Autoimmune hemolytic anemia • G6PD deficiency
• Microangiopathic hemolytic anemia • Autoimmune hemolytic anemia
• Microangiopathic hemolytic anemia (DIC, TTP, HUS, aHUS)
aHUS, Atypical hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HUS, hemolytic uremic syndrome;
MDS, myelodysplastic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

For a newborn review:

1. Complete blood cell count
2. Reticulocyte count
3. Peripheral blood smear

Reticulocyte count Reticulocyte count

Corrected reticulocyte count <2% or absolute Corrected reticulocyte count >2% or absolute
reticulocyte count <100,000/uL reticulocyte count ≥100,000/uL

Congenital hypoplastic anemia Direct antiglobulin test

Transcobalamin II deficiency
Negative Positive
Immune hemolytic anemia
ABO
MCV Rh
Minor blood group

Low Normal or elevated

Chronic intrauterine blood loss
α-Thalassemia syndrome Review of peripheral blood smear

Normal Abnormal
Blood loss Membrane disorders
Iatrogenic (blood sampling) Hereditary spherocytosis
Fetomaternal/fetoplacental Hereditary elliptocytosis
Twin-to-twin Hereditary stomatocytosis
Internal hemorrhage Metabolic disorders
Galactosemia G6PD deficiency
Infection Pyruvate kinase deficiency
Bacterial Infection
Viral Disseminated intravascular
Toxoplasmosis coagulation
Congenital syphilis
Rare causes
Hexokinase deficiency
Fig. 34.3  APPROACH TO THE DIFFERENTIAL DIAGNOSIS OF ANEMIA IN A NEWBORN. G6PD,
Glucose-6-phosphate dehydrogenase; MCV, mean corpuscular volume.

hyperbilirubinemia that occurs. After true hemolysis has been identi-
fied in an infant, the differential diagnosis is relatively limited
(Fig. 34.3). Immune-mediated hemolysis may result from ABO, Rh,
or minor blood group incompatibility.17 Other causes include meta-
bolic disorders and disorders of the RBC membrane. Of note,
however, is the fact that hemoglobinopathies, such as sickle cell
disease and β-thalassemia, are silent during the newborn period and
only become manifest at 4 to 6 months of age when the fetal-to-adult
hemoglobin transition has been completed. Newborn screening
programs in the United States may provide salient information in
this regard on the presence or absence of a hemoglobinopathy.
Alternatively, ethnic background and family history may be helpful
in arriving at the appropriate diagnosis.
Anemia in Adults
Hypoproliferative anemia in adults is relatively common. If acute
blood loss is excluded, hypoproliferative causes are the most common
entities associated with anemia in adults. These are iron deficiency,
inflammation (anemia of chronic disease), and renal disease
(Fig. 34.4). The megaloblastic anemias that represent maturation

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 462 Part V  Red Blood Cells

For a child or adult review:

1. Complete blood cell count
2. Reticulocyte count
3. Peripheral blood smear

Reticulocyte count Reticulocyte count

Corrected reticulocyte count <2% or absolute Corrected reticulocyte count >2% or absolute
reticulocyte count <100,000/uL reticulocyte count ≥100,000/uL

Hypoproliferative anemia Response to blood loss or

hemolytic anemia
Categorize based on MCV and RDW

Low MCV, = Anemia of chronic disease Review peripheral blood smear

Normal RDW
Normal MCV, = Anemia of chronic disease
Normal RDW Send specific diagnostic tests as
appropriate
High MCV, = Chemotherapy/antivirals/alcohol
Normal RDW Aplastic anemia Differential diagnoses/
Low MCV, = Iron deficiency anemia tests to obtain:
High RDW
Hemoglobinopathies/
Normal MCV, = Early iron, folate, or vitamin B12 deficiency
hemoglobin electrophoresis
High RDW Myelodysplasia
Immune hemolytic anemias/
Dimorphic anemia
direct antiglobulin test
High MCV, = Folate or vitamin B12 deficiency Infectious causes of hemolysis/
High RDW Myelodysplasia thick smear, serology
Membrane abnormalities/
osmotic fragility; PNH screen
Review peripheral blood smear
Metabolic abnormalities/
Heinz body prep; G6PD assay
Send specific diagnostic tests as appropriate (iron Mechanical hemolysis/coagulation
studies, folate and B12 levels, erythropoietin level) tests

Proceed to bone marrow examination if diagnosis

remains unclear
Fig. 34.4  APPROACH TO THE DIFFERENTIAL DIAGNOSES OF ANEMIA IN ADULTS AND
CHILDREN. G6PD, Glucose-6-phosphate dehydrogenase; MCV, mean corpuscular volume; PNH, paroxys-
mal nocturnal hemoglobinuria; RDW, red blood cell distribution width.

abnormalities, including folate and vitamin B12 deficiency, are often
categorized along with the hypoproliferative anemias because they
present with a low reticulocyte count as well. Drugs and toxins such
as ethanol can also be associated with hypoproliferative anemia. Pure
RBC aplasia may be associated with other diseases (thymoma) or
viral infection (parvovirus B19) or be idiopathic.18 Finally, MDS may
present with hypoproliferative anemia, as may an infiltrative process
such as myelofibrosis or acute leukemia. The distinction between the
various causes of anemia is facilitated by historical factors, physical
findings, and concomitant laboratory abnormalities in conjunction
with review of the MCV and RBC distribution width (RDW) along
with the peripheral blood smear. In the setting of a low reticulocyte
count, MCV values below 70 fL are most commonly associated with
iron-deficiency anemia, and those above 120 fL are most commonly
associated with folate or vitamin B12 deficiency. The differential
diagnosis broadens for MCV values that fall just outside of the
normal range. For example, in the setting of a low reticulocyte count,
MCV values in the range from 75 to 80 fL may be associated with
iron-deficiency anemia, the anemia of inflammation, and endocrine
causes of anemia. MCV values between 100 and 110 fL may be
associated with folate or vitamin B12 deficiency, aplastic anemia,
MDS, liver disease, and immune hemolytic anemias.
Hemolytic anemia in adults is less common than hypoproliferative
anemia, and the differential diagnosis is broad. Congenital causes
associated with mild to moderate hemolysis may be clinically silent
until detected later in life.19 This is particularly the case for milder
cases of β-thalassemia intermedia, sickle cell (SC) disease and sickle-
β+-thalassemia, and hereditary spherocytosis. Additionally, the most
common RBC enzymopathy (which is also the one of the most
common human enzyme defect deficiencies), G6PD deficiency,
does not present until individuals encounter oxidant stress either
because of infection or drugs such as sulfonamides and antima-
larials.20 Acquired hemolytic anemias include autoimmune hemolytic
anemia, which is often associated with hematologic malignancies
or rheumatologic disorders, and the microangiopathic hemolytic
anemias, including disseminated intravascular coagulation (DIC),
thrombotic thrombocytopenic purpura (TTP), and HUS.21 Distinc-
tion of the various causes of hemolytic anemia is also facilitated by
the associated historical features, physical findings, and laboratory
abnormalities of the clinical presentation. For these disorders, review
of the peripheral blood smear may be particularly revealing as to the
etiology.
SYSTEMIC APPROACH TO ANEMIA
The correct diagnosis of anemia can often be determined by combin-
ing a thorough history and physical examination with review of the
CBC, concentrating particularly on the MCV and RDW, along with
review of the reticulocyte count and the peripheral blood smear.
History and Physical Examination
Anemia can be a primary disorder or secondary to other systemic
processes, thus a careful history and physical examination provide

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valuable insight into the potential cause. Fatigue often accompanies
anemia, but it is very nonspecific and may be related to systemic
illness. Nonetheless, determining the concomitant presence of a
systemic inflammatory disorder, infection, or malignancy that may
be associated with fatigue can be critical in determining the underly-
ing causes of anemia in both adults and children. The medical history
may also be quite informative. For example, a history of diabetes
mellitus can be associated with significantly impaired renal produc-
tion of erythropoietin even in the setting of only a mildly elevated
creatinine level. Because certain medications may be associated with
BM depression or, alternatively, the development of autoimmune
hemolytic anemia, all pharmacologic agents, prescribed and over the
counter, including alternative medicines, should be reviewed. Occu-
pational history is occasionally relevant, as in the case of individuals,
such as welders, who might have been exposed to lead or other
potentially BM toxic agents. Social history can be important. A
history of intravenous drug use might suggest the possibility of virally
transmitted diseases, such as HIV, which may be associated with
anemia. Dietary history is also very important, particularly in young
and elderly individuals with anemia. The finding of pica in adults
(most commonly ice chips or cornstarch) is well known to be associ-
ated with iron-deficiency anemia.22 Ingestion of paint chips may
suggest the need to investigate the possibility of toxic lead ingestion.
A family history of anemia is highly relevant in the evaluation of
children with anemia. However, it is also relevant in adults because
certain congenital anemias, such as milder forms of sickle β+ thalas-
semia and hereditary spherocytosis, occasionally first become clini-
cally apparent in adulthood.
The significance of pallor on physical examination is in many ways
similar to the historic feature of fatigue: it is a common but nonspe-
cific finding. More specific findings may be found in certain types of
anemia. For example, angular cheilitis (cracking at the edges of the
lips) and koilonychia (spooning of the nails) may accompany iron-
deficiency anemia. Splenomegaly may be present in patients with
anemia arising from a wide variety of different causes. When present
early in life, it is suggestive of a congenital hemolytic anemia, such
as thalassemia, sickle cell disease, or hereditary spherocytosis. When
found for the first time later in life, splenomegaly may indicate an
acquired disorder, such as autoimmune hemolytic anemia, lympho-
proliferative disease, or a myeloproliferative disease such as myelofi-
brosis. Other physical findings can also sometimes provide insight
relevant to the investigation of anemia when combined with historical
features and laboratory data. Although anemia itself may lead to the
presence of systolic cardiac murmurs, the finding of an increased
cardiac murmur in an anemic patient with a prosthetic aortic valve
and new microangiopathic change on peripheral smear may indicate
that investigation into the possibility of perivalvular leak or prosthetic
dysfunction is in order.23 Finally, because neurologic manifestations
TABLE
Usefulness of the Mean Corpuscular Value and Red Blood Cell Distribution Width in the Diagnosis of Anemia
34.4
Low MCV (<80 fL) Normal MCV (80–99 fL)
Normal RDW Anemia of chronic disease Acute blood loss
α- or β-Thalassemia trait Anemia of chronic disease
Hemoglobin E trait Anemia of renal disease
Elevated RDW Iron deficiency Early iron, folate, or vitamin B12 deficiency
Sickle cell-β–thalassemia Dimorphic anemia (for example, iron +
folate deficiency)
Sickle cell anemia
Sickle cell disease
Chronic liver disease
Myelodysplasia
MCW, Mean corpuscular value; RDW, red blood cell distribution width.
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Chapter 34  Approach to Anemia in the Adult and Child 463
can accompany or even predate the anemia associated with vitamin
B12 deficiency, findings such as loss of vibration or position sense in
the extremities may be relevant.24
Reticulocyte Count
As a marker of RBC production, the reticulocyte count provides
essential information in directing the initial investigation of anemia.
Modern flow cytometers accurately determine the reticulocyte count
using fluorescent probes that bind to the residual ribonucleic acid
present in newly released RBCs.25 These measurements are useful,
accurate, and reflect the state of erythropoiesis. However, when sig-
nificant numbers of nucleated RBCs or nuclear debris are present in
the peripheral blood, this diagnostic accuracy declines, and manual
counting methods are generally preferable.
When the reticulocyte count is reported as a percentage, it needs
to be adjusted for the total number of RBCs present. This correction
can be made by multiplying the reticulocyte count by the patient’s
hematocrit divided by an age- and sex-appropriate normal hematocrit.
No such correction is necessary when the reticulocyte count is
reported as an absolute number or when it is converted to an absolute
number by multiplying the percentage by the RBC number (in
RBC/µL).
In the absence of anemia, the normal absolute reticulocyte count
is between 25,000 and 75,000/µL. In the presence of anemia, an
absolute reticulocyte count of less than 75,000/µL is indicative of a
hypoproliferative process, and an absolute reticulocyte count of
greater than 100,000/µL is indicative of hemolysis or an appropriate
erythropoietic response to blood loss (see Table 34.2). Reticulocyte
counts between 75,000 and 100,000/µL require interpretation in the
context of other available clinical data, including the severity of
anemia present.
Mean Corpuscular Volume and Red Blood Cell
Distribution Width From the Complete Blood Count
Automated cell counters provide a wealth of information regard-
ing the size, shape, and hemoglobin content of RBCs. The two
parameters most useful in classifying anemia are the MCV and the
RDW. MCV is reported in femtoliters (fL) and reflects average cell
size. RDW is often reported in percent and represents the standard
deviation of RBC volume divided by the mean volume. It reflects
the variation in cell size in the population of RBCs.26 These two
parameters are useful because relatively reproducible changes in
the MCV and RDW are associated with certain types of anemia
(Table 34.4). The MCV and RDW can significantly narrow the
High MCV (≥100 fL)
Aplastic anemia
Chronic liver disease
Chemotherapy, antivirals, or alcohol
Folate or vitamin B12 deficiency
Immune hemolytic anemia
Cytotoxic chemotherapy
Chronic liver disease
Myelodysplasia
Hereditary spherocytosis, hereditary elliptocytosis,
congenital hemoglobinopathies and RBC
enzymopathies
 464 Part V  Red Blood Cells

TABLE Combining the Reticulocyte Count and Red Blood Cell Systematic Approach to the Diagnosis of Anemia
34.5 Parameters for Diagnosis
Integration of historic features and physical findings with thoughtful
Reticulocyte Count Reticulocyte Count
review of the results of the automated complete blood cell count
MCV, RDW <100,000/µL ≥100,000/µL
and peripheral smear often significantly narrows down the differential
Low, normal Anemia of chronic diagnosis of anemia. For example, a patient who has had a gastric
disease bypass eating a normal diet who presents with gradual onset of fatigue
accompanied by the more recent onset of distal paresthesias and a
Normal, normal Anemia of chronic finding of decreased vibration sense in the setting of anemia with sig-
disease nificantly elevated mean corpuscular volume and red blood cell (RBC)
High, normal Chemotherapy, antivirals, Chronic liver disease distribution width values and numerous six-lobed polymorphonuclear
or alcohol leukocytes on peripheral blood smear almost certainly has vitamin
Aplastic anemia B12 deficiency. This is suggested even before the return of specific
laboratory testing because of the relatively narrow differential diagnosis
Low, high Iron-deficiency anemia Sickle cell-β–thalassemia for megaloblastic anemia and the fact that neurologic abnormalities are
Normal, high Early iron, folate, vitamin Sickle cell anemia, not associated with folate deficiency. For the purposes of diagnostic
B12 deficiency sickle cell disease
efficiency, the rewards of correlation of historic features and physical
findings with a careful review of the peripheral blood smear cannot
Myelodysplasia
be overstated.
High, high Folate or vitamin B12 Immune hemolytic Special stains of the peripheral blood smear can be helpful in
deficiency anemia elucidating the cause of anemia. If there is significant nuclear debris
Myelodysplasia Chronic liver disease present, the reticulocyte count obtained by automated methods can
be inaccurate. In such cases, manual counting after staining with new
MCV, Mean corpuscular volume; RDW, red blood cell distribution width.
methylene blue, which stains residual RNA in reticulocytes, permits
accurate enumeration. If bite cells are detected on peripheral smear,
supravital staining with methyl crystal violet can reveal Heinz bodies.
These are aggregates of denatured hemoglobin reflecting an oxidative
differential diagnosis, particularly when combined with the reticulo- insult, most commonly caused by glucose-6-phosphate dehydrogenase
cyte count (Table 34.5). deficiency or, less frequently, by the presence of an unstable hemo-
globin (Fig. 34.5H).
Several commonly encountered findings can be seen in RBCs on the
peripheral blood smear (Table 34.6 and Fig. 34.5). Whereas micro-
Examination of the Peripheral Blood Smear cytic, hypochromic RBCs are suggestive of iron-deficiency anemia
or thalassemia (Fig. 34.5F) macrocytic RBCs with ovalocytes (oval
Despite the development and availability of more sophisticated RBCs) are suggestive of megaloblastic anemias (Fig. 34.5G). Some
diagnostic testing, review of a well-made peripheral blood smear findings reflect organ dysfunction, such as echinocytes (burr cells) in
remains one of the most informative and rewarding diagnostic pro- uremia (Fig. 34.5R) or acanthocytes (spur cells) in severe liver disease
cedures.27 It offers the chance to confirm the findings of the automated (Fig. 34.5S), although acanthocytes may also be seen in rare conditions
CBC count, which can be inaccurate in the presence of nucleated such as abetalipoproteinemia. Target cells may be seen in cases of
RBCs or rouleaux formation. Review of the blood smear also allows liver disease but may also be present in hemoglobinopathies, including
sickle cell disease and thalassemia (Fig. 345W). The presence of
for evaluation of other cell lineages, which might suggest a primary schistocytes or RBC fragmentation often reflects systemic disease,
BM or infiltrative disease. For example, the finding of hyperseg- such as DIC, TTP, or HUS (Fig. 345P). Finding spherocytes on a
mented neutrophils suggests a megaloblastic process, and this mor- smear is suggestive of autoimmune hemolytic anemia or hereditary
phologic abnormality can be seen in the blood smear before there are spherocytosis (Fig. 34.5H). Occasionally, the clue to the correct
significant changes in the hemoglobin or MCV (see box on System- diagnosis of a systemic illness comes in the form of the observa-
atic Approach to the Diagnosis of Anemia). Also, only the blood tion of intraerythrocytic inclusions, such as malarial (Fig. 34.5O) or
smear reveals the unique morphologic changes occurring with several babesial forms, and examination of a thick blood smear may be useful
of the various hemolytic disorders. for the diagnosis of these disorders when a low parasite burden is
suspected.

Bone Marrow Examination

Bone marrow aspiration and biopsy permit evaluation of cellular
morphology and BM architecture, respectively. Special stains, flow
cytometry, cytogenetic analysis, fluorescence in situ hybridization
(FISH), and molecular testing performed on the BM can provide a
wealth of diagnostic information.28 Because of the discomfort
involved in the procedure, however, careful consideration should be
given to determining the array of tests required, so that repeated BM
aspirates or biopsies need not be performed. If there is any consider-
ation of the possibility of myelodysplasia, leukemia, or lymphoma,
an aliquot of anticoagulated aspirate should be set aside at the time
of the initial procedure that can be sent, if necessary, for flow cytom-
etry or cytogenetics after review of the aspirate smear. It should be
noted that even when properly performed, difficulty obtaining a BM
aspirate is commonly observed in certain situations, including myelo-
fibrosis, erythroblastic leukemia (M6), and hairy cell leukemia. In
these cases, touch preps of the BM biopsy may help expedite
diagnosis.
Diagnostic uncertainty in the setting of hypoproliferative anemia
is an indication for BM biopsy. Hematologic disorders such as
myelodysplasia, leukemia, lymphoma, or myeloma may be identified.
Myelodysplasia in the marrow classically includes megaloblastic
change and nuclear budding in maturing erythroblasts, as well as
morphologic abnormalities in other lineages, such as hypolobated
megakaryocytes and hypogranulation of the myeloid lineage.29 A
variety of infiltrative (myelophthisic) processes may be observed.30
These include malignancies such as small-cell lung, breast, and
prostate cancers, which frequently can appear in advanced stages with
BM involvement. Alternatively, granulomas may be present, suggest-
ing the possible presence of mycobacterial disease. In children, dis-
seminated neuroblastoma and rhabdomyosarcoma occasionally can
appear as a myelophthisic anemia.
FUTURE DIRECTIONS
Anemia may represent a primary hematologic disorder or may repre-
sent the manifestation of a systemic process. In children, the former
tends to be somewhat more common than the latter, and in adults,
the converse is true. However, in both children and adults, a system-
atic approach to the evaluation of anemia that includes careful review
of historic features, the CBC count, and peripheral smear facilitates
an efficient diagnosis and minimizes unnecessary testing.

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 Chapter 34  Approach to Anemia in the Adult and Child 465

A B C D E

F G H I J

K L M N O

P Q R S T

U V W X Y
Fig. 34.5  USEFUL PERIPHERAL BLOOD AND RED BLOOD CELL FEATURES IN THE EVALUA-
TION OF ANEMIA. (A) Normal red blood cells (RBCs). Note the central pallor is one-third the diameter
of the entire cell. (B) Rouleaux formation is indicative of increased plasma protein. (C) Agglutination indicates
an antibody-mediated process such as cold agglutinin disease. (D) Polychromatophilic cell. The gray-blue color
is attributable to RNA and the cell is equivalent to a reticulocyte, which must be identified with a reticulocyte
stain. (E) Basophilic stippling. This also is attributable to increased RNA caused either by a left shift in ery-
throid cells or lead toxicity. (F) Hypochromic microcytic cells typical of iron-deficiency anemia. Note the
widened central pallor and the “pencil” cell in the lower left. (G) Macroovalocyte as can be seen in either
megaloblastic anemia or myelodysplastic syndrome. (H) Microspherocytes typical of hereditary spherocytosis.
(I) Elliptocytes (ovalocytes) from a patient with hereditary elliptocytosis. (J) RBC fragments from thermal
injury (burn patient). (K) Nucleated RBC. (L) Howell-Jolly bodies indicative of splenic dysfunction or absence.
(M) Pappenheimer bodies from a patient with sideroblastic anemia. (N) Cabot ring, as can be seen in mega-
loblastic anemia or MDS. (O) Malarial parasites (Plasmodium falciparum). (P) Schistocyte typical of a
microangiopathic hemolytic anemia. (Q) Tear-drop form indicates marrow fibrosis and extramedullary
hematopoiesis. (R) Echinocyte (Burr cell) with rounded edges. (S) Acanthocyte (spur cell) with more irregular
pointed ends. This was from a patient with neuroacanthocytosis. They can also be seen in patients with liver
disease and lipid abnormalities. (T) “Bite” cell from a patient with glucose-6-phosphate dehydrogenase
(G6PD) deficiency. (U) Sickle cell, from a patient with homozygous sickle cell disease. (V) Hemoglobin C
crystal. (W) Target cells. (X) Hemoglobin C disease. Note that the RBC in center has condensed hemoglobin
at each pole. (Y) Heinz body preparation (supravital stain) from a patient with G6PD deficiency. Note that
the cells to the right have increased precipitated hemoglobin.

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 466 Part V  Red Blood Cells
TABLE
Features of the Peripheral Blood Smear
34.6
Red Blood Cell Morphology Definition
Polychromasia Large, bluish RBCs lacking normal central pallor
on peripheral blood smear; bluish stain is the
result of residual ribonucleic acid
Basophilic stippling Many small bluish dots in portion of erythrocytes;
comes from staining of clustered polyribosomes
in young circulating RBCs
Pappenheimer bodies Several grayish, irregularly shaped inclusions in a
portion of erythrocytes visible on peripheral
smear; composed of aggregates of ribosomes,
ferritin, and mitochondria
Heinz bodies Several grayish, round inclusions visible after
supravital staining with methyl crystal violet of
the peripheral blood smear, often in the context
of bite cells; represent aggregates of denatured
hemoglobin
Howell-Jolly bodies Usually one or at most a few purplish inclusions in
the erythrocyte visible on the routine peripheral
blood smear; represent residual fragments of
nuclei containing chromatin
Schistocytes RBCs that are fragmented into a variety of shapes
and sizes, including helmet-shaped cells;
indicative of shearing of the erythrocyte within
the circulation
Spherocytes RBCs that have lost their central pallor and appear
spherical; indicative of loss of cytoskeletal
integrity from internal or external causes
Teardrop cells Pear-shaped erythrocytes visible on peripheral
blood smear; indicative of mechanical stress on
the RBC during release from the BM or passage
through the spleen
Burr cells (echinocytes) RBCs that have smooth undulations present on the
surface circumferentially; pathogenesis unknown
Spur cells (acanthocytes) RBCs that have spiny points present on the
surface circumferentially; reflective of abnormal
lipid composition of RBC membrane
aHUS, Atypical hemolytic uremic syndrome; BM, bone marrow; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HUS, hemolytic
uremic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.
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