PEDIATRIC MEDICINE BOARD REVIEW MANUAL

PUBLISHING STAFF
PRESIDENT, GROUP PUBLISHER
Diagnostic Approach to
Bruce M. White
Common Anemias in
EDITORIAL DIRECTOR
Debra Dreger Pediatrics
SENIOR EDITOR
Becky Krumm Series Editor:
ASSISTANT EDITOR Franklin Trimm, MD
Tricia Carbone Professor and Vice Chair, Pediatrics
Director, Pediatric Residency Program
EXECUTIVE VICE PRESIDENT
Barbara T. White University of South Alabama College of Medicine
Mobile, AL
EXECUTIVE DIRECTOR
OF OPERATIONS
Jean M. Gaul
Contributor:
Felicia L. Wilson, MD
PRODUCTION DIRECTOR Associate Professor of Pediatrics
Suzanne S. Banish
Division of Hematology/Oncology
PRODUCTION ASSOCIATE University of South Alabama College of Medicine
Mary Beth Cunney Mobile, AL
ADVERTISING/PROJECT MANAGER
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SALES & MARKETING MANAGER

Deborah D. Chavis Table of Contents
NOTE FROM THE PUBLISHER: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
This publication has been developed without
involvement of or review by the American Microcytic, Hypochromic Anemias . . . . . . . . . . . 3
Board of Pediatrics.
Normochromic, Normocytic Anemias . . . . . . . . 8
Endorsed by the Macrocytic Anemias . . . . . . . . . . . . . . . . . . . . . 10
Association for Hospital
Medical Education
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
The Association for Hospital Medical Education
endorses HOSPITAL PHYSICIAN for the pur- References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
pose of presenting the latest developments in
medical education as they affect residency pro-
grams and clinical hospital practice. Cover Illustration by Stacey Caiazzo
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Pediatric Medicine Volume 1, Part 4 1

 PEDIATRIC MEDICINE BOARD REVIEW MANUAL
Diagnostic Approach to
Common Anemias in Pediatrics
Felicia L. Wilson, MD
INTRODUCTION
Anemia is generally defined as an abnormal
decrease in the number of circulating erythrocytes or in
the hemoglobin concentration and the hematocrit to
levels that are 2 standard deviations below the mean for
the normal population.1 Anemia is not a diagnosis in
itself; rather, it is a symptom of an underlying disease.
Therefore, the evaluation of anemia is directed at elu-
cidating the underlying cause. Table 1 and Table 2 show
important features in patient history and physical find-
ings that can yield valuable information, considerably
narrowing possible causes for anemia and reducing the
necessity of performing expensive tests.
COMPLETE BLOOD COUNT
The complete blood count (CBC) remains a practical
starting point in the laboratory evaluation and classifica-
tion of anemias and consists of hemoglobin level, hema-
tocrit, erythrocyte count, mean corpuscular volume
(MCV), mean corpuscular hemoglobin (MCH), mean
corpuscular hemoglobin concentration (MCHC), leuko-
cyte count, and platelet count. The CBC results deter-
mine whether the problem is anemia alone, anemia with
leukopenia or thrombocytopenia, or pancytopenia, enti-
ties that would significantly alter the differential diag-
nosis. On newer cell counters, the red cell distribution
width (RDW) is available and serves as a quantitative
measure of the degree of variability in the size and shape
of the erythrocytes (anisocytosisexcessive variation in
size; poikylocytosisexcessive variation in shape). The
reticulocyte count, a measure of bone marrow erythro-
cyte production, is another helpful parameter in the ini-
tial work-up. Lastly, examination of the peripheral blood
smear can be particularly useful in confirming the results
of the CBC, as well as providing morphologic clues to the
diagnosis.
When analyzing the CBC, it is important to consider
developmental variations in reference to the hemoglo-
bin level, the hematocrit, and erythrocyte indices in the
2 Hospital Physician Board Review Manual
infant or child. Normal values in the pediatric years are
listed in Table 3. Hemoglobin levels and hematocrit are
relatively high in the newborn period, with mean values
of 18.5 g/dL and 56%, respectively. At birth, the infant
moves from a relatively hypoxic intrauterine environ-
ment and an arterial oxygen saturation of 45% to a nor-
moxic environment where arterial saturation increases to
95% with the onset of respiration.2 This change causes an
abrupt cessation in erythropoietin production and a halt
in erythropoiesis. In addition, fetal erythrocytes in the
newborn have a shortened lifespan of 60 to 70 days, com-
pared to the 120-day lifespan of adult erythrocytes. The
rapid growth of the newborn baby is accompanied by an
increase in plasma volume, which results in a dilutional
effect to further decrease hemoglobin levels and hemat-
ocrit. A nadir is reached at approximately 6 to 8 weeks of
age for the term infant and earlierat around 5 weeks of
agefor the premature infant. Hemoglobin and hemat-
ocrit levels then steadily increase, reaching adult levels at
puberty. This condition is referred to as physiologic anemia
of infancy and is an extrauterine adaptation to life rather
than a pathologic anemia.
CLASSIFICATION OF ANEMIAS
Anemias may be classified on the basis of erythrocyte
size (MCV). Microcytic, hypochromic anemias are the
most common class of anemias in pediatric years. The
MCV is below the lower limit of normal for age. In chil-
dren between the ages of 2 years to 10 years, the lower
limit of normal for MCV is 70 fL plus the age in years.
These anemias are caused by impaired synthesis of the
heme or globin components of hemoglobin.
Normochromic, normocytic anemias are charac-
terized by an MCV in the normal range. They are fur-
ther classified by the reticulocyte count and are caused
by hemorrhage, hemolysis, or hypoproduction of the
bone marrow.
Macrocytic anemias are characterized by an MCV
above the upper limit of normal, which is obtained by
adding 0.6 fL per year to 84 fL beyond the first year of
life until the upper limit of 96 fL in adults is reached.3
 Common Anemias in Pediatrics

Table 1. Historical Factors of Importance in Evaluating Pediatric Patients with Anemia

Factor Considerations
Age Nutritional iron deficiency is never responsible for anemia in term infants prior to 6 months of age; it is seen
rarely in premature infants prior to doubling of their birth weight. Anemia manifesting itself in the neonatal peri-
od generally is the result of recent blood loss, isoimmunization, or initial manifestation of a congenital hemolytic
anemia or congenital infection. Anemia first detected at ages 3 to 6 months suggests a congenital disorder of
hemoglobin synthesis or hemoglobin structure.
Sex Consider X-linked disorders in males (G6PD deficiency, phosphoglycerate kinase deficiency).
Race Hemoglobin S and C more common in blacks; -thalassemia more common in whites; -thalassemia trait
most common among black and yellow races.
Ethnic Thalassemia syndromes most common among patients of Mediterranean origin. G6PD deficiency observed
with increased frequency among Sephardic Jews, Filipinos, Greeks, Sardinians, and Kurds.
Neonatal History of hyperbilirubinemia in the newborn period suggests the presence of a congenital hemolytic anemia (eg,
hereditary spherocytosis, G6PD deficiency). Prematurity predisposes to early development of iron deficiency.
Diet Document sources of iron, vitamin B12, folic acid, and vitamin E in the diet. History of pica, geophagia, or
pagophagia suggests presence of iron deficiency.
Drugs Oxidant-induced hemolytic anemia, phenytoin-induced megaloblastic anemia, drug-induced aplastic anemia
Infection Hepatitis-induced aplastic anemia, infection-induced red cell aplastic or hemolytic anemia
Inheritance Family history of anemia, jaundice, gallstones, or splenomegaly
Diarrhea Suspect small bowel disease with malabsorption of folate or vitamin B12. Suspect inflammatory bowel disease
with blood loss. Suspect exudative enteropathy with blood loss.

Adapted from Oski FA, Brugnara C, Nathan DG. Disorders of erythrocyte production. In: Nathan DG, Orkin SH, editors. Nathan and Oskis
hematology of infancy and childhood. Vol 1. 5th Ed. Philadelphia: WB Saunders; 1998:377. With permission from Elsevier.

These anemias also are further classified by the reticu-
locyte count (indicating hemolysis or bone marrow fail-
ure), and by the presence or absence of megaloblastic
changes (indicating nutritional deficiencies).
This review focuses on the most common causes of
anemia in children within the context of the changing
epidemiologic pattern of childhood anemia. Emphasis
is placed on microcytic, hypochromic anemias, as this is
the most common group seen in pediatrics. A brief
overview of normochromic, normocytic anemias, as well
as of macrocytic anemias, which are even less common,
is provided in order to review their diagnostic approach.
potassium 2 weeks ago, and has been doing well since
that time. He is on an iron-fortified formula and eats
a balanced diet of table food with some baby food.
Results of the physical examination are normal. After
he leaves the clinic, the CBC is reported to include a
hemoglobin level of 10.0 g/dL and a MCV of 69 fL,
with normal leukocyte and platelet counts.
Should the patient have further evaluation of this
mild anemia?
Would an empiric trial of iron be appropriate?
Should screening be done for thalassemia trait or
lead toxicity?

MICROCYTIC, HYPOCHROMIC ANEMIAS DIFFERENTIAL DIAGNOSIS OF MICROCYTIC ANEMIAS

CASE 1 PRESENTATION
Patient 1 is a 12-month-old African American boy
who presents for a 1-year well child check. His moth-
er reports that he has been doing well except for
2 episodes of otitis media in the past 2 months. He
completed a 10-day course of amoxicillin/clavulanate
In normal hematopoiesis, erythrocytes are thought
to be released from the marrow when they achieve their
full complement of hemoglobin. Microcytic, hypo-
chromic anemias are associated with defects in hemo-
globin production. This is because the erythrocyte
keeps dividing until it reaches a reasonable hemoglobin
content, at which time it is released into the peripheral
blood.4 Defective heme synthesis may result from iron

Pediatric Medicine Volume 1, Part 4 3

 Common Anemias in Pediatrics

Table 2. Physical Findings as Clues to the Etiology of Anemia in Children

Finding Possible Etiologies

Skin
Hyperpigmentation Fanconis aplastic anemia
Petechiae, purpura Autoimmune hemolytic anemia with thrombocytopenia, hemolytic-
uremic syndrome, bone marrow aplasia, bone marrow infiltration
Carotenemia Suspect iron deficiency in infants
Jaundice Hemolytic anemia, hepatitis, aplastic anemia
Cavernous hemangioma Microangiopathic hemolytic anemia
Ulcers on lower extremities S and C hemoglobinopathies, thalassemia
Facies
Frontal bossing, prominence of the malar and Congenital hemolytic anemias, thalassemia major, severe iron deficiency
maxillary bones
Eyes
Microcornea Fanconis aplastic anemia
Tortuosity of the conjunctival and retinal vessels S and C hemoglobinopathies
Microaneurysms of retinal vessels S and C hemoglobinopathies
Cataracts G6PD deficiency, galactosemia with hemolytic anemia in newborn period
Vitreous hemorrhages S hemoglobinopathy
Retinal hemorrhages Chronic, severe anemia
Edema of the eyelids Infectious mononucleosis, exudative enteropathy with iron deficiency,
renal failure
Blindness Osteopetrosis
Mouth
Glossitis Vitamin B12 deficiency, iron deficiency
Angular stomatitis Iron deficiency
Chest
Unilateral absence of the pectoral muscles Polands syndrome (increased incidence of leukemia)
Shield chest Diamond-Blackfan syndrome
Hands
Triphalangeal thumbs Red cell aplasia
Hypoplasia of the thenar eminence Fanconis aplastic anemia
Spoon nails Iron deficiency
Spleen
Enlargement Congenital hemolytic anemia, leukemia, lymphoma, acute infection,
portal hypertension

Adapted from Oski FA, Brugnara C, Nathan DG. Disorders of erythrocyte production. In: Nathan DG, Orkin SH, editors. Nathan and Oskis
hematology of infancy and childhood. Vol 1. 5th Ed. Philadelphia: WB Saunders; 1998:378. With permission from Elsevier.

deficiency, abnormal iron metabolism (owing to acute Iron-Deficiency Anemia

or chronic inflammation or infection), metabolic ab- Iron deficiency is the most common cause of anemia
normalities (sideroblastic anemias), or toxicity (eg, lead in children. Most cases occur because the dietary intake
poisoning). Defective globin synthesis is characteristic of iron is inadequate to meet the requirements for
of the thalassemia syndromes. rapid growth. This is mainly seen in infants and results

4 Hospital Physician Board Review Manual

 Common Anemias in Pediatrics

Table 3. Normal Erythrocyte Values in the Pediatric Years

Hemoglobin (g/dL) Hematocrit (%) MCV (fL)

Lower Lower Lower Reticulocytes
Age Mean* Limit* Mean* Limit* Mean* Limit* (%)
13 days (term infant) 18.5 14.5 56 45 108 95 37
1 month 14.0 10.0 43 31 104 85 0.11.7
2 months 11.5 09.0 35 28 96 77 0.11.7
36 months 11.5 09.5 35 29 91 74 0.11.7
6 months2 years 12.0 11.0 36 33 78 70 0.72.3
26 years 12.5 11.5 37 34 81 75 0.51.0
612 years 13.5 11.5 40 35 86 77 0.51.0
1218 years
Female 14.0 12.0 41 36 90 78 0.51.0
Male 14.5 13.0 43 37 88 78 0.51.0

MCV = mean corpuscular volume.

*Mean and lower limit of normal. Lower limit is 2 standard deviations below the mean.

Adapted from Dallman PR, Siimes MA. Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr 1979;94:2631;
data from Forestier F et al. Pediatr Res 1986;20:342.

from a failure to introduce iron-containing foods at the
age of 5 to 6 months (for full-term infants), the time
when the endowment of iron provided in the last
trimester of pregnancy has been exhausted. In prema-
ture infants, anemia may occur before 6 months of age
because iron stores at birth may have been inadequate
owing to curtailment of the pregnancy. Iron-deficiency
anemia also occurs during adolescence, when rapid
growth puts excessive demands on iron stores; this is
especially a problem in girls, who lose iron with menses.
It is always important to rule out iron deficiency
resulting from blood loss. Prenatal iron loss can result
from fetomaternal transfusion or twin-to-twin transfu-
sion. In older infants and children, blood loss may be
occult and may be caused by parasitic infestations,
inflammatory bowel disease, Meckels diverticulum,
polyps, cows milk enteropathy, celiac disease, drugs (eg,
nonsteroidal anti-inflammatory agents), or idiopathic
pulmonary hemosiderosis.
Anemia of Inflammation
Anemia of inflammation is second in incidence only
to iron-deficiency anemia. Since the advent of the
Women, Infants, and Children (WIC) program in the
United States, the incidence of anemia due to iron defi-
ciency has declined and may eventually be surpassed by
anemia of inflammation. The inflammation may be sec-
ondary to infection, collagen vascular disease, or malig-
nancy. The association between various infections and
anemia has long been observed, but it has only been in
recent years that the role of mild and common child-
hood infections (eg, otitis media, upper respiratory tract
infection, gastroenteritis) in causing anemia has been
clarified. Fever of longer than 3 days duration or recent
immunization with live measles virus vaccine also can
mildly depress the hemoglobin level, causing anemia.5
Sideroblastic Anemias
Sideroblastic anemias are rare in children and occur
because of a metabolic dysfunction in which the incorpo-
ration of iron into hemoglobin is blocked. Instead, iron
accumulates in the mitochondria found in a perinuclear
distribution and imparts a characteristic ring around the
nucleus when stained for iron content. Therefore, sider-
oblastic anemias are identified by an excess of ringed
sideroblasts in the marrow (> 10% of nucleated cells) hav-
ing 4 or more siderotic, perinuclear granules (represent-
ing iron-laden mitochondria).6 Conditions that result in
sideroblastic anemia in childhood are pyridoxine defi-
ciency, pyridoxine dependency, and lead poisoning.
Plumbism (lead poisoning) may be combined with,
and enhanced by, iron deficiency in children with pica.
Some of the effects of plumbism may be attributed to
inhibition of ferrochelatase, the enzyme that incorpo-
rates iron into the protoporphyrin ring, resulting in
increased levels of free erythrocyte porphyrin. Inhibition

Pediatric Medicine Volume 1, Part 4 5

 Common Anemias in Pediatrics

Table 4. Pertinent Findings in Microcytic Hypochromic Anemia

Red Cell Bone

Erythrocyte Distribution Anisopoikilo- Basophilic Marrow
Cause of Anemia Count Width cytosis Stippling Iron
Iron deficiency Decreased Increased Yes No Decreased
Thalassemia minor Normal or Normal No Yes Increased
increased
Sideroblastic anemias
Hereditary Decreased Variable Variable Yes Increased ringed
sideroblasts
Acquired Decreased Dimorphic Yes Yes Increased
population ringed sidero-
blasts
Chronic disease Decreased Variable Variable No Decreased in
siderocytes;
increased in
RE cells

RE = reticuloendothelial.

Adapted with permission from Perkins S. Hypochromic microcytic anemias. In: Kjeldsberg, CR, editor. Practical diagnosis of hematologic disor-
ders. 3rd ed. Chicago: ASCP Press; 2000:27.

of pyrimidine-5-nucleotidase, the enzyme responsible selection of tests to arrive at a definitive diagnosis in a

for cleaving the nucleotides that remain after nuclear
extrusion from the erythrocyte, accounts for the riboso-
mal RNA and mitochondrial fragments that appear as
coarse basophilic stippling in cells affected by plumbism.7
Thalassemias
The thalassemias are hereditary defects in the syn-
thesis of normal globin polypeptide chains. Patients
with anemia caused by mild forms of thalassemia are
encountered frequently in clinical practice. However,
the severe forms are relatively rare and are blatant
hemolytic anemias that are not easily confused with
other hypochromic, microcytic anemias.
The overall prevalence of the -thalassemia trait is
approximately 3% to 8% in Americans of Greek or
Italian ancestry, 5% to 15% in those of southeast Asian
ancestry, and 6% to 11% in African Americans. In addi-
tion, more than 20% of southeast Asian immigrants and
up to 24% of African Americans are estimated to be
silent carriers. The -thalassemia trait occurs with in-
creased frequency in African Americans (1%) and
Southeast Asians (4%).5,8
LABORATORY EVALUATION
In patients with a microcytic anemia, details of the
history and physical examination should always guide
cost-effective manner. Characteristic features of the CBC
and peripheral blood smear also should be noted, and
are presented in Table 4. Anemia of inflammation is
similar to iron deficiency anemia; both are characterized
by hypochromia and microcytosis. Anisocytosis and
poikylocytosis (as manifested by a high RDW) are char-
acteristic of iron deficiency but are not seen in the ane-
mia of inflammation. In early or mild iron deficiency,
however, these morphologic abnormalities may be
absent.
The hypochromia and microcytosis of thalassemia
are generally of a greater magnitude than that observed
in the same degree of anemia in the anemia of inflam-
mation or in iron deficiency. MCV and MCHC are
therefore lower in patients with thalassemia. In addi-
tion, elevated erythrocyte counts and the presence of
target cells and cells exhibiting basophilic stippling are
commonly seen in patients with thalassemia but not in
those with anemia of inflammation or iron deficiency.
The Mentzer index (erythrocyte count divided by the
MCV) is useful in distinguishing thalassemia minor
from iron deficiency. A Mentzer index of less than 11.5
suggests thalassemia minor, whereas an index of greater
than 13.5 suggests iron deficiency.
Hematologic features useful in distinguishing lead poi-
soning from iron deficiency include basophilic stippling,

6 Hospital Physician Board Review Manual

 Common Anemias in Pediatrics

Table 5. Results of Iron Studies in Hypochromic Anemias

Total Soluble Serum Bone

Serum Iron-Binding Percent Transferrin Marrow
Cause of Anemia Iron Level Capacity Saturation Receptor Level Storage Iron
Iron deficiency Decreased Increased Decreased High Decreased
Thalassemias Increased or Decreased or Increased or Variable, may Increased or
normal normal normal be high normal
Sideroblastic anemias Increased Decreased or Increased Variable, may Increased
normal be high
Chronic disease Decreased Decreased Decreased Normal Increased

Adapted with permission from Perkins S. Hypochromic microcytic anemia. In: Kjeldsberg, CR, editor. Practical diagnosis of hematologic disorders.
3rd ed. Chicago: ASCP Press; 2000:28.

poor response to iron treatment, and ringed sideroblas-
tosis in the marrow. Of note, the basophilic stippling in
lead poisoning is coarser than that seen in thalassemia.
In addition, sideroblastic anemias have a characteristic
dimorphic population of microcytic and normocytic or
macrocytic cells.
Because iron deficiency is the most common cause
of anemia and has adverse effects on behavior and
development, iron studies serve as a useful guide in the
initial work-up of hypochromic, microcytic anemias.
Tests to evaluate iron status include serum iron level,
total iron-binding capacity (TIBC), serum ferritin level,
and serum soluble transferrin receptor level. It is
important to note that serum iron concentrations show
wide diurnal variations, with highest levels obtained in
the morning. Therefore, samples should be obtained in
the morning. Although bone marrow examination is
usually not clinically indicated to confirm the diagnosis
of iron-deficiency anemia, it is the most direct means
for assessing body iron stores. Table 5 shows results of
iron studies typical of various hypochromic anemias. A
trial of iron supplementation is commonly used to diag-
nose iron deficiency instead of obtaining iron studies
when the history, physical examination, and CBC with
differential are suggestive. A 1-month trial of oral iron
at a dosage of 6 mg of elemental iron/kg of body weight
divided into 2 or 3 doses daily should result in a more
than 1 g/dL increment increase in hemoglobin.
If thalassemia is suspected on the basis of a high ery-
throcyte count and a Mentzer index of less than 11.5,
hemoglobin evaluation should be performed using
electrophoresis, high performance liquid chromatogra-
phy (HPLC), or isoelectric focusing. In patients with
-thalassemia trait, hemoglobin evaluation usually re-
veals an increase in hemoglobin A2 and hemoglobin F,
whereas in patients with -thalassemia trait, findings
may be normal unless performed in the newborn peri-
od. Family studies are useful in the evaluation of pa-
tients with thalassemia trait.
Other studies that may be performed in the evalua-
tion of patients with microcytic, hypochromic anemias
include the erythrocyte sedimentation rate, which is usu-
ally elevated in infection and inflammation. Urinalysis
and stool guaiac testing should be performed to rule out
occult blood loss. Although bone marrow examination is
not usually required for the evaluation of microcytic,
hypochromic anemias, it is important in the diagnosis of
sideroblastic anemia.
EVALUATION OF PATIENT 1
The remainder of the CBC results come back.
The erythrocyte count is 4.1 106/mm3 (normal,
3.85.2 106/mm3), the RDW is 12 (normal, < 14)
and the blood smear is normal. These results, along
with the history of recent infection, suggest the diag-
nosis of anemia of inflammation. The most prudent
approach is to wait for the inflammation to resolve
prior to further evaluation. A repeat CBC is per-
formed 1 month later with normal results, and no fur-
ther evaluation is necessary.
ANEMIA OF INFLAMMATION
Pathophysiology
Serum iron levels and TIBC are labile. After the onset
of acute inflammation, both the serum iron and the
TIBC fall within the first 24 hours and decrease to almost
half of their previous levels within 48 hours.9 The
macrophages that store iron bind to the iron excessively,
preventing its release to the marrow for erythropoiesis. In
the presence of infection, this lability probably protects

Pediatric Medicine Volume 1, Part 4 7

 Common Anemias in Pediatrics
the host by partially inhibiting bacterial growth and sub-
sequent invasion by decreasing the amount of iron avail-
able to the organisms. Serum iron levels are low not only
because macrophages do not release iron, but also
because of decreased absorption from the gut. These
changes may persist for a month or more as the inflam-
mation resolves. Therefore, children should be screened
for anemia when they are well.
Clinical Presentation
Anemia of inflammation is a benign, mild to moder-
ate anemia. Antecedent infections as well as immuniza-
tions can significantly affect hemoglobin concentration
resulting in anemia. In addition, collagen vascular dis-
eases and malignancy can play a role in the develop-
ment of anemia. The anemia resolves when the under-
lying disease process is adequately treated. Therefore, a
diligent search to determine the exact nature of the
inflammation is essential.
Management of Anemia of Inflammation
If anemia of inflammation is considered likely, the
best approach is to wait for resolution of the inflamma-
tion before pursuing a work-up. Resolution may take
1 to 3 months. In the meantime, treatment should be
directed at investigating the underlying cause of inflam-
mation, if not already known. Iron therapy is not indi-
cated and should be avoided. Blood transfusion should
be considered only if the patient is symptomatic from
the anemia, a rare occurrence when the hemoglobin
level is above 7 g/dL, as in the case patient. One inter-
esting approach to treatment of patients with severe
anemia of inflammation (hemoglobin 78 g/dL or
less) is the use of recombinant human erythropoietin,
which has shown some promise in adult studies, but
awaits further investigation in pediatric patients.10 12
NORMOCHROMIC, NORMOCYTIC ANEMIAS
CASE 2 PRESENTATION
Patient 2 is an 18-month-old African American girl
who was brought to the emergency room with low-
grade fever, decreased appetite, and painful swelling of
her hands. Her parents report that they gave her a dose
of acetaminophen at home, but she did not show any
signs of relief. On physical examination, she is fussy but
consolable and is tachycardic with a grade III/VI systolic
ejection murmur. The spleen is palpable 3 cm below
the left costal margin. The CBC reveals a hemoglobin
level of 8.3 gm/dL, a hematocrit of 24%, MCV of 78 fL,
8 Hospital Physician Board Review Manual
erythrocyte count of 3.2 106/mm3, and a reticulocyte
count of 8%. The peripheral blood smear shows some
target cells and a rare sickle cell.
What test would establish this patients definitive
diagnosis?
DIFFERENTIAL DIAGNOSIS OF NORMOCHROMIC,
NORMOCYTIC ANEMIAS
Normochromic, normocytic anemias are a hetero-
geneous group of disorders that can be further classi-
fied by the reticulocyte count. The normal range of the
reticulocyte count in the absence of anemia is shown in
Table 3. Normochromic, normocytic anemias are
caused by hemorrhage, hemolysis, or hypoproduction
of erythrocytes by the bone marrow. Elevated reticulo-
cyte counts are indicative of hemorrhage or hemolysis.
A low reticulocyte count usually suggests bone marrow
failure.
Reticulocytosis
Reticulocytosis in the presence of a normochromic,
normocytic anemia and without evidence of blood loss
is caused by a hemolytic process. Differential diagnosis
of hemolytic anemias rests largely in the recognition of
specific morphologic abnormalities on the peripheral
blood smear followed by appropriate specific laborato-
ry tests.
Hemolytic anemias are caused either by inherited
intracorpuscular defects or by acquired extracorpuscu-
lar defects. Intracorpuscular defects involve abnormali-
ties of the erythrocyte membrane, enzymes, or globin.
Membrane defects include hereditary spherocytosis,
elliptocytosis, or stomatocytosis. Paroxysmal nocturnal
hemoglobinuria is an uncommon, nonhereditary mem-
brane defect in which erythrocytes acquire an abnormal
sensitivity to complement. Enzymopathies generally
involve either the glycolytic pathway (the Embden-
Meyerhof pathway) or the hexose monophosphate
shunt. The most common glycolytic enzyme deficiency
is that of pyruvate kinase, whereas the most common
hexose monophosphate shunt enzyme deficiency is that
of glucose-6-phosphate dehydrogenase (G6PD). He-
moglobinopathies (eg, sickle cell diseases, thalassemias)
result from a qualitative or quantitative change in one of
the globin polypeptide chains.
Antibody-mediated hemolytic anemias can be
autoimmune or isoimmune. Autoimmune hemolytic
anemias are caused by antibodies generated within an
individual against self erythrocytes. These anemias may
be idiopathic or may result from infection, drugs,
malignancy, or collagen vascular diseases. Isoimmune
 Common Anemias in Pediatrics
hemolytic anemias result from antibodies produced by
one individual against erythrocytes from another indi-
vidual. These include hemolytic disease of the new-
born and hemolytic transfusion reactions.
Microangiopathic hemolytic anemias result from
mechanical damage to the erythrocytes caused by irreg-
ularities in the vascular endothelium. These occur in
association with disseminated intravascular coagulation
and hemolytic-uremic syndrome.
Reticulocytopenia
Normochromic, normocytic anemia with reticulocy-
topenia usually suggests bone marrow failure resulting in
pure red cell aplasia or pancytopenia. Pure red cell
aplasias can be congenital or acquired. The congenital
form, transmitted in an autosomal fashion, is Diamond-
Blackfan anemia. Although considered here with nor-
mocytic anemias, Diamond-Blackfan anemia is usually
macrocytic. Acquired pure red cell aplasia, or transient
erythroblastopenia of childhood, most likely results from
suppression by an antecedent viral infection, although a
specific cause has not been well documented. Viral infec-
tion with parvovirus-B19 can lead to aplastic crisis in
patients with a chronic hemolytic disorder as well as in
immunocompromised patients who are unable to
mount an antibody response and clear the infection.
EVALUATION OF PATIENT 2
A history of dactylitis in the hands and feet of an
African American child should raise high suspicion for
sickle cell disease (SCD). This patients physical find-
ings are characteristic of the hand-foot syndrome
caused by vaso-occlusive crisis. Splenomegaly is often
seen in children with SCD, but the spleen has auto-
infarcted by age 5 years in the severe forms. Hemo-
globinopathies often result in a characteristic peripher-
al blood smear which is also diagnostic. The presence of
sickle cells on the smear does establish the diagnosis of
some form of SCD in this patient.
SICKLE CELL DISEASE
Pathophysiology
SCD is a group of hemoglobinopathies estimated to
affect more than 70,000 African Americans. It is the most
common cause of hemolytic anemia in the African
American population, and the gene prevalence among
African Americans is 8%. More than 2000 babies with
SCD are born in the United States each year, making it
the most prevalent genetic disease among African
Americans.13 However, this represents only a small per-
centage of the total cases worldwide. It has been estimat-
ed that in Africa alone, 120,000 babies are born each year
with SCD.14 SCD is characterized by the production of
sickle hemoglobin (Hb S) due to an abnormal gene that
substitutes valine for glutamic acid in the sixth position of
the -globin chain. Homozygous individuals have sickle
cell anemia (Hb SS), whereas compound heterozygous
individuals have sickle hemoglobin C disease (Hb SC),
sickle beta zero (S0) thalassemia, or sickle beta plus
(S+) thalassemia. These 4 genotypes account for most
cases of SCD in the United States. Gererally, individuals
with Hb SS and S0 thalassemia are more severely affect-
ed than children with Hb SC or S+ thalassemia.
The pathogenesis of SCD has been attributed to
polymerization of deoxygenated Hb S, leading to
altered shape and deformability of the erythrocyte. The
clinical consequences are 2-fold, manifesting as chron-
ic hemolytic anemia and vaso-occlusion. The many
complications encountered in SCD include recurrent
pain episodes, infection, splenic and liver dysfunction,
and central nervous system involvement. The clinical
course (and therefore, treatment) of SCD varies and is
severe in Hb SS, moderate to severe in S0 thalassemia
and mild to moderate in S+ thalassemia and Hb SC.
Fetal hemoglobin (Hb F) is present in large amounts
at birth and has been shown to inhibit sickling in vitro
by interfering with the polymerization of Hb S. As levels
of Hb F decrease, the level of Hb S increases. Because
of the protective effects of Hb F, the clinical manifesta-
tions of SCD generally do not occur until the infant is a
few months old.
The earliest clinical manifestation of SCD in many
infants occurs at approximately 6 months of age, and is
characterized by painful swelling of the dorsum of the
hands and feet. This hand-foot syndrome is caused by
vaso-occlusion in the metacarpal and metatarsal bones,
resulting in ischemic tissue injury. During this same peri-
od, progressive anemia with jaundice and splenomegaly
develops and is variable among different forms of SCD.
Tissue damage to the spleen can lead to functional
asplenia, making overwhelming infection with encapsu-
lated organisms (primarily pneumococcus), the most
common cause of death. As with other manifestations of
SCD, the development of splenic atrophy and dysfunc-
tion varies among the different forms of SCD.
In a national multicenter study, penicillin prophylaxis
resulted in an 84% decrease in the incidence of pneu-
mococcal bacteremia in young children with sickle cell
anemia and has become the standard of care for children
with Hb SS and S0 thalassemia.15,16 Routine use of peni-
cillin prophylaxis for infants and children with Hb SC
and S+ thalassemia is controversial because the in-
creased risk of severe infection is less than in Hb SS and
S0 thalassemia. Recognizing that early detection and
Pediatric Medicine Volume 1, Part 4 9
 Common Anemias in Pediatrics
institution of penicillin prophylaxis can prevent death
and serious morbidity in infants who have sickle cell ane-
mia, 46 states in this country have instituted mandatory
newborn screening for SCD. The other 4 states have insti-
tuted screening for selected populations, universal or
limited pilot programs, or screening by request.17
Another leading cause of death in children with
SCD is the acute splenic sequestration crisis. In Hb SS
and S0 thalassemia, these episodes can occur as early as
2 months of age and are unusual after 3 years of age. In
fact, splenomegaly may persist in other forms of disease
(Hb SC and S+ thalassemia) and splenic sequestration
crises can occur in older children and adults. Most of
these episodes are mild, but severe and fatal episodes
have occurred in some patients.
For reasons that are not clearly understood, the
spleen suddenly traps a large portion of the blood vol-
ume. Patients may suddenly become weak, tachycardic,
and dyspneic; and have a rapidly distending abdomen,
left-sided abdominal pain, and shock. Sequestration may
also take place in the liver, but because it is not as disten-
sible as the spleen, there is seldom pooling of a signifi-
cant amount of blood to cause cardiovascular collapse.
Vaso-occlusion and tissue ischemia in SCD can result
in acute or chronic injury to virtually every organ of the
body. However, a detailed discussion of the diverse clin-
ical manifestations of SCD is beyond the scope of this
review.
Laboratory Evaluation of Hemoglobinopathies
Hemoglobin electrophoresis is the principal proce-
dure used to separate, detect, and identify abnormal
hemoglobins. In some laboratories, this is supplemented
or replaced by HPLC analysis. Normal adult hemoglobin
is a tetrameric protein composed of 4 globin polypeptide
chains: 2 alpha and 2 beta chains that pair (designated
22). Although adult hemoglobin is present at birth,
Hb F (22) predominates at birth and during the first
few months of life. Within the first year of life, however,
Hb F is replaced by the other adult hemoglobins. The
normal adult proportion of hemoglobins is 97% Hb A
(22), 2% Hb A2 (22) and 1% Hb F. Higher levels of
Hb F are associated with less severe disease, and knowing
the Hb F level can therefore help with prognosis. Repeat
tests at an older age may be required to establish the sta-
ble Hb F level. Hemoglobin evaluation studies also
should be performed on family members, if possible.
Management of Sickle Cell Disease
Patient 2 should be hospitalized for further manage-
ment. Therapy for pain control includes administration
of intravenous fluids and parenteral opioids. In addition,
10 Hospital Physician Board Review Manual
blood and other appropriate cultures should be obtained,
and broad-spectrum antibiotics should be started as soon
as possible. The spleen size should be monitored fre-
quently for any signs of acute sequestration crisis.
At discharge, prophylactic penicillin should be started
at a dose of 125 mg twice daily and continued until the
child is 5 years old. Ongoing comprehensive medical
care should be provided, including extensive parental
education, timely immunizations, prompt evaluation and
aggressive management of complications, genetic coun-
seling, and hemoglobin evaluation studies also should be
performed on family members.
Hydroxyurea therapy has been shown to ameliorate
the clinical course of sickle cell anemia in adults by
increasing the production of Hb F and inhibiting sick-
ling.16 18 Concerns about potential adverse effects on
growth as well as the possibility of teratogenic or car-
cinogenic effects led to an initial reluctance to use
hydroxyurea in children. Phase I and II multicenter
pediatric trials using hydroxyurea in children ages 5 to
16 years with severe sickle cell anemia have shown no
adverse effects on height, weight gain, or pubertal
development.19 Recently, the results of a 2-year pilot
study in very young children (ages 6 to 24 months)
showed that hydroxyurea may prove to be effective not
only in preventing pain, but also in delaying or pre-
venting the organ damage associated with SCD.20
Successful allogeneic bone marrow transplanta-
tion (BMT) provides a hematologic cure for SCD.
Currently, the event-free survival rate following BMT
for SCD is 82%.21 The short-term and long-term
transplant-related complications remain substantial
barriers to performing BMT to all patients with SCD
who would benefit. Novel conditioning regimens that
minimize transplant-associated toxicity have been
developed and show promise for wider application of
BMT.21,22 Perhaps in the future, gene therapy for
hemoglobinopathies also will be possible.
MACROCYTIC ANEMIAS
CASE 2 CONTINUATION
Patient 2 is discharged from the hospital after 3 days,
and is placed on penicillin prophylaxis. She does well
for 2 years. When she is 3 years old, her hematocrit is
noted to gradually fall to a level of 18% with a decrease
in her reticulocyte count to 3%. The MCV is noted to
increase to 96 fL. The peripheral blood smear reveals
target cells and sickled cells, as were noted previously,
but these cells are now accompanied by an increase in
 Common Anemias in Pediatrics
hypersegmented neutrophils and the presence of some
oval macrocytes.
What is the most likely cause of patient 2s macro-
cytic anemia?
Is it related to her SCD?
DIFFERENTIAL DIAGNOSIS OF MACROCYTIC ANEMIAS
Macrocytic anemias are characterized by MCVs above
the upper limit of normal and are not common in pedi-
atric patients. Macrocytic anemias may be associated with
megaloblastosis, indicating decreased DNA synthesis and
asynchrony of maturation between cytoplasm and nucle-
us. This results in impaired synthesis of DNA relative to
RNA and protein synthesis. Therefore, these anemias
result from a relative decrease in the factors needed in
DNA replication and are usually caused by a deficiency of
folate, vitamin B12, or both. Except in infants, total body
stores of folate are moderate and are sufficient for
approximately 3 to 5 months, whereas vitamin B12 stores
are abundant, lasting 2 to 5 years. Therefore, folate defi-
ciency is more common in the general population, but is
usually less severe in its effects than vitamin B12 deficien-
cy. Increased demand for folate occurs in the presence of
conditions characterized by increased cell turnover, in-
cluding chronic hemolysis (caused by SCD in patient 2),
pregnancy, and malignancy. Relative folate deficiency
may develop if the diet does not provide adequate folate
to meet these needs. A much less common cause of
megaloblastic anemia is hereditary orotic aciduria, a con-
dition which is characterized by defective nucleic acid
processing. Macrocytosis in the absence of megaloblastic
changes occurs in patients with liver disease, hypothy-
roidism, Diamond-Blackfan anemia, Fanconis anemia,
and preleukemia syndromes. The reticulocytosis that
occurs in patients with hemolysis or hemorrhage may
falsely elevate the MCV because these young erythrocytes
are considerably larger than mature cells, with some
approaching 150 fL. Neonatal erythrocytes are larger
than those seen in older infants, children, and adults,
with MCVs ranging from 95 fL to 120 fL. Nonmegalo-
blastic macrocytic anemias are extremely rare in children
and are outside the scope of this review.
LABORATORY EVALUATION OF MEGALOBLASTIC ANEMIAS
The primary laboratory tests used in the diagnosis of
megaloblastic anemias include measurements of serum
folate and vitamin B12 levels, as well as erythrocyte folate
levels. Erythrocyte folate determination is a more reli-
able measurement of the status of folate stores than the
serum folate level. Folates are found in substantial
quantities in the mature erythrocyte, but they have no
known function there. Because erythrocytes are meta-
bolically inactive, the erythrocyte folate levels reflect the
patients folate status at the time these cells were pro-
duced. Serum homocysteine levels are elevated in the
presence of folate deficiency because methylation of
homocysteine to form methionine requires folate as a
cofactor. The level of vitamin B12 in the blood is a useful
measure of the patients body stores. As with folate defi-
ciency, serum homocysteine levels are elevated in the
presence of vitamin B12 deficiency because this nutrient
is required for the conversion of homocysteine to
methionine. Vitamin B12 is required for the conversion
of methylmalonyl CoA to succinyl CoA; therefore,
methylmalonic acid is elevated in vitamin B12 deficiency
and is a helpful diagnostic aid.
Morphologic abnormalities characteristic of folate defi-
ciency may be seen on the peripheral blood smear. Hy-
persegmentation of neutrophils is among the earliest
findings, and neutropenia is present in severe cases.
Macro-ovalocytosis and anisocytosis are typical erythrocyte
abnormalities. In severe cases, thrombocytopenia is seen.
FOLATE DEFICIENCY
Pathophysiology
Folate deficiency is the most common cause of
megaloblastic anemia in the general population. Folate
plays an important role as a carrier of single-carbon
fragments, such as methyl, formyl, and methylene
groups. Of major importance in erythrocyte produc-
tion is the reaction in which deoxyuridylate is convert-
ed to thymidylate. This reaction, which appears to be
rate-limiting in DNA synthesis, requires methylene
tetrahydrofolate.23 Folate also plays an important role in
central nervous system methylation of homocysteine to
methionine.
Biochemical manifestations of folate deficiency in-
clude asynchrony in maturation between the cytoplasm
and nucleus resulting in impaired synthesis of DNA rela-
tive to RNA and protein synthesis Other consequences
include ineffective erythropoiesis with intramedullary
hemolysis and impaired utilization of iron.
Management
The diagnosis of folate deficiency is confirmed by
the demonstration of a decreased folate level and a
hematologic response to a test dose of folic acid. Pe-
diatric patients with folate deficiency should receive
0.5 to 1.0 mg of orally administered folic acid daily until
the anemia and megaloblastosis are corrected. Patients
diagnosed with chronic hemolytic anemias should take
folic acid 1 mg daily to prevent folate deficiency.
Pediatric Medicine Volume 1, Part 4 11
 Common Anemias in Pediatrics
SUMMARY
The initial diagnostic approach to the anemic patient
includes a detailed history and physical examination
and a minimum of essential laboratory tests. Careful
scrutiny of the peripheral blood smear is always helpful
and may provide morphologic clues to the diagnosis,
thereby minimizing expensive and unnecessary tests.
The pattern of anemia in infancy and childhood has
changed over the past decade. Although iron-deficiency
anemia remains the most common cause of anemia in
the United States, its incidence is declining, and the ane-
mia of inflammation may eventually surpass it. The
growing Asian and African American populations in the
United States along with newborn screening for hemo-
globinopathies has resulted in more frequent identifica-
tion of these disorders. Furthermore, during the course
of a disease, classification of a patients anemia may
change from one category to another as a result of addi-
tional clinical or pathologic variables.
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