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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
Patricia Payne Castle

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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rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
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authors and do not necessarily reflect those of Turner White Communications, Inc.

Pediatric Medicine Volume 1, Part 4 1


PEDIATRIC MEDICINE BOARD REVIEW MANUAL

Diagnostic Approach to
Common Anemias in Pediatrics
Felicia L. Wilson, MD

infant or child. Normal values in the pediatric years are


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

2 Hospital Physician Board Review Manual


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

MICROCYTIC, HYPOCHROMIC ANEMIAS DIFFERENTIAL DIAGNOSIS OF MICROCYTIC ANEMIAS


In normal hematopoiesis, erythrocytes are thought
to be released from the marrow when they achieve their
CASE 1 PRESENTATION full complement of hemoglobin. Microcytic, hypo-
Patient 1 is a 12-month-old African American boy chromic anemias are associated with defects in hemo-
who presents for a 1-year well child check. His moth- globin production. This is because the erythrocyte
er reports that he has been doing well except for keeps dividing until it reaches a reasonable hemoglobin
2 episodes of otitis media in the past 2 months. He content, at which time it is released into the peripheral
completed a 10-day course of amoxicillin/clavulanate 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 nancy. The association between various infections and
age of 5 to 6 months (for full-term infants), the time anemia has long been observed, but it has only been in
when the endowment of iron provided in the last recent years that the role of mild and common child-
trimester of pregnancy has been exhausted. In prema- hood infections (eg, otitis media, upper respiratory tract
ture infants, anemia may occur before 6 months of age infection, gastroenteritis) in causing anemia has been
because iron stores at birth may have been inadequate clarified. Fever of longer than 3 days duration or recent
owing to curtailment of the pregnancy. Iron-deficiency immunization with live measles virus vaccine also can
anemia also occurs during adolescence, when rapid mildly depress the hemoglobin level, causing anemia.5
growth puts excessive demands on iron stores; this is
especially a problem in girls, who lose iron with menses. Sideroblastic Anemias
It is always important to rule out iron deficiency Sideroblastic anemias are rare in children and occur
resulting from blood loss. Prenatal iron loss can result because of a metabolic dysfunction in which the incorpo-
from fetomaternal transfusion or twin-to-twin transfu- ration of iron into hemoglobin is blocked. Instead, iron
sion. In older infants and children, blood loss may be accumulates in the mitochondria found in a perinuclear
occult and may be caused by parasitic infestations, distribution and imparts a characteristic ring around the
inflammatory bowel disease, Meckels diverticulum, nucleus when stained for iron content. Therefore, sider-
polyps, cows milk enteropathy, celiac disease, drugs (eg, oblastic anemias are identified by an excess of ringed
nonsteroidal anti-inflammatory agents), or idiopathic sideroblasts in the marrow (> 10% of nucleated cells) hav-
pulmonary hemosiderosis. ing 4 or more siderotic, perinuclear granules (represent-
ing iron-laden mitochondria).6 Conditions that result in
Anemia of Inflammation sideroblastic anemia in childhood are pyridoxine defi-
Anemia of inflammation is second in incidence only ciency, pyridoxine dependency, and lead poisoning.
to iron-deficiency anemia. Since the advent of the Plumbism (lead poisoning) may be combined with,
Women, Infants, and Children (WIC) program in the and enhanced by, iron deficiency in children with pica.
United States, the incidence of anemia due to iron defi- Some of the effects of plumbism may be attributed to
ciency has declined and may eventually be surpassed by inhibition of ferrochelatase, the enzyme that incorpo-
anemia of inflammation. The inflammation may be sec- rates iron into the protoporphyrin ring, resulting in
ondary to infection, collagen vascular disease, or malig- 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 cost-effective manner. Characteristic features of the CBC
extrusion from the erythrocyte, accounts for the riboso- and peripheral blood smear also should be noted, and
mal RNA and mitochondrial fragments that appear as are presented in Table 4. Anemia of inflammation is
coarse basophilic stippling in cells affected by plumbism.7 similar to iron deficiency anemia; both are characterized
by hypochromia and microcytosis. Anisocytosis and
Thalassemias poikylocytosis (as manifested by a high RDW) are char-
The thalassemias are hereditary defects in the syn- acteristic of iron deficiency but are not seen in the ane-
thesis of normal globin polypeptide chains. Patients mia of inflammation. In early or mild iron deficiency,
with anemia caused by mild forms of thalassemia are however, these morphologic abnormalities may be
encountered frequently in clinical practice. However, absent.
the severe forms are relatively rare and are blatant The hypochromia and microcytosis of thalassemia
hemolytic anemias that are not easily confused with are generally of a greater magnitude than that observed
other hypochromic, microcytic anemias. in the same degree of anemia in the anemia of inflam-
The overall prevalence of the -thalassemia trait is mation or in iron deficiency. MCV and MCHC are
approximately 3% to 8% in Americans of Greek or therefore lower in patients with thalassemia. In addi-
Italian ancestry, 5% to 15% in those of southeast Asian tion, elevated erythrocyte counts and the presence of
ancestry, and 6% to 11% in African Americans. In addi- target cells and cells exhibiting basophilic stippling are
tion, more than 20% of southeast Asian immigrants and commonly seen in patients with thalassemia but not in
up to 24% of African Americans are estimated to be those with anemia of inflammation or iron deficiency.
silent carriers. The -thalassemia trait occurs with in- The Mentzer index (erythrocyte count divided by the
creased frequency in African Americans (1%) and MCV) is useful in distinguishing thalassemia minor
Southeast Asians (4%).5,8 from iron deficiency. A Mentzer index of less than 11.5
suggests thalassemia minor, whereas an index of greater
LABORATORY EVALUATION than 13.5 suggests iron deficiency.
In patients with a microcytic anemia, details of the Hematologic features useful in distinguishing lead poi-
history and physical examination should always guide 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- whereas in patients with -thalassemia trait, findings
tosis in the marrow. Of note, the basophilic stippling in may be normal unless performed in the newborn peri-
lead poisoning is coarser than that seen in thalassemia. od. Family studies are useful in the evaluation of pa-
In addition, sideroblastic anemias have a characteristic tients with thalassemia trait.
dimorphic population of microcytic and normocytic or Other studies that may be performed in the evalua-
macrocytic cells. tion of patients with microcytic, hypochromic anemias
Because iron deficiency is the most common cause include the erythrocyte sedimentation rate, which is usu-
of anemia and has adverse effects on behavior and ally elevated in infection and inflammation. Urinalysis
development, iron studies serve as a useful guide in the and stool guaiac testing should be performed to rule out
initial work-up of hypochromic, microcytic anemias. occult blood loss. Although bone marrow examination is
Tests to evaluate iron status include serum iron level, not usually required for the evaluation of microcytic,
total iron-binding capacity (TIBC), serum ferritin level, hypochromic anemias, it is important in the diagnosis of
and serum soluble transferrin receptor level. It is sideroblastic anemia.
important to note that serum iron concentrations show
wide diurnal variations, with highest levels obtained in EVALUATION OF PATIENT 1
the morning. Therefore, samples should be obtained in The remainder of the CBC results come back.
the morning. Although bone marrow examination is The erythrocyte count is 4.1 106/mm3 (normal,
usually not clinically indicated to confirm the diagnosis 3.85.2 106/mm3), the RDW is 12 (normal, < 14)
of iron-deficiency anemia, it is the most direct means and the blood smear is normal. These results, along
for assessing body iron stores. Table 5 shows results of with the history of recent infection, suggest the diag-
iron studies typical of various hypochromic anemias. A nosis of anemia of inflammation. The most prudent
trial of iron supplementation is commonly used to diag- approach is to wait for the inflammation to resolve
nose iron deficiency instead of obtaining iron studies prior to further evaluation. A repeat CBC is per-
when the history, physical examination, and CBC with formed 1 month later with normal results, and no fur-
differential are suggestive. A 1-month trial of oral iron ther evaluation is necessary.
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 ANEMIA OF INFLAMMATION
than 1 g/dL increment increase in hemoglobin. Pathophysiology
If thalassemia is suspected on the basis of a high ery- Serum iron levels and TIBC are labile. After the onset
throcyte count and a Mentzer index of less than 11.5, of acute inflammation, both the serum iron and the
hemoglobin evaluation should be performed using TIBC fall within the first 24 hours and decrease to almost
electrophoresis, high performance liquid chromatogra- half of their previous levels within 48 hours.9 The
phy (HPLC), or isoelectric focusing. In patients with macrophages that store iron bind to the iron excessively,
-thalassemia trait, hemoglobin evaluation usually re- preventing its release to the marrow for erythropoiesis. In
veals an increase in hemoglobin A2 and hemoglobin F, 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- erythrocyte count of 3.2 106/mm3, and a reticulocyte
sequent invasion by decreasing the amount of iron avail- count of 8%. The peripheral blood smear shows some
able to the organisms. Serum iron levels are low not only target cells and a rare sickle cell.
because macrophages do not release iron, but also
because of decreased absorption from the gut. These What test would establish this patients definitive
changes may persist for a month or more as the inflam- diagnosis?
mation resolves. Therefore, children should be screened
for anemia when they are well. DIFFERENTIAL DIAGNOSIS OF NORMOCHROMIC,
NORMOCYTIC ANEMIAS
Clinical Presentation Normochromic, normocytic anemias are a hetero-
Anemia of inflammation is a benign, mild to moder- geneous group of disorders that can be further classi-
ate anemia. Antecedent infections as well as immuniza- fied by the reticulocyte count. The normal range of the
tions can significantly affect hemoglobin concentration reticulocyte count in the absence of anemia is shown in
resulting in anemia. In addition, collagen vascular dis- Table 3. Normochromic, normocytic anemias are
eases and malignancy can play a role in the develop- caused by hemorrhage, hemolysis, or hypoproduction
ment of anemia. The anemia resolves when the under- of erythrocytes by the bone marrow. Elevated reticulo-
lying disease process is adequately treated. Therefore, a cyte counts are indicative of hemorrhage or hemolysis.
diligent search to determine the exact nature of the A low reticulocyte count usually suggests bone marrow
inflammation is essential. failure.

Management of Anemia of Inflammation Reticulocytosis


If anemia of inflammation is considered likely, the Reticulocytosis in the presence of a normochromic,
best approach is to wait for resolution of the inflamma- normocytic anemia and without evidence of blood loss
tion before pursuing a work-up. Resolution may take is caused by a hemolytic process. Differential diagnosis
1 to 3 months. In the meantime, treatment should be of hemolytic anemias rests largely in the recognition of
directed at investigating the underlying cause of inflam- specific morphologic abnormalities on the peripheral
mation, if not already known. Iron therapy is not indi- blood smear followed by appropriate specific laborato-
cated and should be avoided. Blood transfusion should ry tests.
be considered only if the patient is symptomatic from Hemolytic anemias are caused either by inherited
the anemia, a rare occurrence when the hemoglobin intracorpuscular defects or by acquired extracorpuscu-
level is above 7 g/dL, as in the case patient. One inter- lar defects. Intracorpuscular defects involve abnormali-
esting approach to treatment of patients with severe ties of the erythrocyte membrane, enzymes, or globin.
anemia of inflammation (hemoglobin 78 g/dL or Membrane defects include hereditary spherocytosis,
less) is the use of recombinant human erythropoietin, elliptocytosis, or stomatocytosis. Paroxysmal nocturnal
which has shown some promise in adult studies, but hemoglobinuria is an uncommon, nonhereditary mem-
awaits further investigation in pediatric patients.10 12 brane defect in which erythrocytes acquire an abnormal
sensitivity to complement. Enzymopathies generally
involve either the glycolytic pathway (the Embden-
NORMOCHROMIC, NORMOCYTIC ANEMIAS Meyerhof pathway) or the hexose monophosphate
shunt. The most common glycolytic enzyme deficiency
is that of pyruvate kinase, whereas the most common
CASE 2 PRESENTATION hexose monophosphate shunt enzyme deficiency is that
Patient 2 is an 18-month-old African American girl of glucose-6-phosphate dehydrogenase (G6PD). He-
who was brought to the emergency room with low- moglobinopathies (eg, sickle cell diseases, thalassemias)
grade fever, decreased appetite, and painful swelling of result from a qualitative or quantitative change in one of
her hands. Her parents report that they gave her a dose the globin polypeptide chains.
of acetaminophen at home, but she did not show any Antibody-mediated hemolytic anemias can be
signs of relief. On physical examination, she is fussy but autoimmune or isoimmune. Autoimmune hemolytic
consolable and is tachycardic with a grade III/VI systolic anemias are caused by antibodies generated within an
ejection murmur. The spleen is palpable 3 cm below individual against self erythrocytes. These anemias may
the left costal margin. The CBC reveals a hemoglobin be idiopathic or may result from infection, drugs,
level of 8.3 gm/dL, a hematocrit of 24%, MCV of 78 fL, malignancy, or collagen vascular diseases. Isoimmune

8 Hospital Physician Board Review Manual


Common Anemias in Pediatrics

hemolytic anemias result from antibodies produced by with SCD.14 SCD is characterized by the production of
one individual against erythrocytes from another indi- sickle hemoglobin (Hb S) due to an abnormal gene that
vidual. These include hemolytic disease of the new- substitutes valine for glutamic acid in the sixth position of
born and hemolytic transfusion reactions. the -globin chain. Homozygous individuals have sickle
Microangiopathic hemolytic anemias result from cell anemia (Hb SS), whereas compound heterozygous
mechanical damage to the erythrocytes caused by irreg- individuals have sickle hemoglobin C disease (Hb SC),
ularities in the vascular endothelium. These occur in sickle beta zero (S0) thalassemia, or sickle beta plus
association with disseminated intravascular coagulation (S+) thalassemia. These 4 genotypes account for most
and hemolytic-uremic syndrome. cases of SCD in the United States. Gererally, individuals
with Hb SS and S0 thalassemia are more severely affect-
Reticulocytopenia ed than children with Hb SC or S+ thalassemia.
Normochromic, normocytic anemia with reticulocy- The pathogenesis of SCD has been attributed to
topenia usually suggests bone marrow failure resulting in polymerization of deoxygenated Hb S, leading to
pure red cell aplasia or pancytopenia. Pure red cell altered shape and deformability of the erythrocyte. The
aplasias can be congenital or acquired. The congenital clinical consequences are 2-fold, manifesting as chron-
form, transmitted in an autosomal fashion, is Diamond- ic hemolytic anemia and vaso-occlusion. The many
Blackfan anemia. Although considered here with nor- complications encountered in SCD include recurrent
mocytic anemias, Diamond-Blackfan anemia is usually pain episodes, infection, splenic and liver dysfunction,
macrocytic. Acquired pure red cell aplasia, or transient and central nervous system involvement. The clinical
erythroblastopenia of childhood, most likely results from course (and therefore, treatment) of SCD varies and is
suppression by an antecedent viral infection, although a severe in Hb SS, moderate to severe in S0 thalassemia
specific cause has not been well documented. Viral infec- and mild to moderate in S+ thalassemia and Hb SC.
tion with parvovirus-B19 can lead to aplastic crisis in Fetal hemoglobin (Hb F) is present in large amounts
patients with a chronic hemolytic disorder as well as in at birth and has been shown to inhibit sickling in vitro
immunocompromised patients who are unable to by interfering with the polymerization of Hb S. As levels
mount an antibody response and clear the infection. of Hb F decrease, the level of Hb S increases. Because
of the protective effects of Hb F, the clinical manifesta-
EVALUATION OF PATIENT 2 tions of SCD generally do not occur until the infant is a
A history of dactylitis in the hands and feet of an few months old.
African American child should raise high suspicion for The earliest clinical manifestation of SCD in many
sickle cell disease (SCD). This patients physical find- infants occurs at approximately 6 months of age, and is
ings are characteristic of the hand-foot syndrome characterized by painful swelling of the dorsum of the
caused by vaso-occlusive crisis. Splenomegaly is often hands and feet. This hand-foot syndrome is caused by
seen in children with SCD, but the spleen has auto- vaso-occlusion in the metacarpal and metatarsal bones,
infarcted by age 5 years in the severe forms. Hemo- resulting in ischemic tissue injury. During this same peri-
globinopathies often result in a characteristic peripher- od, progressive anemia with jaundice and splenomegaly
al blood smear which is also diagnostic. The presence of develops and is variable among different forms of SCD.
sickle cells on the smear does establish the diagnosis of Tissue damage to the spleen can lead to functional
some form of SCD in this patient. asplenia, making overwhelming infection with encapsu-
lated organisms (primarily pneumococcus), the most
SICKLE CELL DISEASE common cause of death. As with other manifestations of
Pathophysiology SCD, the development of splenic atrophy and dysfunc-
SCD is a group of hemoglobinopathies estimated to tion varies among the different forms of SCD.
affect more than 70,000 African Americans. It is the most In a national multicenter study, penicillin prophylaxis
common cause of hemolytic anemia in the African resulted in an 84% decrease in the incidence of pneu-
American population, and the gene prevalence among mococcal bacteremia in young children with sickle cell
African Americans is 8%. More than 2000 babies with anemia and has become the standard of care for children
SCD are born in the United States each year, making it with Hb SS and S0 thalassemia.15,16 Routine use of peni-
the most prevalent genetic disease among African cillin prophylaxis for infants and children with Hb SC
Americans.13 However, this represents only a small per- and S+ thalassemia is controversial because the in-
centage of the total cases worldwide. It has been estimat- creased risk of severe infection is less than in Hb SS and
ed that in Africa alone, 120,000 babies are born each year 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 blood and other appropriate cultures should be obtained,
and serious morbidity in infants who have sickle cell ane- and broad-spectrum antibiotics should be started as soon
mia, 46 states in this country have instituted mandatory as possible. The spleen size should be monitored fre-
newborn screening for SCD. The other 4 states have insti- quently for any signs of acute sequestration crisis.
tuted screening for selected populations, universal or At discharge, prophylactic penicillin should be started
limited pilot programs, or screening by request.17 at a dose of 125 mg twice daily and continued until the
Another leading cause of death in children with child is 5 years old. Ongoing comprehensive medical
SCD is the acute splenic sequestration crisis. In Hb SS care should be provided, including extensive parental
and S0 thalassemia, these episodes can occur as early as education, timely immunizations, prompt evaluation and
2 months of age and are unusual after 3 years of age. In aggressive management of complications, genetic coun-
fact, splenomegaly may persist in other forms of disease seling, and hemoglobin evaluation studies also should be
(Hb SC and S+ thalassemia) and splenic sequestration performed on family members.
crises can occur in older children and adults. Most of Hydroxyurea therapy has been shown to ameliorate
these episodes are mild, but severe and fatal episodes the clinical course of sickle cell anemia in adults by
have occurred in some patients. increasing the production of Hb F and inhibiting sick-
For reasons that are not clearly understood, the ling.16 18 Concerns about potential adverse effects on
spleen suddenly traps a large portion of the blood vol- growth as well as the possibility of teratogenic or car-
ume. Patients may suddenly become weak, tachycardic, cinogenic effects led to an initial reluctance to use
and dyspneic; and have a rapidly distending abdomen, hydroxyurea in children. Phase I and II multicenter
left-sided abdominal pain, and shock. Sequestration may pediatric trials using hydroxyurea in children ages 5 to
also take place in the liver, but because it is not as disten- 16 years with severe sickle cell anemia have shown no
sible as the spleen, there is seldom pooling of a signifi- adverse effects on height, weight gain, or pubertal
cant amount of blood to cause cardiovascular collapse. development.19 Recently, the results of a 2-year pilot
Vaso-occlusion and tissue ischemia in SCD can result study in very young children (ages 6 to 24 months)
in acute or chronic injury to virtually every organ of the showed that hydroxyurea may prove to be effective not
body. However, a detailed discussion of the diverse clin- only in preventing pain, but also in delaying or pre-
ical manifestations of SCD is beyond the scope of this venting the organ damage associated with SCD.20
review. Successful allogeneic bone marrow transplanta-
tion (BMT) provides a hematologic cure for SCD.
Laboratory Evaluation of Hemoglobinopathies Currently, the event-free survival rate following BMT
Hemoglobin electrophoresis is the principal proce- for SCD is 82%.21 The short-term and long-term
dure used to separate, detect, and identify abnormal transplant-related complications remain substantial
hemoglobins. In some laboratories, this is supplemented barriers to performing BMT to all patients with SCD
or replaced by HPLC analysis. Normal adult hemoglobin who would benefit. Novel conditioning regimens that
is a tetrameric protein composed of 4 globin polypeptide minimize transplant-associated toxicity have been
chains: 2 alpha and 2 beta chains that pair (designated developed and show promise for wider application of
22). Although adult hemoglobin is present at birth, BMT.21,22 Perhaps in the future, gene therapy for
Hb F (22) predominates at birth and during the first hemoglobinopathies also will be possible.
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 MACROCYTIC ANEMIAS
(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 CASE 2 CONTINUATION
tests at an older age may be required to establish the sta- Patient 2 is discharged from the hospital after 3 days,
ble Hb F level. Hemoglobin evaluation studies also and is placed on penicillin prophylaxis. She does well
should be performed on family members, if possible. for 2 years. When she is 3 years old, her hematocrit is
noted to gradually fall to a level of 18% with a decrease
Management of Sickle Cell Disease in her reticulocyte count to 3%. The MCV is noted to
Patient 2 should be hospitalized for further manage- increase to 96 fL. The peripheral blood smear reveals
ment. Therapy for pain control includes administration target cells and sickled cells, as were noted previously,
of intravenous fluids and parenteral opioids. In addition, but these cells are now accompanied by an increase in

10 Hospital Physician Board Review Manual


Common Anemias in Pediatrics

hypersegmented neutrophils and the presence of some known function there. Because erythrocytes are meta-
oval macrocytes. bolically inactive, the erythrocyte folate levels reflect the
patients folate status at the time these cells were pro-
What is the most likely cause of patient 2s macro- duced. Serum homocysteine levels are elevated in the
cytic anemia? presence of folate deficiency because methylation of
Is it related to her SCD? homocysteine to form methionine requires folate as a
cofactor. The level of vitamin B12 in the blood is a useful
DIFFERENTIAL DIAGNOSIS OF MACROCYTIC ANEMIAS measure of the patients body stores. As with folate defi-
Macrocytic anemias are characterized by MCVs above ciency, serum homocysteine levels are elevated in the
the upper limit of normal and are not common in pedi- presence of vitamin B12 deficiency because this nutrient
atric patients. Macrocytic anemias may be associated with is required for the conversion of homocysteine to
megaloblastosis, indicating decreased DNA synthesis and methionine. Vitamin B12 is required for the conversion
asynchrony of maturation between cytoplasm and nucle- of methylmalonyl CoA to succinyl CoA; therefore,
us. This results in impaired synthesis of DNA relative to methylmalonic acid is elevated in vitamin B12 deficiency
RNA and protein synthesis. Therefore, these anemias and is a helpful diagnostic aid.
result from a relative decrease in the factors needed in Morphologic abnormalities characteristic of folate defi-
DNA replication and are usually caused by a deficiency of ciency may be seen on the peripheral blood smear. Hy-
folate, vitamin B12, or both. Except in infants, total body persegmentation of neutrophils is among the earliest
stores of folate are moderate and are sufficient for findings, and neutropenia is present in severe cases.
approximately 3 to 5 months, whereas vitamin B12 stores Macro-ovalocytosis and anisocytosis are typical erythrocyte
are abundant, lasting 2 to 5 years. Therefore, folate defi- abnormalities. In severe cases, thrombocytopenia is seen.
ciency is more common in the general population, but is
usually less severe in its effects than vitamin B12 deficien- FOLATE DEFICIENCY
cy. Increased demand for folate occurs in the presence of Pathophysiology
conditions characterized by increased cell turnover, in- Folate deficiency is the most common cause of
cluding chronic hemolysis (caused by SCD in patient 2), megaloblastic anemia in the general population. Folate
pregnancy, and malignancy. Relative folate deficiency plays an important role as a carrier of single-carbon
may develop if the diet does not provide adequate folate fragments, such as methyl, formyl, and methylene
to meet these needs. A much less common cause of groups. Of major importance in erythrocyte produc-
megaloblastic anemia is hereditary orotic aciduria, a con- tion is the reaction in which deoxyuridylate is convert-
dition which is characterized by defective nucleic acid ed to thymidylate. This reaction, which appears to be
processing. Macrocytosis in the absence of megaloblastic rate-limiting in DNA synthesis, requires methylene
changes occurs in patients with liver disease, hypothy- tetrahydrofolate.23 Folate also plays an important role in
roidism, Diamond-Blackfan anemia, Fanconis anemia, central nervous system methylation of homocysteine to
and preleukemia syndromes. The reticulocytosis that methionine.
occurs in patients with hemolysis or hemorrhage may Biochemical manifestations of folate deficiency in-
falsely elevate the MCV because these young erythrocytes clude asynchrony in maturation between the cytoplasm
are considerably larger than mature cells, with some and nucleus resulting in impaired synthesis of DNA rela-
approaching 150 fL. Neonatal erythrocytes are larger tive to RNA and protein synthesis Other consequences
than those seen in older infants, children, and adults, include ineffective erythropoiesis with intramedullary
with MCVs ranging from 95 fL to 120 fL. Nonmegalo- hemolysis and impaired utilization of iron.
blastic macrocytic anemias are extremely rare in children
and are outside the scope of this review. Management
The diagnosis of folate deficiency is confirmed by
LABORATORY EVALUATION OF MEGALOBLASTIC ANEMIAS the demonstration of a decreased folate level and a
The primary laboratory tests used in the diagnosis of hematologic response to a test dose of folic acid. Pe-
megaloblastic anemias include measurements of serum diatric patients with folate deficiency should receive
folate and vitamin B12 levels, as well as erythrocyte folate 0.5 to 1.0 mg of orally administered folic acid daily until
levels. Erythrocyte folate determination is a more reli- the anemia and megaloblastosis are corrected. Patients
able measurement of the status of folate stores than the diagnosed with chronic hemolytic anemias should take
serum folate level. Folates are found in substantial folic acid 1 mg daily to prevent folate deficiency.
quantities in the mature erythrocyte, but they have no

Pediatric Medicine Volume 1, Part 4 11


Common Anemias in Pediatrics

9. Means RT Jr. The anemia of chronic disorders. In:


SUMMARY Wintrobe MM, Lee GR, editors. Wintrobes clinical hema-
tology. 10th ed. Baltimore: Williams & Wilkins; 1999:
101121.
The initial diagnostic approach to the anemic patient
includes a detailed history and physical examination 10. Spivak JL. Recombinant human erythropoietin and the
and a minimum of essential laboratory tests. Careful anemia of cancer. Blood 1994; 84:9971004.
scrutiny of the peripheral blood smear is always helpful 11. Sears DA. Anemia of chronic disease. Med Clin North
and may provide morphologic clues to the diagnosis, Am 1992;76:56779.
thereby minimizing expensive and unnecessary tests. 12. Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of
The pattern of anemia in infancy and childhood has recombinant human erythropoietin in correction of ane-
changed over the past decade. Although iron-deficiency mia in rheumatoid arthritis. Am J Med 1990;89:1618.
anemia remains the most common cause of anemia in 13. The Council of Regional Networks for Genetics Services
the United States, its incidence is declining, and the ane- (CORN). National Newborn Screening Report1992.
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Genetic Services; 1995.
growing Asian and African American populations in the
United States along with newborn screening for hemo- 14. Fleming AF. The presentation, management and pre-
vention of crisis in sickle cell disease in Africa. Blood Rev
globinopathies has resulted in more frequent identifica-
1989;3:1828.
tion of these disorders. Furthermore, during the course
of a disease, classification of a patients anemia may 15. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with
oral penicillin in children with sickle cell anemia. A ran-
change from one category to another as a result of addi-
domized trial. N Engl J Med 1986;314:15939.
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16. Falletta JM, Woods GM, Verter JI, et al. Discontinuing
penicillin prophylaxis in children with sickle cell anemia.
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12 Hospital Physician Board Review Manual