Anemia in The Pediatric Patient

Review Series
PEDIATRIC HEMATOLOGY
Anemia in the pediatric patient

Patrick G. Gallagher
Departments of Pediatrics, Pathology, and Genetics, Yale University School of Medicine, New Haven, CT
KEY POINTS The World Health Organization estimates that approximately a quarter of the world’s
population suffers from anemia, including almost half of preschool-age children. Globally,
Anemia is a major global
Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

burden, affecting almost iron deficiency anemia is the most common cause of anemia. Other important causes of
2 billion people anemia in children are hemoglobinopathies, infection, and other chronic diseases. Anemia
worldwide, particularly is associated with increased morbidity, including neurologic complications, increased risk of
infants and young
low birth weight, infection, and heart failure, as well as increased mortality. When approaching
children.
a child with anemia, detailed historical information, particularly diet, environmental exposures,
Population approaches and family history, often yield important clues to the diagnosis. Dysmorphic features on
are being employed to
physical examination may indicate syndromic causes of anemia. Diagnostic testing involves a
treat dietary anemia, and
therapeutic advances are stepwise approach utilizing various laboratory techniques. The increasing availability of genetic
improving care for testing is providing new mechanistic insights into inherited anemias and allowing diagnosis in
inherited anemias. many previously undiagnosed cases. Population-based approaches are being taken to address
nutritional anemias. Novel pharmacologic agents and advances in gene therapy-based
therapeutics have the potential to ameliorate anemia-associated disease and provide treatment strategies even in the most
difficult and complex cases.
Introduction smoking. Normalized Hb value curves have been developed for

children living at high altitudes.4 In addition, genome-wide asso-
Anemia is the most common hematologic abnormality identified
ciation studies have revealed individual genetic variation contrib-
in infants and children. Approximately a quarter of the world’s
utes to differences in erythrocyte indices.5
population suffers from anemia, almost 2 billion people, with
almost half of children ,5 years of age affected in 2016.1 Ane-
mia is associated with increased morbidity and mortality in chil- Classification of anemia
dren, particularly children of preschool age. There are many
Anemia can be classified in many ways, such as congenital or
causes of anemia, both inherited and acquired, and these
acquired, acute or chronic, hemolytic or nonhemolytic, based on
causes vary widely in populations across the world. Anemia is
peripheral blood (PB) smear findings, or based on erythrocyte
not a specific disease entity per se but represents a heteroge-
size. Hemolytic anemia may be further classified as inherited or
neous group of pathologic conditions. Anemia is defined quanti-
acquired, immune or nonimmune, acute or chronic, whether
tatively as a decreased number of circulating erythrocytes or
functionally as a condition where numbers of erythrocytes, car- hemolysis occurs in the vasculature (intravascular) or the reticulo-
riers of oxygen, are insufficient to meet metabolic demands. In endothelial system (extravascular), and whether there is a cellular
practice, anemia is defined by hemoglobin (Hb), hematocrit, or defect of the erythrocyte (intrinsic) or extracellular (extrinsic)
red blood cell count levels lower than the normal age- and sex- abnormality. Whereas most intrinsic defects are inherited, such
adjusted ranges. as membrane disorders, metabolic defects, and Hb disorders,
most extrinsic defects are acquired, such as immune-mediated
Use of appropriate ranges when defining anemia is important.2,3 anemia, systemic disease, and drug- or toxin-mediated effects.
Throughout the first year of life, erythrocytes lose their fetal and A few disorders, such as paroxysmal nocturnal hemoglobinuria,
neonatal characteristics, changing globin composition, metabo- exhibit intrinsic and extrinsic hemolysis. Table 2 shows some
lism, size, volume, membrane structure, and function. These causes of hemolytic anemia.
changes are reflected by decreases in Hb, as well as mean cor-
puscular volume (MCV), mean corpuscular Hb (MCH), and mean One clinically useful classification based on MCV and reticulo-
corpuscular Hb concentration (MCHC) (Table 1). Hb levels grad- cyte count (Figure 2) initially classifies anemias as microcytic, nor-
ually increase during childhood then level off during adulthood.1 mocytic, and macrocytic based on MCV, then further refines the
After puberty, gender differences occur due to menstruation differential diagnoses based on the reticulocyte count. This clas-
and subsequent iron loss in females (Figure 1). Other factors sification scheme will be used to review etiologies of anemia in
influence Hb levels, such as diet, living at high altitudes, or infants and children.
blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 571

Table 1. Normal hematologic values during the first year of life in healthy term infants*
Age (mo)
0.5 (n 5 232) 1 (n 5 240) 2 (n 5 241) 4 (n 5 52) 6 (n 5 52) 9 (n 5 56) 12 (n 5 56)

Hb (g/dL, mean 6 SE), 16.6 6 6 0.11 13.9 6 0.10 11.2 6 0.06 12.2 6 0.14 12.6 6 0.10 12.7 6 0.09 12.7 6 0.09
(22 SD) (13.4) (10.7) (9.4) (10.3) (11.1) (11.4) (11.3)
Hematocrit 53 6 0.4 44 6 0.3 35 6 0.2 38 6 0.4 36 6 0.3 36 6 0.3 37 6 0.3

(%, mean 6 SE), (41) (33) (28) (32) (31) (32) (33)
(22 SD)
RBC count (31012/L, 4.9 6 0.03 4.3 6 0.03 3.7 6 0.02 4.3 6 0.06 4.7 6 0.05 4.7 6 0.04 4.7 6 0.04
mean 6 SE), (22 (3.9-5.9) (3.3-5.3) (3.1-4.3) (3.5-5.1) (3.9-5.5) (4.0-5.3) (4.1-5.3)
SD 1 2 SD)
MCH (pg, mean 6 SE), 33.6 6 0.1 32.5 6 0.1 30.4 6 0.1 28.6 6 0.2 26.8 6 0.2 27.3 6 0.2 26.8 6 0.2

(22 SD) (30) (29) (27) (25) (24) (25) (24)
MCV (fL, mean 6 SE), 105.3 6 0.6 101.3 6 0.3 94.8 6 0.3 86.7 6 0.8 76.3 6 0.6 77.7 6 0.5 77.7 6 0.5
(22 SD) (88) (91) (84) (76) (68) (70) (71)
MCHC (g/dL, 314 6 1.1 318 6 1.2 318 6 1.1 327 6 2.7 350 6 1.7 349 6 1.6 343 6 1.5
mean 6 SE), (22 SD) (281) (281) (283) (288) (327) (324) (321)
Values at the ages of 0.5, 1, and 2 mo were obtained from the entire group, and those at the later ages were obtained from the iron supplemented infant group after exclusion of
iron deficiency.121
*These values were obtained from a selected group of 256 healthy term infants followed at the Helsinki University Central Hospital who were receiving continuous iron
supplementation and who had normal values for transferrin saturation and serum ferritin.
200
Both sexes
Males
180 180
Females
Minus 2SD (both sexes)

160
Minus 2SD (males)
Hemoglobin concentration (g/L)
155
152
145 Minus 2SD (females)
140 140 140 140 140 141
138
135 135
130 130
128
125
120 120 120 120
118 116
115 115 115 114
112 110
100
95 95
80
60
n
ys
rs
rs
rs
s
th
th
ar
ar
ar
ar
ar
r
a
bo
da
ye
ye
ye
ye
ye
ye
ye
ye
on
on
ew
28
18
49
69
70
88
5–
2–
1
N
6–
–
3–
0.
12
18
49
Age
Figure 1. Mean Hb concentrations by age and sex (22 SD values). Compiled from data from the United States, Europe, and White populations. Used with permis-
sion from Chaparro and Suchdev.1
572 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

Table 2. Etiologies of hemolytic anemia Table 2. (continued)
Intrinsic hemolysis Posttransplant

Hemoglobin disorders Cold agglutinins
a-Thalassemias Primary
b-Thalassemias Secondary
Sickle cell disease Infection (e.g., Mycoplasma, Epstein-Barr virus)
Unstable hemoglobins Malignancy
Membrane defects Lymphoid
Hereditary spherocytosis Nonlymphoid
Hereditary elliptocytosis, pyropoikilocytosis and related Paroxysmal cold hemoglobinuria
disorders
Immune
Hereditary stomatocytosis syndromes
Postinfectious

Xerocytosis
Other
Hydrocytosis
Recluse spider venom
Rh null syndrome
Clostridial sepsis
GLUT1 deficiency
Erythrocyte fragmentation
Tangier disease
Primary thrombotic microangiopathy (TMA)
Abetalipoproteinemia
Inherited
Phytosterolemia
ADAMTS13 deficiency/TTP (mutations in ADAMTS13)
Enzymopathies
Complement-mediated (mutations in CFH, CFI, CFB,
HMP shunt abnormality C3, CD46, etc.)
Glucose-6-phosphate dehydrogenase Metabolism mediated (MMACHC mutations)
Embden-Meyerhof defect (glycolysis) Coagulation-mediated (DGKE, PLG, THBD mutations)
Pyruvate kinase Acquired
Hexokinase TTP (autoantibody)
Glucose phosphate isomerase Shiga toxin-mediated TMA (SH-TTP)
Phosphofructokinase Drug-mediated (immune mediated)
Triosephosphate kinase Drug-mediated (toxic dose-related)
Phosphoglycerate kinase Complement-mediated (antibody)
Aldolase Systemic disorders
Glutathione metabolism defect DIC, many causes
9
5 nucleotidase deficiency HELLP syndrome
Extrinsic hemolysis Malignancy
Immune mediated Malignant hypertension
Primary Scleroderma renal crisis
Warm-reactive autoimmune hemolytic anemia Antiphospholipid syndrome
Alloimmune hemolytic anemia Infection
Acute hemolytic transfusion reaction Complicated malaria
Delayed hemolytic transfusion reaction Clostridia or Haemophilus influenzae type b
Drug-induced hemolytic anemias (some types) Isolated intravascular sites of hemolysis
Secondary Kasabach-Merritt syndrome
Autoimmune or inflammatory disorders Renal artery stenosis
Evans syndrome Large vessel thrombi
Primary immunodeficiency Severe aortic coarctation
Wiskott-Aldrich syndrome TIPS
Common variable immune deficiency Vasculitis
Acquired immunodeficiency Dysfunctional cardiac valves or cardiac assist devices
HIV infection March hemoglobinuria, extreme running
Malignancy Other mechanical causes
Infection Heat denaturation (blood warmer, thermal burns)
PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 573

Table 2. (continued) reducing oxygen affinity, and shifting the oxygen dissociation
curve to the right to enhance erythrocyte release of oxygen to
Osmotic stress
the tissues, increasing cardiac output, and selectively shunting
Drowning blood to vital organs.6
Mechanical trauma
March hemoglobinuria Symptoms and signs vary based on the duration and severity of
anemia. Patients with acute, severe anemia are overtly symp-
Marathon runners, etc.
tomatic with hypoxia, hypovolemic shock, congestive heart fail-
Direct trauma
ure, and seizures which may lead to death. Common findings in
“Cell saver” devices chronic anemia include pallor, dyspnea, fatigue, exercise intoler-
Thrombectomy ance, dizziness, anorexia, and syncope. If there is hemolysis,
Cardiac bypass jaundice and dark urine may be present. In young children,
chronic anemia may lead to poor growth and failure to thrive,
Extracorporeal membrane oxygenation
and if there is iron deficiency or iron deficiency anemia, affects
Dialysis
on neurocognitive and behavioral development. Patients with

Hypersplenism mild to moderate chronic anemia are sometimes asymptomatic
relative to the degree of anemia as compensatory mechanisms
have had time to be activated.
Approach to the anemic child
Laboratory investigation
Diagnostic evaluation of the anemic child combines history,
physical examination, and laboratory investigation. Initial basic laboratory evaluation includes a complete blood
count (CBC), examination of a PB smear, reticulocyte count,
History and physical direct antiglobulin test (DAT), and serum bilirubin determination.
CBC allows assessment of the anemia and identifies whether
Patient and family history often reveal important clues to the eti-
ology of anemia. Review of birth history should include labor, there are concomitant alterations in leukocyte and platelet counts
delivery, and neonatal course, including the history of anemia, to suggest a disorder not confined to the erythrocyte lineage or
jaundice, phototherapy, or blood transfusion. History of other indicating systemic illness. Examination of erythrocyte indices
medical issues and medication use should be elicited. History of may give clues to the diagnosis; for instance, microcytosis in an
trauma, infections, surgery, travel, and exposure to drugs, chem- anemic infant may suggest the presence of a hemoglobinopathy
icals, toxins, or oxidants should be sought, as should sources of or iron deficiency, whereas an elevated mean corpuscular Hb
blood loss such as epistaxis, gastrointestinal (GI) bleeding, or in concentration may suggest a disorder of the erythrocyte mem-
young women, dysmenorrhea. Dietary history should include a brane such as hereditary spherocytosis. The PB smear may pro-
review of growth and food intake focusing on key nutrients such vide insights into the diagnosis such as spherocytes in hereditary
as iron, folate, vitamin B12, and in infants, milk intake. The age spherocytosis or autoimmune hemolytic anemia, elliptocytes in
of the patient should be considered as different disorders are hereditary elliptocytosis, fragmented cells, schistocytes, and hel-
common in different age groups (Figure 3). met cells in microangiopathic hemolytic anemia, target cells in
hemoglobinopathies, liver disease, and post-splenectomy, and
A family medical review should include the history of anemia, inclusions of various types seen in malaria or babesiosis. Red cell
jaundice, splenomegaly, gallstones, blood or autoimmune dis- distribution width is a measure of the size and volume of popula-
eases, bleeding disorders, splenectomy, or cholecystectomy. tions of circulating erythrocytes. When used with other indices, it
may provide clues to the diagnosis, such as thalassemia. Reticulo-
Physical findings often reflect the timing, severity, and type of cyte Hb concentration is included on many cell counters, provid-
anemia. When anemia is severe and acute, patients are in dis- ing information on iron status.
tress with tachypnea, tachycardia, pallor, and poor perfusion.
Other findings may include a systolic ejection heart murmur, dis- An elevated reticulocyte count indicates increased erythropoietic
tended neck veins, wheezing, and hepatomegaly. If anemia is response to blood loss or hemolysis, whereas a low reticulocyte
chronic, pallor or jaundice may be prominent findings. Jaundice, count, especially relative to the degree of anemia, indicates
scleral icterus, and splenomegaly may be present in either acute inadequate erythropoietic response. A positive DAT test sug-
or chronic anemia. Petechiae, ecchymoses, and purpura may gests immune-mediated hemolysis. The presence of anemia
provide clues to the diagnosis. Findings of dysmorphic features, with findings of hemolysis on PB smear and hyperbilirubinemia
especially craniofacial and limb abnormalities, or signs of sys- in a child with a negative DAT suggests an intrinsic erythrocyte
temic disease suggest features of one of the genetic syndromes defect. The child with acute onset normocytic, normochromic
associated with anemia. Significant vascular abnormalities may nonhemolytic anemia and a negative DAT test should be sus-
indicate localized coagulopathy. pected of having had acute blood loss. Additional diagnostic
evaluation is indicated. The use of a diagnostic algorithm may
Clinical manifestations facilitate evaluation (Figure 2).
The delivery of oxygen throughout the body is the primary role
of the erythrocyte. When anemia develops and tissue oxygen is The utilization of DNA sequencing methodologies has greatly
compromised, the body compensates in several ways, including improved the accuracy of precise genetic diagnosis in many
increasing erythropoietin production to increase red blood cell cases of inherited anemias.7,8 Now available from commercial
production, increasing erythrocyte 2,3-diphosphoglycerate, laboratories, various diagnostic strategies, including targeted

Anemia
MCV decreased MCV normal MCV increased
Retic decreased or normal Retic increased Retic decreased or normal Retic increased Retic decreased or normal Retic increased
Iron deficiency Thalassemia syndromes Chronic disease Immune hemolysis Vitamin B12 deficiency Active hemolysis with
Thalassemia trait Hb E Acute inflammation Membrane disorders Folate deficiency brisk reticulocytosis
Lead poisoning Hb C Acute hemorrhage Metabolic defects Bone marrow failure
Sideroblastic anemia Transient erythroblastopenia Unstable hemoglobins Aplastic anemia
Microangiopathic hemolysis Diamond-Blackfan anemia
DIC Shwachman-Diamond syndrome

HUS Dyskeratosis congenita
TTP Myelodysplastic syndrome
Paroxysmal nocturnal Drug induced
hemoglobinuria Congenital dyserythropoietic anemia
Oxidant exposure Hypothyroidism
Wilson disease Copper deficiency
Infectious suppression
Marrow replacement syndromes
Toxins and medications
Figure 2. An approach to anemia based on mean corpuscular volume and reticulocyte count.
gene capture, gene panels, and whole-exome sequencing, have hemolysis is typically inherited. Extrinsic hemolysis is associated
been used as effective tools for identification of disease-causing with disorders outside the erythrocyte, such as autoimmune
mutations. Genetic testing has allowed new mechanistic insights hemolytic anemia (AIHA), most cases of microangiopathic hemo-
into many inherited anemias and provided the answer in many lysis such as thrombotic thrombocytopenic purpura (TTP), infec-
previously undiagnosed cases. Current molecular genetic analy- tion, mechanical injury, toxins such as lead or copper, and drugs
ses have potential pitfalls, including detecting variants of such as penicillins, quinine, quinidine, methyldopa, and clopi-
unknown significance, making genetic diagnosis uncertain in dogrel. Most cases of extrinsic hemolysis are acquired.
some cases, and the inability to detect mutations in distant regu-
latory elements, deep intronic splicing mutations, and intragenic Interestingly, infectious causes of hemolysis may be due to
deletions.9 Whole genome sequencing, employed primarily on direct action of toxins on the erythrocyte, such as by Clostridium
a research basis to date, has provided the precise genetic diag- perfringens, by direct invasion and destruction of the erythrocyte
nosis in some cases.10 by the organism, such as malaria, or by antibody production
after viral infection.
Normocytic anemia Laboratory hallmarks of hemolysis include anemia and reticulocy-
Many pediatric anemias are associated with normocytic erythro-
tosis. In cases where there is concomitant nutritional deficiency,
cyte indices, MCV 80-100 fL.
marrow dysfunction, toxin exposure, or infection, particularly par-
vovirus infection, the reticulocyte response may be blunted. The
Normocytic anemia with elevated
blood smear shows polychromasia, schistocytes, and fragmented
reticulocyte count
forms, which are particularly prominent in cases where there is
This large group of pediatric anemias includes inherited disor-
shear stress or toxin-induced hemolysis. Unconjugated bilirubin,
ders of the erythrocyte membrane, cellular metabolism, and
lactate dehydrogenase, and aspartate aminotransferase levels
unstable Hbs, as well as acquired disorders including immune
may be elevated. Haptoglobin is often decreased. If hemolysis is
hemolysis and microangiopathic disorders such as hemolytic
intravascular, hemoglobinuria may lead to a positive urine dip-
uremic syndrome, thrombotic thrombocytopenic purpura, and
stick without red blood cells on microscopy.
disseminated intravascular coagulation.
A hallmark of many of these disorders is hemolysis, premature Nonimmune hemolysis

breakdown of erythrocytes. Mechanisms of hemolysis include Nonimmune hemolysis is associated with intrinsic disorders of
poor deformability of the erythrocyte leading to splenic trapping the erythrocyte, including membrane abnormalities, defects of
and subsequent phagocytosis, antibody-mediated destruction metabolism, and unstable Hbs. Microangiopathic hemolysis is
through phagocytosis or direct complement activation, fragmen- associated with hemolytic uremic syndrome, TTP, and dissemi-
tation due to microthrombi or direct mechanical trauma, oxida- nated intravascular coagulation (DIC).
tion, or direct cellular destruction. Hemolysis can be classified in
several ways, such as immune or nonimmune and intrinsic or Erythrocyte membrane disorders Disorders of the erythro-
extrinsic. Intrinsic hemolysis is due to intrinsic erythrocyte defects cyte membrane present at any age, in utero, in the neonatal
such as disorders of Hb, membrane, or metabolism. Intrinsic period, in childhood, and some escape detection until late in life.

Anemia in infants and children
Age Newborn Infant Toddler Preschool Child Preteen Teenager
(0–30 days) (0–1 year) (2–3 years) (4–5 years) (6–9 years) (10–12 years) (13–18 years)
Disorder
Membrane defects
Abnormalities of
metabolism
Unstable hemoglobins
Sideroblastic anemia
D-Thalassemia

E-Thalassemia
Sickle cell disease
Congenital
dyserythropoietic anemia
Diamond-Blackfan anemia
Fanconi anemia
Hemolytic uremic
syndrome
Thrombotic
thrombocytopenic purpura
Disseminated intravascular
coagulation
Hemorrhage
Chronic inflammation
Malignancies
Neonatal alloimmune
hemolytic disease
Primary autoimmune
hemolytic anemia
Secondary autoimmune
hemolytic anemia
Aplastic anemia
Iron deficiency
B12 deficiency
Folate deficiency
Figure 3. Anemia by age.
Hereditary spherocytosis The hereditary spherocytosis (HS) syn- anemia. Severely affected patients may be transfusion-
dromes are associated with qualitative or quantitative defects in dependent, often exhibiting autosomal recessive inheritance.
major erythrocyte membrane proteins, including ankyrin-1, Diagnosis of HS is straightforward in the child with a positive
b-spectrin, band 3, a-spectrin, and protein 4.1R.11 Clinical sever- family history and nonimmune spherocytic hemolytic anemia. PB
ity ranges from asymptomatic patients with well-compensated smear shows variable numbers of spherocytes (Figure 4). Diag-
HS to severe, transfusion-dependent patients. In about three- nostic testing includes eosin-5-maleimide (EMA) flow cytometry
quarters of cases, inheritance is autosomal dominant. Most HS or osmotic fragility (OF) testing. In some cases, EMA binding or
patients exhibit mild to moderate hemolytic anemia, with some OF may be normal. Diagnostic molecular testing is gaining
mild cases exhibiting well-compensated hemolysis without in popularity.

Splenectomy used to be performed routinely in the manage- laboratory, and genetic heterogeneity. Enzyme or antioxidant
ment of HS. Now, due to concerns of sepsis after splenectomy deficiency or impaired function leads to hemolysis.
and long-term risks of vascular disease, including pulmonary
hypertension, thrombosis risk, and atherosclerosis, its use is cur- Glucose-6-phosphate dehydrogenase (G6PD) deficiency The
rently based on disease severity and symptomatology. Most most common metabolic abnormality of the erythrocyte is
advocate for splenectomy in HS patients with severe HS who G6PD deficiency, affecting .400 million people worldwide.13 Its
exhibit growth failure, exercise intolerance, skeletal abnormali- high prevalence is attributed to genetic selection as G6PD-
ties, or extramedullary hematopoiesis. In cases of moderate HS, deficient erythrocytes demonstrate a selective advantage
splenectomy should be decided by well-informed patients, their against Plasmodium falciparum infection.
families, and caregivers.
In normal erythrocytes, reduced glutathione (GSH) detoxifies
Hereditary elliptocytosis, hereditary pyropoikilocytosis, and intracellular oxidants. In G6PD deficiency, the inability to gener-
related disorders The hereditary elliptocytosis (HE) syndromes ate NADPH leads to insufficient amounts of GSH, allowing oxi-
are typically asymptomatic, occurring primarily in individuals of dants free to damage critical erythrocyte proteins. Oxidation of
African descent, and are discovered during unrelated laboratory Hb sulfhydryl groups produces methemoglobin and intracellular

testing. The exceptions are hemolytic HE and the related disor- precipitates of Hb known as Heinz bodies. Erythrocytes are par-
der hereditary pyropoikilocytosis (HPP), when hemolysis, anemia, ticularly susceptible to oxidative stress as the hexose monophos-
and jaundice may be severe. HPP is a rare variant of HE. In HPP, phate shunt is their only source of NADPH.
hemolysis is severe, the MCV is low (50-65 fl), and the blood
smear exhibits erythrocyte morphology reminiscent of that seen Hundreds of mutations in the G6PD gene, located at Xq28,
in thermal burns with elliptocytes, poikilocytes, pyknocytes, frag- have been described, primarily missense mutations influencing
mented cells, and microspherocytes. enzyme kinetics, stability, or both. Because it is located on the X
chromosome, G6PD deficiency primarily affects males, as they
In both hemolytic HE and HPP, most patients have parents with only carry 1 G6PD allele. Females can express 1 or 2 G6PD
typical HE and thus are homozygotes or compound heterozy- types and may be affected by G6PD deficiency depending on
gotes for spectrin defects inherited from each of the parents. In the degree of Lyonization of individual alleles. Only 1 X chromo-
many patients, hemolysis abates during infancy, and the clinical some is active in any given cell, the Lyon hypothesis; thus,
picture evolves to typical HE with minimal to no anemia in child- G6PD activity depends on the expression of wild type or mutant
hood. In severe cases that do not improve, splenectomy has alleles. In women heterozygous for G6PD deficiency, average
been successfully used. G6PD activity may be normal, mildly, moderately, or severely
reduced, depending on the degree of Lyonization, making these
Hereditary stomatocytosis syndromes The hereditary stomatocy- G6PD-deficient erythrocytes susceptible to the same oxidant
tosis (HSt) syndromes12 are a heterogeneous group of disorders stress as G6PD-deficient cells in men. Typically, the overall
characterized by abnormal permeability of erythrocytes to degree of hemolysis in G6PD-deficient women is less because
sodium and potassium, leading to alterations in water content. there is a smaller population of cells susceptible to oxidative
Subtypes of HSt have presented in the perinatal period with stress.
hydrops fetalis, hemolytic anemia, and hyperbilirubinemia, with
others presenting with nonimmune hydrops fetalis unrelated to G6PD deficiency is often classified into 3 clinical syndromes: 1)
the degree of fetal anemia. Hereditary xerocytosis has been neonatal jaundice (NNJ), 2) CNSHA, and 3) acute hemolysis
linked to mutations in the mammalian mechanosensory transduc- after exposure to an oxidative stressor. NNJ typically has an
tion protein PIEZO1 or the calcium-activated Gardos channel. onset on the second or third day of life. While the degree is vari-
able, severe cases resulting in kernicterus or even death have
Patients present with variable degrees of anemia and few to been described. In most cases, phototherapy is adequate ther-
many stomatocytes on PB smear. In the most common subtype, apy, with extreme cases requiring exchange transfusion. Anemia
dehydrated hereditary stomatocytosis, or hereditary xerocytosis, is uncommon in NNJ. In G6PD deficiency with CNSHA, there is
erythrocyte potassium concentration and total monovalent cat- chronic anemia, which may be exacerbated by oxidant expo-
ion content are decreased, reflected in elevated MCHC and sure. Acute hemolysis after oxidant exposure, such as a sulfa
MCV and decreased erythrocyte osmotic fragility. Treatment is drug, ascorbic acid, or fava beans, may occur at any age.
supportive. Splenectomy is not recommended due to the ap- Oxidant-induced hemolysis has occurred after maternal oxidant
parent predisposition to major thromboses after splenectomy. ingestion in utero in the G6PD-deficient fetus and in the breast-
Another unusual manifestation of hereditary xerocytosis is the fed, G6PD-deficient infant.
propensity for iron overload, particularly in adulthood, indepen-
dent of transfusion history. Patients typically present with fever, nausea, abdominal pain,
diarrhea, jaundice, and dark urine within 48 hours of oxidant
Defects of erythrocyte metabolism Disorders of erythrocyte exposure. The spleen and liver may be enlarged and tender.
metabolism comprise a small but important group of inherited Laboratory findings include normochromic, normocytic anemia
disorders. Often termed congenital nonspherocytic hemolytic with anisocytosis, and reticulocytosis. Evidence of hemolysis may
anemia (CNSHA), this group includes disorders not due to be seen. Heinz bodies, a classic finding in G6PD deficiency, may
immune-mediated disturbances, thalassemia or sickle cell dis- be seen. However, they are rapidly cleared from the circulation
ease (SCD), or erythrocyte membrane disorders. These include and may not be found. Additional laboratory findings include
abnormalities of glutathione, nucleotide, or glucose metabolism. free Hb in the blood and hemoglobinuria. Semiquantitative
Like the HS syndromes, these disorders have significant clinical, screening tests are available, but these are unreliable after an

A B

C D
E F
Figure 4. PB smears. PB smears from (A) hereditary spherocytosis. Dense, spherical-shaped erythrocytes are seen. (B) b-Thalassemia major. Hypochromic, microcytic erythro-
cytes, anisocytosis, and a nucleated red blood cell are seen. (C) Sideroblastic anemia. Polychromasia, anisopoikilocytosis, and basophilic stippling are seen in a case of X-linked con-
genital sideroblastic anemia. (D) Thrombotic thrombocytopenic purpura. Anisopoikilocytosis and marked schistocytosis are seen on the smear of an infant with Upshaw-Schulman
syndrome. (E) Iron deficiency. Significant anisocytosis, hypochromia, and microcytosis are seen. (F) Vitamin B12 deficiency. Macro-ovalocytes, microcytes, and hypersegmented
neutrophils are seen. Erythrocyte basophilic stippling is shown in inset. These images were originally published in the ASH Image Bank. (A) Teresa Scordino, Hereditary
spherocytosis, 2016, #00060308. (B) Girish Venkataraman, b-thalassemia major, 2018, #00062081; (C) Katherine Calvo, Congenital sideroblastic anemia peripheral blood, 2015;
#00060064; (D) Helle Borgstrøm Hager and Mari Tjernsmo Andersen, Thrombotic thrombocytopenic purpura, #00061402; (E) Iron deficiency anemia moderate, 2015, #00060219.
(F) Volodymyr Shponka and Maria Proytcheva, Megaloblastic anemia caused by severe B12 deficiency in a breastfed infant. 2017, #00061082. © The American Society of Hematology.
acute hemolytic episode and do not typically detect female het- Defects in enzymes of the Embden-Meyerhof glycolytic path-
erozygotes. Direct functional assays and DNA diagnosis can way, except for X-linked phosphoglycerate kinase, are inherited
confirm the diagnosis. in an autosomal recessive manner. Pyruvate kinase deficiency

(PKD), the most common abnormality of the Embden-Meyerhof some malignancies and vascular malformations. In these dis-
pathway, is clinically heterogeneous, ranging from well- eases, DIC is suspected when there is bleeding and/or thrombo-
compensated anemia to transfusion dependence.14 Typical pre- sis in a patient with thrombocytopenia, hypofibrinogenemia,
sentation is in infancy or early childhood with jaundice, pallor, prolonged clotting times, and increased fibrin degradation prod-
and anemia. The need for phototherapy and transfusion is com- ucts. Therapy for DIC is generally supportive, with the focus on
mon in the neonatal period. Complications of PKD include gall- the treatment of the underlying disease.
stones and iron overload. Splenectomy improves anemia in
many patients. Initial trials with oral, small molecule allosteric Kasabach-Merritt syndrome (KMS) is a rare, local consumptive
activators of pyruvate kinase show promise for patients with coagulopathy that presents in the neonatal period with hypofi-
structural variants of pyruvate kinase. brinogenemia, thrombocytopenia, and microangiopathic anemia
in association with an enlarging vascular malformation.17 The
Other rare defects of the Embden-Meyerhof pathway present in anemia and coagulopathy, which may be severe, improve with
infants and children with jaundice and anemia.15 These include regression or removal of the tumor. Treatment of KMS focuses
glucose phosphate isomerase deficiency, hexokinase deficiency, on the treatment of the vascular malformation and may include
2,3-biphosphoglycerate mutase deficiency, and phosphoglycer- surgery, embolization, steroids, vincristine, or mTOR inhibitors.18

ate kinase deficiency.16 Disorders of glutathione metabolism Hematologic abnormalities are treated supportively.
include g-glutamyl cysteine synthetase and glutathione synthe-
tase deficiency, which also present with anemia in infancy or HUS The triad of HUS is thrombotic microangiopathy with
childhood. Diagnosis of metabolic defects is confirmed by eryth- hemolytic anemia, thrombocytopenia, and renal involvement.19
rocyte enzyme analyses or molecular testing. HUS is a common cause of acute renal impairment in children,
especially those ,5 years old.20 Typical HUS is caused by
Unstable Hbs Unstable hemoglobinopathies, due to structural Shiga-like toxin produced by Escherichia coli (O157:H7) or Shiga
abnormalities of the a- or b-globin chain, are an underappreci- toxin produced by Shigella dysenteriae. Atypical HUS, defined
ated and underdiagnosed cause of dominantly inherited as HUS without Shiga toxin, is associated with bacterial infection,
CNSHA.16 Unstable Hb leads to precipitates of heme and globin medications, or immune-associated processes that lead to endo-
chain fragments forming Heinz bodies, the basis for the name thelial damage. Infections associated with atypical HUS include
congenital Heinz body hemolytic anemia. Unstable Hbs are infections caused by Streptococcus pneumoniae, Clostridium
detected by heat or isopropyl alcohol precipitation testing as not difficile, Mycoplasma pneumoniae, HIV, histoplasmosis, influenza
all unstable Hbs are associated with abnormally migrating bands A virus, and coxsackievirus. Medications associated with atypical
on Hb electrophoresis. Molecular testing can verify the diagnosis. HUS include mitomycin C, cyclosporine, quinine, cisplatin, and
Treatment is supportive. cocaine. Patients with atypical familial HUS, a rare subtype due
to inherited variants of the complement pathway that lead to
Two unstable Hbs present with hemolytic anemia in early endothelial damage, may suffer recurrent episodes of HUS.
infancy. Hb Hasharon is a mutant a-globin that, when paired
with g-globin, produces an unstable Hb. However, when mutant Patients initially present with fever, abdominal pain, nausea,
Hb Hasharon chains are paired with b-globin, it is no longer vomiting, and diarrhea which is often bloody.19 As the disease
unstable, attributed to the 10-fold higher affinity between a and progresses, symptoms of anemia, jaundice, pallor, fatigue, renal
b chains than between a and g chains. Hb F Poole is an unstable impairment, hematuria, oliguria, or anuria develop. Laboratory
Hb due to mutation in the g-globin chain. Hb Hasharon, Hb F findings include thrombocytopenia and anemia, as well as find-
Poole, and other unstable Hb variants influencing fetal Hb struc- ings of hemolysis and renal dysfunction. Treatment includes sup-
ture and function produce hemolytic anemia in early infancy portive care and terminal complement blockade with
resolve as the fetal-to-adult Hb switch occurs. eculizumab.21 A subset of patients develop oliguric renal failure
requiring dialysis. Patients with atypical familial HUS may require
Hb Koln, the most common unstable Hb, is associated with plasma exchange. The long-term prognosis is good if there is
compensated reticulocytosis, sometimes with erythrocytosis if prompt initiation of supportive therapy. Patients with severe coli-
the degree of hypoxia is greater than the degree of hemolysis. tis may develop intestinal strictures, while those with severe
While inherited in an autosomal-dominant manner, de novo renal injury may develop chronic renal failure.
mutations are common.
TTP TTP is thrombotic microangiopathy characterized by
SCD is considered with thalassemia syndromes. thrombocytopenia, microangiopathic hemolytic anemia, fever,
mucosal and skin bleeding, and ischemic changes in many
Microangiopathic hemolysis Thrombotic microangiopathy, organs, particularly the brain, kidney, and heart, accompanied
clot formation in small blood vessels throughout the body, can by marked deficiency of functional ADAMTS13.22 TTP is primar-
lead to microangiopathic hemolytic anemia and thrombocytope- ily a disease of adults and is characterized by circulating anti-
nia. Disseminated intravascular coagulation, hemolytic uremic bodies to ADAMTS13. Much less commonly, the absence of
syndrome (HUS), and TTP are the most common causes of functional ADAMTS13 is due to recessively inherited mutations
microangiopathic hemolysis in childhood. in ADAMTS13, Upshaw-Schulman syndrome (USS).23
Disseminated intravascular coagulation (DIC) DIC is a common Approximately a third of pediatric TTP cases are associated with
cause of anemia in critically ill infants and children. It is often USS, with the remainder of pediatric cases being acquired. The
associated with sepsis, meningitis, necrotizing enterocolitis, first episode of TTP in USS typically occurs in infancy or early child-
respiratory failure, pancreatitis, severe liver failure, as well as hood with variable disease severity correlating with genotype and

other unknown genetic or environmental influences. PB smear disease. Neurologic, psychiatric, renal, and joint manifestations
shows anisopoikilocytosis and marked schistocytosis. Treatment is may also be found. Hemolytic anemia may be severe and is
with plasma exchange and, as indicated, steroids, rituximab, and sometimes the presenting sign.30 Neutropenia and thrombocy-
other immune modulators. Caplacizumab shows good efficacy in topenia may be observed. Treatment includes chelation, zinc
adults and may ultimately replace plasma exchange.24,25 supplementations, and liver transplantation in selected cases.
Paroxysmal nocturnal hemoglobinuria (PNH) PNH, an Immune hemolysis

acquired disorder of the cell membranes of multipotent marrow Immune-mediated hemolysis in the pediatric age group includes
stem cells, is rare in children.26 Somatic mutation in a hemato- neonatal alloimmune hemolytic disease, primary autoimmune
poietic stem cell propagates into clonal populations of mutant hemolytic anemia, and secondary autoimmune hemolytic ane-
blood cells susceptible to complement-mediated destruction, mia. In some cases of immune-mediated anemia, antibodies are
particularly clonal-derived erythrocytes, deficient in proteins that against antigens expressed on early erythroid progenitor cells,
impede complement-mediated lysis via the constitutively-active leading to an inappropriately low reticulocyte count clouding
alternative pathway.27 About two-thirds of pediatric patients the diagnosis.31,32 Similarly, diagnosis of immune-mediated ane-
have marrow failure, and the remainder have either intermittent mia in infants at their physiologic nadir with relative reticulocyto-

or chronic anemia, often with leukopenia and thrombocytope- penia may be challenging.
nia. Hypoplastic or aplastic pancytopenia may precede or follow
the diagnosis of PNH. Thrombosis and thromboembolism may Neonatal alloimmune hemolytic anemia Neonatal alloim-
occur. In rare cases, PNH may progress to acute myelogenous mune hemolytic anemia occurs when maternal antibodies pro-
leukemia. Mortality is related to the development of aplastic duced against incompatible antigens present on fetal red blood
anemia or thrombotic complications. Prior to eculizumab, the cells cross the placenta and attack fetal erythrocytes.33 After
survival rate for children was 80% at 5 years, 60% at 10 years,
birth, maternal antibodies continue to circulate and attack neo-
and 28% at 20 years.
natal erythrocytes. This may lead to hemolysis with neonatal
anemia and hyperbilirubinemia requiring treatment with photo-
The severity of normocytic anemia is variable, and findings of
therapy, erythrocyte transfusion, or exchange transfusion. While
chronic intravascular hemolysis are common. Poikilocytosis and
Rh-linked hemolysis has markedly decreased after the introduc-
anisocytosis are seen on PB smear. Hemoglobinuria is rarely
tion of anti-D immunoglobulin prophylaxis, it remains a problem
seen in children compared with adults with PNH. Levels of eryth-
worldwide. ABO incompatibility, usually adequately treated by
rocyte acetylcholinesterase activity and decay-accelerating factor
phototherapy alone, is now the most common cause of blood
are decreased. Flow cytometry reveals low levels of CD59 on
group incompatibility in Western countries. Alloimmunization to
erythrocytes and low levels of CD55 and CD59 on granulocytes.
other erythrocyte antigens such as Kell, Fy, Jk, C, and E may
Aerolysin testing of granulocytes and monocytes increases the
also lead to neonatal alloimmune hemolytic anemia.
sensitivity of detection by binding to glycosylphosphatidylinosi-
tol anchors. Treatment is with eculizumab, a monoclonal anti-
AIHA AIHA, acquired hemolysis caused by the production of
body against complement component C5 that interrupts the
formation of the membrane attack complex, blocking down- antibodies acting against the host’s own erythrocyte antigens, is
stream complement destruction of erythrocytes and activation of uncommon in children, with a peak incidence ,5 years of
platelets. Because of the cost and lifelong duration of eculizu- age.34 It is classified as primary AIHA (comprising 30% to 40%
mab treatment in children or cases of severe aplastic anemia, of pediatric cases in which no cause is found) or secondary
hematopoietic stem cell transplant (HSCT) is considered. AIHA (comprising 60% to 70% of cases where a triggering event
is identified).
Oxidant exposure Oxidant hemolysis is not always associated
with an inherited metabolic abnormality of the erythrocyte, par- Demonstration of a positive DAT in a patient with hemolysis of
ticularly in neonates. After a presumed exposure, there is acute- unexplained cause is found in most cases of AIHA. The DAT
onset hemolytic anemia and hyperbilirubinemia with “bite” and detects immunoglobulins, typically IgG, or complement bound
“blister” cells and other irregularly shaped red cells on PB to the erythrocyte. However, a positive DAT is not specific, as it
smear. Typically, no obvious source for the presumed oxidant may be associated with several diseases such as malignancy,
stress is identified, and the episode resolves in a few days. systemic lupus erythematosus, liver or kidney disease, or chronic
Transfusion is rarely required. infection, possibly via the passive deposition of immunoglobu-
lins or immune complexes onto the erythrocyte. The indirect
Other causes of hemolysis Other causes of hemolysis include antiglobulin test detects erythrocyte antibodies in patient serum
snake bites, toxin exposure, galactosemia, prolonged or recurrent by incubating patient serum with a panel of known erythrocyte
metabolic acidosis, lysosomal storage disease, and some amino antigens and observing whether agglutination occurs.
acidopathies. In pregnancy, HELLP syndrome28 (hemolysis, ele-
vated liver enzymes, and low platelet count) may occur, particularly Primary AIHA Primary AIHA is immune-mediated hemolysis
in pregnancies complicated by preeclampsia or eclampsia. The not associated with systemic illness, although in some cases, a
primary treatment is delivering the baby as soon as possible. history of a recent infectious disease is obtained.34 The role of
infection as the initiating rather than causal factor in childhood
Wilson disease Wilson disease is a rare inherited disorder of AIHA is unknown.
copper metabolism due to mutation in ATP7B, a copper trans-
porting ATPase, that leads to copper overload in the liver, brain, Warm-reactive AIHA is the most common subtype of primary
and other organs.29 Children have significant, progressive liver AIHA, associated with an IgG antibody that reacts at 37 C, rarely

fixes complement, with extravascular hemolysis.35,36 In these dark urine. If anemia is severe, there may be signs of cardiovas-
patients, 3 patterns of reactivity may be noted on DAT: IgG cular compromise, acute renal insufficiency, and neurologic find-
alone, C3d alone, or both. The second form is paroxysmal cold ings. Important in the investigation of secondary AIHA is the
hemoglobinuria. In this condition seen primarily in children, IgG- consideration that hemolysis may be one of the initial manifesta-
type antibodies bind and fix complement at 4 C and cause tions of a serious systemic disease. Treatment includes treating
intravascular hemolysis. It is common after a viral-like infectious the associated systemic illness with specific therapy similar to
illness. The third form is cold agglutinin disease, which is more that of primary AIHA, including steroids, IVIG, and rituximab.
common in adults and is characterized by an IgM type antibody
that binds red blood cells (RBCs) below 37 C, fixes complement, Normocytic anemia with normal or decreased
and leads to both extravascular and intravascular hemolysis. reticulocyte count
Standard DAT cannot detect IgM coating RBCs. Thus, DAT is This category of anemias is associated with acute blood loss
typically positive only for complement. In children, it is usually due to hemorrhage, early stages of acute hemolysis, chronic dis-
seen after Mycoplasma infection. ease, acute inflammatory states, and malignancies.
In a few settings, patients with AIHA may have a negative DAT Acute hemorrhage Acute trauma due to motor vehicle acci-

test when there is a low-affinity antibody, an immunoglobulin dents, falls, and assaults are 3 of the most common causes of
not tested for is present (eg, IgA), or there are low levels of trauma in pediatric patients associated with acute hemorrhage.
erythrocyte-bound antibody.37 Additional testing, such as the In some cases, a high index of suspicion is needed when blood
indirect antiglobulin test or super Coombs testing, enhanced
loss may be occult (eg, from a ruptured spleen or lacerated liver)
Coombs testing that utilizes different techniques to detect low-
due to an event not initially reported, such as a sports collision
affinity antibodies, erythrocyte-bound antibodies below the limit
or a bicycle fall.43 Outside of trauma, in older children, the GI
of detection of the standard DAT, IgA antibody, erythrocyte-
tract is a common site of blood loss associated with a variety of
bound IgM, monomeric IgM antibody, and IgM warm anti-
disorders, including Meckel’s diverticulum, ulcerative colitis,
body,38 is necessary to discern the diagnosis. Children with
Crohn’s disease, single or multiple polyps, esophageal and gas-
DAT-negative AIHA often have a less severe clinical course and
tric varices, and in menstruating girls, blood loss due to dysmen-
respond well to steroid therapy.
orrhea. Dysmenorrhea may be associated with von Willebrand
disease and other bleeding disorders, so it is important to
Primary AIHA is usually a self-limiting illness. Recurrence is
inquire about frequent nose bleeds, easy bruising, and family
uncommon. If anemia is severe, a course of steroids is pre-
history of the same. In neonates, acute blood loss may have
scribed,39 sometimes with IVIG. Second-line therapy, including
occurred due to fetomaternal or fetoplacental hemorrhage,
anti-CD20 monoclonal antibody therapy with rituximab, immu-
abruptio placentae, or placenta previa.
nomodulatory drugs such as danazol, azathioprine, cyclosporine,
high-dose cyclophosphamide, and vincristine, may be required
Acute hemolysis Patients with acute onset hemolysis may pre-
if there is no response to steroids or there is steroid depen-
sent with marked normocytic anemia before there has been a
dence. Third-line therapy considers splenectomy. Overall mortal-
ity is a few percent. reticulocyte response. This may be the presentation of AIHA
after viral or Mycoplasma infection. Acute hemolysis may occur
Secondary AIHA Secondary AIHA is immune-mediated hemo- after an acute oxidant challenge in patients with G6PD defi-
lysis associated with systemic illness. These include infection ciency, an unstable Hb, or metabolic defects. It may occur with
with a variety of organisms such as Epstein-Barr virus, cytomega- acute splenic sequestration in SCD and other disorders. S. pneu-
lovirus (CMV), Mycoplasma, pneumococcus, and parvovirus, moniae infection may produce an enzyme that exposes the
malignancy such as Hodgkin lymphoma, autoimmune diseases Thomsen-Friedenreich cryptoantigen (or T antigen) found on
such as systemic lupus erythematosus, rheumatoid arthritis, erythrocytes, platelets, and glomeruli. Antibodies to the T anti-
ulcerative colitis, Evans syndrome, and autoimmune lympho- gen, which are normally found in human serum, bind the
proliferative syndrome, liver disease (particularly giant cell exposed T antigen, and the antigen-antibody reaction leads to
hepatitis) after solid organ or hematopoietic cell transplanta- atypical HUS and hemolytic anemia.44 A similar situation may
tion,40,41 and inherited and acquired immunodeficiency occur in neonates with necrotizing enterocolitis and Clostridium
syndromes such as common variable immunodeficiency. This welchii or C. perfringens infection.45 One of the toxins produced
is the basis for the recommendation to examine serum immu- by clostridial organisms cleaves sialic acids from erythrocyte
noglobulins, antinuclear antibodies, and lymphocyte subsets membrane glycoproteins exposing the T antigen. Transfusion of
in children presenting with AIHA.40 adult blood, which almost always contains anti-T antibodies,
may lead to severe, rapidly progressive intravascular hemolysis
Another type of secondary AIHA is drug-associated immune causing acute renal failure, hypovolemic shock, and death. In
hemolytic anemia.42 Suspicion for this diagnosis is when there is hospitalized patients, hemolysis may occur after transfusion reac-
acute onset of hemolysis after initiation of a potentially offend- tion from major blood group incompatibility.
ing drug. Cases have been described after administration of cef-
triaxone, piperacillin, fludarabine, cefotetan, and diclofenac have Chronic disease/inflammation Anemia of chronic disease/
been implicated. Specialized laboratory testing may aid in the inflammation is found in patients with a wide variety of disor-
diagnosis. ders, infection, malignancies, renal disease, rheumatologic disor-
ders, heart failure, chronic lung disease, and GI diseases such as
Many children with secondary AIHA present with signs of acute ulcerative colitis, Crohn’s disease, and celiac disease. Several
hemolysis with abrupt onset of pallor, jaundice, fatigue, and factors contribute to anemia. These include mild hemolysis,

decreased sensitivity of erythroid precursors to erythropoietin functional outcomes such as impaired neurocognitive develop-
due to inflammatory cell-produced cytokines, and inflammation- ment, exercise performance, and pregnancy outcome.53
mediated increased synthesis of hepcidin, which binds ferropor-
tin, blocks iron export from the liver and GI tract, and decreases Laboratory testing reveals decreased Hb levels, decreased mean
iron levels available to developing erythroid cells.46 Many of corpuscular volume, and decreased mean corpuscular Hb level.
these patients also have iron deficiency and chronic inflamma- PB smear shows significant anisocytosis, hypochromia, and micro-
tion, exacerbating the anemia. cytosis (Figure 4). A variety of tests have been employed in the
assessment of iron deficiency anemia (Figure 5).53 Decreased
Anemia of chronic disease/inflammation is typically normocytic serum ferritin ,10-12 mg/L in conjunction with a normal
but may be microcytic if iron deficiency is prominent. Erythropoi- C-reactive protein, decreased reticulocyte Hb concentration
etin levels are low commensurate to the degree of anemia. (CHr), decreased serum iron levels, and decreased transferrin
Hepcidin levels, erythrocyte sedimentation rate, and C-reactive saturation are indicative of iron deficiency. CHr, a good indica-
protein levels are often elevated. Treatment of the underlying tor of iron availability and iron-deficient erythropoiesis, is a pop-
condition improves the anemia. In some patients, erythropoietin- ular test as it is easily obtained from most automated blood cell
stimulating agents are prescribed. Severe cases require analyzers. The RDW is elevated in iron deficiency. In otherwise

transfusion. well children, a trial of iron supplementation without additional
laboratory testing is a strategy frequently used to diagnose iron
Transient erythroblastopenia of childhood (TEC) TEC is a deficiency.
rare red cell aplasia of young children or infants, usually occurring
after a viral infection.47 Normocytic normochromic anemia and Treatment is with an iron-rich diet and oral iron supplementa-
reticulocytopenia are sometimes accompanied by neutropenia tion. Infants ,1 year of age should be provided breast milk
and thrombocytosis. Marrow examination is normal. After 1 to or iron-fortified formula, and cow’s milk avoided. In addition,
2 months, patients undergo spontaneous recovery. after 6 months of age, foods rich in iron, such as iron-fortified
cereal and pureed meats, can be given. After a year of age,
cow’s milk intake should be limited. Supplementation is initi-
Microcytic anemia ated with 3 mg/kg ferrous sulfate given once a day in the
Microcytic anemia with normal or decreased morning or between meals without milk or other dairy prod-
ucts, which may inhibit absorption.54 In adolescents, treat-
reticulocyte count
ment includes appropriate nutritional intake, as poor dietary
Iron deficiency anemia Iron deficiency and iron deficiency ane-
habits often contribute to iron deficiency, and 60 mg elemen-
mia are common throughout the world.48 Among children in
tal iron twice a day.55 After initiating therapy, follow-up labo-
developing countries, iron deficiency is the most common nutri-
ratory testing should be performed in 2 to 4 weeks, assessing
tional deficiency, whereas in industrialized countries, while the
reticulocyte and Hb response.
incidence is decreasing, attributed in part to iron fortification of
infant formulas and cereals, it remains a common cause of anemia
In cases of iron deficiency unresponsive to oral therapy, poor
in children and adolescents. The link of iron deficiency, even with-
compliance to therapy, persistent low-iron diet, ongoing malab-
out anemia and more important than anemia, is the relationship sorption or blood loss, and an incorrect diagnosis should be
between iron deficiency and cognitive defects,49 some of which considered. Conditions in the differential diagnosis include
may be reversible. cow’s milk protein-induced colitis, celiac disease, inflammatory
bowel disease, malaria, hookworm, schistosomiasis, as well as
The American Academy of Pediatrics recommends universal screen- thalassemia trait or presence of the anemia of chronic inflamma-
ing for anemia in all children around 1 year of age, including assess- tion. In the anemia of chronic inflammation, systemic immune
ing for risk factors such as history of prematurity, low birth weight, activation leads to alterations in iron metabolism leading to iron
lead exposure, exclusive breastfeeding without iron supplementa- retention in macrophages and reduced iron absorption, with
tion beyond 4 months, as well as feeding problems, poor growth, iron deficiency one of the contributors to anemia.56 In refractory
low socioeconomic status, Mexican American descent, and special cases, the diagnosis of iron-refractory iron deficiency anemia
health care needs.50 Iron deficiency occurring in older children and (IRIDA), a recessively inherited disorder due to mutations in
adolescents may be associated with poor diet, malabsorption syn- TMPRS6, should be considered.57 In both anemia of chronic
dromes, and chronic blood loss, particularly in menstruating girls inflammation and IRIDA, dysregulation of hepcidin,53 the pri-
and women. In developing countries, infection with hookworm and mary regulator of systemic iron homeostasis, lead to iron-
schistosomiasis are important causes of iron deficiency. restricted or iron-deficient erythropoiesis with poor response to
oral iron therapy.58
Iron deficiency is often symptomatic and may or may not be
accompanied by anemia. Signs of iron deficiency in infants In some cases, parental iron supplementation may be indicated.
include poor feeding and irritability.51 In older children and Patients with poor compliance or oral iron tolerance, malabsorp-
adolescents, iron deficiency may be associated with lethargy, tion due to various GI disorders, ongoing, controlled blood loss,
fatigue, pallor, difficulty concentrating, headache, and tinnitus. and patients with anemia of chronic inflammation or IRIDA are
Other signs may include atrophic glossitis, alopecia, dry hair, candidates for parenteral iron.
dry skin, and koilonychia. Some iron-deficient patients exhibit
pica, the compulsive ingestion of nonnutritive substances, Lead intoxication Ingestion of lead-contaminated dust and
sometimes attributed to lack of iron in some areas of the paint chips from interior surfaces of older homes with deteriorat-
brain.52 Iron deficiency has been associated with poorer ing lead-based paint and exposure to soil contaminated by

Iron Low iron stores Absolute Absolute Functional iron Functional iron Iron-refractory
repletion iron deficiency iron deficiency deficiency deficiency with iron deficiency
(non-anaemic) (anaemia) absolute iron anaemia due to
deficiency TMPRSS6 variants
Body iron stores and iron available for erythropoiesis Body iron stores
Inadequate Adequate
Body iron stores
Iron available
for erythropoiesis Body iron stores
and iron available
for erythropoiesis
No systemic inflammation Systemic inflammation No systemic

inflammation
Symptoms Nil Asymptomatic or Asymptomatic or Likely Symptoms of Symptoms of Symptomatic iron

midly symptomatic symptomatic: fatigue, symptomatic, underlying underlying deficiency anaemia

(eg, fatigue); poor concentration, decompensation condition; condition;
possible reduced dizziness, tinnitus, if severe or poor symptoms of symptoms of
physical or cognitive headache, pica, or medical reserves anaemia anaemia
function; underlying restless legs
condition could be
evident (eg,
bleeding or
nutrition)
Haemoglobin Normal Normal Normal or Reduced Mild to moderate Mild to moderate Reduced
low-normal (anaemic) anaemia anaemia (anaemic)
Mean cell Normal Normal Normal or reduced Reduced Normal or mild Reduced Reduced
volume and reduction
mean cell
haemoglobin
concentration
Ferritin !30–60 Pg/L 15–30 Pg/L 15–30 Pg/L 15–30 Pg/L Normal or 70–100 Pg/L Typically
increased depending on 20–50 Pg/L
depending on degree of
inflammation and inflammation
body iron stores
Transferrin !20% Usually !20% 20% 15% Usually 20% 20% 20%, usually 5%
saturation
Reticulocyte Normal Normal Low Low Low Low Low

haemoglobin
content*
Soluble Normal Normal Increased Increased Normal Normal or Increased
transferrin increased
receptor*
Hepcidin* Normal Low-normal Low Very low Increased relative Normal or High relative to
to transferrin reduced transferrin
saturation saturation
Bone marrow Normal Detectable or Absent Absent Detectable Absent Absent or trace
stainable iron absent
Figure 5. Markers of iron deficiency. *Diagnostic thresholds for reticulocyte Hb content vary between the type of blood cell analyzer as well as for hepcidin and
soluble transferrin receptor assays. Reprinted with permission from Pasricha et al.120
leaded gasoline and lead-based paints are the most common The Centers for Disease Control and Prevention (CDC) and the
causes of lead poisoning in the United States. Other sources of American Academy of Pediatrics both recommend targeted
lead include contaminated drinking water, imported food in sol- screening of all Medicaid-enrolled and -eligible children, as well
dered cans, imported chocolate and candy, and ceramic pot- as those who were born outside of the United States.59 Studies
tery. There is no lead poisoning-specific signs or symptoms, have shown an association between low iron levels and elevated
only nonspecific findings such as abdominal pain, constipation, blood lead levels in infants and children, supporting theories
nausea, vomiting, decreased growth, delayed sexual maturation, that iron deficiency increases a child's susceptibility to lead poi-
increased dental caries, and impaired neurologic development. soning and sufficient iron stores reduce the risk of lead poison-
A high index of suspicion is required. Associated anemia is ing. Treatment includes removal of the child from the offending
hemolytic as lead poisoning is accompanied by an acquired environment or removal of the cause of the exposure. In more
deficiency of erythrocyte pyrimidine 59 -nucleotidase. severe cases, chelation is required. With these measures, anemia

Features of hypochromic anemias
Ferritin Serum TIBC Transferrin Red cell Marrow
iron saturation distribution storage iron
width
Iron deficiency anemia Low Low High Low High Low
Thalassemias Normal to Normal to Low to Normal to Normal Normal to

high high normal high high
Sideroblastic anemias High Normal to Low to High High High

high normal

Anemia of chronic Normal to Low Low to Low Normal Low to
disease high normal normal
Figure 6. Features of hypochromic anemias.
resolves. The CDC recommends all lead-intoxicated children be elevated RDW, PB smear with microcytosis, marked hypochromia,
tested for concomitant iron deficiency. The association between anisocytosis, poikilocytosis, target cells, and occasional sidero-
iron deficiency, pica, and lead intoxication has been known for cytes (Figure 4). Bone marrow (BM) aspirate shows abundant ring
centuries. sideroblasts. Anemia is normocytic or macrocytic in females as
skewed X-chromosome inactivation in hematopoietic stem and
Hb disorders Microcytosis with mild to no anemia and minimal progenitor cells leads to predominantly nonviable erythroid pre-
reticulocytosis may be due to a- or b-thalassemia trait or hetero- cursors carrying a mutant ALAS2 allele that undergo intramedul-
zygous gdb-thalassemia. Determining the etiology of microcytic lary hemolysis while circulating erythrocytes represent the
anemia includes assessment of iron stores and Hb electrophore- progeny of erythroid precursors carrying the normal ALAS2 allele.
sis (Figure 5). The RDW is elevated in over half the cases of iron Erythropoietin drives increase production of these normal erythro-
deficiency anemia but normal in the thalassemia trait. A Mentzer cytes with rapid release from the marrow leading to macrocytosis.
index (MCV/RBC) of ,13 suggests thalassemia trait, whereas
.13 suggests iron deficiency.60 Treatment of syndromic CSA is primarily related to the nonhe-
matologic features of the disease and their management. Treat-
Sideroblastic anemias The congenital sideroblastic anemias ment of nonsyndromic CSA revolves around the treatment of
(CSAs) are rare disorders of mitochondrial dysfunction due to anemia and prevention of iron overload.61 Vitamin B6, an essen-
defects in heme biosynthesis, iron-sulfur cluster biogenesis, gen- tial cofactor for the ALAS enzyme, supplements are prescribed
eralized mitochondrial protein synthesis, or abnormalities in spe- in cases of XLAS.
cific mitochondrial respiratory chain proteins involved in
oxidative phosphorylation.61 CSAs are classified into syndromic Microcytic anemia with increased
and nonsyndromic forms. reticulocyte count
Disorders of Hb Disorders of Hb, including thalassemia syn-
Syndromic CSAs include TRNT1 mutations manifest by sidero- dromes and SCD, are among the most common monogenic
blastic anemia, B-cell immunodeficiency, periodic fevers, and disorders worldwide.64 The thalassemias are disorders character-
developmental delay, mutations in PUS1, YARS2, LARS2 manifest ized by a decreased or absent globin chain production due to
by myopathy, lactic acidosis, sideroblastic anemia, and ABCB7 numerous point mutations or deletions in either the a- or
mutations associated with ataxia. Nonsyndromic CSA presents b-globin genes. Globin chain deficiency leads to ineffective
with isolated anemia without other clinical manifestations and erythropoiesis as excessive unpaired globin chains produce
includes X-linked sideroblastic anemia (XLSA) due to heterozy- insoluble tetramers leading to oxidant damage of erythrocyte
gous mutations in ALAS2, which encodes the erythroid-specific membrane lipids and proteins.
form of the heme biosynthetic enzyme 5-aminolevulinate syn-
thase,62 or less commonly, mutations in SLC25A38, HSPA9, Similar to G6PD deficiency, thalassemic-deficient erythrocytes
HSCB, NDUFB11, GLRX5, and FECH.63 demonstrate a selective advantage against P. falciparum infection,
leading to a high frequency of Hb disorders worldwide via natural
XLSA is the most common nonsyndromic CSA.62 Patients present selection. Other contributors to the high frequency of thalassemia
with microcytic anemia, which may be severe, requiring transfu- in southern Asia, the Middle East, the Mediterranean, and North
sion support. Laboratory findings include microcytic anemia, and Central Africa are gene drift and founder effects. Mass

migration out of areas of high prevalence has led to the finding of hyperbilirubinemia.70 A few patients suffer from nonimmune
thalassemia in most countries worldwide, including the United hydrops fetalis in utero, with microcytosis and red cell fragmen-
States, Canada, northern Europe, Australia, and South America.65 tation. Hb electrophoresis is diagnostic, demonstrating Hb Barts
and Hb H, b4.
Differences in the clinical manifestations of the thalassemia syn-
dromes are due to developmental differences in globin chain b-Globin defects
synthesis. The primary embryonic a-like globin, z-globin, is pro- gdb- and «gdb-thalassemia Large deletions of the b-globin
duced in the yolk sac as early as 3 weeks gestation. By 9 weeks gene cluster lead to the phenotype of gdb- and «gdb-
of gestation, a-globin is the primary fetal a-like globin, with only thalassemia.71,72 Patients present with significant hypochromic
small amounts of the embryonic z-globin found. A-globin contin- hemolytic anemia with prominent normoblastosis in the neonatal
ues to be the primary a-like chain throughout infancy and into period. Over time, the anemia improves, and erythrocyte mor-
adulthood. In contrast, the switch from fetal to adult b-like glo- phology evolves to that similar to the b-thalassemia trait. An
bin chains, g- to b-globin, is not complete until 6 to 12 months interesting feature of gdb-thalassemia is the finding of normal
after birth. The primary embryonic b-like globin is «-globin, HbA2 levels, often leading to misdiagnosis as iron deficiency.
whose production roughly parallels that of z-globin. Beginning

at 3 to 4 weeks gestation, g-globin production begins, replacing b-Thalassemia Numerous b-globin gene mutations, usually
«-globin by 9 weeks gestation. a and g chains pair to produce point mutations or small deletions, lead to disease of variable
fetal Hb (HbF) (a2g2). B-globin production begins increasing in severity.73 Inheritance of a single heterozygous mutation leads to
the third trimester and eventually replaces HbF with adult Hb the phenotype of b-thalassemia trait or minor, characterized by
(HbA) (a2b2) by 6 to 12 months after birth. Thus, abnormalities mild microcytic anemia. b-Thalassemia trait is often discovered
of a-globin, such as homozygous a-thalassemia, lead to severe when a child with microcytic anemia does not respond to an
anemia in utero, whereas abnormalities of b-globin, such as empiric trial of iron supplementation. Inheritance of 2 b-globin
homozygous b-thalassemia and SCD, do not typically manifest mutations, one associated with a mild phenotype, leads to
in the first few months of life while HbF levels are still high. b-thalassemia intermedia, characterized by clinical severity
between b-thalassemia trait and b-thalassemia major. Thalasse-
a-Globin defects The clinical picture in the a-thalassemia syn- mia intermedia patients have symptoms ranging from mild ane-
dromes is related to the numbers of functional a-globin genes mia with little need for transfusion to chronic hemolytic anemia
present.66 Deletion of 1 a-globin gene leads to an asymptom- developing transfusion dependence later in life.74 Patients
atic carrier state. Deletion of 2 a-globin genes leads to develop iron overload, splenomegaly, leg ulcers, thrombophilia,
a-thalassemia trait with mild hypochromic, microcytic anemia. and bony abnormalities. Treatment, outlined in a series of guide-
Deletion of 3 a-globin genes leads to Hb H disease with vari- lines,75 may include transfusion, iron chelation, even splenec-
able anemia, from mild to very severe. Deletion of all a-globin tomy, despite increased risk for thrombosis after splenectomy,76
genes leads to homozygous a-thalassemia. In some cases, and HSCT, is tailored to patient disease severity.
a-globin defects are due to nondeletional variants such as non-
sense and nonsense mutations. Overall, the clinical manifesta- Inheritance of 2 severe b-globin gene mutations in a compound
tions of nondeletional a-thalassemia are variable. The most heterozygous or homozygous manner leads to b-thalassemia
common of these, Hb Constant Spring, common in Southeast major. Symptoms of anemia, including poor growth, irritability,
Asia and the Mediterranean, is associated with a more severe and lethargy, develop during the second 6 months after birth as
phenotype than deletional types of a-thalassemia.67 fetal Hb levels decline; thus, severe microcytic anemia in an
older infant with these findings should prompt investigation for
Homozygous a-thalassemia In homozygous a-thalassemia, the b-thalassemia major. If untreated, ineffective erythropoiesis may
primary Hb present is a tetramer of unpaired non-a chains, g4, lead to hepatosplenomegaly, frontal bossing, and paravertebral
known as Hb Barts. Most cases lead to the death of the affected pseudotumors. There is microcytic, hypochromic hemolytic ane-
fetus in utero from severe hemolytic anemia, congestive heart mia with poikilocytosis, target cells, teardrop cells, and frag-
failure, and nonimmune hydrops fetalis.66 Mothers of affected ments on PB smear (Figure 4). Hb electrophoresis is diagnostic.
fetuses are at risk of numerous complications, including Treatment includes chronic transfusions, chelation, erythroid
pregnancy-induced hypertension, antepartum hemorrhage, diffi- maturation agents such as luspatercept, and consideration for
cult delivery, retained placenta, and post-partum hemor- HSCT. Recent advances in gene therapy may provide alternative
rhage.68,69 Survival of the homozygous fetus to late gestation therapeutic options.77
depends on the presence and amount of embryonic Hb Port-
land, z2g2. In the few cases where an infant with homozygous HbE The HbE allele is due to a splicing mutation of the
a-thalassemia is born alive without prior intervention, death b-globin gene that is transcribed at reduced levels and trans-
from cardiopulmonary collapse usually occurs shortly after birth. lated into an abnormal b-globin protein. Reduced expression of
Genetic screening of at-risk populations has allowed the identifi- this abnormal b-globin leads to clinical findings similar to the
cation of couples at risk for conceiving an affected fetus. In a b-thalassemia trait. HbE is common in individuals from the
few cases, in utero and postnatal transfusion therapy with iron Indian subcontinent and Southeast Asia. Because b-thalassemia
chelation have led to survival. HSCT is an option for affected variants are also common in these regions, the coinheritance of
patients. Long-term complications include growth failure and b-thalassemia and HbE alleles occurs frequently.78 Clinical find-
neurodevelopmental disability in 20%.69 ings are heterogeneous, ranging from mild to moderate micro-
cytic anemia to severe transfusion-dependent anemia. The
Hb H disease Patients with Hb H disease present in the neona- diagnosis should be suspected when a child of Asian ancestry
tal period with hypochromic, microcytic hemolytic anemia and presents with microcytic anemia of unknown cause with normal

iron indices. Diagnosis is by Hb electrophoresis. Treatment is Nutritional anemias
based on disease severity. Chelation may be required when iron Vitamin B12 deficiency Vitamin B12 deficiency in pediatric
overload occurs. patients is found when there is a decreased intake, reduced
absorption, or inherited abnormalities of vitamin B12 absorption,
SCD SCD is the most common inherited blood disorder in the transport, or metabolism.84 Decreased intake is associated with
United States, affecting 100 000 people,79 impacting 1 out of a strict vegetarian diet or breastfeeding by a vitamin B12-
365 African American births and 1 out of 1630 Hispanic Ameri- deficient mother. Decreased absorption is associated with
can births. It affects millions of people worldwide, especially decreased stomach acid, gastrectomy, bowel resection, poor
peoples in or whose ancestors originated from sub-Saharan pancreatic function, parasitic infection, bacterial overgrowth,
Africa, South America, the Caribbean, Central America, Saudi Crohn’s disease, or celiac disease. Inherited disorders include
Arabia, India, Turkey, Greece, and Italy. The most common and abnormalities of intrinsic factor, transcobalamin-II deficiency,
most severe type is homozygous SS disease, followed by SCD cobalamin R-binder protein deficiency, defects in vitamin B12
and sickle-b–thalassemia. The sickle mutation, Glu6Val, leads to intestinal absorption known as Imerslund-Gr€ asbeck syndrome,
the expression of sickle Hb, which is susceptible to polymeriza- and several very rare metabolic disorders. Antibody-mediated
tion under deoxygenated conditions changing erythrocyte vitamin B12-deficient pernicious anemia, common in adults, is

deformability.80 This leads to hemolysis of poorly deformable rare in childhood.
sickle erythrocytes, blood vessel vaso-occlusion, and an array of
other pathophysiologic findings. Vitamin B12 deficiency typically presents with poor growth,
developmental delay, and neurologic abnormalities such as
Clinical complications include painful vaso-occlusive epi- weakness or irritability.84 Macrocytic anemia, and sometimes
sodes, splenic dysfunction, and multiorgan disease, includ- pancytopenia, is observed with anisocytosis, basophilic stippling,
ing the risk of stroke.80 Diagnosis in most cases is made by and hyper segmented neutrophils on PB smear. In a few cases,
newborn screening Hb electrophoresis. Clinicians should infants have presented with transfusion-dependent anemia.
suspect SCD in immigrant children from countries without Treatment of symptomatic B12 deficiency is with vitamin B12,
newborn screening programs presenting with complications along with dietary or medication adjustments as indicated.
of the disease, such as hemolytic anemia, sepsis, or dactyli-
tis.81 Treatment is tailored to the patient and may include Folate deficiency Folate deficiency in pediatric patients is
transfusion therapy, induction of HbF with hydroxyurea, found when there is a decreased intake, reduced absorption,
upregulation of antioxidant and reactive oxygen species impaired utilization, or increased requirements. Decreased intake
scavenging processes by L-glutamine, antiadhesion therapy is seen in infancy when there is feeding of a folate-poor diet such
with an anti-P–selectin antibody crizanlizumab, and stabiliz- as goat’s milk or milk that has been boiled. In older children,
ing sickle Hb to its high-oxygen affinity R-state via allosteric decreased intake is associated with poor dietary habits, although
modification with voxelotor.82 HSCT, especially if a sibling- dietary-associated folate deficiency has decreased since 1998
matched donor is available, is a consideration. New gene when the US Food and Drug Administration required manufac-
therapy approaches may provide additional therapeutic turers to add folic acid to enriched flour, bread, cereal, pasta,
approaches. rice, and other grain products to decrease the risk of neural tube
defects. Impaired folate absorption is seen in patients with celiac
HbC The HbC allele, Glu6Lys, is a common structural variant disease, congenital malabsorption syndromes, after intestinal
of b-globin associated with mild disease. Patients with the resection, and those receiving certain medications such as sulfa-
HbC trait, HbAC, are phenotypically normal, while patients salazine. Impaired utilization of folate is seen in patients receiving
with homozygous HbC, HbCC, exhibit very mild hemolysis. folic acid antagonists such as methotrexate, sulfa antibiotics, and
When HbC is inherited in trans to Hb S (HbS), it produces an several antiepileptics. Increased folate requirements are seen dur-
SCD phenotype.83 Sickle cell (SC) erythrocytes demonstrate ing pregnancy, in preterm infants, and in patients with hyperthy-
dehydration, increased viscosity, and intracellular sickling. roidism, malignancies, and chronic hemolytic disease.
HbSC patients demonstrate many of the same findings as
Hb SS patients but in lesser forms. Some prominent pheno- The megaloblastic anemia of folate deficiency in infants and chil-
typic features of HbSC disease include retinitis, osteonecro- dren is like that observed in adults. Treatment depends on treat-
sis, and acute chest syndrome. ment of the underlying cause and supplementation.85 Folate
deficiency due to dietary deficiency or increased demands is
best treated with folate supplements along with a folate-rich
Macrocytic anemia diet. Deficiency due to folic acid antagonists such as sulfa drugs
Macrocytic anemia with normal or decreased is treated with folate supplementation or by reducing or elimi-
reticulocyte count nating the offending drug.
Erythrocyte underproduction is an uncommon cause of anemia
in pediatric patients. Associated abnormalities include nutritional Genetic syndromes
deficiencies, genetic syndromes, congenital dyserythropoietic Diamond-Blackfan anemia (DBA) DBA is a disorder character-
anemias, BM replacement syndromes, drug-induced anemia, ized by congenital erythroid cell aplasia typically diagnosed in
infectious suppression, and other rare causes. Depending on the the first year of life.85 About half of cases are sporadic, and half
time in the disease course and any associated diagnoses, ane- are dominantly inherited, with rare cases exhibiting X-linked
mia may be normocytic, microcytic, or macrocytic, particularly inheritance. Nonhematologic abnormalities may first bring
for nutritional and infectious etiologies of anemia. patients to medical attention. These include small for gestational

age, abnormalities of the thumb or radius, microcephaly, hyper- Shwachman-Diamond syndrome (SDS) SDS is a rare disorder
telorism, flat nose, low set ears, cleft or high arched palate, ret- presenting in infancy with exocrine pancreatic insufficiency, poor
rognathia, and less commonly, genitourinary, cardiac, or bony growth, skeletal abnormalities, and BM failure. Neutropenia is
defects. Laboratory findings include macrocytic anemia, low often the first hematologic abnormality, progressing to include
reticulocyte count, elevated erythrocyte adenosine deaminase in anemia or pancytopenia.91 Patients also may experience poor
80% to 85% of cases, and elevated HbF. BM examination shows growth, developmental and intellectual delays, and frequent
normal cellularity with a paucity of erythrocyte precursors, or in infections. Laboratory findings show varying degrees of cytope-
severe cases, marked myeloid predominance (Figure 7). Genetic nias. BM cellularity is variable, ranging from high to low, with
testing may be performed. elements of dysplasia. Cytogenetic abnormalities of chromo-
some 7 may be found. With advancing age, SDS patients are at
DBA is caused by a number of mutations, many in ribosomal risk for the development of myelodysplastic syndrome or acute
protein genes, including RPS19 (most common), RPL5, RPS10, myeloid leukemia.92
RPL11, RPL35A, RPS7, RPS17, RPS24, RPS26, RPL19, RPL26,
RPS29, RPL31, RPS28, RPS20, RPL15, RPL17, TSR2, and GATA1 Diagnosis is made based on symptoms, clinical findings and
genes.86 Treatment includes transfusions, steroids, or HSCT.87 course, and genetic testing. Most cases are due to reces-

DBA patients have an increased risk of myelodysplastic syn- sively inherited mutations in the SBDS (most common),
drome, certain cancers, adrenal insufficiency, hypogonadism, or DNAJC21, or EFL1 genes,91 or rarely with dominant or de
hypothyroidism later in life. novo mutations in SRP54. Treatment is based on associated
findings such as the replacement of missing pancreatic
Aase syndrome Aase syndrome is a very rare, congenital enzymes and a special diet with fat-soluble vitamins. Patients
hypoplastic anemia with triphalangeal thumbs.88 Poor growth with severe anemia may require blood transfusions. HSCT is
and other bony abnormalities, including a hypoplastic radius, an option in severe cases.
may be seen. In affected families, autosomal recessive inheri-
tance has been suggested. Due to overlapping features, some Dyskeratosis congenita (DC) DC is characterized classically
have suggested Aase syndrome is a variant of DBA. by the triad of oral leukoplakia, nail dystrophy, and lacy skin pig-
mentation. However, clinical severity is variable, and this triad is
Fanconi anemia (FA) FA is a BM failure syndrome due to not required for diagnosis. Skin and nail findings often present
defects in the FA pathway, a biochemical network important for
early in childhood, followed by BM failure, which occurs by 20
DNA repair, DNA replication, and other cellular processes. FA is
years in over two-thirds of patients. Anemia in childhood is
due to recessively inherited mutations in 1 of at least 22 genes,
uncommon.93 Other complications include the development of
with most cases due to mutations in 1 of 3 genes, FANCA,
pulmonary fibrosis, myelodysplastic syndrome, leukemia, and
FANCC, and FANCG, important components of the FA pathway
other cancers. DC is caused by mutations in genes encoding
core complex.89 Similar to DBA, nonhematologic abnormalities
proteins influencing telomere length, leading to abnormal telo-
may first bring patients to medical attention. These include small
mere shortening.94 Diagnosis is made by clinical signs and
for gestational age, abnormalities of the thumb or radius,
symptoms, analysis of telomere length in PB granulocytes and
patches of abnormal skin pigmentation, genitourinary, cranial, or
lymphocytes, and genetic testing. Treatment focuses on strate-
heart defects, abnormalities of the eye, and hearing loss. FA
gies to preserve the skin, liver, and lungs. HSCT and solid organ
patients diagnosed in infancy appear to have a higher incidence
transplantation have been employed.95
of multisystem involvement than those diagnosed later in life.
Progressive hematologic dysfunction and marrow failure develop
Pearson syndrome Pearson syndrome is a rare mitochondrial
during childhood.
DNA deletion disorder associated with macrocytic anemia, met-
Pancytopenia leads to symptoms of frequent infection, excessive abolic acidosis, and exocrine pancreatic insufficiency attributed
bleeding, and anemia. As adults, many FA patients experience to a lack of enzymes involved in oxidative phosphorylation.96
infertility. They are at risk of developing solid tumors and other Some patients lack metabolic abnormalities and exhibit only
cancers and are particularly prone to the development of myelo- sideroblastic anemia. Neutropenia and thrombocytopenia, typi-
dysplastic syndrome and acute myelogenous leukemia.90 cally mild, may also be present.
FA is diagnosed based on symptoms, clinical findings and Other disorders Other disorders that may present with pancy-
course, and laboratory testing. Blood counts may reveal neutro- topenia include congenital amegakaryocytic thrombocytopenia
penia, thrombocytopenia, and macrocytic anemia with reticulo- and hemophagocytic lymphohistiocytosis.
cytopenia. HbF levels are sometimes elevated. BM examination
is variable, ranging from normal cellularity to total aplasia, some- Aplastic anemia
times with dysplastic features. Clonal cytogenetic abnormalities Idiopathic acquired aplastic anemia is a rare, life-threatening BM
may be identified in marrow samples of older patients. The failure syndrome characterized by severe persistent pancytope-
chromosome breakage test demonstrates marked chromosome nia and hypocellular BM (Figure 7) in the absence of major dys-
breakage in lymphocytes or fibroblasts cultured with a DNA plastic signs or marrow fibrosis.97 It is more common in older
crosslinking agent such as mitomycin C or diepoxybutane due children and adolescents. Known associations include infection,
to the underlying defect in DNA repair. Genetic testing may be particularly viral infection, malignancies, autoimmune disease,
confirmatory. Treatment is variable and is based on disease medications, toxins, and after radiation or chemotherapy. The
severity. In some cases, growth factors or androgens may be pathophysiology is unknown. One model suggests a dysregu-
administered. HSCT is the only curative therapy. lated immune system leads to autoreactive T-cell destruction of

A B

C D
Figure 7. BM examination. (A) Diamond-Blackfan anemia. BM aspirate shows a marked myeloid predominance. (B) Acquired aplastic anemia. High-power image of a
hematoxylin and eosin-stained BM biopsy section from a teenage girl showing profound hypocellularity. The few remaining hematopoietic cells are lymphocytes,
plasma cells, and macrophages with pigment in their cytoplasm. (C) Congenital dyserythropoietic anemia (CDA) type II. BM aspirate shows binucleated and
multinucleated erythroid precursors. (D) Neuroblastoma. BM biopsy shows clumps of metastatic neuroblastoma cells. These images were originally published in the
ASH Image Bank. (A) Amy Duffield, Diamond Blackfan Anemia Aspirate, 2015, #00060078. (B) Kristian T. Schafernak, Acquired Aplastic Anemia, 2016, #00060876.
(C) Kristian T. Schafernak, Congenital Dyserythropoietic Anemia, Type II, 2016, #00060891. (D) Suzanne Vercauteren. Neuroblastoma Bone Marrow, 2015, #00060131.
© The American Society of Hematology.
hematopoietic stem and progenitor cells in a genetically suscep- distinct chromatin bridges between erythroid cells, and binucle-
tible host. When considering the diagnosis, inherited BM failure ated normoblasts. Inheritance is autosomal recessive due to
syndromes should be excluded. Patients with acquired aplastic mutations in most cases in condanin-1, CDAN1, or rarely
anemia are typically treated with immunosuppressive therapy or CDIN1. In a few cases, the genetic cause is unknown. Treatment
HSCT.98,99 includes supportive care, interferon administration, and in severe
cases, HSCT. Iron overload may occur.
Congenital dyserythropoietic anemia (CDA) Type II CDA is characterized by moderate to severe macrocytic
CDA syndromes are a group of disorders characterized by anemia anemia with relative reticulocytopenia.102 Presentation in the
with ineffective erythropoiesis and reticulocytopenia relative to the neonatal period with anemia and jaundice occurs in about one-
degree of anemia.100 The CDAs are heterogeneous in their clinical quarter of cases. In childhood, jaundice, hepatosplenomegaly,
and laboratory manifestations as well as their genetic etiologies. and gall stones are common. Nonhematologic manifestations
are rare. Marrow examination shows marked bi- and multi-
Type I CDA is characterized by mild to moderate macrocytic nucleated erythroblasts (Figure 7). Marrow iron is typically
anemia with relative reticulocytopenia.101 Jaundice and hepatos- increased. Inheritance is autosomal recessive due to mutations
plenomegaly may be present. Nonhematologic manifestations in SEC23B, a protein involved in vesicle transport. Treatment
include poor growth and syndactyly of the fingers or toes. Mar- includes supportive care, splenectomy, and in some cases,
row examination shows megaloblastoid erythroid hyperplasia, HSCT. Significant iron overload often requires therapy.

Type III CDA, like type II, is characterized by moderate to severe patterns of inheritance and clinical severity. The recessively inher-
macrocytic anemia with relative reticulocytopenia. Nonhemato- ited, malignant form of osteopetrosis presents in the neonatal
logic manifestations include a hair-on-end appearance on a skull period with craniomegaly, bony sclerosis, hepatosplenomegaly,
radiograph. Marrow examination shows multinuclear erythroblasts, and abnormalities of hematopoiesis, including progressive ane-
even gigantoblasts (up to 12 nuclei). Inheritance is autosomal mia. Failure of osteoclasts to resorb and remodel bone leads to
dominant due to mutations in KIF23, a member of the kinesin- progressive obliteration of the BM cavity. This leads to extrame-
like protein family.103 Treatment includes supportive care. Iron dullary hematopoiesis in the spleen and liver and gradually wors-
overload may require therapy. Affected patients have an increased ening macrocytic anemia with reticulocytosis.110 Many patients
prevalence of lymphoproliferative disorders in adulthood. An auto- with malignant recessive osteopetrosis become transfusion-
somal recessive form of CDAIII without skull defects due to muta- dependent. Hypersplenism may contribute to anemia, thrombo-
tions in RACGAP1, the partner of MKLP1 in the centralspindlin cytopenia, and neutropenia. Treatment is HSCT.111
complex, has recently been described.104
Myelodysplastic syndromes (MDSs)
Several variant CDAs have been described. X-linked anemia and MDSs in children are a rare, heterogeneous group of clonal dis-
thrombocytopenia presenting in utero or in the neonatal period orders which, in contrast to adults, rarely exhibit refractory ane-

due to defects in the transcription factor GATA1 have been mia and ringed sideroblasts and are rarely associated with
described.105 Marrow examination shows severe dyserythropoie- -del(5q) chromosome.112 Similarly, whereas adults frequently
sis. Severe anemia presenting in utero or the neonatal period present with isolated macrocytic anemia, children may present
due to a mutation in the transcription factor KLF1 has been with cytopenias including macrocytic anemia, thrombocytopenia,
described. Affected patients have severe hemolysis, ineffective neutropenia, as well as elevated HbF.113 Pediatric MDSs are
erythropoiesis, elevated HbF, and alterations in many membrane associated with inherited BM syndromes, previous exposure to
proteins, including those carrying various blood group antigens. cytotoxic agents including alkylating agents and topoisomerase
CDA with anemia, extramedullary erythropoiesis, dysmorphic inhibitors, and genetic germline predisposition.114 Genes associ-
features, skeletal anomalies, cholestatic liver disease, diarrhea, ated with MDS in adults such as TET2, DNMT3A, TP53, and spli-
and poor growth presenting in the neonatal period has been ceosome complex mutations are not linked to pediatric MDS
described in patients with mevalonate kinase deficiency.106 CDA but instead are associated with somatic driver mutations in Ras
presenting in infancy with exocrine pancreatic insufficiency and pathway genes, SETBP1, GATA2, RUNX1, ASXL1, and RAS
calvarial hyperostosis has been described due to mutations in oncogenes.115 Germline mutations in GATA2, ETV6, SRP72, and
COX4I2, a component of the cytochrome c oxidase complex.107 SAMD9/SAMD9-L predispose individuals to MDS or acute mye-
loid leukemia. Treatment regimens are complex, but many
CDA with neurodevelopmental delay due to mutations in the involve HSCT.113
VPS4A gene, which encodes an ATPase involved in regulating
endosomal protein sorting.108 Infectious suppression
In addition to hemolysis, infection may lead to BM suppression
BM replacement syndromes with resultant cytopenias. Infectious suppression has been asso-
Anemia can develop as a secondary effect of infiltration of the BM ciated with several viral infections, including parvovirus B19,
by cells not typically found in the marrow, such as leukemia, meta- human immunodeficiency virus, Epstein-Barr virus, CMV, hepati-
static cancer, particularly neuroblastoma in pediatric patients (Fig- tis A, B, C, and E, and T-cell leukemia-lymphoma virus. It has
ure 7), granulomatous lesions, storage diseases such as been described in patients with tuberculosis, streptococcal infec-
mucopolysaccharidosis type VII, or myelodysplasia and myelofi- tions, and those with overwhelming sepsis. In some cases of
brosis. Laboratory findings including pancytopenia, relative reticu- infection there may be hemolysis along with marrow suppres-
locytopenia, normoblasts and red cell teardrops, giant platelets, sion, particularly in malaria and CMV infection.
and immature leukocytes are seen on PB smear. BM examination
shows infiltration by the invading cancer, granulomatous disease, Parvovirus B19 infection is a significant cause of anemia in sus-
abnormal storage cells, or fibrosis. ceptible patients.116 Parvovirus B19 is the cause of the common
childhood illness, erythema infectiosum, also known as Fifth dis-
Transient myeloproliferative disorder (TMD) Unique to ease, characterized by fever, chills, vomiting, and diarrhea, and
infancy, TMD is characterized by the proliferation of myeloblasts a maculopapular exanthem on the face mimicking “slapped
in the liver, marrow, and blood mimicking congenital leukemia, cheeks” which appear with the resolution of the fever. During
typically in patients with trisomy 21.109 Anemia and thrombocy- infection, parvovirus B19 selectively infects erythroid precursors
topenia are common. In contrast to congenital leukemia, spon- and inhibits their growth, leading to an acute decrease in Hb
taneous remission occurs in most cases. However, after and reticulocytopenia, which gradually resolves. This drop in Hb
remission, 20% of patients will later develop acute mye- is tolerated by normal children and adults. However, in patients
loid leukemia. with chronic hemolysis and shortened erythrocyte life span, such
as those with inherited hemolytic anemias, interruption of eryth-
Osteopetrosis Osteopetrosis syndromes are a group of rare, ropoiesis leads to acute anemia with reticulocytopenia that can
inherited skeletal disorders characterized by increased bone den- lead to significant symptomatology, including cardiovascular
sity and abnormal bone growth. Clinical findings are heteroge- compromise and death. Treatment for this group of patients is
neous, ranging from neonatal onset with life-threatening supportive. Another susceptible host is the fetus, who may
complications to incidental findings identified on chest radiograph acquire infection from the mother. Serial in utero transfusions
in an adult. At least 10 genes have been implicated with varying may be necessary. Chronic anemia due to persistent parvovirus

B19 infection may occur in patients with compromised immune findings include, in some cases, anisocytosis and acanthocytes
systems due to inherited or acquired causes. Treatment may on PB smear. Anemia corrects with the treatment of hypothyroid-
include transfusion, adjustment of immune-modulating medica- ism. Population studies indicate anemia is common in patients
tions, or immunoglobulin (IVIG). with both hyperthyroidism and hypothyroidism.
Medication- or toxin-induced suppression Splenic sequestration Several disorders are associated with
BM suppression is associated with the administration of numer- significant splenomegaly, which may lead to hypersplenism and
ous medications, particularly chemotherapeutic and antineoplas-
pancytopenia. A combination of hemolysis, sequestration, and
tic agents and medications affecting the immune system. Other
premature destruction of blood cells contributes to pancytope-
implicated medications include azathioprine, chloramphenicol,
nia. BM examination reveals normal cell number and prolifera-
meclofenamic acid, phenylbutazone, quinidine, trimethoprim-
tion. When pancytopenia is caused by splenic sequestration,
sulfadiazine, and albendazole. Anticonvulsant medications, par-
splenectomy may be curative.
ticularly carbamazepine, phenytoin, and valproic acid, have
been associated with an aplastic anemia-like picture. In most
cases, effects are dose-related, and marrow recovery is seen Macrocytic anemia with increased

after discontinuation of the offending agent. In a few cases, reticulocyte count
treatment with recombinant human erythropoietin led to ery- Active hemolysis with brisk reticulocytosis is the most common
throid hypoplasia with a hyporegenerative anemia due to the etiology of macrocytic anemia with elevated reticulocyte count.
production of antierythropoietin antibodies.
Toxic chemicals found in various preparations such as pesticides Conclusions

and insecticides, arsenic found in contaminated groundwater,
Anemia is a commonly encountered problem in pediatrics. There
and benzene found in gasoline have been linked to aplastic ane-
is a broad differential diagnosis that can be narrowed by careful
mia and/or marrow suppression.
review of the patient’s and family’s history, physical examination,
and laboratory testing. Knowledge and application of appropri-
Copper deficiency Copper deficiency may be caused by inad-
equate intake as occurs in anorexia nervosa, malnutrition, vegan ate treatment strategies will allow for the best outcome.
diets, parenteral nutrition, and postpyloric feeds, increased
demand as occurs in pregnant or lactating women and growing
premature infants, abnormal copper metabolism as occurs in
Acknowledgments
This work was supported in part by grants 5P01DK032094,
Menkes disease and familial hypoceruloplasminemia, and inade- RO1DK111539, and 5R01DK104046 from the National Institutes of
quate absorption or increased loss in inflammatory bowel dis- Health, National Institute of Diabetes and Digestive and Kidney
ease, Crohn’s disease, celiac disease, and recently after bariatric Diseases.
surgery.117 Copper deficiency has neurologic and hematologic
manifestations.118 Neurologic findings mimic subacute com-
bined degeneration, myeloneuropathy, and optic neuropathy. Authorship
Hematological manifestations include anemia, sometimes with Conflict-of-interest disclosure: The author declares no competing finan-
neutropenia and thrombocytopenia.119 Similar to myelodyspla- cial interests.
sia, marrow examination shows dysplastic erythroid precursors
Correspondence: Patrick G. Gallagher, Departments of Pediatrics,
with ring sideroblasts, nuclear budding, and multilobulation.
Pathology, and Genetics, Yale University School of Medicine, 333
Unlike MDS, copper-deficient marrow demonstrates cytoplasmic Cedar St, PO Box 208064, New Haven, CT; e-mail: patrick.gallagher@
vacuolization in erythroid and myeloid cells. Hematologic find- yale.edu.
ings are reversible with copper supplementation, whereas neu-
rological manifestations are only partially reversible.
Footnote
Other causes Submitted 17 February 2021; accepted 1 October 2021; prepublished
Thyroid disorders Macrocytic and normocytic anemias have online on Blood First Edition 25 February 2022. DOI 10.1182/
been described in patients with hypothyroidism. Additional blood.2020006479.
REFERENCES 3. Henry E, Christensen RD. Reference 5. Timmer T, Tanck MWT, Huis In ’t Veld EMJ,
1. Chaparro CM, Suchdev PS. Anemia intervals in neonatal hematology. et al. Associations between single nucleotide
epidemiology, pathophysiology, and etiology Clin Perinatol. 2015;42(3):483-497. polymorphisms and erythrocyte parameters
in low- and middle-income countries. Ann N in humans: a systematic literature review.
4. Ocas-C ordova S, Tapia V, Gonzales GF. Mutat Res Rev Mutat Res. 2019;779:58-67.
Y Acad Sci. 2019;1450(1):15-31. Hemoglobin concentration in
children at different altitudes in Peru: 6. Metivier F, Marchais SJ, Guerin AP, Pannier
2. Zierk J, Hirschmann J, Toddenroth D, et al. proposal for [Hb] correction for B, London GM. Pathophysiology of
Next-generation reference intervals for altitude to diagnose anemia and anaemia: focus on the heart and blood
pediatric hematology. Clin Chem Lab Med. polycythemia. High Alt Med Biol. vessels. Nephrol Dial Transplant. 2000;
2019;57(10):1595-1607. 2018;19(4):398-403. 15(suppl 3):14-18.

7. Fermo E, Vercellati C, Marcello AP, et al. 23. Kremer Hovinga JA, Coppo P, L€ ammle B, mechanisms in a single laboratory. Acta
Targeted next generation sequencing and Moake JL, Miyata T, Vanhoorelbeke K. Haematol. 2018;140(1):10-17.
diagnosis of congenital hemolytic anemias: Thrombotic thrombocytopenic purpura.
Nat Rev Dis Primers. 2017;3(1):17020. 38. Go RS, Winters JL, Kay NE. How I treat
a three years experience monocentric
autoimmune hemolytic anemia. Blood.
study. Front Physiol. 2021;12:684569.
24. Siddiqui A, Journeycake JM, Borogovac A, 2017;129(22):2971-2979.
8. Russo R, Andolfo I, Manna F, et al. Multi- George JN. Recognizing and managing
hereditary and acquired thrombotic 39. Sankaran J, Rodriguez V, Jacob EK, Kreuter
gene panel testing improves diagnosis and
thrombocytopenic purpura in infants and JD, Go RS. Autoimmune hemolytic anemia
management of patients with hereditary
children. Pediatr Blood Cancer. 2021;68(5): in children: Mayo Clinic experience.
anemias. Am J Hematol. 2018;93(5):
e28949. J Pediatr Hematol Oncol. 2016;38(3):
672-682. e120-e124.
9. Sankaran VG, Gallagher PG. Applications 25. Scully M, Cataland SR, Peyvandi F, et al;
HERCULES Investigators. Caplacizumab 40. Kalfa TA. Warm antibody autoimmune
of high-throughput DNA sequencing to hemolytic anemia. Hematology (Am Soc
treatment for acquired thrombotic
benign hematology. Blood. 2013;122(22): Hematol Educ Program). 2016;2016(1):
thrombocytopenic purpura. N Engl J Med.
3575-3582. 690-697.
2019;380(4):335-346.
10. Gallagher PG, Maksimova Y, Lezon-Geyda 41. Kruizinga MD, van Tol MJD, Bekker V,
26. van den Heuvel-Eibrink MM. Paroxysmal
K, et al. Aberrant splicing contributes to et al. Risk Factors, Treatment, and Immune
nocturnal hemoglobinuria in children.

severe a-spectrin-linked congenital Dysregulation in Autoimmune Cytopenia
Paediatr Drugs. 2007;9(1):11-16.
hemolytic anemia. J Clin Invest. 2019; after Allogeneic Hematopoietic Stem Cell
129(7):2878-2887. 27. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Transplantation in Pediatric Patients. Biol
Paroxysmal nocturnal haemoglobinuria. Nat Blood Marrow Transplant. 2018;24(4):
11. Narla J, Mohandas N. Red cell membrane Rev Dis Primers. 2017;3(1):17028. 772-778.
disorders. Int J Lab Hematol. 2017;
39(suppl 1):47-52. 28. Wallace K, Harris S, Addison A, Bean C. 42. Hill QA, Stamps R, Massey E, Grainger JD,
HELLP syndrome: pathophysiology and Provan D, Hill A; British Society for
12. Gallagher PG. Disorders of erythrocyte current therapies. Curr Pharm Biotechnol. Haematology Guidelines. Guidelines on
hydration. Blood. 2017;130(25):2699-2708. 2018;19(10):816-826. the management of drug-induced immune
and secondary autoimmune, haemolytic
13. Luzzatto L, Ally M, Notaro R. Glucose-6- 29. Fernando M, van Mourik I, Wassmer E, anaemia. Br J Haematol. 2017;177(2):
phosphate dehydrogenase deficiency. Kelly D. Wilson disease in children and 208-220.
Blood. 2020;136(11):1225-1240. adolescents. Arch Dis Child. 2020;105(5):
499-505. 43. Notrica DM, Sayrs LW, Bhatia A, et al. The
14. Grace RF, Bianchi P, van Beers EJ, et al. incidence of delayed splenic bleeding in
Clinical spectrum of pyruvate kinase 30. El Raziky MS, Ali A, El Shahawy A, Hamdy pediatric blunt trauma. J Pediatr Surg.
deficiency: data from the Pyruvate Kinase MM. Acute hemolytic anemia as an initial 2018;53(2):339-343.
Deficiency Natural History Study. Blood. presentation of Wilson disease in children.
2018;131(20):2183-2192. J Pediatr Hematol Oncol. 2014;36(3): 44. Spinale JM, Ruebner RL, Kaplan BS,
173-178. Copelovitch L. Update on Streptococcus
15. Grace RF, Glader B. Red blood cell enzyme pneumoniae associated hemolytic uremic
disorders. Pediatr Clin North Am. 2018; 31. Flegel WA. Pathogenesis and mechanisms syndrome. Curr Opin Pediatr. 2013;25(2):
65(3):579-595. of antibody-mediated hemolysis. 203-208.
Transfusion. 2015;55(suppl 2):S47-S58.
16. Gallagher PG. Diagnosis and management 45. Moh-Klaren J, Bodivit G, Jugie M, et al.
of rare congenital nonimmune hemolytic 32. Conley CL, Lippman SM, Ness PM, Petz Severe hemolysis after plasma transfusion
disease. Hematology Am Soc Hematol LD, Branch DR, Gallagher MT. Autoimmune in a neonate with necrotizing enterocolitis,
Educ Program. 2015;2015:392-399. hemolytic anemia with reticulocytopenia Clostridium perfringens infection, and red
and erythroid marrow. N Engl J Med. 1982; blood cell T-polyagglutination. Transfusion.
17. Tribolet S, Hoyoux C, Boon LM, et al. A not 306(5):281-286. 2017;57(11):2571-2577.
so harmless mass: kaposiform
hemangioendothelioma complicated by a 33. Hendrickson JE, Delaney M. Hemolytic 46. Ganz T. Anemia of inflammation. N Engl J
disease of the fetus and newborn: modern Med. 2019;381(12):1148-1157.
Kasabach-Merritt phenomenon. Arch
practice and future investigations. Transfus
Pediatr. 2019;26(6):365-369.
Med Rev. 2016;30(4):159-164. 47. Burns RA, Woodward GA. Transient
18. Adams DM, Ricci KW. Vascular anomalies: erythroblastopenia of childhood: a review
34. Hill QA, Stamps R, Massey E, Grainger JD, for the pediatric emergency medicine
diagnosis of complicated anomalies and
Provan D, Hill A; British Society for physician. Pediatr Emerg Care. 2019;35(3):
new medical treatment options. Hematol
Haematology. The diagnosis and 237-240.
Oncol Clin North Am. 2019;33(3):455-470. management of primary autoimmune
haemolytic anaemia. Br J Haematol. 2017; 48. Camaschella C. Iron-deficiency anemia.
19. Walsh PR, Johnson S. Treatment and
176(3):395-411. N Engl J Med. 2015;372(19):1832-1843.
management of children with haemolytic
uraemic syndrome. Arch Dis Child. 2018; 35. Aladjidi N, Leverger G, Leblanc T, et al; 49. McCann S, Perapoch Amad o M, Moore SE.
103(3):285-291. Centre de R ef
erence National des The Role of iron in brain development: a
Cytopenies Auto-immunes de l’Enfant systematic review. Nutrients. 2020;12(7):
20. Manrique-Caballero CL, Peerapornratana S,
(CEREVANCE). New insights into childhood 2001.
Formeck C, Del Rio-Pertuz G, Gomez autoimmune hemolytic anemia: a French
Danies H, Kellum JA. Typical and atypical national observational study of 265 chil- 50. Baker RD, Greer FR; Committee on
hemolytic uremic syndrome in the critically dren. Haematologica. 2011;96(5):655-663. Nutrition American Academy of Pediatrics.
ill. Crit Care Clin. 2020;36(2):333-356. Diagnosis and prevention of iron deficiency
€ Erdem AY, Çulha V, Kara
36. Yaralı N, Bilir OA, and iron-deficiency anemia in infants and
21. Avila Bernabeu AI, Cavero Escribano T, €
A, Ozbek N. Clinical features and treatment young children (0-3 years of age).
Cao Vilarino M. Atypical hemolytic uremic of primary autoimmune hemolytic anemia Pediatrics. 2010;126(5):1040-1050.
syndrome: new challenges in the in childhood. Transfus Apheresis Sci. 2018;
complement blockage era. Nephron. 2020; 57(5):665-668. 51. Iron needs of babies and children. Paediatr
144(11):537-549. Child Health. 2007;12(4):333-336.
37. Kamesaki T, Kajii E. A comprehensive
22. Joly BS, Coppo P, Veyradier A. Pediatric diagnostic algorithm for direct antiglobulin 52. Borgna-Pignatti C, Zanella S. Pica as a
thrombotic thrombocytopenic purpura. Eur test-negative autoimmune hemolytic ane- manifestation of iron deficiency. Expert Rev
J Haematol. 2018;101(4):425-434. mia reveals the relative ratio of three Hematol. 2016;9(11):1075-1080.

53. Pasricha SR, Tye-Din J, Muckenthaler MU, Hematology Am Soc Hematol Educ blackfan anemia [published correction
Swinkels DW. Iron deficiency. Lancet. 2021; Program. 2009;2009:26-34. appears in Am J Hun Genet.
397(10270):233-248. 2019;104(2):356]. Am J Hum Genet. 2018;
71. Repnikova E, Roberts J, Mc Dermott S, 103(6):930-947.
54. Powers JM, Buchanan GR, Adix L, Zhang S, et al. Clinical and molecular
Gao A, McCavit TL. Effect of low-dose fer- characterization of novel deletions causing 87. Bartels M, Bierings M. How I manage
rous sulfate vs iron polysaccharide complex epsilon gamma delta beta thalassemia: children with diamond-blackfan anaemia.
on hemoglobin concentration in young Report of two cases. Pathol Res Pract. Br J Haematol. 2019;184(2):123-133.
children with nutritional iron-deficiency 2019;215(10):152578.
anemia: a randomized clinical trial. JAMA. 88. Muis N, Beemer FA, van Dijken P, Klep-de
2017;317(22):2297-2304. 72. Bollekens JA, Forget BG. Delta beta Pater JM. The Aase syndrome. Case report
thalassemia and hereditary persistence of and review of the literature. Eur J Pediatr.
55. De Andrade Cairo RC, Rodrigues Silva L, fetal hemoglobin. Hematol Oncol Clin 1986;145(1-2):153-157.
Carneiro Bustani N, Ferreira Marques CD. North Am. 1991;5(3):399-422.
Iron deficiency anemia in adolescents; a 89. Fiesco-Roa MO, Giri N, McReynolds LJ,
literature review. Nutr Hosp. 2014;29(6): 73. Cao A, Galanello R. Beta-thalassemia. Best AF, Alter BP. Genotype-phenotype
1240-1249. Genet Med. 2010;12(2):61-76. associations in Fanconi anemia: A literature
review. Blood Rev. 2019;37:100589.
56. Weiss G, Ganz T, Goodnough LT. Anemia 74. Asadov C, Alimirzoeva Z, Mammadova T,
of inflammation. Blood. 2019;133(1):40-50. Aliyeva G, Gafarova S, Mammadov J. 90. Nalepa G, Clapp DW. Fanconi anaemia

b-Thalassemia intermedia: a comprehensive and cancer: an intricate relationship. Nat
57. Camaschella C, Nai A, Silvestri L. Iron overview and novel approaches. Int J Rev Cancer. 2018;18(3):168-185.
metabolism and iron disorders revisited in Hematol. 2018;108(1):5-21.
the hepcidin era. Haematologica. 2020; 91. Bezzerri V, Cipolli M. Shwachman-Diamond
105(2):260-272. 75. Taher A, Vichinsky E, Musallam K, syndrome: molecular mechanisms and
Cappellini MD, Viprakasit V. In: Weatherall current perspectives. Mol Diagn Ther.
58. Pagani A, Nai A, Silvestri L, Camaschella C. D, ed. Guidelines for the management of 2019;23(2):281-290.
Hepcidin and anemia: a tight relationship. non transfusion dependent thalassaemia
Front Physiol. 2019;10:1294. (NTDT). Nicosia (Cyprus): Thalassaemia 92. Myers KC, Furutani E, Weller E, et al.
International Federation; 2013. Clinical features and outcomes of patients
59. Prevention of childhood lead toxicity. with Shwachman-Diamond syndrome and
Pediatrics. 2016;138(1):e20201014. 76. Taher AT, Musallam KM, Karimi M, et al. myelodysplastic syndrome or acute mye-
Splenectomy and thrombosis: the case of loid leukaemia: a multicentre, retrospec-
60. Aydogan G, Keskin S, Akici F, et al. Causes thalassemia intermedia. J Thromb tive, cohort study. Lancet Haematol. 2020;
of hypochromic microcytic anemia in Haemost. 2010;8(10):2152-2158. 7(3):e238-e246.
children and evaluation of laboratory
parameters in the differentiation. J Pediatr 77. Khandros E, Kwiatkowski JL. Beta 93. Khincha PP, Savage SA. Neonatal
Hematol Oncol. 2019;41(4):e221-e223. thalassemia: monitoring and new treatment manifestations of inherited bone marrow
approaches. Hematol Oncol Clin North failure syndromes. Semin Fetal Neonatal
61. Abu-Zeinah G, DeSancho MT. Am. 2019;33(3):339-353. Med. 2016;21(1):57-65.
Understanding sideroblastic anemia: an
overview of genetics, epidemiology, 78. Fucharoen S, Weatherall DJ. The 94. Stoopler ET, Shanti RM. Dyskeratosis
pathophysiology and current therapeutic hemoglobin E thalassemias. Cold Spring congenita. Mayo Clin Proc. 2019;94(9):
options. J Blood Med. 2020;11:305-318. Harb Perspect Med. 2012;2(8):a011734. 1668-1669.
62. Fouquet C, Le Rouzic MA, Leblanc T, et al. 79. Lee L, Smith-Whitley K, Banks S, Puckrein 95. Niewisch MR, Savage SA. An update on
Genotype/phenotype correlations of G. Reducing health care disparities in sickle the biology and management of
childhood-onset congenital sideroblastic cell disease: a review. Public Health Rep. dyskeratosis congenita and related
anaemia in a European cohort. Br J Haematol. 2019;134(6):599-607. telomere biology disorders. Expert Rev
2019;187(4):530-542. Hematol. 2019;12(12):1037-1052.
80. Piel FB, Steinberg MH, Rees DC. Sickle cell
63. Ducamp S, Fleming MD. The molecular disease. N Engl J Med. 2017;376(16): 96. Wild KT, Goldstein AC, Muraresku C,
genetics of sideroblastic anemia. Blood. 1561-1573. Ganetzky RD. Broadening the phenotypic
2019;133(1):59-69. spectrum of Pearson syndrome: five new
81. Thornburg CD, Ware RE. Children with cases and a review of the literature. Am J
64. Piel FB. The present and future global sickle cell disease migrating to the United Med Genet A. 2020;182(2):365-373.
burden of the inherited disorders of States from sub-Saharan Africa. Pediatr
hemoglobin. Hematol Oncol Clin Blood Cancer. 2018;65(6):e27000. 97. Schoettler ML, Nathan DG. The
North Am. 2016;30(2):327-341. pathophysiology of acquired aplastic
82. Hoppe C, Neumayr L. Sickle cell disease: anemia: current concepts revisited.
65. Origa R. b-Thalassemia. Genet Med. 2017; monitoring, current treatment, and Hematol Oncol Clin North Am. 2018;32(4):
19(6):609-619. therapeutics under development. Hematol 581-594.
Oncol Clin North Am. 2019;33(3):355-371.
66. Piel FB, Weatherall DJ. The a-thalassemias. 98. Yoshida N, Kojima S. Updated guidelines
N Engl J Med. 2014;371(20):1908-1916. 83. Pecker LH, Schaefer BA, Luchtman-Jones L. for the treatment of acquired aplastic
Knowledge insufficient: the management of anemia in children. Curr Oncol Rep. 2018;
67. Kalle Kwaifa I, Lai MI, Md Noor S. Non- haemoglobin SC disease. Br J Haematol. 20(9):67.
deletional alpha thalassaemia: a review. 2017;176(4):515-526.
Orphanet J Rare Dis. 2020;15(1):166. 99. Rogers ZR, Nakano TA, Olson TS, et al.
84. Green R, Allen LH, Bjørke-Monsen AL, Immunosuppressive therapy for pediatric
68. Leung WC, Leung KY, Lau ET, Tang MH, et al. Vitamin B12 deficiency [published aplastic anemia: a North American
Chan V. Alpha-thalassaemia. Semin Fetal correction appears in Nat Rev Dis Primers. Pediatric Aplastic Anemia Consortium
Neonatal Med. 2008;13(4):215-222. 2017;3:17054]. Nat Rev Dis Primers. 2017; study. Haematologica. 2019;104(10):1974-
3(1):17040. 1983.
69. Songdej D, Babbs C, Higgs DR; BHFS
International Consortium. An international 85. Socha DS, DeSouza SI, Flagg A, Sekeres M, 100. Gambale A, Iolascon A, Andolfo I, Russo R.
registry of survivors with Hb Bart’s hydrops Rogers HJ. Severe megaloblastic anemia: Diagnosis and management of congenital
fetalis syndrome. Blood. 2017;129(10): vitamin deficiency and other causes. Cleve dyserythropoietic anemias. Expert Rev
1251-1259. Clin J Med. 2020;87(3):153-164. Hematol. 2016;9(3):283-296.
70. Fucharoen S, Viprakasit V. Hb H disease: 86. Ulirsch JC, Verboon JM, Kazerounian S, 101. Roy NBA, Babbs C. The pathogenesis,
clinical course and disease modifiers. et al. The genetic landscape of diamond- diagnosis and management of congenital

dyserythropoietic anaemia type I. Br J dyserythropoeitic anemia, and calvarial 115. Schwartz JR, Ma J, Lamprecht T, et al. The
Haematol. 2019;185(3):436-449. hyperostosis are caused by a mutation in genomic landscape of pediatric
the COX4I2 gene. Am J Hum Genet. 2009; myelodysplastic syndromes. Nat Commun.
102. Satchwell TJ, Pellegrin S, Bianchi P, et al. 84(3):412-417.
Characteristic phenotypes associated with 2017;8(1):1557.
congenital dyserythropoietic anemia (type 108. Seu KG, Trump LR, Emberesh S, et al.
116. Landry ML. Parvovirus B19. Microbiol
II) manifest at different stages of VPS4A mutations in humans cause
Spectr. 2016;4(3).
erythropoiesis. Haematologica. 2013; syndromic congenital dyserythropoietic
98(11):1788-1796. anemia due to cytokinesis and trafficking 117. Altarelli M, Ben-Hamouda N, Schneider A,
defects. Am J Hum Genet. 2020;107(6): Berger MM. Copper deficiency: causes,
103. Liljeholm M, Irvine AF, Vikberg AL, et al. 1149-1156.
Congenital dyserythropoietic anemia type manifestations, and treatment. Nutr Clin
III (CDA III) is caused by a mutation in 109. Watanabe K. Recent advances in the Pract. 2019;34(4):504-513.
kinesin family member, KIF23. Blood. 2013; understanding of transient abnormal
121(23):4791-4799. 118. Zemrani B, Bines JE. Recent insights into
myelopoiesis in Down syndrome. Pediatr
Int (Roma). 2019;61(3):222-229. trace element deficiencies: causes,
104. Romero-Cortadellas L, Hern eandez G, recognition and correction. Curr Opin
Xeenia Ferrer-Cortes, et al. Autosomal 110. Teti A, Teitelbaum SL. Congenital disorders Gastroenterol. 2020;36(2):110-117.
recessive congenital dyserythropoietic of bone and blood. Bone. 2019;119:71-81.
anemia type III is caused by mutations in 119. Myint ZW, Oo TH, Thein KZ, Tun AM,

the centralspindlin RACGAP1 component 111. Even-Or E, Stepensky P. How we approach Saeed H. Copper deficiency anemia:
[abstract]. Blood. 2021;138(suppl 1). malignant infantile osteopetrosis. Pediatr review article. Ann Hematol. 2018;97(9):
Abstract. 847. Blood Cancer. 2021;68(3):e28841. 1527-1534.
105. Nichols KE, Crispino JD, Poncz M, et al. 112. Hasle H, Niemeyer CM, Chessells JM, et al. 120. Pasricha SR, Tye-Dine J, Muckenthaler MU,
Familial dyserythropoietic anaemia and A pediatric approach to the WHO
Swinkels DW. Iron deficiency. Lancet. 2021;
thrombocytopenia due to an inherited classification of myelodysplastic and
397(10270):233-248.
mutation in GATA1. Nat Genet. 2000;24(3): myeloproliferative diseases. Leukemia.
266-270. 2003;17(2):277-28 121. Saarinen MU, Siimes MA. Developmental
106. Steiner LA, Ehrenkranz RA, Peterec SM, 113. Locatelli F, Strahm B. How I treat changes in red blood cell counts and
Steiner RD, Reyes-Mugica M, Gallagher myelodysplastic syndromes of childhood. indices of infants after exclusion of iron
PG. Perinatal onset mevalonate kinase Blood. 2018;131(13):1406-1414. deficiency by laboratory criteria and
deficiency. Pediatr Dev Pathol. 2011;14(4): continuous iron supplementation. J Pediatr.
301-306. 114. Hasle H, Niemeyer CM. Advances in the 1978;92(3):412-416.
prognostication and management of
107. Shteyer E, Saada A, Shaag A, et al. advanced MDS in children. Br J Haematol.
Exocrine pancreatic insufficiency, 2011;154(2):185-195. © 2022 by The American Society of Hematology

Anemia in The Pediatric Patient

Uploaded by

Copyright:

Available Formats

Anemia in The Pediatric Patient

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Anemia in The Pediatric Patient

Uploaded by

Copyright:

Available Formats

Review Series

Anemia in the pediatric patient

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

Introduction smoking. Normalized Hb value curves have been developed for

blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 571

0.5 (n 5 232) 1 (n 5 240) 2 (n 5 241) 4 (n 5 52) 6 (n 5 52) 9 (n 5 56) 12 (n 5 56)

Hematocrit 53 6 0.4 44 6 0.3 35 6 0.2 38 6 0.4 36 6 0.3 36 6 0.3 37 6 0.3

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

Minus 2SD (both sexes)

572 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

Intrinsic hemolysis Posttransplant

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

Extrinsic hemolysis Malignancy

Immune mediated Malignant hypertension

Primary Scleroderma renal crisis

Warm-reactive autoimmune hemolytic anemia Antiphospholipid syndrome

Alloimmune hemolytic anemia Infection

Acute hemolytic transfusion reaction Complicated malaria

Delayed hemolytic transfusion reaction Clostridia or Haemophilus inﬂuenzae type b

Drug-induced hemolytic anemias (some types) Isolated intravascular sites of hemolysis

Secondary Kasabach-Merritt syndrome

Autoimmune or inﬂammatory disorders Renal artery stenosis

Evans syndrome Large vessel thrombi

Primary immunodeﬁciency Severe aortic coarctation

Wiskott-Aldrich syndrome TIPS

Common variable immune deﬁciency Vasculitis

Acquired immunodeﬁciency Dysfunctional cardiac valves or cardiac assist devices

HIV infection March hemoglobinuria, extreme running

Malignancy Other mechanical causes

Infection Heat denaturation (blood warmer, thermal burns)

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 573

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

574 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

MCV decreased MCV normal MCV increased

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

A hallmark of many of these disorders is hemolysis, premature Nonimmune hemolysis

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 575

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

Sickle cell disease

Figure 3. Anemia by age.

576 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 577

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

578 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 579

Paroxysmal nocturnal hemoglobinuria (PNH) PNH, an Immune hemolysis

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

580 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 581

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

582 blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 GALLAGHER

No systemic inflammation Systemic inflammation No systemic

Symptoms Nil Asymptomatic or Asymptomatic or Likely Symptoms of Symptoms of Symptomatic iron

Downloaded from http://ashpublications.org/blood/article-pdf/140/6/571/1912940/bloodbld2020006479c.pdf by guest on 27 November 2023

Reticulocyte Normal Normal Low Low Low Low Low

PEDIATRIC ANEMIA blood® 11 AUGUST 2022 | VOLUME 140, NUMBER 6 583