Anemia Na Criança - Abordagem Ao Doente

08/05/2023, 11:19 Anemia na Criança - Abordagem ao Doente
Anemia na Criança - Abordagem ao Doente
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Fundo
● A anemia é comumente definida em crianças como um nível de hemoglobina ≥ 2 desvios padrão abaixo
do normal para idade e sexo.
⚬ A anemia é uma condição comum em crianças, com uma prevalência global de 43% em crianças < 5
anos de idade, de acordo com a análise mais recente da Organização Mundial da Saúde em 2011.
⚬ A deficiência de ferro é a causa mais comum de anemia em crianças, mas uma ampla gama de
etiologias hereditárias e adquiridas deve ser considerada.
● A anemia geralmente é assintomática e pode ser detectada na triagem ou durante a avaliação de

outras condições.
● Também pode causar sintomas agudos e pode estar associada a sequelas neurocognitivas de longo
prazo.
● A abordagem da anemia em crianças é direcionada para a identificação da causa básica, a fim de

possibilitar tratamento que melhore os sintomas (se presentes) e evite ou reduza complicações a curto
e longo prazo .
Avaliação
● Realize uma história completa e exame físico , incluindo a avaliação de:
⚬ sinais comuns de anemia, como fadiga, palidez, diminuição do apetite e dor de cabeça
⚬ sinais que podem indicar anemia grave, como taquicardia, taquipnéia e hipotensão
⚬ achados que podem sugerir uma causa subjacente , por exemplo, icterícia (sugere hemólise), pica
(pode sugerir deficiência de ferro) ou características dismórficas
● Um hemograma completo (CBC) é o teste de diagnóstico inicial usual .
⚬ A hemoglobin level ≥ 2 standard deviations below normal for age and gender confirms anemia.
⚬ Evaluate the mean corpuscular volume (MCV) in order to classify the anemia as microcytic,
normocytic, or macrocytic.
⚬ Additional testing to consider includes a reticulocyte count, peripheral blood smear, and condition-
specific testing as indicated based on the suspected underlying cause.
● Evaluation of microcytic anemia.
⚬ A trial of oral iron supplementation may be sufficient for diagnosing iron deficiency in children with
mild anemia and low dietary iron intake. A hemoglobin increase of > 1 g/dL (10 g/L) confirms the
diagnosis.
⚬ In other children or if unresponsive to iron supplementation, perform iron studies, and consider
hemoglobin electrophoresis (to detect thalassemia or other hemoglobinopathy) and lead level.
● Evaluation of normocytic anemia.
⚬ Obtain a reticulocyte count and peripheral blood smear.

⚬ If the reticulocyte count is high, assess for hemolysis.
– For hemolytic anemia, evaluate the peripheral smear and perform additional testing as indicated
(based on clinical presentation and suspected underlying cause) to identify congenital
enzymopathies, membranopathies, and hemoglobinopathies, and autoimmune hemolytic
anemias.
https://www.dynamed.com/approach-to/anemia-in-children-approach-to-the-patient 1/56
– For nonhemolytic anemia, consider assessments for blood loss and/or hypersplenism.
⚬ If the reticulocyte count is low, consider testing for
– anemia of inflammation
– liver or kidney disease
– endocrine disorders
– bone marrow disorders (such as leukemia or myelofibrosis), especially if there are abnormalities
seen on a peripheral smear
● Evaluation of macrocytic anemia:
⚬ Assess the peripheral blood smear for hypersegmented neutrophils (indicative of megaloblastic
anemia).
⚬ For megaloblastic anemia, assess for folate and vitamin B12 deficiencies.
⚬ For nonmegaloblastic anemia, assess the reticulocyte count.
– If the reticulocyte count is low, assess for bone marrow disorders, liver disease, or
hypothyroidism.
– If the reticulocyte count is high, assess for hemolysis or hemorrhage.
● Refer to pediatric hematologist if cause remains unclear after testing.
Management
● Emergency management of children with anemia who are hemodynamically unstable:
⚬ Assess for sources of active bleeding and control bleeding if possible.

⚬ Consider blood transfusion based on overall clinical status, not just hemoglobin level.
– Consider fluid resuscitation with crystalloids if needed while awaiting transfusion.

– In life-threatening situations, uncross-matched blood may be used until fully cross-matched
blood is available.
● General management depends on the underlying etiology.
⚬ Treat the underlying cause if possible, for example:
– nutritional supplementation to correct iron, vitamin B12, or folate deficiency

– removal of toxin or trigger, such as lead abatement for lead poisoning or drug
discontinuation/replacement for drug-induced immune hemolytic anemia
⚬ Consider other definitive treatments as appropriate, for example:
– hormone replacement therapy for endocrine disorders

– corticosteroids for autoimmune hemolytic anemia
– antibiotics or antiviral medications for infection
– transplante de células-tronco hematopoiéticas (HSCT) para mielofibrose primária , anemia
aplástica ou anemia sideroblástica
⚬ Considere medidas de suporte conforme necessário, como transfusão de glóbulos vermelhos e

agentes estimuladores da eritropoiese.
Algoritmos
Imagem 1 de 8
Diagnóstico e tratamento da anemia em crianças
Última revisão em 2021.
Copyright ©2021 EBSCO Information Services.
Tópicos relacionados
● Anemia em Adultos - Abordagem ao Paciente
● Anemia ferropriva em crianças
● Anemia da Inflamação
Informações gerais
Descrição
● , ,
anemia é um nível de hemoglobina abaixo do normal para idade e sexo 1 2 3
● a deficiência de ferro é a causa mais comum de anemia em crianças, mas uma ampla variedade de
, ,
etiologias hereditárias e adquiridas deve ser considerada 1 2 3
● a anemia costuma ser assintomática, mas pode causar sintomas agudos, como fadiga ou pica, e pode
estar associada a sequelas neurocognitivas de longo prazo 1
Definições
● definições gerais de anemia incluem
⚬ hemoglobin or hematocrit level < 2.5th percentile for age, gender, and race 1
⚬ hemoglobin level ≥ 2 standard deviations (SD) below normal for age in children < 12 years old, and >
2 SD below normal for age and gender in children ≥ 12 years old 2
Table 1. Hemoglobin Levels -2 Standard Deviations Below Mean by Age
Age -2 Standard Deviations
Birth (term infant) 13.5 g/dL (135 g/L)
1 month 10.7 g/dL (107 g/L)
2 months 9.4 g/dL (94 g/L)
3-6 months 9.5 g/dL (95 g/L)
6 months to 2 years 10.5 g/dL (105 g/L)
2-6 years 11.5 g/dL (115 g/L)
6-12 years 11.5 g/dL (115 g/L)
12-18 years (males) 13 g/dL (130 g/L)
12-18 years (females) 12 g/dL (120 g/L)
● additional age-based definitions
⚬ World Health Organization (WHO) hemoglobin cut-offs for diagnosing anemia at sea level
– 11 g/dL (110 g/L) in children aged 6-59 months

– 11.5 g/dL (115 g/L) in children aged 5-11 years
– 12 g/dL (120 g/L) in adolescents aged 12-14 years
– 12 g/dL in nonpregnant girls > 15 years old, 11 g/dL if pregnant
– 13 g/dL (130 g/L) in boys ≥ 15 years old
– Reference - WHO VMNIS 2011 PDF
⚬ Global Burden of Disease Group 2013 hemoglobin thresholds for anemia
– 13 g/dL in infants < 1 month old

– 10 g/dL (100 g/L) in children aged 1 month to 5 years
– 11 g/dL in children > 5 years old (10 g/dL if pregnant)
– Reference - Hematol Oncol Clin North Am 2016 Apr;30(2):247
Classifications
Classification by Severity
Table 2. Classification of Severity of Anemia by Hemoglobin Concentration According

to Global Burden of Disease Group 2013
Population Mild Anemia* Moderate Severe Anemia*

Anemia*
Infants < 1 month 13-14.9 g/dL (130- 9-12.9 (90-129 < 9 g/dL (90 g/L)
old 149 g/L) g/L)
Population Mild Anemia* Moderate Severe Anemia*

Anemia*
Children aged 1 10-10.9 g/dL (100- 7-9.9 g/dL (70-99 < 7 g/dL (70 g/L)
month to 5 years 109 g/L) g/L)
Children aged 5- 11-11.4 g/dL (110- 8-10.9 g/dL (80- < 8 g/dL (80 g/L)
14 years 114 g/L) 109 g/L)
Pregnant girls ≥ 5 10-10.9 g/dL (100- 7-9.9 g/dL (70-99 < 7 g/dL (70 g/L)
years old 109 g/L) g/L)
Nonpregnant girls 11-11.9 g/dL (110- 8-10.9 g/dL (80- < 8 g/dL (80 g/L)
≥ 5 years old 119 g/L) 109 g/L)
Boys ≥ 5 years old 11-12.9 g/dL (110- 8-10.9 g/dL (80- < 8 g/dL (80 g/L)
129 g/L) 109 g/L)
* Hemoglobin concentration.
Reference - Hematol Oncol Clin North Am 2016 Apr;30(2):247 .
Table 3. Classification of Severity of Anemia by Hemoglobin Concentration According

to WHO Recommendations for Diagnosing Anemia at Sea Level
Population Nonanemia Mild Anemia Moderate Severe

Anemia Anemia
Children ≥ 11 g/dL 10.10.9 g/dL 7-9.9 g/dL ≤ 7 g/dL (70

aged 6-59 (110 g/L) (100-109 g/L) (70-99 g/L) g/L)
months
Children ≥ 11.5 g/dL 11-11/4 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

aged 5-11 (115 g/L) (110-114 g/L) (80-109 g/L) g/L)
years
Children ≥ 12 g/dL 11-11.9 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

aged 12-14 (120 g/L) (110-119 g/L) (80-109 g/L) g/L)
years
Population Nonanemia Mild Anemia Moderate Severe

Anemia Anemia
Nonpregnant ≥ 12 g/dL 11-11.9 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

women (≥ 15 (120 g/L) (110-119 g/L) (80-109 g/L) g/L)
years old)
Pregnant ≥ 11 g/dL 10-10.9 g/dL 7-9.9 g/dL ≤ 7 g/dL (70

women (110 g/L) (100-109 g/L) (70-99 g/L) g/L)
Men (≥ 15 ≥ 13 g/dL 11-12.9 g/DL 8-10.9 g/dL ≤ 8 g/dL (80

years old) (130 g/L) (110-129 g/L) (80-109 g/L) g/L)
Abbreviation: WHO, World Health Organization.
Reference - WHO 2011 PDF .
Classification by Red Blood Cell Size
● anemia classification by erythrocyte mean corpuscular volume (MCV)
⚬ microcytic anemia
– MCV below normal for age and gender

– suggests impaired hemoglobin synthesis
⚬ macrocytic anemia
– MCV above normal for age and gender

– can be further categorized as
● megaloblastic anemia - suggests DNA synthesis defect

● nonmegaloblastic anemia - suggests reticulocytosis, liver disease, or splenic dysfunction in
children, and red cell membrane defects in adults
⚬ normocytic anemia
– MCV within normal range for age and gender

– may occur in early stage of anemia, or may result from simultaneous processes causing
concurrent increase and decrease in red cell size
⚬ Reference - Med Clin North Am 2017 Mar;101(2):263
● MCV reference ranges by age and gender
⚬ references ranges are for whole blood, normal values may vary by lab
⚬ birth (cord blood): 98-118 femtoliters (fL)
⚬ age 2 weeks to 2 years: 70-84 fL
⚬ age 2-5 years: 73-85 fL
⚬ age 9-12 years: 76-90 fL
⚬ boys aged 12-14 years: 77-94 fL
⚬ girls aged12-14 years: 73-95 fL
⚬ girls aged 15-17 years: 78-98 fL
⚬ see Erythrocyte mean corpuscular volume determination for additional information
Classification by Underlying Process
● anemia can be categorized according to phase of red blood cell (RBC) lifecycle affected 1
⚬ anemias due to decreased RBC production by bone marrow

⚬ anemias due to increased RBC destruction (hemolysis)
⚬ anemias due to increased RBC loss (bleeding)
● a low reticulocyte count in the presence of anemia suggests impaired bone marrow function, while
reticulocytosis suggests increased RBC turnover due to hemolysis or bleeding 2
Incidence and Prevalence
STUDY
● SUMMARY
estimated 43% global prevalence of anemia in children aged 6-59 months in 2011
SYSTEMATIC REVIEW: WHO 2015 PDF

Details
⚬ based on World Health Organization (WHO) analysis of nationally representative data from 95
countries
⚬ anemia (defined as hemoglobin < 11 g/dL) in estimated 273.2 million children
– global prevalence 43%

– highest prevalence in African Region (62%)
– United States prevalence 6%
⚬ Reference - WHO 2015 PDF
Differential Diagnosis
Causes of Microcytic Anemia
● iron deficiency (most common cause of anemia in children) 1 , 2 , 3
● anemia of inflammation 1 , 2 (also called anemia of chronic disease)
● thalassemia - alpha-thalassemia, beta-thalassemia major and intermedia, beta-thalassemia minor 1 , 2 , 3
● other hemoglobinopathies such as hemoglobin E and hemoglobin C disorders
● infection 1 , 2 , 3
● lead poisoning 1
● sideroblastic anemia 3
Causes of Macrocytic Anemia
● megaloblastic anemia (reticulocyte count typically low)
⚬ vitamin B12 deficiency 1 , 2 , 3 (including pernicious anemia)

⚬ folate deficiency 1 , 2 , 3
⚬ inborn errors of metabolism 3 (for example, thiamine-responsive megaloblastic anemia [Semin

Hematol 2015 Oct;52(4):279 ] or hereditary orotic aciduria [Online Mendelian Inheritance in Man
(OMIM) #258900 ])
⚬ bone marrow disorders such as leukemia or myelofibrosis 2
⚬ congenital dyserythropoietic anemia 3
⚬ drugs that interfere with DNA synthesis or affect B12 or folate absorption or metabolism, for
example
– methotrexate
– purine and pyrimidine nucleoside analogues
– folate analogues
– antiseizure medication
– metformin
– sulfasalazine
– Reference - Semin Hematol 2015 Oct;52(4):279
● nonmegaloblastic anemia
⚬ with low reticulocyte count
– hypothyroidism 1 , 2
– liver disease 1 , 2
– aplastic anemia, including heritable disorders such as
● Fanconi anemia
● Diamond-Blackfan anemia
● dyskeratosis congenita
– other bone marrow disorders 1 , 2 , 3
⚬ with high reticulocyte count
– hemolysis 1 , 2 , 3
– hemorrhage 1 , 2 , 3
– hypersplenism 2 , 3
Causes of Normocytic Anemia
● with high reticulocyte count
⚬ hemolytic disease of the fetus and newborn (HDFN) 3

⚬ congenital hemolytic anemias, for example hereditary spherocytosis and glucose-6-phosphate
dehydrogenase deficiency 1 , 2 , 3
⚬ immune hemolytic anemia, for example warm autoimmune hemolytic anemia, cold autoimmune
hemolytic anemia, and drug-induced immune hemolytic anemia 3
⚬ acquired nonimmune hemolytic anemia, for example in hemolytic uremic syndrome 3 or mechanical
destruction by prosthetic heart valves (Am Fam Physician 2010 Jun 15;81(12):1462 )
⚬ hypersplenism 2 , 3
⚬ acute blood loss 1 , 2 , 3
⚬ sickle cell disease 2
● with low reticulocyte count
⚬ infection (congenital or postnatal), such as 1 , 2 , 3
– parvovirus B19
– Epstein-Barr virus
– cytomegalovirus
– human herpesvirus-6
– HIV
⚬ transient erythroblastopenia of childhood 1 , 2 , 3
⚬ anemia of inflammation 1 , 2 (also called anemia of chronic disease)
⚬ bone marrow disorders such as leukemia or myelofibrosis 2

⚬ renal disease 2 , 3
⚬ liver disease 1 , 2
⚬ endocrine dysfunction such as thyroid disease 2 , 3
Frequency of Causes by Age

Causes in Neonates
● blood loss, for example due to
⚬ placental abruption
⚬ birth trauma (see also Operative Vaginal Birth)
⚬ twin-twin transfusion syndrome
● hemolytic disease of the fetus and newborn (HDFN)
● congenital hemolytic anemias, including
⚬ hereditary spherocytosis
⚬ glucose-6-phosphate dehydrogenase (G6PD) deficiency
● congenital infections, including
⚬ parvovirus B19
⚬ HIV
⚬ rubella
⚬ syphilis
⚬ sepsis
● Fanconi anemia
● Diamond-Blackfan anemia (congenital red cell aplasia)
● Reference - Am Fam Physician 2010 Jun 15;81(12):1462
Causes in Infants and Toddlers
● iron deficiency
● concurrent viral or bacterial infection
● blood loss due to trauma or upper or lower gastrointestinal bleeding
● hemoglobinopathies
⚬ sickle cell disease

⚬ thalassemias
– alpha-thalassemia
– beta-thalassemia minor
– beta-thalassemia major and intermedia
● red blood cell (RBC) enzyme defects
⚬ G6PD deficiency
⚬ pyruvate kinase deficiency
● red blood cell membrane defects
⚬ hereditary elliptocytosis
● acquired hemolytic anemias
⚬ autoimmune hemolytic anemia (AIHA)
– warm AIHA
– cold AIHA (cold agglutinin disease or paroxysmal cold hemoglobinuria [Donath-Landsteiner
syndrome])
– mixed AIHA
– drug-induced immune hemolytic anemia
⚬ hemolytic uremic syndrome

⚬ disseminated intravascular coagulation (DIC)
● transient erythroblastopenia of childhood (immune reaction against erythroid progenitor cells, typically
following viral infection or toxin ingestion)
● leukemia
● myelofibrosis
● lead poisoning
● hexokinase deficiency due to autosomal recessive mutation and characterized by severe

nonspherocytic hemolytic anemia beginning in infancy reported in 17 families (orphanet 2020 Jul 7 )
Causes in Older Children
● iron deficiency
● chronic disease such as
⚬ renal disease
⚬ liver disease
⚬ hypothyroidism
● blood loss
⚬ trauma
⚬ upper or lower gastrointestinal bleeding
⚬ menstruation
● hemoglobinopathies
⚬ sickle cell disease

⚬ thalassemias
– alpha-thalassemia
– beta-thalassemia major and intermedia
– beta-thalassemia minor
● red blood cell membrane defects
⚬ hereditary elliptocytosis
● acquired hemolytic anemias
⚬ AIHA
– warm AIHA
– cold AIHA (cold agglutinin disease or paroxysmal cold hemoglobinuria [Donath-Landsteiner
syndrome])
– mixed AIHA
– drug-induced immune hemolytic anemia

⚬ hemolytic uremic syndrome
⚬ DIC
● bone marrow disorders such as leukemia and myelofibrosis
Pathogenesis
Normal Erythropoiesis and Red Blood Cell Life Cycle
● red blood cell (RBC) function
⚬ RBCs carry oxygen from lungs to other organs

⚬ RBC component responsible for oxygen carrying capacity is hemoglobin (Hb), a protein that binds
oxygen in the lungs and releases it to other organs where it is required for cellular oxidative
respiration by mitochondria
– Hb concentration is reflective of number of RBCs in circulation and major determinant of oxygen
delivery
– maintenance of stable Hb concentration is governed by ability to produce RBCs in response to
blood loss, natural aging of RBCs, and RBC destruction
⚬ RBCs are also involved in transit of carbon dioxide and nitric oxide, both involved in cellular
respiration and tissue oxygen supply
⚬ Reference - Blood Rev 2014 Mar;28(2):49
● RBC life cycle
⚬ RBCs arise from hematopoietic progenitor and precursor cells in bone marrow, develop into
reticulocytes and are released into circulation, then continue to develop into mature erythrocytes
⚬ typical RBC lifespan is 100-120 days, followed by apoptosis
⚬ Reference - Hematol Oncol Clin North Am 2017 Dec;31(6):1045 and Blood Rev 2014 Mar;28(2):49
● maintaining balance between RBC production and loss depends on
⚬ appropriate stimulation of erythropoiesis

⚬ ability of precursor cells in bone marrow to respond to stimulus
⚬ availability of nutrients essential for erythropoiesis such as iron, vitamin B12, and folate
⚬ normal RBC lifespan
⚬ Reference - Hematol Oncol Clin North Am 2012 Apr;26(2):205
● RBC production
⚬ regulated by erythropoietin (EPO), a hormone secreted by renal peritubular cells when renal cells
detect low oxygen levels
– production of EPO is regulated by transcription factor hypoxia-inducible factor 2-alpha (HIF2-
alpha)
● under normoxic conditions, EPO levels are maintained at a low level by oxygen-dependent
degradation of HIF2-alpha
● under hypoxic conditions such as anemia, HIF2-alpha is stabilized, leading to increased
expression and secretion of EPO
– EPO binds to its transmembrane receptor on erythroid progenitor cell surface, triggering a series
of cell signaling pathways that lead to suppression of apoptosis; EPO also suppresses apoptosis
of terminally differentiating erythroblasts
– increased survival of erythroid progenitors and terminally differentiating erythroblasts in

response to elevated EPO leads to reticulocytosis
– as reticulocytes mature into RBCs and oxygen delivery normalizes, EPO production is reduced
and rate of erythropoiesis returns to normal
⚬ reticulocyte maturation
– reticulocytes are irregularly shaped cells, about 24%-35% larger than mature RBCs that still
contain residual surface proteins of erythroblasts as well as organelles such as ribosomes,
endoplasmic reticulum, and mitochondria
– residual internal organelles are lost in the first 1-2 days in circulation, and plasma membrane and
underlying cytoskeleton are remodeled to produce mature RBCs with a characteristic biconcave
discoid shape
– during reticulocyte maturation, about one-quarter of cell volume is lost, resulting in a large
surface-to-volume ratio which allows efficient oxygen diffusion and delivery to meet the body's
requirements
⚬ response to blood loss or hemolysis
– if transient, reticulocyte production occurs at a rate greater than normal and slows down as
Hb/hematocrit (Hct) recovers to baseline values
– rate of recovery is tightly regulated by EPO so that overcompensation of Hb/Hct does not occur
– with ongoing hemolysis or hemorrhage, rate of erythropoiesis nears but generally does not reach
normal steady-state levels
⚬ Reference - Blood Rev 2014 Mar;28(2):49
● Hb synthesis
⚬ each RBC contains 4 Hb molecules; Hb is composed of 2 pairs of globin chains, each having an iron-
containing heme complex for binding of oxygen (Hematol Oncol Clin North Am 2017 Dec;31(6):1045
)
⚬ heme is generated when iron is incorporated into protoporphyrin IX
– about 80% of body iron is used for Hb synthesis

– iron is transported from plasma into erythroblast by its carrier protein, transferrin; iron-
transferrin complex binds to surface transferrin receptors on erythroblasts and are then
endocytosed
– after endosomal acidification, iron is released from transferrin and transported into the
mitochondria by divalent metal transporter 1 (DMT1) where it is then inserted into
protoporphyrin IX, generating heme
– heme exits mitochondria through a heme-export channel (FLVCR1b), and enters cytoplasm where
it is incorporated into globin chains to produce Hb
– Reference - Blood Rev 2014 Mar;28(2):49
⚬ globin chain synthesis
– controlled by 2 multigene clusters on
● chromosome 16 encoding alpha-like globins

● chromosome 11 encoding beta-like globins
– temporal regulation of specific genes within multigene clusters during development results in
production of different Hb tetramers during embryonic, fetal, and later life
– within beta-globin gene cluster
● genes are arranged in order of developmental expression (embryonic gene [epsilon], 2 fetal
genes [gamma], and 2 adult genes [delta and beta])
● epsilon gene is expressed only in early embryonic life
● 2 gamma-genes located downstream from the epsilon-gene encode gamma-globin and are
expressed during fetal development, resulting in incorporation into fetal Hb (HbF) along with
alpha-globin (alpha2gamma2); HbF predominates through most of gestation and remains as
minor component of total Hb into adulthood
● delta gene is located between gamma-globin genes and beta-globin gene; transition from
delta to gamma gene expression begins before birth and continues to age 6 months, forming
a minor Hb component HbA2 (alpha2delta2) into adulthood
● beta-gene product combines with alpha gene product to form HbA (alpha2beta2), which
accounts for > 95% of Hgb in RBCs beyond age 6 months
– Reference - Lancet 2018 Jan 13;391(10116):155
⚬ depending on genetic background, other variants of Hb may be found in circulation at varying levels,
affecting oxygen-carrying capacity of RBCs due to their altered oxygen affinity, shorter life-span, and
increased hemolysis as a result of reduced stability; Hb variants include
– HbS - predominant form of Hb in sickle cell disease
– HbC
– HbE
– thalassemia
– Reference - Hematol Oncol Clin North Am 2017 Dec;31(6):1045
● other factors affecting RBC function and survival
⚬ RBC membrane integrity
– RBC membrane is highly elastic and able to undergo rapid reversible deformation while
maintaining its integrity
– deformability of membrane allows RBC to withstand and respond to externally imposed fluid
shear stress as it travels through circulation, while maintaining constant membrane surface area
without resulting in cell fragmentation
– elasticity of RBC membrane is a result of composite structure of plasma membrane envelope
(lipid bilayer) which is anchored in two-dimensional elastic network of spectrin-based
cytoskeleton through transmembrane proteins embedded in the lipid bilayer
● membrane skeleton is anchored to the lipid bilayer by Band 3, RhAG, ankyrin, protein 4.2, and
spectrin through vertical linkages
● loss of any of the components of vertical anchoring process leads to loss of membrane
cohesion and cell surface area
– mechanical integrity of RBC membrane is maintained by horizontal linkages between spectrin

dimers and between spectrin, actin, and protein 4.1R in the junctional complex within the
spectrin-based cytoskeleton
– loss of horizontal linkages result in reduced membrane integrity
– as RBCs age, their membranes lose deformability, reducing their ability to deliver oxygen;
nondeformable cells are trapped primarily in the spleen, leading to hemolysis
– Reference - Int J Lab Hematol 2017 May;39 Suppl 1:47
⚬ RBC enzyme activity
– mature RBCs are able to survive > 100 days in circulation despite being anucleate and lacking
ribosomes and mitochondria
– main metabolic substrate of RBCs is glucose, which is metabolized by glycolytic and hexose
monophosphate shunt/glutathione pathways
– glycolysis results in production of
● adenosine triphosphate (ATP) - used as an energy source
● nicotinamide adenine dinucleotide (NAD) - cofactor for methemoglobin reduction by

cytochrome b5 reductase
● 2,3-diphosphoglycerate (2,3-DPG) - intermediate that modulates Hb-oxygen affinity
– hexose monophosphate shunt/glutathione metabolism pathway is responsible for detoxification
of oxidants produced by medications, toxins, and infections to help protect RBCs from oxidant
injury
– Reference - Pediatr Clin North Am 2018 Jun;65(3):579
● RBC removal
⚬ process by which the body recognizes older or damaged RBCs is not well understood, but likely
involves recognition of decreased deformability or alterations in the RBC membrane
⚬ RBC destruction occurs in 2 sites
– extravascular hemolysis - RBCs are engulfed by macrophages in spleen and liver and heme is
cleaved into iron and biliverdin, which is further converted to bilirubin
– intravascular hemolysis - normally accounts for only small fraction of RBC destruction
● circulating haptoglobin binds to free Hb, and haptoglobin-Hb complexes are eliminated by
liver
● Hb is then converted to iron and biliverdin, which is further converted to bilirubin
⚬ Reference - Hematol Oncol Clin North Am 2012 Apr;26(2):205
Pathogenesis of Anemia
● anemia results from erythrocyte production insufficient to replace those removed from circulation via
normal apoptosis or pathologic processes (Blood Rev 2014 Mar;28(2):49 )
● pathogenic mechanisms
⚬ increased red blood cell (RBC) loss (nonhypoproliferative anemia)
– RBCs may be lost from circulation due to bleeding, destruction, or sequestration
● reticulocyte count is frequently increased, reflecting compensatory response to high RBC

turnover
● examples include
⚬ blood loss due to gastrointestinal bleeding or menstruation

⚬ increased destruction due to
– inherited hemoglobinopathies, or RBC membrane or enzyme defects

– immune- or infection-mediated hemolysis
● Reference - Hematol Oncol Clin North Am 2012 Apr;26(2):205
– pathogenesis of nonhypoproliferative anemia
● loss of RBCs caused by acute blood loss
⚬ hemoglobin (Hb) and hematocrit (Hct) are initially normal; values do not reflect amount of
blood lost since both RBCs and plasma are lost together
⚬ Hb and Hct levels decrease as plasma volume deficit is replaced by movement of fluid from
the extravascular space to intravascular space, typically within 36-48 hours after a bleeding
event
⚬ Reference - Obstet Gynecol Clin North Am 2016 Jun;43(2):247
● loss of RBCs by hemolysis
⚬ inherited or acquired defect in RBC deformability, oxygen transportation, or protection

against oxidant damage can lead to loss of RBC integrity and shortened survival in
circulation (Obstet Gynecol Clin North Am 2016 Jun;43(2):247 )
⚬ pathogenesis of hemolytic anemia often involves both intravascular and extravascular RBC
destruction; causes may include
– mechanical destruction of RBC
– physical trauma
– repetitive trauma to vascular bed causing RBC destruction

– shearing of RBCs may occur due to malfunctioning prosthetic or native cardiac
valves
– RBCs passing through obstructed small vessels, which may occur in the setting of
microangiopathic hemolysis for example, thrombotic thrombocytopenic purpura
(TTP) and other causes of thrombotic microangiopathy
– injury from
– infections, for example
– malaria and parasites live within RBCs; intravascular hemolysis occurs

as parasites reproduce within RBCs
– toxins produced by O157:H7, or species can result in
direct RBC destruction
– other toxins such as copper

– heat injury
– rupture of RBCs from infusion of hypotonic solutions

– Reference - Med Clin North Am 2017 Mar;101(2):263
– immune-mediated destruction of RBCs due to
– autoantibodies that can develop after exposure to neoplastic or infectious agents, or

certain drugs; may also be idiopathic (see also Autoimmune Hemolytic Anemia)
– alloantibodies that can develop after sensitization and exposure to allergenic RBCs
(for example, due to transfusion of ABO incompatible blood products) (see also Red
Blood Cell Transfusion)
– Reference - Hematol Oncol Clin North Am 2012 Apr;26(2):205
– disorders that lead to alterations of Hb such as
– sickle cell disease

– thalassemia
– References - Int J Lab Hematol 2017 May;39 Suppl 1:47 , Pediatr Clin North Am
2018 Jun;65(3):579
– disorders that lead to alterations of RBC membrane integrity
– disorders that reduce deformability of RBCs cause RBCs to be sequestered, mainly in

the spleen, leading to reduced RBC life span and anemia
– mutations of genes encoding proteins that maintain integrity and large surface area
of RBC membrane lead to hemolytic anemia (for example, hereditary spherocytosis
and hereditary elliptocytosis)
– Reference - Int J Lab Hematol 2017 May;39 Suppl 1:47
– disorders that lead to impaired activity of RBC enzyme activity
– impairment of glycolytic enzymes (as seen with pyruvate kinase deficiency) results in
decreased ability to generate adenosine triphosphate (ATP) and accumulation of
intermediates within the glycolytic pathway; reduction in ATP levels leads to
membrane defects and RBCs are destroyed mainly in the spleen, or in the liver after
escape from spleen
– impairment of hexose monophosphate shunt pathway (as seen with glucose-6-

phosphate dehydrogenase (G6PD) deficiency and related enzyme disorders )
increases the risk of RBC exposure to oxidant injury and leads to RBC cell membrane
to become more rigid and nondeformable, leading to destruction by the
reticuloendothelial system
– Reference - Pediatr Clin North Am 2018 Jun;65(3):579
● anemia due to increased plasma volume (rather than reduction in RBC mass)
⚬ fluid overload from IV fluids (Hematol Oncol Clin North Am 2012 Apr;26(2):205
)
⚬ anemia during pregnancy - plasma volume increases by nearly 50% in third trimester, while
RBC mass only increases about 25%, leading to decrease in Hb and Hct (Obstet Gynecol Clin
North Am 2016 Jun;43(2):247 )
⚬ inadequate RBC production (hypoproliferative anemia)
– inappropriately low reticulocyte count in presence of anemia suggests impaired erythropoietic

response
– failure to increase erythrocyte production may be due to
● deficiency in nutrients that support erythropoiesis, especially iron, vitamin B12, and folate
● liver, kidney, thyroid, or other organ dysfunction
● bone marrow disorders such as leukemia or myelofibrosis - bone marrow infiltration or
scarring can impair hematopoiesis
● bone marrow suppression (for example due to medication or infection)
● anemia of inflammation
● pathogenesis based on RBC size
⚬ mean corpuscular volume (MCV) may suggest pathogenesis of anemia

⚬ microcytic anemia
– suggests defective hemoglobin synthesis

– may be due to
● lack of or reduced globin production (as in thalassemia)

● restricted iron delivery to heme group (as in iron deficiency anemia and anemia of
inflammation)
● defects in heme group synthesis (as in sideroblastic anemia)
– Reference - N Engl J Med 2014 Oct 2;371(14):1324
⚬ macrocytic anemia
– suggests RBC membrane or DNA synthesis defect

– megaloblastic macrocytosis
● seen in anemia caused by defects in DNA synthesis and repair, typically as a result of
deficiency or disruption of thymidine synthesis, leading to mismatch substitution of uracil for
thymidine in maturing hematopoietic progenitor cells and delay in nuclear maturation
(compared to cytoplasmic maturation)
● delay in nuclear maturation thought to result in unbalanced cell growth, defects in cell division,
and loss of defective hematopoietic precursors by apoptosis
● often caused by deficiency in vitamin B12 and/or folate which are both required for synthesis
of thymidylate for DNA synthesis
● can also be caused by drugs that
⚬ affect DNA synthesis or absorption, metabolism, or processing of vitamin B12 and/or folate
⚬ are purine and pyrimidine analogues that interfere with DNA synthesis
● Reference - Semin Hematol 2015 Oct;52(4):279 and Med Clin North Am 2017
Mar;101(2):297
– nonmegaloblastic macrocytosis - thought to be associated with RBC membrane defects and may
be seen in the setting of liver disease or hypothyroidism (Med Clin North Am 2017 Mar;101(2):263
)
– reticulocytosis can contribute to or cause increased MCV because reticulocytes are larger than
mature erythrocytes (Med Clin North Am 2017 Mar;101(2):263 )
⚬ normocytic anemia may represent early stage of anemia, or may result from simultaneous
processes causing concurrent increase and decrease in MCV (for example iron deficiency and
comorbid liver disease) (Med Clin North Am 2017 Mar;101(2):263 )
Effects of Anemia
● reduced hemoglobin levels reduce oxygen delivery to tissues 3
● physiologic compensatory mechanisms include
⚬ increasing cardiac output, including by 3
– raising heart rate (Ann Am Thorac Soc 2017 Jul;14(7):1216 )

– increasing stroke volume (Can Med Assoc 1997 Jun;156 (11 suppl): S27 PDF )
– decreasing systemic vascular resistance (Ann Am Thorac Soc 2017 Jul;14(7):1216 )
⚬ increasing plasma volume
– leads to increased cardiac output and helps maintain blood pressure

– decreased viscosity allows greater movement of red blood cells
– Reference - Med Clin North Am 2017 Mar;101(2):263
⚬ decreasing hemoglobin–oxygen binding affinity - increase in 2,3-diphosphoglycerate shifts the

oxyhemoglobin dissociation curve to the right, resulting in increased release of oxygen to tissues
(Med Clin North Am 2017 Mar;101(2):263 )
● effects of severe acute anemia may include 3
⚬ fatigue, tachycardia, shortness of breath

⚬ hypotension
⚬ confusion
⚬ heart failure
⚬ gastrointestinal ischemia
⚬ multiorgan failure
● chronic anemia 3
⚬ effects may overlap with effects of underlying cause

⚬ sequelae may include
– bone distortion and fragility - may be related to expansion of marrow space to compensate for
anemia
– hepatosplenomegaly - may be due to extramedullary erythropoiesis, hepatic iron overload (due
to increased intestinal absorption or repeated transfusion), or splenic processing of hemolyzed
RBCs
– poor growth
– pubertal delay
– neurocognitive impairments
– stroke
– cardiomegaly, electrocardiographic abnormalities, heart failure
History and Physical

Clinical Presentation
Overview
● anemia is often asymptomatic in children, and may be detected on screening or during evaluation for
other conditions 3
● symptoms, if present, often include 1 , 3
⚬ fatigue
⚬ pallor
⚬ decreased appetite
⚬ headache
⚬ irritability
● in severe or acute anemia, presentation may also include 3
⚬ tachycardia
⚬ shortness of breath
⚬ confusion
⚬ hypotension
⚬ heart failure
⚬ multiorgan failure
● additional findings may help identify underlying cause, for example 1 , 3
⚬ jaundice suggests hemolytic process

⚬ dysmorphic features may suggest syndromic causes
⚬ pica may suggest iron deficiency
● mean corpuscular volume (MCV) is usually helpful in narrowing the differential, with additional testing
as indicated based on clinical presentation 2
Microcytic Anemias
● anemia is typically microcytic and hypochromic, reticulocyte count low
● usually asymptomatic, often discovered during screening of high-risk infants and children or during
workup for another complaint
● when symptomatic, most common symptoms include pallor, fatigue, dyspnea, headache
● other symptoms may include
⚬ pica
⚬ diffuse alopecia, dry rough skin, dry damaged hair
⚬ glossitis
⚬ koilonychia (spoon-shaped nails)
⚬ symptoms of restless legs syndrome
⚬ tachycardia
● confirmation of iron deficiency can be based on either of
⚬ 1-month trial of oral iron supplementation - increase in hemoglobin of > 1 g/dL at end of trial
confirms diagnosis
⚬ blood indicators of low iron such as
– decreased serum ferritin, transferrin saturation, or reticulocyte hemoglobin content (CHr)

– increased transferrin receptor 1 (TfR1)
● see Iron Deficiency Anemia in Children for details
● anemia is typically microcytic and hypochromic, and usually develops at blood lead level (BLL) ≥ 10
mcg/dL
● children with elevated BLL often appear asymptomatic, but even low levels are associated with adverse
cognitive and behavioral effects such as learning disorders, attention deficits, and language difficulties
● higher BLLs may be associated with gastrointestinal symptoms and central nervous system
manifestations ranging from clumsiness to seizure and coma
● BLL ≥ 5 mcg/dL is considered elevated
⚬ lead toxicity often identified through targeted screening based on risk for lead exposure, following
local and state recommendations
⚬ American Academy of Pediatrics (AAP) recommends blood testing to identify anemia and iron
insufficiency in all children with BLL ≥ 5 mcg/dL, Centers for Disease Control and Prevention (CDC)
recommends testing for children with BLL ≥ 20 mcg/dL
● seeLead Poisoning in Children for details
● hereditary hemoglobinopathies most common in persons of Mediterranean, Southeast Asian, or African

descent 1
● anemia is typically microcytic and hypochromic 1 , 2 , 3
● alpha-thalassemia
⚬ autosomal recessive alpha globin chain deficiency

⚬ severity and additional clinical features depend on number of functioning alpha globin genes
– alpha-thalassemia silent carrier - 3 functional copies, mild anemia or completely asymptomatic

– alpha-thalassemia trait - 2 functional copies, mild-to-moderate anemia
– hemoglobin H (HbH) disease - 1 functional copy, mild-to-moderate hemolytic anemia and
moderate reticulocytosis is typical; however anemia can be severe, requiring regular transfusions;
other features may include
● mild jaundice
● moderate hepatosplenomegaly
● moderate bone remodelling
● growth retardation
– hemoglobin Bart hydrops fetalis syndrome - no functional copies, moderate-to-severe anemia,

severe anisopoikilocytosis, and very high reticulocyte count, other features include
● hepatosplenomegaly
● pleural or pericardial effusions, cardiac failure
● general edema
● enlarged and friable placenta
⚬ qualitative and quantitative hemoglobin analysis by either electrophoresis and/or high-performance

liquid chromatography may be used to identify amount and type of hemoglobin present
⚬ molecular genetic testing can confirm diagnosis
⚬ see Alpha-Thalassemia for details
● beta-thalassemia
⚬ caused by point mutation in beta globin gene

⚬ beta-thalassemia minor - mildly reduced beta-globin chain production, usually asymptomatic but
mild anemia with mild reticulocytosis possible
⚬ beta-thalassemia intermedia - mild-to-moderate reduction in beta globin synthesis, mild anemia
– symptoms may develop at age 2-6 years or as late as adulthood

– findings in children may include poor growth and failure of sexual maturation
⚬ beta-thalassemia major - greatly reduced beta globin synthesis, severe anemia
– typically presents at age < 2 years with failure to thrive and hepatosplenomegaly
– if inadequately treated, symptoms may progress to include jaundice, growth retardation,
craniofacial changes, and leg deformities
⚬ hemoglobin electrophoresis confirms diagnosis

⚬ see Beta-Thalassemia Major and Intermedia and Beta-Thalassemia Minor for details
● group of inherited and acquired anemias characterized by ring sideroblasts (erythroblasts with iron-
laden mitochondria) in bone marrow
⚬ congenital sideroblastic anemia is most commonly due to either of 2 mutations
– X-linked sideroblastic anemia (XLSA) due to germline mutations in
● defective heme synthesis typically results in mild-to-moderate microcytic hypochromic anemia

● defective erythropoiesis triggers increased iron absorption and reticuloendothelial iron
release, leading to parenchymal iron overload
● may present childhood or adolescence with symptoms of anemia, or in adulthood with
symptoms of anemia or iron overload
– autosomal recessive sideroblastic anemia due to mutations in - defective heme

synthesis results in severe microcytic hypochromic anemia
– Reference - Hematology Am Soc Hematol Educ Program 2015;2015:19
⚬ acquired sideroblastic anemias may be due to
– drugs (such as chloramphenicol, isoniazid, linezolid, penicillamine)

– lead or zinc toxicity
– copper deficiency
– excess alcohol intake
– myeloid neoplasms associated with myelodysplastic syndrome (clonal acquired sideroblastic
anemia), for example
● myelodysplastic syndromes with ring sideroblasts (also called refractory anemia with ring
sideroblasts [RARS])
● myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (also
called RARS with thrombocytosis)
● see Myelodysplastic Syndrome (MDS) for additional information
– Reference - Am J Hematol 2019 Apr;94(4):475
● diagnosis
⚬ Prussian blue staining of bone marrow smear shows erythroblasts with perinuclear ring of blue
granules, indicative iron-loaded mitochondria
⚬ genetic testing can confirm congenital causes, and may identify somatic mutations in some patients
with myeloid neoplasms
Reference - Hematology Am Soc Hematol Educ Program 2015;2015:19
⚬
Macrocytic Anemias
● anemia is typically megaloblastic (as indicated by presence of hypersegmented neutrophils) with oval
macrocytes and low reticulocyte count
● may be asymptomatic or can present with
⚬ anemia-related symptoms
⚬ neurologic symptoms such as paresthesias, gait disturbance, sensory deficits, mild cognitive
impairment (see Neurologic Manifestations of Vitamin B12 Deficiency for details)
● causes of vitamin B12 deficiency include
⚬ impaired gastrointestinal absorption, for example due to
– immunological disorders such as pernicious anemia

– gastric or ileal resection or disease
– medications
⚬ inadequate intake, for example due to vegan diet (or maternal vegan diet during pregnancy or
breastfeeding)
⚬ increased requirement, for example due to hemolysis
⚬ genetic disorders affecting B12 metabolism, such as cbID inborn error of cobalamin metabolism
● testing
⚬ low serum vitamin B12 level can confirm diagnosis

⚬ increased methylmalonic acid and total homocysteine levels support diagnosis, and may be useful if
B12 deficiency suspected but serum B12 level is indeterminate
⚬ additional testing may be indicated if underlying cause of deficiency is unclear
● see Vitamin B12 Deficiency for details
● anemia is typically megaloblastic (as indicated by presence of hypersegmented neutrophils) with oval
macrocytes and low reticulocyte count
● may be asymptomatic or can present with
⚬ neurologic manifestations such as peripheral neuropathy, depression, optic neuropathy, myelopathy
⚬ glossitis, mouth ulcers
⚬ pancytopenia
⚬ neural tube defects due to maternal folate deficiency
● causes of folate deficiency include
⚬ inadequate intake due to poor diet

⚬ impaired absorption, for example due to
– inflammatory bowel disease, celiac disease, tropical sprue

– jejunal resection
– drugs
– genetic disorder ( mutation)
⚬ impaired metabolism due to drugs such as folate analogs and trimethoprim

⚬ increased requirement or loss, for example due to dialysis or exfoliative skin disease
● testing
⚬ serum folate level < 3 mcg/L (7 nmol/L) indicates folate deficiency

⚬ assess for coexisting vitamin B12 deficiency
● see Folate Deficiency for details
● anemia is typically macrocytic but nonmegaloblastic with low reticulocyte count 2
● presentation may include
⚬ linear growth failure, weight gain
⚬ fatigue, cold intolerance
⚬ constipation or obstipation
⚬ developmental delay or learning difficulties
⚬ goiter
● free tetraiodothyronine (T4) and thyroid-stimulating hormone (TSH) levels are initial tests for suspected
hypothyroidism
⚬ low T4 and elevated TSH suggests primary hypothyroidism
⚬ low T4 and normal or low TSH suggests secondary (pituitary etiology) or tertiary (hypothalamic
etiology) hypothyroidism
⚬ elevated T4 and triiodothyronine (T3) with elevated or normal TSH may suggest thyroid hormone
resistance
● additional testing (such as imaging, pituitary function testing) may be indicated to evaluate underlying
cause
● see Acquired Hypothyroidism in Children for details
● see also Congenital Hypothyroidism
● anemia is typically macrocytic with round macrocytes and low reticulocyte count, can also be
normocytic
● may be asymptomatic, or may present with
⚬ hepatomegaly, jaundice, or symptoms related to underlying cause of liver disease
● testing
⚬ tests for assessing disease severity and complications include liver function tests and coagulation
studies
⚬ tests to determine etiology are based on suspected underlying cause, for example
– hepatitis B and hepatitis C serology

– alpha-1 antitrypsin levels
– serum ceruloplasmin and serum copper for suspected Wilson disease
– liver and spleen imaging
● see Anemia Associated With Liver Disease for details
● inherited or acquired condition characterized by hypocellular bone marrow resulting in progressive

pancytopenia
● anemia is typically macrocytic with low reticulocyte, granulocyte, and platelet count
● inherited causes include
⚬ Fanconi anemia
⚬ Diamond-Blackfan anemia
⚬ dyskeratosis congenita
● acquired aplastic anemia is most commonly idiopathic (presumed immune mediated), and less
commonly due to infection, drugs, nutritional deficiency, or exposure to chemicals or radiation
● clinical presentation often includes
⚬ bruising, petechiae, epistaxis, or menorrhagia due to thrombocytopenia
⚬ fever or infection due to neutropenia
● diagnostic criteria include
⚬ pancytopenia with ≥ 2 of
– hemoglobin < 10 g/dL (100 g/L)

– neutrophil count < 1.5 × 109/L
– platelet count < 50 × 109/L
⚬ hypocellular bone marrow without dysplasia or fibrosis
● additional testing is directed toward excluding other causes and identifying etiology, for example
⚬ vitamin B12 and folate levels to assess for nutritional deficits

⚬ liver function tests to assess for hepatitis
⚬ viral serology to assess for infection
⚬ chromosome breakage test for suspected Fanconi anemia
⚬ telomere length testing and gene sequencing for suspected dyskeratosis congenita
● see Aplastic Anemia and Pure Red Cell Aplasia (PRCA) for details
Normocytic Anemias
● hemolysis is caused by production of maternal antibodies against fetal red blood cells expressing a
paternally derived antigen
● anemia is typically normocytic with increased reticulocyte count
● HDFN may be identified prenatally
⚬ at first prenatal visit, pregnant women should have blood antigen typing for ABO and RhD groups
and maternal antibody screening that detects immunoglobulin G (Ig)G
⚬ sensitized pregnancies (red blood cell antibodies present) can be monitored for HDFN with repeated
antibody titers and fetal ultrasound
● common findings in neonates include
⚬ signs of anemia such as poor feeding, tachycardia, tachypnea, hypoxia

⚬ hyperbilirubinemia
● diagnosis
⚬ in addition to low hemoglobin/hematocrit and reticulocytosis, blood test results suggestive of

hemolysis include
– increased lactic dehydrogenase, bilirubin, and carboxyhemoglobin
– decreased red cell count, increased red cell distribution
– nucleated red blood cells, spherocytosis, and polychromasia on peripheral smear
⚬ prenatal diagnosis is based on monitoring at-risk pregnancies with serial antibody titers and
ultrasound
– women with history of HDFN or critical titer of alloantibody should have regular monitoring with
Doppler ultrasound to assess fetal middle cerebral artery (MCA) peak systolic velocity
– peak systolic velocity > 1.5 times median for gestational age may indicate moderate-to-severe
anemia
– cordocentesis to determine fetal hematocrit or hemoglobin levels can confirm anemia
● see Hemolytic Disease of the Fetus and Newborn (HDFN)
● also called anemia of chronic disease
● anemia is typically normocytic and normochromic (may become microcytic and hypochromic as disease
progresses) with low reticulocyte count
● symptoms may include fatigue, weakness, decreased exercise tolerance, and impaired learning and
memory
● additional symptoms may be related to underlying cause, such as autoimmune disease, inflammatory
bowel disease, infection, chronic kidney disease, cancer, and heart failure
● diagnostic testing
⚬ elevated markers of inflammation (such as C-reactive protein [CRP] or erythrocyte sedimentation

rate [ESR]) support diagnosis of anemia of inflammation
⚬ perform iron studies to exclude iron deficiency as alternative diagnosis or coexisting condition
⚬ consider additional blood tests as indicated to help identify other coexisting anemias, metabolic
deficiencies, or organ dysfunction contributing to anemia (for example, renal and liver function tests,
vitamin B12 level)
● see Anemia of Inflammation for details
● congenital red blood cell membrane disorder (autosomal dominant in about 75%, autosomal recessive
or de novo mutations in about 25%) most common in persons of Northern European and North
American descent
● anemia can be absent to severe, and is typically normocytic with increased reticulocyte count
● symptom onset may occur at any age, even in utero
⚬ neonates may present with jaundice within first few days of life, and develop signs of severe anemia
over first few weeks of life
⚬ older infants and children often present with jaundice and splenomegaly
⚬ mild hereditary spherocytosis (HS) is usually asymptomatic, with minimal hemolysis and anemia
unless exacerbated by illness, pregnancy, or other triggers
⚬ moderate HS may be associated with symptomatic anemia and usually presents in childhood
⚬ moderately severe HS is associated with symptomatic anemia and often presents in neonatal period
⚬ severe HS is associated with life-threatening symptomatic anemia and often presents in neonatal
period or in utero
● diagnosis established in children with all of
⚬ splenomegaly
⚬ family history of hereditary spherocytosis
⚬ anemia with increased mean corpuscular hemoglobin concentration (MCHC)
spherocytes on peripheral blood smear
⚬⚬ increased reticulocytes
● if diagnosis unclear after initial testing, further testing may include
⚬ eosin-5-maleimide flow cytometry test (EMA test)

⚬ osmotic fragility test
⚬ cryohemolysis test
⚬ sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of red blood cell
membrane
● see Red Blood Cell Membrane Disorders for details
● anemia is typically normocytic with increased reticulocyte count 1 , 2 , 3
● x-linked disorder caused by mutations in gene, resulting in decreased activity of G6PD, an

enzyme required for maintaining erythrocyte integrity
⚬ typically asymptomatic, but clinical manifestations may include
– neonatal jaundice
– acute hemolytic anemia upon exposure to certain medications, infections, or ingestion of fava
beans
– chronic nonspherocytic hemolytic anemia
⚬ testing
– findings suggestive of hemolysis include elevated bilirubin and lactate dehydrogenase, decreased
haptoglobin
– direct measurement of G6PD activity normalized by red blood cell count or hemoglobin
concentration is gold standard for assessing G6PD status, options include
● quantitative spectrophotometric analysis
● semiquantitative assays such as fluorescent spot test and formazan-based spot test
– genetic testing to identify pathogenic mutation possible, but is a poor predictor of enzyme
deficiency due to X-linked mosaicism that arises from random X-inactivation in individual red
blood cells
⚬ see Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency and Related Enzyme Disorders for
details
● acquired premature destruction of red blood cells (RBCs) by antibodies that target RBC antigens
combined with inadequate bone marrow compensation
● anemia is typically normocytic with increased reticulocyte count; however macrocytosis possible
● subtypes include
⚬ warm autoimmune hemolytic anemia

⚬ cold autoimmune hemolytic anemia (includes cold agglutinin disease syndrome and paroxysmal cold
hemoglobinuria)
⚬ mixed AIHA (warm and cold)
⚬ drug-induced immune hemolytic anemia
● occurs mostly in adults but may develop after a viral illness in children with primary immunodeficiency
disease or autoimmune lymphoproliferative syndrome
⚬ hemolysis-related symptoms such as jaundice, dark urine, left upper quadrant fullness, and
hepatosplenomegaly
⚬ type-specific findings such as history of acrocyanosis and/or Raynaud phenomenon in cold
agglutinin disease
● clinicopathological diagnosis is based on demonstrating hemolytic anemia and serological evidence of

anti-RBC autoantibodies
⚬ findings suggestive of hemolysis include elevated bilirubin and lactate dehydrogenase, decreased
haptoglobin, and presence of urinary hemosiderin
⚬ perform direct antiglobulin test (DAT) to confirm immune-mediated mechanism of hemolysis
⚬ additional type-specific testing may be indicated, as well as testing to identify underlying conditions
contributing to AIHA (such as immunological diseases)
● see Autoimmune Hemolytic Anemia for details
● see also
⚬ Warm Autoimmune Hemolytic Anemia

⚬ Cold Autoimmune Hemolytic Anemia
⚬ Paroxysmal Cold Hemoglobinuria
⚬ Mixed Autoimmune Hemolytic Anemia
⚬ Drug-Induced Immune Hemolytic Anemia
● acquired or hereditary type of thrombotic microangiopathy characterized predominantly by renal

impairment/failure
⚬ most commonly caused by Shiga toxin-producing (usually serotype 0157)
⚬ atypical hemolytic uremic syndrome (HUS) is HUS in absence of coexisting infection or underlying
disease, and accounts for about 10% of HUS in children
● anemia is typically normocytic with increased reticulocyte count, thrombocytopenia, and schistocytes
on peripheral blood smear (suggestive of microangiopathy)
● typical presentation of Shiga toxin-related HUS is triad of thrombocytopenia, microangiopathic

hemolytic anemia, and acute kidney injury following episode of gastroenteritis that is characterized by
acute onset of nausea, vomiting, abdominal pain, and profuse diarrhea
● other findings may include
⚬ symptoms of anemia
⚬ easy bruising
⚬ oliguria or anuria
● diagnosis
⚬ blood test findings suggestive of HUS include
– microangiopathic hemolytic anemia

– thrombocytopenia (platelet count < 150 × 109/L or > 25% fall from baseline)
– serum creatinine level > 1.5 times standard values for age and gender (indicative of acute kidney
injury
⚬ Shiga toxin-related HUS is usually confirmed with stool studies (polymerase chain reaction [PCR] for
Shiga toxin, or culture and serotyping), serologic testing may be considered if stool studies not
informative
⚬ atypical HUS diagnosis usually established by excluding other causes of thrombotic

microangiopathy, complement testing may be considered to support diagnosis and guide
management
● see Shiga Toxin-related Hemolytic Uremic Syndrome and Atypical Hemolytic Uremic Syndrome for
details
● group of autosomal recessive disorders characterized by propensity for erythrocytes to change into
crescent (sickle) shapes, which results in vascular occlusion, chronic hemolysis, and highly variable
clinical phenotypes that may include a range of acute and chronic complications
● anemia is typically normocytic or macrocytic with increased reticulocyte count in sickle cell anemia, may
be normocytic or microcytic in other genotypes (for example, sickle hemoglobin C disease)
● usually identified on newborn screening, later presentation may include signs and symptoms of
vascular occlusion or hemolysis such as
⚬ vaso-occlusive pain, dactylitis
⚬ anemia
⚬ acute chest syndrome
⚬ severe or recurrent musculoskeletal or abdominal pain
⚬ aplastic crisis caused by parvovirus B19 infection
⚬ splenic sequestration
● hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), or other testing to

identify hemoglobin S confirms diagnosis
● see Sickle Cell Disease in Infants and Children for details
● infection can lead to cytokine-mediated suppression of red blood cell production (Am Fam Physician
2010 Jun 15;81(12):1462 )
● anemia is typically normocytic with low reticulocyte count 1 , 2 , 3
● infection can also trigger hemolytic crisis in children with some underlying conditions (for example
hereditary spherocytosis or sickle cell disease) 1
● children may present with signs of infection such as fever, rash, or respiratory or gastrointestinal
symptoms
● findings that may suggest a congenital infection include
⚬ microcephaly, intrauterine growth restriction, hydrops fetalis

⚬ ophthalmologic abnormalities, hearing deficits, congenital heart disease
⚬ hepatosplenomegaly, jaundice
⚬ rash
⚬ intracranial calcifications, hydrocephalus
⚬ see Overview of TORCH Infections for details
● diagnosis is cause specific, and may include microbiologic testing to identify pathogen
● see also
⚬ Fever and Rash - Approach to the Patient

⚬ Parvovirus B19 Infection and Congenital Parvovirus B19 Infection
⚬ Epstein-Barr Virus-associated Infectious Mononucleosis
⚬ Cytomegalovirus (CMV) Infection in Immunocompetent Patients and Congenital Cytomegalovirus

(CMV) Infection and CMV in Pregnancy
⚬ Roseola Infantum
⚬ Overview of HIV Infection
⚬ Congenital Rubella Syndrome
● pure red cell aplasia usually occurring in children ≤ 4 years old, likely caused by immune-mediated
inhibition of erythroid progenitor cell development
● etiology unclear, although a history of viral illness is often reported
● anemia is typically normocytic with low reticulocyte count
● children often present with symptoms of anemia, and may have signs of significant anemia such as
systolic ejection murmur (due to increased flow)
● less commonly, neurologic abnormalities of unclear etiology may be present such as
⚬ altered mental status

⚬ gait disturbances
⚬ abnormal extraocular eye movements
⚬ transient hemiparesis
● diagnosis is based on excluding other causes of anemia
⚬ typical blood test results
– normocytic anemia without reticulocytosis (may become macrocytic with increased reticulocyte
count during recovery phase)
– normal white blood cell and platelet counts (neutropenia and mild thrombocytosis or
thrombocytopenia possible, but alternative diagnoses and further testing should be considered)
– normal iron studies, vitamin B12, and folic acid
– normal haptoglobin and direct antiglobulin test, no other evidence of hemolysis
⚬ bone marrow aspiration usually not required for diagnosis, but if performed shows absence or
reduced numbers of mature erythroid precursors and no other abnormalities
● Reference - Pediatr Emerg Care 2019 Mar;35(3):237
● anemia of chronic kidney disease (CKD) is typically normocytic and normochromic with low reticulocyte
count
● CKD may be asymptomatic, or may present with growth impairment/failure to thrive, polydipsia, or
polyuria
● symptoms of anemia may develop as renal disease progresses
● diagnosis
⚬ CKD diagnosed based on presence of either of the following for ≥ 3 months
– reduced glomerular filtration rate (GFR)

– evidence of kidney damage (such as increased urinary total protein or albumin excretion rate for
age, structural abnormality on imaging, or urine sediment abnormalities)
⚬ exclude other causes of anemia such as blood loss or nutritional deficiency
● see Anemia of Chronic Kidney Disease and Chronic Kidney Disease (CKD) in Children for details
● anemia associated with endocrine disorders is typically normocytic and normochromic with low
reticulocyte count, though hypothyroidism may be associated with macrocytosis
● endocrine disorders associated with anemia may include
⚬ diabetes mellitus
⚬ hypo- or hyperthyroidism
⚬ hypogonadism
⚬ hypopituitarism
⚬ primary hyperparathyroidism
⚬ Addison disease
⚬ Cushing disease
⚬ growth hormone deficiency
● may be asymptomatic or may present with symptoms of anemia
● diagnosis
⚬ diagnose endocrine dysfunction based on disease-specific features or criteria

⚬ exclude other causes of anemia such iron or vitamin B12 deficiency
● see Anemia Associated With Endocrine Dysfunction for details
● anemia is typically normocytic with low reticulocyte count 2
⚬ fever due to leukemia or neutropenia-related infection
⚬ bleeding, petechiae, or bruising due to thrombocytopenia
⚬ bone or joint pain, limp
⚬ lymphadenopathy
⚬ splenomegaly, hepatomegaly
● diagnosis
⚬ blood test findings other than anemia may include
– thrombocytopenia
– neutropenia or hyperleukocytosis
– blasts on peripheral smear
⚬ bone marrow biopsy demonstrating lymphoblasts confirms diagnosis, flow cytometry identifies
immunophenotype
● see Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL) in Children for details
● anemia is typically normocytic with low reticulocyte count (Am Fam Physician 2010 Jun 15;81(12):1462
)
● primary myelofibrosis is a myeloproliferative neoplasm that is rare in children
⚬ fevers
⚬ symptoms/signs related to thrombocytopenia or neutropenia (such as easy bruising or frequent
infections)
⚬ organomegaly
● diagnosis
⚬ blood test findings other than anemia may include
– thrombocytopenia
– neutropenia
– leukoerythroblastosis (presence of nucleated red cells, teardrop-shaped erythrocytes, and
immature granulocytes) possible, but less common than in adults
⚬ bone marrow aspirate can confirm diagnosis but may be difficult to obtain due to extensive marrow
fibrosis, findings may include
– hypercellularity
– megakaryocytic hyperplasia and dysplasia
– granulocyte proliferation
– decreased erythroid precursors
– reticulin and/or collagen fibrosis
● Reference - J Hematop 2015 Sep;8(3):143
● see also Primary Myelofibrosis (PMF)
History
History of Present Illness (HPI)
● HPI is directed toward identifying risk factors and possible causes of anemia
● ask about 1 , 2 , 3
⚬ anemia-related symptoms, including onset, duration, and severity

⚬ bleeding or bruising
⚬ jaundice or dark urine (may suggest hemolysis)
⚬ pain
⚬ current or recent illnesses
⚬ diet
⚬ pica
Medication History
● ask about medications, for example
⚬ drugs that may interfere with nutrient absorption or metabolism

⚬ drugs that may trigger drug-induced immune hemolytic anemia or sideroblastic anemia
Past Medical History (PMH)
● ask about prenatal, birth, and neonatal history including
⚬ hydrops fetalis (Am Fam Physician 2010 Jun 15;81(12):1462 )

⚬ prematurity 2
⚬ low birth weight 2
⚬ congenital anomalies that may suggest genetic disorder 3
⚬ findings that may suggest congenital infection, such as
– microcephaly, intrauterine growth restriction, hydrops fetalis

– ophthalmologic abnormalities, hearing deficits, congenital heart disease
– hepatosplenomegaly, jaundice
– rash
– intracranial calcifications, hydrocephalus

– see Overview of TORCH Infections for details
⚬ maternal diet 2
● ask about 1 , 2
⚬ growth
⚬ chronic disease
Family History (FH)
● ask about 2
⚬ family history of anemia

⚬ ethnicity
Physical
General Physical
● vital signs
⚬ tachycardia, tachypnea, and hypotension possible, and may suggest severe or acute anemia 3
⚬ fever may suggest infection 1 or neoplasm (Am Fam Physician 2010 Jun 15;81(12):1462 )
● assess for pallor - conjunctival, tongue, and palmar/solar pallor may be more reliable indicators of
anemia than cutaneous pallor (due to ethnicity-related variability in skin tone) 3
● assess for dysmorphic features, for example 3
⚬ frontal bossing, prominent malar eminence, and depressed nasal bridge may suggest thalassemia
⚬ hypertelorism, flat nasal bridge, cleft palate, and abnormal thumbs may suggest Diamond-Blackfan
anemia
● assess for growth impairment and pubertal delay 3
⚬ may be related to chronic anemia, underlying cause of anemia, or both

⚬ poor growth common in chronic kidney disease and genetic disorders such as thalassemia major
and Diamond-Blackfan anemia
⚬ poor growth and pubertal delay common in sickle cell disease
Skin
● assess for 1 , 2 , 3
⚬ pallor
⚬ jaundice
⚬ signs of bleeding such as bruising or petechiae
⚬ rash
● assess for abnormal pigmentation or lesions that may suggest syndromic or other cause, for example
⚬ hyperpigmentation or cafe au lait spots may suggest Fanconi anemia

⚬ diffuse alopecia, dry rough skin, dry damaged hair, and koilonychia (spoon-shaped nails) may
suggest iron deficiency anemia
HEENT
● assess for signs of anemia such as conjunctival and tongue pallor 3
● scleral icterus may suggest hemolysis 3
● assess for craniofacial abnormalities and lesions, for example
⚬ microcephaly or ophthalmologic abnormalities (such as microphthalmia, cataracts, chorioretinitis)

may suggest congenital infection
⚬ frontal and posterior bossing, prominent malar eminence, hypertrophic maxilla, and upper lip
retraction may suggest thalassemia major 3
⚬ glossitis or stomatitis may suggest iron deficiency anemia; glossitis may also suggest vitamin B12
deficiency
Neck
● assess for
⚬ thyroid enlargement (see Acquired Hypothyroidism in Children for additional information)

⚬ jugular venous distention (anemia can lead to heart failure)
Cardiac
● compensatory increase in cardiac output can lead to changes such as 1 , 3
⚬ flow murmur
⚬ cardiomegaly
⚬ heart failure
● assess for
⚬ jugular venous distention

⚬ displaced apical impulse
⚬ S3, S4
⚬ see Heart Failure With Preserved Ejection Fraction (HFpEF) for additional information
Abdomen
● assess for hepatomegaly/splenomegaly 1 , 2 , 3
Extremities
● koilonychia (spoon-shaped nails) may suggest iron deficiency anemia
● thumb abnormalities may suggest Diamond-Blackfan anemia (StatPearls 2019 Nov 23 ) or Fanconi
anemia
Neuro
● neurocognitive deficits, developmental delay, and behavior problems may be due to chronic anemia or
causes of anemia such as iron deficiency and lead poisoning 1
Rectal
● rectal exam (with stool guaiac) may be indicated to detect gastrointestinal bleeding if anemia suspected
due to blood loss 2
Diagnostic Testing
Initial Testing
● complete blood count is most common initial test to identify or confirm low hemoglobin (Hgb) level 2
⚬ Hgb level ≥ 2 standard deviations (SD) below normal for age and gender confirms anemia
⚬ evaluate mean corpuscular volume (MCV) based on age- and gender-appropriate norms to classify
anemia as microcytic, normocytic, or macrocytic
● additional testing often includes 1 , 2 , 3
⚬ reticulocyte count - high reticulocyte count indicates increased red blood cell turnover, low count
indicates bone marrow hypofunction
⚬ peripheral blood smear to assess cell morphology
● further testing may be indicated based on suspected underlying cause 1 , 2 , 3
Evaluation of Microcytic Anemia
● microcytic anemia suggests impaired hemoglobin synthesis (Med Clin North Am 2017 Mar;101(2):263
)
● in children with mild anemia and history of low dietary iron intake, suspect iron deficiency anemia 2
⚬ treat with oral iron supplementation (such as ferrous sulphate, ferrous gluconate, ferrous fumarate)
for 1 month then retest
⚬ hemoglobin increase of > 1 g/dL (10 g/L) at end of trial confirms diagnosis
● testing in children with more severe anemia, history inconsistent with low dietary iron intake, or
unresponsive to trial of oral iron supplementation should include indicators of iron status such as 2
⚬ serum ferritin (requires parallel measurement of C-reactive protein)
⚬ reticulocyte hemoglobin content (CHr)
⚬ transferrin receptor 1 (TfR1)
⚬ transferrin saturation
⚬ see Iron Deficiency Anemia in Children for details
● if findings are inconsistent with iron deficiency, perform additional testing to identify other causes of
anemia such as 2
⚬ hemoglobin electrophoresis to assess for thalassemia or other hemoglobinopathy (see Alpha-
thalassemia, Beta-thalassemia major and intermedia and Beta-Thalassemia Minor for details)
⚬ lead level (see Lead Poisoning in Children for details)
● if no cause identified, refer to pediatric hematologist 2
Evaluation of Normocytic Anemia
● in addition to known causes of normocytic anemia, consider that normocytic anemia may occur in early
stage of micro- or macrocytic anemia, or may result from simultaneous processes causing concurrent
increase and decrease in red cell size (Med Clin North Am 2017 Mar;101(2):263 )
● obtain reticulocyte count and peripheral blood smear 2
● if reticulocyte count high (indicative of increased red cell turnover) 2
⚬ assess for hemolysis, as indicated by
– increased bilirubin
– increased lactate dehydrogenase
– decreased haptoglobin
– findings on peripheral blood smear
⚬ if hemolysis present, cause-specific testing for hemolytic anemia may include
– measurement of enzyme activity to assess for enzymopathy, for example
● glucose-6-phosphate dehydrogenase (G6PD) activity for suspected G6PD deficiency
⚬ direct measurement of G6PD activity normalized by red blood cell count or hemoglobin
concentration is gold standard for assessing G6PD status, options include
– quantitative spectrophotometric analysis
– semiquantitative assays such as fluorescent spot test and formazan-based spot test
⚬ genetic testing to identify pathogenic mutation possible, but is a poor predictor of
enzyme deficiency due to X-linked mosaicism that arises from random X-inactivation in
individual red blood cells
⚬ see Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency and Related Enzyme Disorders
for details
● pyruvate kinase activity for suspected pyruvate kinase deficiency
● red cell enzymopathy panel if unclear which enzyme may be deficient
– antibody testing to assess for autoimmune hemolytic anemia (AIHA)
● perform direct antiglobulin test (DAT) to confirm immune-mediated mechanism of hemolysis
● additional type-specific testing may be indicated, as well as testing to identify underlying
conditions contributing to AIHA (such as immunological diseases)
● see also

– evaluations for membranopathies such as hereditary spherocytosis (HS)
● in children with splenomegaly and family history of HS, diagnosis is confirmed in those with all
of the following
⚬ increased reticulocyte count
⚬ anemia with increased mean corpuscular hemoglobin concentration (MCHC)
⚬ spherocytes on peripheral blood smear
● if diagnosis unclear, further testing may include
⚬ eosin-5-maleimide flow cytometry test

⚬ osmotic fragility test
⚬ cryohemolysis test
⚬ sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of red
blood cell membrane
– testing for hemoglobinopathies such as sickle cell disease
● peripheral blood smear may show sickle cells, target cells, polychromasia, and Howell-Jolly
bodies
● testing to identify hemoglobin S (HbS) confirms diagnosis and may include
⚬ isoelectric focusing (IEF)

⚬ cellulose-acetate hemoglobin electrophoresis
⚬ capillary electrophoresis
⚬ high-performance liquid chromatography (HPLC)
⚬ DNA analysis or parental testing in selected patients
● solubility tests are not definitive for diagnosis and should be avoided in newborns because of
false negatives in presence of fetal hemoglobin (HbF)
⚬ if no evidence of hemolysis, consider assessments for blood loss and/or hypersplenism for example
– stool guaiac or nasogastric or orogastric aspiration to detect gastrointestinal bleeding (see Acute
Upper Gastrointestinal Bleeding in Children - Approach to the Patient and Acute Lower
Gastrointestinal Bleeding in Children - Approach to the Patient for details)
– abdominal imaging to confirm splenomegaly, and possibly bone marrow and/or spleen biopsy to
assess for hypersplenism (see Splenomegaly in Children - Approach to the Patient and
Splenomegaly in Adults - Approach to the Patient for additional information)
● if reticulocyte count low (indicative of bone marrow hypofunction)
⚬ consider testing for 2
– liver, thyroid, renal, or other chronic condition

– bone marrow disorders such as leukemia or myelofibrosis, especially if abnormalities seen on
peripheral smear
⚬ anemia of inflammation
– perform iron studies to exclude iron deficiency as alternative diagnosis or coexisting condition
– elevated markers of inflammation (such as C-reactive protein [CRP] or erythrocyte sedimentation
rate [ESR]) support diagnosis
– consider additional blood tests as indicated to help identify other coexisting anemias, metabolic
deficiencies, or organ dysfunction contributing to anemia (for example, renal and liver function
tests, vitamin B12 level)
– see Anemia of Inflammation for details
⚬ kidney disease
– diagnose chronic kidney disease based on presence of either of the following for ≥ 3 months
● reduced glomerular filtration rate (GFR)

● evidence of kidney damage (such as increased urinary total protein or albumin excretion rate
for age, structural abnormality on imaging, or urine sediment abnormalities)
– exclude other causes of anemia such as blood loss or nutritional deficiency

– see Anemia of Chronic Kidney Disease and Chronic Kidney Disease (CKD) in Children for details
⚬ liver disease
– evaluation of disease severity and complications include liver function tests and coagulation
studies
– tests to determine etiology are based on suspected underlying cause, for example
● hepatitis B and hepatitis C serology

● liver and spleen imaging
● alpha-1 antitrypsin levels
● serum ceruloplasmin and serum copper for suspected Wilson disease
– see Anemia Associated With Liver Disease for details
⚬ endocrine disorders
– measure hormone levels based on specific dysfunction suspected, for example
● thyroid function studies for suspected hyperthyroidism

● testosterone levels for suspected hypogonadism
● see also
⚬ Diabetes Mellitus Type 1 and Diabetes Mellitus Type 2 in Children and Adolescents
⚬ Hypopituitarism
⚬ Primary Hyperparathyroidism
⚬ Adrenal Insufficiency in Children
⚬ Cushing Disease
⚬ Growth Hormone Deficiency in Children

– see Anemia Associated With Endocrine Dysfunction for details
⚬ leukemia
– blasts may be present on peripheral smear

– additional findings may include thrombocytopenia, neutropenia, or hyperleukocytosis
– bone marrow biopsy demonstrating blasts confirms diagnosis, flow cytometry identifies
immunophenotype
– see Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL) in Children for details
– see also Acute Myeloid Leukemia (AML)
⚬ primary myelofibrosis
– leukoerythroblastosis (presence of nucleated red cells, teardrop-shaped erythrocytes, and

immature granulocytes) possible
– additional findings may include thrombocytopenia and neutropenia
– bone marrow aspirate can confirm diagnosis but may be difficult to obtain due to extensive
marrow fibrosis, findings may include
● hypercellularity
● megakaryocytic hyperplasia and dysplasia
● granulocyte proliferation
● decreased erythroid precursors
● reticulin and/or collagen fibrosis
– Reference - J Hematop 2015 Sep;8(3):143

– see also Primary Myelofibrosis (PMF)
● if cause remains unclear after testing, refer to pediatric hematologist 2
Evaluation of Macrocytic Anemia
● macrocytic anemia suggests red cell membrane defect or DNA synthesis defect, but can also be due to
reticulocytosis
⚬ megaloblastic anemia suggests DNA synthesis defect
⚬ nonmegaloblastic anemia suggests red cell membrane defect
● assess peripheral blood smear for hypersegmented neutrophils (indicative of megaloblastic anemia) 2
● for megaloblastic anemia
⚬ measure serum folate and vitamin B12 levels to identify folate deficiency or vitamin B12 deficiency 2
– if either level low, consider folate or vitamin B12 supplementation as indicated, with referral to
pediatric hematologist if no improvement in anemia
– if both levels low or normal, refer to pediatric hematologist to consider evaluation for bone
marrow disorder
● for nonmegaloblastic anemia
⚬ assess reticulocyte count 2

⚬ if reticulocyte count low
– assess for 2
● bone marrow disorders

● liver disease
● hypothyroidism
⚬ if reticulocyte count high, assess for hemolysis or hemorrhage 2
● if cause remains unclear after testing, refer to pediatric hematologist 2
Hemoglobin and MCV Reference Values
● hemoglobin cutoffs for anemia in children
Table 4. Hemoglobin Levels -2 Standard Deviations Below Mean by Age
Birth (term infant) 13.5 g/dL (135 g/L)
1 month 10.7 g/dL (107 g/L)
2 months 9.4 g/dL (94 g/L)
3-6 months 9.5 g/dL (95 g/L)
6 months to 2 years 10.5 g/dL (105 g/L)
2-6 years 11.5 g/dL (115 g/L)
6-12 years 11.5 g/dL (115 g/L)
12-18 years (males) 13 g/dL (130 g/L)
12-18 years (females) 12 g/dL (120 g/L)
Reference - Am Fam Physician 2016 Feb 15;93(4):270

⚬ additional age-based definitions
– World Health Organization (WHO) hemoglobin cutoffs for diagnosing anemia at sea level
● 11 g/dL (110 g/L) in children aged 6-59 months

● 11.5 g/dL (115 g/L) in children aged 5-11 years
● 12 g/dL (120 g/L) in adolescents aged 12-14 years
● 12 g/dL in nonpregnant girls > 15 years old, 11 g/dL if pregnant
● 13 g/dL (130 g/L) in boys ≥ 15 years old
● Reference - WHO VMNIS 2011 PDF
– Global Burden of Disease Group 2013 hemoglobin thresholds for anemia
● 13 g/dL in infants < 1 month old

● 10 g/dL (100 g/L) in children aged 1 month to 5 years
● 11 g/dL in children > 5 years old (10 g/dL if pregnant)
● mean corpuscular volume (MCV) reference ranges in children
⚬ references ranges are for whole blood, normal values may vary by lab
⚬ birth (cord blood): 98-118 femtoliters (fL)
⚬ age 2 weeks to 2 years: 70-84 fL
⚬ age 9-12 years: 76-90 fL
⚬ see Erythrocyte mean corpuscular volume determination for additional information
Select Red Blood Cell Morphology
● peripheral blood smear can be useful in helping to determine possible causes of anemia 1 , 2 , 3
● features such as red cell size, shape, and color may help narrow the differential (Med Clin North Am
2017 Mar;101(2):263 )
● non-red-cell findings are also important in the evaluation of anemia, for example the presence of
hypersegmented neutrophils (indicative of megaloblastic anemia) 1 , 2
● reticulocytes
⚬ immature nonnucleated red blood cells (RBCs) usually present in circulation for about a day before
losing RNA and becoming mature red cells
⚬ increased number indicates appropriate marrow response to anemia, low number indicates marrow
hypofunction
⚬ reticulocytosis may be seen with blood loss, hemolysis, and other conditions with high red cell
turnover
● coarse basophilic stippling
⚬ basophilic inclusions consisting of precipitated ribosomes and RNA within RBCs

⚬ indicates defective hemoglobin synthesis
⚬ consider hemoglobinopathies (for example thalassemia), lead poisoning, marrow stress
Image 2 of 8
Basophilic stippling
Basophilic stippling is characterized by the presence of

blue granules representing ribosomal precipitates
dispersed within the cytoplasm of erythrocytes.
Used with permission from the American College of Physicians.
● schistocytes
⚬ also called helmet cells

⚬ red cell fragments with 2-3 pointed ends
⚬ suggests microangiopathic hemolytic anemia, for example due to mechanical heart valve
Image 3 of 8
Schistocytes
Peripheral blood smear demonstrating schistocytes in a

patient with TTP. Abbreviation: TTP, thrombotic
thrombocytopenic purpura.
● Howell-Jolly bodies
⚬ nuclear remnants appearing as dense basophilic inclusions at red cell periphery

⚬ usually removed by spleen, so presence on peripheral smear suggests splenic dysfunction
Image 4 of 8
Howell-Jolly bodies
This peripheral blood smear shows target cells,

acanthocytes, and Howell-Jolly bodies. Howell-Jolly
bodies are dense, blue, spherical cellular inclusions that
represent a small nuclear remnant that are normally
removed by the spleen.
● nucleated RBCs
⚬ usually removed by spleen, so presence on peripheral smear suggests splenic dysfunction or

increased red cell production (Med Clin North Am 2017 Mar;101(2):263 )
Image 5 of 8
Nucleated red blood cells
Two immature erythrocytes indicated by the presence

of the nuclei and basophilic cytoplasm. Magnification
x100; light micrograph, Wright-Giemsa stain.
Image courtesy of Science Photo Library
● spherocytes
⚬ small round deeply red RBCs without central pallor

⚬ loss of red cell membrane converts normally biconcave disk-shaped red cell into a sphere
⚬ increased number of spherocytes may be seen in conditions such as hereditary spherocytosis,
autoimmune hemolytic anemias, and microangiopathic hemolytic anemias
Image 6 of 8
Spherocytes
Spherocytes are characterized by erythrocytes with a

spherical shape and lack of central pallor (red arrow).
Spherocytes may be seen in hereditary spherocytosis
and warm autoimmune hemolytic anemia. The larger
and lighter pinks cells are reticulocytes (blue arrow).
● target cells
⚬ RBC with bull's-eye appearance due to excess membrane for amount of hemoglobin in cell
⚬ may be seen in conditions such as thalassemia, hemoglobin C and hemoglobin E disorders, and liver
disease
● elliptocytes
⚬ also called ovalocytes

⚬ elongated or oval RBCs due to membranopathy or cytoskeletal protein abnormalities
⚬ may be seen in conditions such as iron deficiency anemia and hereditary elliptocytosis
● tear drop cells
⚬ also called dacrocytes

⚬ tear drop shape is due to extension of cytoplasm which forms tail-like projection
⚬ may be seen in conditions such as myelofibrosis and severe iron deficiency
Image 7 of 8
Teardrop cells
A dacrocyte (or dacryocyte) is a type of poikilocyte that

is shaped like a teardrop (a teardrop cell). A marked
increase of dacrocytes is known as dacrocytosis. These
teardrop cells are found primarily in diseases with bone
marrow fibrosis. Light micrograph, Wright-Giemsa stain.
Magnification: 100x.
Image courtesy of Science Photo Library.
● sickle cells
⚬ elongated RBCs with point at each end

⚬ seen in conditions such as sickle cell disease, sickle trait, and hemoglobin SC disease
Image 8 of 8
Sickle cell disease
Peripheral blood smear shows sickle cells, target cells,

polychromasia, and Howell-Jolly bodies.
● bite cells
⚬ also called degmacytes

⚬ edge of RBC contains a bite-like semicircular defect
⚬ seen in drug-induced hemolysis and glucose-6-phosphate dehydrogenase deficiency
● Heinz bodies
⚬ precipitates of oxidized hemoglobin within RBC

⚬ cause membrane damage leading to hemolysis
⚬ seen in conditions such as thalassemia and glucose-6-phosphate dehydrogenase deficiency
⚬ see Alpha-Thalassemia, Beta-Thalassemia Major and Intermedia, and Glucose-6-phosphate
Dehydrogenase (G6PD) Deficiency and Related Enzyme Disorders for additional information
● ghost cells
⚬ unstained RBC that may indicate fetomaternal hemorrhage

⚬ Kleihauer-Betke test (KB test) stains for hemoglobin after exposure of maternal blood smear to acid
⚬ fetal hemoglobin is more acid-tolerant than maternal hemoglobin, so fetal cells will stain but
maternal cells appear as "ghosts"
⚬ see Fetomaternal Hemorrhage for additional information
⚬ ghost cells and hemi-ghost cells may also occur in glucose-6-phosphate dehydrogenase deficiency
(Ann Biol Clin (Paris) 2016 Jun 1;74(3):299 )
Management
Emergency Management
● acute management of children with anemia who are hemodynamically unstable
⚬ assess for sources of active bleeding and treat if possible
– ultrasound, computed tomography, endoscopy, or other imaging may be needed to detect

internal bleeding
– refer to surgery, gastroenterology, interventional radiology, or other specialty as indicated
⚬ consider blood transfusion
– no specific hemoglobin level should trigger transfusion
● decision to transfuse should take into consideration overall clinical status

● recommendations on hemoglobin thresholds and clinical indications for transfusion vary
– consider fluid resuscitation with crystalloids if needed while awaiting transfusion
● will increase cardiac preload, but is only a temporary measure due to lack of oxygen carrying
capacity
● administer carefully to avoid hemodilution resulting in exacerbation of anemia-related

sequelae
– in life-threatening situations, uncrossmatched blood may be used until fully crossmatched blood
is available
⚬ Reference - Hematol Oncol Clin North Am 2017 Dec;31(6):1045
● see also
⚬ Red Blood Cell Transfusion

⚬ Blood Products Administration
⚬ Massive Transfusion
⚬ Fluid Selection for IV Fluid Resuscitation
⚬ Bedside Assessment of Hemodynamic Status - Emergency Management
General Management
● management depends on the underlying cause of anemia 1 , 2 , 3
● definitive treatment is possible for some conditions, for example
⚬ nutritional supplementation to correct iron, vitamin B12, or folate deficiency

⚬ removal of toxin or trigger, such as
– lead abatement or chelation for lead poisoning

– drug discontinuation for drug-induced immune hemolytic anemia
⚬ hormone replacement therapy for anemia due to endocrine dysfunction

⚬ corticosteroids for some types of autoimmune hemolytic anemia
⚬ antibiotics or antiviral medications for infection-related anemia
⚬ hematopoietic stem cell transplantation (HSCT) for primary myelofibrosis, aplastic anemia, or
sideroblastic anemia
● if definitive treatment not available, feasible, or appropriate, general supportive measures may include
⚬ red blood cell transfusion (with chelation therapy for transfusion-associated iron overload as
needed)
⚬ erythropoiesis-stimulating agents
⚬ splenectomy for symptomatic splenomegaly
Cause-specific Management
Microcytic Anemias
● usual treatment is oral iron therapy
● consider IV iron supplementation as first-line therapy in
⚬ children with gastrointestinal disorders such as celiac disease or inflammatory bowel disease
⚬ children on chronic dialysis and erythropoiesis-stimulating agents
● for severe iron deficiency anemia in children with or at risk for heart failure, give red cell transfusion
followed by iron supplementation
● see Iron Deficiency Anemia in Children for details
● management of children with blood lead level (BLL) ≥ 5 mcg/dL should include
⚬ notification of local or state health department to request environmental assessments and lead
hazard reduction as indicated
⚬ ongoing monitoring of BLL
⚬ ongoing developmental assessments
● outpatient chelation therapy (such as succimer [Chemet] orally) may be indicated for BLL ≥ 45-69
mcg/dL
● inpatient chelation therapy (such as edetate calcium disodium intramuscularly or IV and dimercaprol
[BAL] intramuscularly) is indicated for BLL ≥ 70 mcg/dL
● bowel decontamination may be considered in children with ingested lead-containing objects visible on
abdominal x-ray
● see Lead Poisoning in Children for details
● management depends on thalassemia subtype
● alpha-thalassemia
⚬ alpha-thalassemia silent carrier and alpha-thalassemia trait - mild anemia usually does not require
treatment
⚬ hemoglobin H (HbH) disease
– in most cases treatment is supportive and includes avoidance of oxidative compounds and
medications (due to risk of hemolytic crisis) and prompt treatment of infections
– occasional red blood cell transfusion for hemolytic or aplastic crisis associated with fever or viral
infection
– children with more severe phenotype may require
● regular transfusions
● chelation therapy for iron overload (see Transfusional Iron Overload for additional
information)
● splenectomy for splenomegaly or hypersplenism
⚬ hemoglobin Bart hydrops fetalis syndrome
– many pregnancies are terminated or end in fetal demise

– successful in utero or postnatal hematopoietic stem cell transplants have been reported
⚬ see Alpha-Thalassemia for details
● beta-thalassemia
⚬ beta-thalassemia minor - typically does not require treatment

⚬ beta-thalassemia intermedia and beta-thalassemia major
– blood transfusion
● indicated for severe anemia (hemoglobin [Hb] < 7 g/dL), consider for Hb > 7 g/dL in children
with facial changes, poor growth, bony expansion, or increasing splenomegaly
● regular lifelong blood transfusions required for beta-thalassemia major
– other management may include
● chelation therapy (such as deferasirox or deferoxamine) to treat transfusion-associated iron

overload
● splenectomy for symptomatic splenomegaly, marked increase in blood transfusion
requirements, or increasing iron overload despite adequate chelation
● bone marrow or cord blood transplant (potentially curative)
⚬ see Beta-Thalassemia Major and Intermedia and Beta-Thalassemia Minor for details
● typical management of congenital sideroblastic anemias depends on mutation type and may include
⚬ for X-linked sideroblastic anemia (XLSA) due to germline mutations in
– oral pyridoxine - depending on specific mutation type, hemoglobin level may normalize, improve,
or remain unchanged
– mild phlebotomy as needed for iron overload
⚬ for autosomal recessive sideroblastic anemia due to mutations in
– regular red blood cell transfusions

– chelation therapy for iron overload (see Transfusional Iron Overload for additional information)
– allogenic stem cell transplant
⚬ Reference - Hematology Am Soc Hematol Educ Program 2015;2015:19
● management of acquired sideroblastic anemias
⚬ for drug- or toxin-induced sideroblastic anemia - discontinuation of drug or removal of toxin

⚬ for deficiency-related sideroblastic anemia - replacement therapy, for example oral copper
supplementation for copper deficiency
⚬ for myeloid neoplasms associated with myelodysplastic syndrome
– treat underlying malignancy

– management of symptomatic anemia may include
● lenalidomide
● erythropoiesis-stimulating agents(such as epoetin alfa)
● immunosuppressive therapy
● hypomethylating agents
● allogeneic hematopoietic stem cell transplant (HSCT)
– see Myelodysplastic Syndrome (MDS) for details
Macrocytic Anemias
● treat underlying cause if possible
● give vitamin B12 replacement therapy with cyanocobalamin or hydroxocobalamin
⚬ oral replacement therapy may be as effective as parenteral (if underlying cause is unrelated to
malabsorption)
⚬ monitor for hypokalemia during treatment (production of new erythrocytes results in intracellular
influx of potassium)
● see Vitamin B12 Deficiency for details
● see also
⚬ Vitamin B12
⚬ Pernicious Anemia
● treatment is folic acid replacement therapy
● treat coexisting vitamin B12 deficiency (if present) before starting folic acid supplementation
● see Folate Deficiency for details
● levothyroxine is treatment of choice
● adjust dose as needed based on age, weight, and results of thyroid function tests (repeat abnormal
tests before adjusting dose)
● see Acquired Hypothyroidism in Children for details
● see also
⚬ Thyroid Replacement Therapy

⚬ Congenital Hypothyroidism
● treat underlying cause, for example antiviral therapy as indicated for hepatitis B and hepatitis C
● additional interventions may be indicated for disease- or treatment-related complications, for example
⚬ blood products or medications to treat coagulopathy (see Coagulopathy in Liver Disease for
additional information)
⚬ erythropoiesis-stimulating agents (such as epoetin alfa) or red blood cell transfusion for ribavirin-
related anemia in patients with hepatitis C
● see Anemia Associated With Liver Disease for details
● factors such as age, presence of an appropriate donor for HSCT, disease severity, presence of
comorbidities, and underlying cause should inform treatment decisions
● typical management approach
⚬ for acquired aplastic anemia, eliminate underlying cause if identified (for example, discontinue drug
or treat nutritional deficiency)
⚬ first-line therapy for most children is human leukocyte antigen (HLA)-matched sibling donor HSCT
⚬ if HLA-matched sibling donor HSCT unavailable, consider immunosuppressive therapy with horse
antithymocyte globulin (ATG) plus cyclosporine
⚬ consider matched unrelated donor HSCT if refractory to immunosuppressive therapy
⚬ growth factors such as eltrombopag may also be considered for refractory disease
● protocols for congenital aplastic anemias may vary based on underlying condition
⚬ inherited aplastic anemias are less likely to respond to immunosuppressive therapy, so alternative
donor stem cell transplant may be second-line treatment in some children if matched sibling donor
unavailable
⚬ in Fanconi anemia, matched unrelated donor HSCT may be considered as second-line treatment if
matched sibling donor unavailable, and mismatched unrelated donor or cord blood stem cell
transplantation may also be considered
⚬ in dyskeratosis congenita, HSCT may be considered in children with autosomal dominant disease,
but should be avoided in those with X-linked disease (due to high mortality from liver and
respiratory failure)
⚬ in Blackfan-Diamond anemia, HSCT generally reserved for disease unresponsive to steroids and not
manageable with red cell transfusions
● see Aplastic Anemia and Pure Red Cell Aplasia (PRCA) for details
Normocytic Anemias
● prenatal management
⚬ intrauterine transfusion (IUT) usually indicated for moderate-to-severe fetal anemia if gestational
age considered unacceptable for delivery
⚬ if gestational age considered acceptable for delivery, induction of labor may be reasonable taking
into consideration gestational age, lung maturity, and severity of hyperbilirubinemia
– for mild fetal hemolysis or after intrauterine transfusion up to 36 weeks gestation, induction at
37-38 weeks gestation is reasonable
– for moderate-to-severe anemia at 35 weeks gestation, consider amniocentesis to assess amniotic
fluid bilirubin levels and fetal lung maturity to help determine if/when to induce labor
– for severe fetal hemolysis at 32-34 weeks gestation, delivery may be reasonable after maternal
treatment with steroids to promote fetal pulmonary maturity
● perinatal management - consider delayed umbilical cord clamping to reduce anemia and need for
transfusions
● neonatal management
⚬ closely monitor hemoglobin and bilirubin levels

⚬ treatment of hyperbilirubinemia may include phototherapy, IV immune globulin (IVIG), and exchange
transfusion (see Neonatal Unconjugated Hyperbilirubinemia for details)
⚬ red blood cell transfusions may be indicated to treat anemia; other treatments to support
erythropoiesis may include folic acid and iron supplementation and epoetin alfa
● see Hemolytic Disease of the Fetus and Newborn (HDFN)
● preferred management is treatment of underlying inflammatory condition
● if underlying cause is unknown or its treatment is not feasible, treating the anemia directly may be
beneficial; options include
⚬ iron therapy
⚬ erythropoiesis-stimulating agents (such as epoetin alfa)
⚬ blood transfusion (generally reserved for severe anemia requiring rapid correction)
● see Anemia of Inflammation for details
● management depends on disease severity and complications and may include
⚬ blood transfusions (including in utero transfusions for fetuses with severe hereditary spherocytosis)
⚬ splenectomy
⚬ folic acid supplementation
● management includes avoidance of oxidative stressors, such as certain medications and fava beans
● treatment of neonatal hyperbilirubinemia is similar to treatment of that due to other causes (see
Neonatal Unconjugated Hyperbilirubinemia for details)
● for acute hemolysis
⚬ eliminate or control all potential triggers (for example by discontinuing medication or treating
infection)
⚬ administer oral hydration to prevent hemodynamic shock that may lead to acute renal failure
⚬ consider blood transfusion if hemoglobin < 7 g/dL, or hemoglobin < 9 g/dL with concurrent ongoing
hemolysis
⚬ acute renal failure may occur with severe hemolysis and may require hemodialysis, but renal
function typically recovers after resolution of hemolytic anemia
● see Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency and Related Enzyme Disorders
● emergency management of severe or life-threatening anemia
⚬ give red blood cell transfusion

⚬ for warm AIHA and cold agglutinin disease (CAD), also consider corticosteroids or plasmapheresis
● general management
⚬ consider folic acid supplementation if hemolysis is ongoing

⚬ need for additional pharmacotherapy depends on symptom severity, and treatment is type specific
⚬ primary AIHA
– warm AIHA - first-line treatment is corticosteroids

– CAD - avoidance of exposure to cold in cornerstone of management; first-line treatment is
rituximab, plus fludarabine if clonality has been demonstrated
– paroxysmal cold hemoglobinuria - usually self-limited, consider corticosteroids only for severe or
persistent disease
– mixed AIHA - first-line treatment is corticosteroids
⚬ drug-induced immune hemolytic anemia - discontinue causative drug, efficacy of corticosteroids

unclear
⚬ secondary CAD - underlying conditions contributing to CAD usually treated according to guidelines; if
condition inactive or does not require treatment, management is similar to that for primary CAD
● see also

● supportive measures may include
⚬ IV fluids
⚬ red blood cell transfusions
⚬ antihypertensive agents
⚬ renal replacement therapy, kidney transplantation if renal function not restored after acute phase of
disease
● for atypical hemolytic uremic syndrome (HUS) - start eculizumab early, consider plasma exchange if
eculizumab not available
● for Shiga toxin-related HUS - efficacy of therapeutic plasma exchange or eculizumab unclear, but may
be considered on individual basis for severe disease
● see Shiga Toxin-related Hemolytic Uremic Syndrome
● see also Atypical Hemolytic Uremic Syndrome
● disease modifying measures may include
⚬ hydroxyurea therapy
⚬ glutamine
⚬ transfusion therapy
⚬ hematopoietic stem cell transplantation
⚬ voxelotor
⚬ crizanlizumab
● management also includes treatment and prevention of acute and chronic complications, for example
⚬ empiric antibiotics for febrile illness

⚬ oxygen and hydration for acute vaso-occlusive crisis
⚬ red blood cell transfusion for aplastic crisis
⚬ analgesics for acute or chronic pain
⚬ prophylactic penicillin in children < 5 years old
⚬ pneumococcal and meningococcal vaccines
● see also
⚬ Management of Acute Events of Sickle Cell Disease

⚬ Transfusion Therapy in Sickle Cell Disease
⚬ Chronic Management of Sickle Cell Disease
● management is cause specific
● antibiotics or antivirals may be indicated for some infections
● many infections are self-limited and require only supportive measures
● red blood cell transfusion may be required for severe anemia
● see for additional information
⚬ Fever and Rash - Approach to the Patient

⚬ Parvovirus B19 Infection and Congenital Parvovirus B19 Infection
⚬ Epstein-Barr Virus-associated Infectious Mononucleosis
⚬ Cytomegalovirus (CMV) Infection in Immunocompetent Patients and Congenital Cytomegalovirus
(CMV) Infection and CMV in Pregnancy
⚬ Roseola Infantum
⚬ Overview of HIV Infection
⚬ Congenital Rubella Syndrome
● disease is self-limited and management is generally supportive only
● red blood cell transfusions may be needed for symptomatic anemia
● reticulocytosis occurs at mean 10 days from time of diagnosis, and anemia typically resolves within 1-2
months
● Reference - Pediatr Emerg Care 2019 Mar;35(3):237
● iron therapy may be indicated to
⚬ treat iron deficiency

⚬ prevent iron deficiency while on erythropoietin-stimulating agents (ESAs)
⚬ avoid need for or reduce dose of ESAs
● ESAs may be considered after all correctable causes of anemia have been addressed
● red blood cell transfusion may be considered in urgent situations, but should be avoided if possible to
minimize risk of alloimmunization if renal transplantation is an option
● see Anemia of Chronic Kidney Disease for details
● management of chronic kidney disease may include nutrition support, antihypertensive medication,
recombinant human growth hormone for height deficits, dialysis, and kidney transplant (see Chronic
Kidney Disease (CKD) in Children for details)
● treatment should be guided by underlying endocrine disorder whenever possible
● for diabetes, control blood glucose and treat associated conditions if present (for example, consider
erythropoietin for anemia of chronic kidney disease, iron supplementation for iron deficiency)
● for other disorders, anemia usually resolves or improves with treatment for hormone deficiency or
excess, for example
⚬ for hypothyroidism - thyroxine replacement
⚬ for hyperthyroidism - antithyroid treatment
⚬ for hypogonadism - testosterone replacement therapy
⚬ for hypopituitarism - replacement therapy with a combination of thyroid, adrenal, and gonadal
hormones
⚬ for hyperparathyroidism - parathyroidectomy
⚬ for Addison disease - corticosteroid replacement therapy, plus mineralocorticoid replacement
therapy in children with confirmed aldosterone deficiency
⚬ for Cushing disease - resection of pituitary tumor
⚬ for growth hormone deficiency - recombinant human growth hormone
● see Anemia Associated With Endocrine Dysfunction for additional information
● type of leukemia determines optimal therapy
● risk stratification informs treatment approach
● chemotherapy is mainstay of treatment
● hematopoietic stem cell transplant is generally reserved for children with induction failure or very high
risk for relapse
● see Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL) in Children, Management of

Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL) in Children, and Acute Myeloid
Leukemia (AML) for details
● hematopoietic stem cell transplant is curative
● supportive measures vary depending on symptom type and severity and may include
⚬ red blood cell transfusion
⚬ platelet transfusion
● medications used to treat symptoms in adults but not routinely used in children may include
⚬ Janus kinase (JAK) inhibitors

⚬ hydroxyurea
⚬ interferon-alpha
⚬ androgens
⚬ erythropoiesis-stimulating agents (such as epoetin alfa)
⚬ immunomodulatory agents (such as thalidomide or lenalidomide)
● Reference - J Hematop 2015 Sep;8(3):143
● see also Primary Myelofibrosis (PMF)
Prevention and Screening

Prevention
● American Academy of Pediatrics (AAP) recommendations for prevention of iron deficiency and iron
deficiency anemia in patients aged 0-3 years
⚬ for term infants
– if exclusively or partially breastfed with > 50% of daily feedings from human milk, give elemental
iron 1 mg/kg/day liquid oral supplement beginning at 4 months and continued until
complementary iron-containing foods are started
– if formula fed, iron needs usually met with standard infant formula (iron content 10-12 mg/L) and
iron-containing foods starting after 4-6 months (whole milk not recommended before age 12
months)
– at age 6-12 months, give iron liquid oral supplement if dietary intake < 11 mg/day
⚬ for preterm infants
– if breastfed, give elemental iron 2 mg/kg/day supplement beginning at 1 month until using iron-
fortified formula or eating iron-containing food
– if formula fed, iron needs usually met with standard preterm or term infant formula
– iron supplementation not required in infants with history of multiple red blood cell transfusions
⚬ for children aged 1-3 years, if dietary intake < 7 mg/day, options include
– liquid supplement if patient aged 12-36 months

– chewable multivitamin if patient ≥ 3 years old
⚬ Reference - Pediatrics 2010 Nov;126(5):1040
● World Health Organization 2016 recommendations for iron supplementation
⚬ for children living in settings where anemia prevalence is ≥ 40% in infants and young children
– in children aged 6-23 months, give 10-12.5 mg/day elemental iron as drops or liquid orally for 3
consecutive months each year (WHO Strong recommendation, Moderate-quality evidence) (WHO
2016 PDF )
– in children aged 24-59 months, give 30 mg elemental iron as drops, syrups, or tablets daily for 3
consecutive months each year (WHO Strong recommendation, Very-low quality evidence)
– in children aged 5-12 years, give 30-60 mg/day elemental iron as tablets or capsules for 3
consecutive months (WHO Strong recommendation, High-quality evidence)
– Reference - WHO 2016 PDF
⚬ for nonpregnant menstruating adolescent girls living in settings where anemia prevalence is ≥ 40% in
this age group, give 30-60 mg/day elemental iron as tablet orally for 3 consecutive months each year
(WHO Strong recommendation, Moderate-quality evidence) (WHO 2016 PDF )
● see Iron Deficiency Anemia in Children for additional information
Screening
● American Academy of Pediatrics (AAP) recommendations on screening for iron deficiency anemia
⚬ perform universal anemia screening at age 12 months

⚬ perform risk assessment at well-child visits, with targeted screening in children with risk factors such
as
– low socioeconomic status
– Mexican American heritage
– history of prematurity
– early introduction of cow milk
– poor growth
⚬ Reference - AAP 2020 Recommendations for Preventive Pediatric Health Care
● United States Preventive Services Task Force (USPSTF) 2015 recommendation on screening for iron
deficiency anemia in young children
⚬ no recommendation made due to insufficient evidence to assess balance of benefits and harms of
screening in children aged 6-24 months
⚬ Reference - USPSTF 2015 Sept 7
● Centers for Disease Control and Prevention (CDC) recommendations on screening for iron deficiency
anemia
⚬ consider screening at age < 6 months in preterm and low-birth-weight infants not fed iron-fortified
formula
⚬ screening recommended in children at high risk for iron deficiency anemia at age 9-12 months, 6
months later, and then annually from age 2-5 years; high-risk group includes
– low-income status
– eligibility for Special Supplemental Nutrition Program for Women, Infants, and Children
– migrants and recently arrived refugees
⚬ assess for risk factors at 9-12 months and 6 months later, and screen for anemia if
– preterm or low-birth weight

– fed non-iron-fortified formula for > 2 months
– breastfed and received insufficient iron from supplementary foods after age 6 months
– cow milk introduced at age < 12 months
– > 24 oz of cow milk consumed daily
– special healthcare needs present (such as medications that interfere with iron absorption, chronic
infection, inflammatory disorders, blood loss, dietary restrictions)
⚬ Reference - MMWR Recomm Rep 1998 Apr 3;47(RR-3):1
● see Iron Deficiency Anemia in Children for additional information
Guidelines and Resources

Guidelines
International Guidelines
● World Health Organization (WHO) guideline on hemoglobin concentrations for the diagnosis of anemia
and assessment of severity can be found in WHO 2011 PDF
● North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) position
paper on anemia in children with inflammatory bowel disease can be found in J Pediatr Gastroenterol
Nutr 2020 Oct;71(4):563
United States Guidelines
● American Academy of Pediatrics (AAP) recommendations for preventive pediatric health care can be
found in Pediatrics 2021 Mar;147(3)
● American Academy of Pediatrics (AAP) recommendation on anemia screening (as part of periodicity
schedule for preventive pediatric health care) can be found at AAP 2020 Mar PDF
● Pediatric Critical Care Transfusion and Anemia Expertise Initiative guidelines on RBC transfusion in
critically ill children
⚬ consensus recommendations for RBC transfusion practice in critically ill children can be found in
Pediatr Crit Care Med 2018 Sep;19(9):884
⚬ recommendations on RBC transfusion in general critically ill children based on hemoglobin and/or
physiologic thresholds can be found in Pediatr Crit Care Med 2018 Sep;19(9S Suppl 1):S98
⚬ recommendations on RBC transfusion in critically ill children with non-life-threatening bleeding or
hemorrhagic shock can be found in Pediatr Crit Care Med 2018 Sep;19(9S Suppl 1):S127
European Guidelines
● Paediatric Haemato-Oncology Italian Association recommendation on diagnosis and management of

newly diagnosed childhood autoimmune hemolytic anemia can be found in Blood Transfus 2017
May;15(3):259 full-text
● Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) and Italian Society of
Paediatric Gastroenterology Hepatology and Nutrition (SIGENP) guideline on diagnosis of chronic
anemia in gastrointestinal disorders can be found in Dig Liver Dis 2019 Apr;51(4):471
● Associazione Italiana Onco-Ematologia Pediatrica (AIEOP) guideline on second-line therapy in paediatric

warm autoimmune hemolytic anemia can be found in Blood Transfus 2018 Jul;16(4):352 full-text
● German Society for Pediatrics and Adolescent Medicine (Deutsche Gesellschaft für Kinderheilkunde und
Jugendmedizin)/Society for Pediatric Oncology and Hematology (Gesellschaft für Pädiatrische Onkologie
und Hämatologie) (DGKJ/GPOH) guideline on anemia diagnostics in childhood can be found at
Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) 2018 May PDF
[German]
Review Articles
● review of anemia in childhood can be found in Pediatr Ann 2018 Feb 1;47(2):e42
● review of anemia in children; prevalence, causes, diagnostic workup, and long-term consequences can
be found in Expert Rev Hematol 2017 Nov;10(11):1023
● review of iron deficiency and other types of anemia in infants and children can be found in Am Fam
Physician 2016 Feb 15;93(4):270
● review of evaluation of anemia in children can be found in Am Fam Physician 2010 Jun 15;81(12):1462
MEDLINE Search
● to search MEDLINE for (Anemia in children) with targeted search (Clinical Queries), click therapy ,
diagnosis , or prognosis
Patient Information
● handout from EBSCO Health on
⚬ handout from EBSCO Health Library or in Spanish

⚬ iron deficiency anemia or in Spanish
● parent handout on anemia in children and teens from American Academy of Pediatrics
● handout from Patient UK PDF
References
General References Used
1. Khan L. Anemia in Childhood. Pediatr Ann. 2018 Feb 1;47(2):e42-e47
2. Wang M. Iron Deficiency and Other Types of Anemia in Infants and Children. Am Fam Physician. 2016
Feb 15;93(4):270-8 full-text
3. Allali S, Brousse V, Sacri AS, Chalumeau M, de Montalembert M. Anemia in children: prevalence, causes,
diagnostic work-up, and long-term consequences. Expert Rev Hematol. 2017 Nov;10(11):1023-1028
Recommendation Grading Systems Used
● World Health Organization (WHO) grading system for recommendations
⚬ strength of recommendation
– Strong - desirable effects of adherence to recommendation outweigh undesirable effects; in most

situations recommendation can be adopted as policy
– Conditional
● greater uncertainty about quality of evidence, balance of benefits vs. harms and burdens,
values and preferences, and/or resource use
● local adaptation needs to account for greater variety in values and preferences, or resource
use makes intervention suitable for some locations but not others
● need for substantial debate and involvement of stakeholders before recommendation can be
adopted as policy
⚬ quality of evidence
– High - very confident that true effect lies close to estimate of effect
– Moderate - moderately confident in effect estimate; true effect likely close to estimate of effect,
but possible that it is substantially different
– Low - confidence in effect estimate limited; true effect may be substantially different from
estimate of effect
– Very low - very little confidence in effect estimate; true effect likely to be substantially different
from estimate of effect
⚬ Reference - WHO guideline on daily iron supplementation in infants and children (WHO 2016 PDF )
Synthesized Recommendation Grading System for DynaMed Content
● The DynaMed Team systematically monitors clinical evidence to continuously provide a synthesis of the
most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based
Methodology ).
● Guideline recommendations summarized in the body of a DynaMed topic are provided with the
recommendation grading system used in the original guideline(s), and allow users to quickly see where
guidelines agree and where guidelines differ from each other and from the current evidence.
● In DynaMed content, we synthesize the current evidence, current guidelines from leading authorities,
and clinical expertise to provide recommendations to support clinical decision-making in the Overview
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● We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to

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⚬ Strong recommendations are used when, based on the available evidence, clinicians (without
conflicts of interest) consistently have a high degree of confidence that the desirable consequences
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Anemia na Criança - Abordagem ao Doente

Visão geral e recomendações

● A anemia geralmente é assintomática e pode ser detectada na triagem ou durante a avaliação de

● A abordagem da anemia em crianças é direcionada para a identificação da causa básica, a fim de

● Realize uma história completa e exame físico , incluindo a avaliação de:

● Um hemograma completo (CBC) é o teste de diagnóstico inicial usual .

● Evaluation of microcytic anemia.

● Evaluation of normocytic anemia.

⚬ Obtain a reticulocyte count and peripheral blood smear.

● Evaluation of macrocytic anemia:

● Refer to pediatric hematologist if cause remains unclear after testing.

● Emergency management of children with anemia who are hemodynamically unstable:

⚬ Assess for sources of active bleeding and control bleeding if possible.

– Consider fluid resuscitation with crystalloids if needed while awaiting transfusion.

● General management depends on the underlying etiology.

⚬ Treat the underlying cause if possible, for example:

– nutritional supplementation to correct iron, vitamin B12, or folate deficiency

⚬ Consider other definitive treatments as appropriate, for example:

– hormone replacement therapy for endocrine disorders

⚬ Considere medidas de suporte conforme necessário, como transfusão de glóbulos vermelhos e

Diagnóstico e tratamento da anemia em crianças

Última revisão em 2021.

Copyright ©2021 EBSCO Information Services.

● Anemia ferropriva em crianças

● definições gerais de anemia incluem

Table 1. Hemoglobin Levels -2 Standard Deviations Below Mean by Age

Age -2 Standard Deviations

Birth (term infant) 13.5 g/dL (135 g/L)

1 month 10.7 g/dL (107 g/L)

Age -2 Standard Deviations

2 months 9.4 g/dL (94 g/L)

3-6 months 9.5 g/dL (95 g/L)

6 months to 2 years 10.5 g/dL (105 g/L)

2-6 years 11.5 g/dL (115 g/L)

6-12 years 11.5 g/dL (115 g/L)

12-18 years (males) 13 g/dL (130 g/L)

12-18 years (females) 12 g/dL (120 g/L)

● additional age-based definitions

– 11 g/dL (110 g/L) in children aged 6-59 months

⚬ Global Burden of Disease Group 2013 hemoglobin thresholds for anemia

– 13 g/dL in infants < 1 month old

Table 2. Classification of Severity of Anemia by Hemoglobin Concentration According

Population Mild Anemia* Moderate Severe Anemia*

Population Mild Anemia* Moderate Severe Anemia*

Reference - Hematol Oncol Clin North Am 2016 Apr;30(2):247 .

Table 3. Classification of Severity of Anemia by Hemoglobin Concentration According

Population Nonanemia Mild Anemia Moderate Severe

Children ≥ 11 g/dL 10.10.9 g/dL 7-9.9 g/dL ≤ 7 g/dL (70

Children ≥ 11.5 g/dL 11-11/4 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

Children ≥ 12 g/dL 11-11.9 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

Population Nonanemia Mild Anemia Moderate Severe

Nonpregnant ≥ 12 g/dL 11-11.9 g/dL 8-10.9 g/dL ≤ 8 g/dL (80

Pregnant ≥ 11 g/dL 10-10.9 g/dL 7-9.9 g/dL ≤ 7 g/dL (70

Men (≥ 15 ≥ 13 g/dL 11-12.9 g/DL 8-10.9 g/dL ≤ 8 g/dL (80

Abbreviation: WHO, World Health Organization.

Reference - WHO 2011 PDF .

Classification by Red Blood Cell Size

● anemia classification by erythrocyte mean corpuscular volume (MCV)

– MCV below normal for age and gender

– MCV above normal for age and gender

● megaloblastic anemia - suggests DNA synthesis defect