Approach to a child with anemia.
Viraj.

Overview.
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Importance.
Introduction.
Definition.
Physiology.
Approach.
Summary.

Importance.
• Anaemia is a common and often complex
finding throughout childhood.
• May contribute to excess cardiovascular or
respiratory work (Cohen, 1996).
• About 42% of pregnant women and 47% of
children <5 yr of age in developing countries
are anemic. (nelson)

• Worldwide, anaemia in adults is responsible for
lost productivity, premature deaths, and perinatal
complications (Centers for Disease Control, 2002) and poor
growth, developmental delays, and increased
susceptibility to infection in children (Lesperance et al.,
2002).
• Timely screening coupled with appropriate
diagnostic testing will afford the most optimal
identification and management of childhood
anaemia.

RBC-The important players
• Hemoglobin
– Reversibly binds and transports 02 from lungs to
tissues.
– 4 globin chains & iron.

RBC-The important players
• Iron
– Key element in the production of hemoglobin
– Absorption is poor
• Transferrin
– Iron transporter
• Ferritin
– Iron binder, measure of iron stores, *also acute
phase reactant.*

Definition.
• Anaemia refers to red blood cell (RBC) mass,
amount of hemoglobin, and/or volume of
packed RBCs less than normal, determined
either as a hematocrit or hemoglobin
concentration > 2 standard deviations below
the normal mean for age (Abshire, 2001; Cohen, 1996;
Korones & Cohen, 1997; Walters & Abelson, 1996).

• Infants less than 2 months of age have not yet
established steady state values for hemoglobin or
hematocrit, hence reference ranges for normal
are extensive.
• Children with chronic pulmonary or cardiac
disease experience symptoms traditionally
suggestive of anaemia at hemoglobin and
hematocrit levels above reference cut-offs (Segel,
Hirsh, & Feig, 2002a).

• Anaemia may be mild, moderate, or severe in
nature.
• Mild anaemia: hemoglobin 9.5-11 g/dl, is often
asymptomatic and frequently escapes detection.
• Moderate anaemia: hemoglobin 8-9.5 g/dl, may
present with other symptoms and warrants
timely management to prevent long-term
complications.
• Severe anaemia: hemoglobin < 8 g/dl, will
warrant investigation and prompt management.

Mechanisms of anemia.
• Anaemia conceptually reflects an imbalance
between RBC production and destruction and
may be due to one of three mechanisms.
– Excess RBC loss, as occurs with hemorrhage, may
create anaemia as RBCs are depleted in addition to
loss of intravascular volume.
– Excess or premature RBC destruction, such as from
hemolysis, may create anaemia as RBCs are lost from
circulation prior to their normal turnover.
– A third mechanism, insufficient RBC production, may
create anaemia either from lack of stimulation of
production or lack of RBC precursor availability (Cohen,
1996; Hermiston & Mentzer, 2002; Ioli, 2002).

Burr cells
Target cells

Spur cells
Spherocytes

Heinz body haemolytic anemia.
Bite cells

Basophilic stippling and tear drop cells
Polychromatophilia

Sickle cell
Schistocytes

Tear drop cell
Howell jolly bodies

DIFFERENCES IN THE EVALUATION OF ANEMIA
BETWEEN PEDIATRIC AND ADULT PATIENTS.
• The normal ranges for red blood cell
parameters are significantly different in infants
and children and do not reach adult levels
until adolescence.
• Thus, the determination of whether anemia is
present or not must be made in an ageappropriate context.

• On identification of anemia, the likelihood of
certain diagnostic entities is different in
infants, children, and adults.
• In infants and children, anemia often
represents a nutritional deficiency or a
primary hematologic process, whereas in
adults anemia more commonly is an indicator
of systemic disease or malignancy.

APPROACH TO ANAEMIA
• There are 3 different approaches that can be
taken in determining the cause of anaemia in
a particular child:
• 1. Pathophysiological approach.
• 2. “Scenario approach.”
• 3. Approach based on “Morphologic
classification.”

• Pathophysiologic classification
– Is best suited for relating disease processes to
potential treatment.
– In addition, anemia resulting from deficiency
states occurs in a significant proportion of patients
with normal indices.

• Morphologic classification
– subdivides anemia into
• Macrocytic anemia,
• Normocytic anemia, and
• Microcytic hypochromic anemia.
– The main advantages of this classification are that the
classification is simple, is based on readily available
red cell indices (MCV and MCHC), and forces the
physician to consider the most important types of
curable anemia: vitamin B12 , folic acid, and irondeficiency anemias.
– Such practical considerations have led to wide
acceptance of this classification.

Approach.
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History,
Physical examination.
Complete blood cell count,
Reticulocyte count,
Peripheral blood smear.

History.
• Age :
• Newborn: Hemorrhage, Hemolysis, Infections,
Impaired red cell production.
• Infants & children : Iron deficiency anemia, Vit.B12
deficiency, hemolytic anemias.
• Adolescent, menstruating & pregnant teens : Iron
deficiency.
• Sex : Male : G-6 PD deficiency.
• Race :
• Tribes : Sickle cell anemia,
• Sindhi,punjabi,gujarati : Thalassemia.

• Family history : congenital anemias, hemolytic
anemias.
• (1)X-linked: G6PD def.
• (2)Autosomal dominant: Spherocytosis.
• (3)Autosomal recessive: Sickle cell anemia ,
Fanconi anemia.
• (4)Family member with early age of
cholecystectomy/ splenectomy.
• (5)Ethnicity: Thalassemia; G6PD def.

• H/o gallstones , recurrent jaundice : Hemolytic
anemias.
• Family history of anemia, requirement for
blood transfusions and demise of children:
Thalassemia major.
• H/o Pica, chronic diarrhea, prior surgery, acute
and prolonged infections, liver and renal
diseases.

• H/o tingling sensation , history suggestive of
neuropathy : Vit B 12 deficiency.

Diagnostic Approach-History
• Diarrhea:
– Malabsorption of VitB12/E/Fe.
– Inflammatory bowel disease and anemia of chronic disease
with or without blood loss.
– Milk protein intolerance induced blood loss
– Intestinal resection : Vit B12 def
• Infection:
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Giardia : iron malabsorption
Intestinal bacterial overgrowth: Vit.B12 def
EBV, CMV, Parvovirus : BM suppression
Mycoplasma, Malaria : Hemolysis
Hepatitis : aplastic anemia
Endocarditis, HIV

Diagnostic Approach-History
• Nutrition:
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(1)Cows milk diet : iron def.
(2)Strict vegetarian : Vit B12 def.
(3)Goats milk: Folate def.
(4)Pica: Plumbism, Iron def.
(5) Cholestasis, malabsorption : Vit.E def
• Drugs:
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(1)G6PD:oxidants(sulfa, primaquine, henna)
(2)Immune mediated Hemolysis (penicillin)
(3)Bone marrow suppression (chemotherapy)
(4) Phenytoin increase folate requirement

Physical examination.
• Fever - acute infection, intravascular disease, collagen
vascular disease.
• Jaundice suggests Hemolysis.
• Petechia & Purpura—bleeding tendency.
• Hypertension & edema - renal disease.
• Hepatosplenomegaly and lymphadenopathy —
infiltrative disease.
• Growth failure or poor wt. gain — Anemia of chronic
disease or organ failure.
• Examine stool for blood; urine for hemoglobinuria.

Physical Findings in Anemia
• Skin:
• Hyper pigmentation, café au lait spots - Fanconi
anemia
• Jaundice - Hemolysis
• Petechia & Purpura - BMinfiltration, autoimmune
Hemolysis & thrombocytopenia
• Erythematous rash- Parvovirus , E.B.Virus
• Butterfly rash - SLE;
• Vitiligo – Vit B12 def.
• Head :
• Frontal bossing - Thalassemia major
• Microcephaly - Fanconi anemia

Physical Findings in Anemia
– Eyes:
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Microphthalmia - Fanconi anemia
Retinopathy - Sickle cell disease
Optic atrophy - Osteopetrosis
KF ring - Wilson disease
– Ears:
• Deafness - Osteopetrosis
– Mouth:
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Glossitis-B12 def. , iron def
Angular stomatitis - Iron def
Pigmentation - Peutz Jeghers syndrome
Telangiectasia - Osler Weber Rendu syndrome

Physical Findings in Anemia
• Chest:
• Cardiac murmur-Endocarditis, prosthetic valve
Hemolysis.
• Abdomen:
• Hepatomegaly - Hemolysis, infiltrative tumor,
chronic disease, hemangioma, cholecystitis.
• Splenomegaly - Hemolysis, sickle cell disease,
Thalassemia, malaria, EBvirus, portal hypertension.
• Kidney anomaly - pelvic/absent kidney.

Physical Findings in Anemia
• Extremities :
• Absent thumb-Fanconi anemia
• Spoon nails-Iron deficiency
• Dystrophic nails- Dyskeratosis congenita
• CNS :
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Irritable, apathy - Iron def.
Peripheral neuropathy - lead poisoning
Ataxia, post. Column signs - Vit B12def
Stroke - Sickle cell anemia
• Short stature : Fanconi anemia, Malnutrition.

• Pallor : nail beds, oral mucous membranes
and conjunctivae.
• Observing skin pallor and palmar creases is
insufficient in children as the skin creases do
not show pigmentation. (O.P.GHAI)

Mean Corpuscular Volume
• The average volume of the red blood cells is a
useful red cell index that is used in
classification of anemias and may provide
insights into Pathophysiology of red cell
disorders.
• Usually measured directly with automated
instruments but may also be calculated from
the erythrocyte count and the Hct by means
of the following formula.

Red Cell Distribution Width.
• The RDW is a red cell measurement that
quantitates red cell volume heterogeneity that is
provided by the more modern automated
hematology analyzers and reflects the range of
red cell sizes measured within a sample.
• RDW has been proposed to be useful in early
classification of anemias because it becomes
abnormal earlier in nutritional deficiency anemias
than any of the other red cell parameters,
especially in cases of iron deficiency anemia.

• RDW is particularly useful when characterizing
microcytic anemias, particularly distinguishing
between iron deficiency anemia (high RDW,
normal to low MCV) and uncomplicated
heterozygous Thalassemia (normal RDW, low
MCV).

• RDW is useful as a method for initial
characterization of anemia, particularly
microcytic anemias, although other tests are
usually required to confirm the diagnosis.
• RDW is also useful in identifying red cell
fragmentation, agglutination, or dimorphic
cell populations (including patients who have
had transfusions or have been recently
treated for a nutritional deficiency)

Automated Reticulocyte Counts.
• Determination of the numbers of reticulocytes or
immature, nonnucleated red blood cells that contain
RNA provides useful information about the bone
marrow's capacity to synthesize and release red cells in
response to a physiologic challenge, such as anemia.
• In the past, reticulocyte counts were performed
manually using supravital staining with methylene
blue.
• Reticulocytes will stain precipitated RNA that appears
as a dark blue meshwork or granules (at least two per
cell) allowing reticulocytes to be identified and
enumerated by manual counting methods

• Normal values for reticulocytes in adults are 0.5
to 1.5%, although they may be 2.5 to 6.5% in
newborns (falling to adult levels by the second
week of life).
• Because there are relatively low numbers of
reticulocytes, the CV for reticulocyte counting is
relatively large (10 to 20%).
• To increase accuracy of reticulocyte counting,
alternative methods using flow cytometry and
staining with acridine orange or thioflavin allow
for many more cells to be analyzed, thereby
increasing accuracy and precision of counts.

Reticulocyte Production Index.
• RPI corrects the retics for the degree of anemia
• RPI indicates whether bone marrow is
responding appropriately to anemia
• RPI= Retic x Hb (o) x 0.5 divided by Hb (n)
• RPI > 3 increased production (Hemolysis or blood
loss)
• RPI < 2 decreased production or ineffective
production for the degree of anemia
• Reticulocytopenia—acute onset of anemia,
antibody mediated destruction, BMdisease.

AETIOLOGY
• (1) Inadequate response RPI < 2
– A. Hypochromic microcyctic
– B. Normochromic Normocytic
– C. Macrocytic
• (2)Adequate response RPI > 3
– R/O blood loss---Includes Hemolytic disorders

Corrected reticulocyte count.
• Corrected reticulocyte count = patient reticulocyte
count
patient hematocrit / normal hematocrit.
• High reticulocyte count :
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Hemolysis,
Hemorrhage,
Splenic sequestration,
Sepsis,
Recovery from vitamin or iron deficiency.
• Low reticulocyte count :
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Congenital or acquired,
Aplastic/hypoplastic anemia.
Transient erythroblstopenia of childhood,
Pure red cell aplasia,
BM infiltration

Pathophysiological approach.
• Based on pathophysiology, anemias are
divided into
– Anemia due to acute hemorrhage,
– Anemia due to hypo proliferation,
– Anemia due to Hemolysis.

APPROACH TO HYPOPROLIFERATIVE ANEMIA IN THE CHILD.

APPROACH TO HEMOLYTIC ANEMIA IN THE CHILD.

Approach to a child with anemia(scenario approach)
Anemia (Hb less than normal level)
- No lymph nodes
- No hepatosplenomegaly
- No petechiae or ecchymosis
----- Nutritional iron deficiency or megaloblastic
----- Pure red cell aplasia
----- Thalassemia trait
----- Lead poisoning
----- Renal disease

Anemia (Hb less than normal level)
- No lymph nodes
- No hepatosplenomegaly
- With petechiae and ecchymosis
----- Aplastic anemia
----- Bleeding disorder
----- Coagulation disorder
----- ITP
----- DIC

Anemia (Hb less than normal level)
With hepatosplenomegaly
----- Thalassemia
----- Liver disorders

Anemia (Hb less than normal level)
With petechiae, lymphadenopathy and
hepatosplenomegaly
--- Leukamia
--- Infections
--- DIC

Morphological approach.
• Anemias may be morphologically categorized
on the basis of RBC size (mean corpuscular
volume [MCV]), and microscopic appearance.
• They can be classified as microcytic,
normocytic, or macrocytic based on whether
the MCV is low, normal, or high, respectively.
• RBC size also changes with age, and normal
developmental changes in MCV should be
recognized before a designation is made.

Microcytes
Macrocytes
Normocytes

Approach to Microcytic anemia
Reticulocyte count
Increased
Normal or reduced
Low serum iron
Low ferritin
Increased TIBC
Normal serum iron
Normal TIBC
Normal ferritin
Hemoglobin electrophoresis
Peripheral smear for RBC
morphology,
Tests for hemolysis
(bilirubin,LDH,haptoglobin)
Hemoglobin electrophoresis
Iron deficiency
Low serum iron
Normal or high ferritin
Normal or low TIBC
Raised ESR,CRP
Inflammatory
disease
Hemoglobinopathies
Anemia of chronic
disease
Increased serum iron
Low TIBC
Increased ferritin
Sideroblastic anemia

Approach to Normocytic anemia
Reticulocyte count
Increased
Normal or reduced
Screen for
renal,hepatic,endocrine
disease
Serum iron
Low
Normal or high
BM biopsy
negative
Positive
Anemia of renal,
hepatic, endocrine
disease
Anemia of chronic
disease
Early iron deficiency
Infiltrative disease (leukemia, metastasis,
myelofibrosis)
Aplastic anemia, pure red cell aplasia,
Myelodysplastic syndrome
Positive tests for
Hemolysis
Yes
No
Hemolytic anemia
Hemorrhage
Recovery from nutritional
deficiency, sepsis.

Approach to Macrocytic anemia
Peripheral smear shows hyper segmented neutrophils and macro- ovalocytes.
Yes
Likely megaloblastic
anemia
Likely non
megaloblastic anemia
No
Reticulocyte count
BM Examination to confirm
megaloblastic anemia and vit
B12/folic acid levels or response to
vit B12 /folic acid therapy
Megaloblastic
marrow and
anemia improves
Continue vit B12/folate
Treat underlying cause
Decreased
Increased
Non megaloblastic
Hypothyroidism,
marrow or no
Liver disease
Hemolysis,
improvement
hemorrhage
Investigate for
Drug induced, e.g. phenytoin,
If negative do BM for
Cyanotic heart disease,
Aplastic anemia,
Down syndrome,
Red cell aplasia,
Hypothyroidism
MDS, Sideroblastic anemia

What to do?
• Brief clinical history.
• Physical findings.
• 1st line : Hemoglobin, hematocrit, MCV,
retic.count, peripheral smear.
• 2nd line : Iron studies, evidence of Hemolysis,
electrophoresis.
• 3rd line : bone marrow.

Summary.
• Anaemia is a common and often complex
finding throughout childhood.
• Iron is a Key element in the production of
hemoglobin with poor absorption.
• Infants less than 2 months of age have not yet
established steady state values.

• The determination of whether anemia is
present or not must be made in an ageappropriate context.
• Morphologic classification is widely accepted.
• A systematic approach is the key to diagnosis.

References
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Nelson’s textbook. 17th edition.
Hoffman’s hematology.
William’s hematology. 7th edition.
Wintrobe’s hematology.
O.P.Ghai.

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