Anemia seminar final prevention types based on age

Approach to a Child With Anemia
By. Dr. Zelalem T( R2)
Moderator : Dr. Mamude D. (MD, MPH, Pediatrician,
Consultant Hematologist and Oncologist).
November, 2022

Outline
• Introduction.
• Physiology of RBC synthesis.
• Definition of anemia.
• Classification of anemia.
• Clinical manifestations of anemia.
• Investigations for anemia
• RBC Indices
• Peripheral smear
• Management principles
• Prevention
• References

Introduction
• Anemia is a frequent laboratory abnormality in children
• As many as 70% of children in developing countries will be anemic at
some point by the age of 18 years
• In Ethiopia… EDHS 2016:
-6-59 month… (57%) anemic
-Mild 25%, Moderate, 29%, Severe 3%
• Children in
• rural areas (58%)
• urban areas (49%)

Figure 1. Trends in Childhood Anemia

Overview of Hematopoiesis
 Hematopoiesis (3 Anatomic Stages):
Mesoblastic
Hepatic
Myeloid
• Mesoblastic Hematopoiesis:
Extraembryonic structures (principally in the yolk sac)
Begins between the 10th and 14th days of gestation

Hematopoiesis….
• In hepatic hematopoiesis
• EPO during the 1st and 2nd trimesters, by cells of monocyte and macrophage origin
• After birth, the anatomic site of EPO production shifts to the kidney
• stimulus for this shift is unknown
• might involve the increase in arterial oxygen tension that occurs at birth
• Renal production of EPO is not essential for normal fetal erythropoiesis, as
evidenced by the
• normal serum EPO concentrations and normal hematocrits of anephric fetuses

Normal Red Cells
• No nucleus, enzyme packets.
• Biconcave discs.
• Center 1/3 pallor.
• Pink cytoplasm.
• 100-120 days of life span.
• Size 7-8 mic.

Hemoglobin….
• The major hemoglobin of a normal adult (HbA) is made up of α2β2 polypeptide.
• The major hemoglobin in the fetus (HbF) is made up of α2γ2 polypeptide .
• Two sets of genes for the α chains are located on human chromosome 16.
• Two pairs of alleles provide the genetic information for the structure of α chain.
• The β, γ, and δ genes are closely linked on chromosome 11.

Hemoglobin….
• In embryos of 4-8 weeks of GA, the Gower Hb predominate, but by the 3rd month
it disappears.
• After the 8th week , HbF is the predominant Hb; at 24wk of GA and constitutes
90% of the total Hb, which gradually declines during 3rd trimester.
• At birth HbF averages 70% of the total hemoglobin.
• Synthesis of HbF decreases rapidly postnatally, and by 6-12 month of age only a
trace is present.

Hemoglobin….
• By 6-12 months of age, the normal Hb A pattern appears.
• The minor HbA component HbA2 contains delta (δ) chains and has the structure α2δ2.
• HbA2 is seen only when significant amounts of Hb A are also present.
• At birth, <1% of Hb A2 is seen, but by 12 month of age the normal level of 2.0-3.4%
is attained.
• Throughout life, the normal ratio of HbA to HbA2 is about 30 : 1.

Cont’d…
• Erythrocytes in the fetus are larger than in adults, and at 22-23 wk of GA the MCV can
be as high as 135fL.
• Similarly the MCH is very high at 22-23 wk and falls relatively linearly with advancing
GA.
• In contrast, the mean corpuscular hemoglobin concentration is constant throughout
gestation at 34 ±1 g/dL.
• Although the size and quantity of Hb in erythrocytes diminish during GA, the Hct and
Hb concentration gradually increases.

Difference Between Fetal and Adult Hb
• Fetal Hb binds to oxygen with high affinity than adult Hb to facilitate
oxygen transfer from the mother to fetus in utero.
• It unloads oxygen to tissue readily.
• Resists denaturation in acidic or alkali environment.
• Highest HCT occurs at birth and reach nadir at 8 to 10 weeks .

Definition Of Anemia
• Reduction in the Hb , Hct or RBC mass > 2 SD below the mean for normal
population.
• Is also defined as a reduction of the Hb concentration or RBC volume
below the range of values occurring in healthy persons.
• Normal ranges vary with age , sex & race, (Blacks have 0.5g/dl Hb lower
than whites).

What Happens in Anemia?
 Increased O2 carrying capacity of the blood.
 Few physiological disturbances occur until Hb <7- 8g/dL
 Pallor more evident when Hb< 8g/dL.
 Pallor less obvious in dark skin.
 Younger children less symptoms and signs.
 Gradual drop in Hb cause less symptoms and signs.

Compensatory Mechanisms for low Hb level
• Increase CO & PR to improve blood oxygenation.
• Increase erythropoiesis because of increased EPO production by the
kidneys.
• Blood shunted to O2 sensitive organs (Heart, CNS ).
• Increase in amount of 2,3 bi-phosphoglycerate.

“Shift to the Right” of Oxygen Dissociation Curve

Clinical Assessment
 WHO Grading of Anemia:
 Clinical grading:
Mild: Conjunctival pallor/mucous membrane
Moderate: Obvious skin pallor
Severe: Palmar crease pallor

Clinical Manifestations of Anemia
• Symptoms
-Lethargy & irritability
-Shortness of breath on exertion
-Dizziness
• Signs
- Pale mucous membrane & palmar creases
- Tachycardia
-Cardiac failure (in case of severe anemia)
- Other signs related to underlying disease process.

Classification of Anemia
1. Pathological Classifications
2. Morphological Classifications

Morphological Classification
Hemogram Values
MCV <78fL MCV 78-100fL MCV>100fL

Causes of Anemia in Low & Middle Income Countries

History
• Age: Anemia cut points differ
• Neonate : blood loss, immune hemolytic disease, congenital infection, twin-
twin transfusion, and congenital hemolytic anemia (hereditary spherocytosis,
G6DP), late hypo regenerative anemia , Pearson marrow pancreases syndrome.
 8-12 weeks: physiologic anaemia of infancy occur.
 3- 6 weeks: anaemia of prematurity.
 3- 6 months: hemoglobinopathies.

Cont’d….
 6 months - 2 years nutritional anaemia.
 Diamond blackfan syndrome: 2 to 6 months.
 Transient erythroblastopenia of childhood: 3 month to 3 years.
 Fanconi’s anaemia:4 to 6 years of age.

Cont’d….
• Sex: G6PD deficiency in males (X –linked), X-linked sideroblastic anemia.
• Post menarchial girls: Excessive menstrual bleeding.
• Race & Ethnicity:
• Thalassemia in Mediterranean & S.E Asian descents.
• Hemoglobin S & C in blacks & Hispanic population.
• G6PD deficiency Sephardic Jews, Filipinos, Greeks, Sardinians, Kurds, and black
population.
• Severity & initiation of symptoms: Chronic anemia are asymptomatic b/c
of body compensatory ability, acute anemia - more symptomatic.

Cont’d…
• Hemolytic episodes:
• Prior history of anemia- duration , cause & treatment.
• History of repeated blood transfusions.
• Blood loss history: gastrointestinal tract, including changes in stool color,
the identification of blood in stools, and history of bowel symptoms.
• Teenagers have excessive menstrual losses, menstrual history including
duration of periods, flow, quantitation and saturation of tampons or pads,
should be obtained.

Cont’d…
 Underlying Medical & Surgical conditions:
• Diarrhea: Malabsorption of Vitamin B12, iron.
• Intestinal resection: Vitamin B12 deficiency
• Giardiasis: Iron malabsorption
• Intestinal bacterial overgrowth: Vitamin B12 deficiency
• EBV, CMV, Parvovirus: Bone marrow suppression
•
Mycoplasma , Malaria: Hemolysis

Cont’d….
Drugs or Toxin exposure:
 Bone marrow suppression (chemotherapy).
 Phenytoin, phenobarbital,…folate
Nutritional History:
 Cow’s milk diet: iron deficiency.
 Goat’s milk: Folate deficiency.
 Strict vegetarian:Vitamin B12 deficiency.
 Starvation and generalized malnutrition and the amount taken.

Cont’d…
 Birth History:
 A birth and neonatal Hx
 including infant and mother's blood type, a history of anemia in the early neonatal
period.
• Gestational age at birth
 Developmental History:
Loss of milestones or developmental delay in infants with megaloblastic
anemia may signify abnormalities in the cobalamin pathway
 Underlying medical condition=TB, RVI , Renal disease.

Cont’d….
Family History :
 X-linked: G6PD deficiency.
 Autosomal dominant: Spherocytosis.
 Autosomal recessive: Sickle cell, Fanconi’s anemia.
 Ethnicity: Thalassemia; G6PD deficiency.

Physical Examination
General Appearance

Cont’d…
 Vital sign
-Fever= Acute infection, Collagen vascular disease
-HTN=Renal origin
-Tachycardia/Tachypenea= Degree of anemia
 A/M
-Stunted = Fanconi, Malnutrition
-Microcephally = Fanconi anemia, Diamond blackfan
 Growth failure or poor weight gain=Anemia of chronic disease

Cont’d…
• HEENT
-Head- Frontal bossing, prominence malar = Thalassemia, Congenital
hemolytic anemia

Cont’d…
- Eyes:Microphthalmia : Fanconi anemia
-Cataracts: G6PD deficiency, galactosemia with hemolytic anemia
-Blue sclera: IDA, collagen vascular disease
-Jaundice: hemolysis , hepatitis
-Edema of eyelids: infectious mononucleosis, renal failure

Cont’d…
-Mouth -Glossitis= Vitamin B12, IDA
-Angular stomatitis=IDA
-Cleft lip and palate = DBA

Cont’d…
 LGS
-LAP-infiltrative diseases
 Chest
-Wide spread nipples--DBA
 CVS
- Murmur -Endocarditis , prosthetic valve hemolysis
 Abdomen
-HSM—infiltrative, tumor , hemolysis, chronic disease

Cont’d…
Skin:
-Hyperpigmentation, café au lait spots- Fanconi anemia
-Petechiae, Purpura -BM infiltration, autoimmune hemolysis
&thrombocytopenia
-Jaundice---- Hemolysis, Hepatitis
-Erythematous rash– Parvovirus, EBV
-Malar rash– SLE
-Spoon nails—IDA
-Vitiligo – Vitamin B12 deficiency

Cont’d…
• MSS - Absent thumb = Fanconi anemia
-Triphalangeal thumb, Thenar eminence hypoplesia=DBF
-Edema– Renal failure, protein loosing enteropathy.
 CNS
-Irritability, apathy=IDA
- Blindness= Osteopetrosis
- Deafness= Osteopetrosis
-Ataxia, posterior column sign = Vitamin B12 deficiency
-Peripheral neuropathy= lead poisoning
-Stroke = Sickle cell anemia, paroxysmal nocturnal hemoglobinuria.

Laboratory Evaluation
The most important test is CBC.
• RBC indices.
• Reticulocyte count.
• Blood smear.
• Other CBC parameters

1.RBC Indices
 1.1. MCV
-Represent the mean value of RBC’s size in the blood sample.
-Normal value vary based on age.
-MCV value with in 2SD considered normocytic.
-Infants have high value.
-It increase with a decrease in gestational age.
-70 +age in years: estimate lower level of MCV.
-Less sensitive to small populations of microcytes/ macrocytes.
-Misleading- RBC agglutination, distortions in cell shape, very high numbers
of WBCs, and sudden osmotic swelling in hyperglycemia and hypernatremia.

Cont’d….
1.2. Mentzer index is defined as Mean Corpuscular Volume per Red
Cell Count (MCV/RBC Count):
-value < 13 states haemoglobin defect,
-value >13 suggests iron deficiency.

1.3. Mean Cell Hemoglobin
• MCH: Amount of hemoglobin in each individual red blood cells
MCH=HGB*10
RBC
• Patients with iron deficiency or thalassemia who are unable to synthesize
normal amounts of Hb show significant reductions in the MCH.

1.4. MCHC
 MCHC = Hb (g/dl) / Hct.
 Gram of Hb per 100 ml of RBC.
 Values vary based on age.
 Normal value 33-35gm/dl (normochromic)
 High value > 35 is characteristic of Spherocytosis , hemolytic anemia.
 Low value is most commonly seen in IDA

2. Reticulocyte Count
• Reticulocytes : are the youngest red cells in the circulation, and are
identified via the presence of residual RNA, which gives them a blue tint
on standard Wright-Giemsa stains.
• Reported as percentage of RBC population.
-Normal value -1%
-Newborns -2-6%

Reticulocyte
• No definite nucleus
• Reticulum of RNA
• Deep blue staining
• Light blue cytoplasm
• Cell size about 10 µ

Cont’d…
• Normal range depend on Hb level , higher when low Hb.
• To distinguish impaired erythropoiesis from increased erythrocyte
destruction.
• Because the retic count is reported as % of total RBCs, pts with moderate
to severe anemia may have an elevated retic count that is inadequate.

Cont’d…
• It must be corrected for the reduction in red cell count to accurately
reflect erythrocyte production.
• This correction is made by calculating reticulocyte index:

Cont’d…
 RPI indicates whether bone marrow is responding appropriately to anemia.
 The normal reticulocyte index is 1.0; therefore, the index measures the fold
increase in erythropoiesis.
 Elevated RPI (>3%)-suggest active erythropoiesis in response to hemolysis,
bleeding, replacement treatment( iron), recovery from TEC.
 Low RPI (<3%)-suboptimal BM response (aplasia, malignancy, infection ,
toxic agent…)

3. Red Cell Distribution Width(RDW)
• Is a quantitative measure of the variability of RBC size in the same sample.
• Normal value 12-14%.
• Useful to differentiate IDA from thalassemia.
• High value –IDA , normal in thalassemia
• Sensitive indicator of RBC size changes before the RBC indices affected.

Red Cell Distribution Width
RDW-CV
 Ratio of the width of the red
blood cell distribution curve
at 1 SD divided by the MCV
• Normal RDW-CV =13 ± 1 %
• MCV will influence the
result.
RDW-SD
Direct measurement of the
red blood cell distribution
• Width taken at the 20%
frequency level.
• More sensitive to the
appearance of minor
populations

4.Variations in RBC Size & Shape
• Anisocytosis -Variations in size (e.g.microcytes)
• Poikilocytosis -Variations in shape (e.g.target cells)
• Hypochromia -Increased central pallor due to decrease in hemoglobin.

Anisocytosis - Macrocytic Anemia

Peripheral Smear
• Blood smear is very helpful in studying the size, shape and intensity
of staining of RBC.
• Interpretation of these changes will indicate the most likely DDx.
- A) RBC size
- Normal RBC has the same diameter as the nucleus of small
lymphocyte
-microcytosis/macrocytosis

Central Pallor
• Increased central pallor = IDA/thalassemia
• Small, dark dense hyperchromatic, no central pallor RBC=Spherocytes

Cont’d…
C) Fragmented cells – MAHA, DIC,TTP, Kasabach merit syndrome.
d) Other Features:
 Sickle cells- ss disease, sc disease
 Elliptocytes- hereditary elliptositosis, IDA, megaloblastic anemia
 Target cells- hemoglobinopathies, liver disease

Shistocytes
1. MAHA
2. Prosthetic valves
3. Uremia
4. Malignant HT
Fragmented, Helmet or triangle shaped RBC

Target Cells
• Diagnostic possibilities:
• Liver disease
• Hemoglobinopathies
• Post-splenectomy
• Lipid disorders

5. Other CBC Elements
RBC Count
• In case of Microcytic Hypochromic anemia:
1. Low RBC count indicate a lack of production of RBC as in IDA.
2. Normal/raised RBC count as in thalassemia.

WBC and Platelet
 Anemia could be an isolated finding or associated with other abnormalities.
 High WBC & platelet and later anemia can be seen in =Infection &
inflammation.
 High platelet & anemia can be seen in patients with= hemolysis /IDA.
 Low platelet with anemia seen in patients with =HUS/Evans syndrome.
 Pancytopenia is seen in- BMF, Leukemia.

Other Laboratory Tests
 Bilirubin level
 Direct antiglobulin test or Coombs test
 Hemoglobin electrophoresis
 Red cell enzyme studies-enzymopathy
 Osmotic fragility (spherocytosis)
 Iron, TIBC, ferritin

Cont’d…
 Folate, vitamin B12 (macrocytic)
 Bone marrow aspiration and biopsy
 Viral titers (e.g. Epstein-Barr virus, cytomegalovirus)
 BUN/ creatinine
 TFT, LDH

Treatment Principles of Anemia
1. Iron Deficiency Anemia
Oral ferrous salts 3-6 mg/kg of elemental iron ,maximum dose would be 150-200 mg of
elemental iron daily.
Parenteral iron dextran preparations are only used when malabsorption is present or
when compliance is poor.
Iron therapy may increase the virulence of malaria and certain Gram-negative
bacteria, particularly in developing countries.
Iron overdose is associated with Yersinia infection.
Nutritional counseling--
Blood transfusion(if sever or pt has HF/imminent HF--conservative
Failure to respond to therapy?

Treatment of Megaloblastic Anemia
oFolic acid orally or parenterally at 0.5-1.0 mg/day.
oIf diagnosis is in doubt, smaller doses of folate (0.1 mg/day)for 1 wk as a
diagnostic test, because a hematologic response can be expected within 72 hr
o Doses of folate >0.1 mg can correct the anemia of vitamin B 12 deficiency.
o Treatment should be continued for 3-4 wk
o Maintenance therapy with a multivitamin (containing 0.2 mg of folate) is
adequate.

Cont’d….
The physiologic requirement for vitamin B 12 is about 1-3 µg/day.
Parenteral (i.e., intramuscular or deep subcutaneous) Cbl, in a dose of
1000 micrograms (1000 mcg, 1 mg) every day for one week, followed
by 1 mg every week for four weeks and then, if the underlying
disorder persists (e.g., PA, surgical removal of the terminal ileum), 1
mg every month for the remainder of the patient's life.

Prevention of Anemia
• Increase the production and consumption of iron-rich foods, primarily animal-
sources such as meat (especially red meat), poultry and fish, but also iron-rich
plant sources such as legumes.
• Increase consumption of foods that are rich in vitamin A/carotenoid, such as
green leafy vegetables, orange-fleshed fruits and vegetables, dairy products,
eggs, liver and fish oils.
• Add fruits and vegetables that are rich in citric or ascorbic acid (e.g. citrus fruits)
to the diet, to increase the absorption of non-haem iron.
• Vitamin C degrades with cooking, so consumption of uncooked (or lightly
cooked) fruits and vegetables with high vitamin C content should be encouraged

Cont’d…
• Identify and promote culturally appropriate and feasible methods of food
processing and preparation, to improve bioavailability and absorption.
• Iron: germination, fermentation and soaking may improve absorption.
• Vitamin A: short cooking times and steaming rather than boiling will
maintain pro-vitamin A activity.
• Avoid combining known inhibitors of iron absorption with meals that
are high in iron content; for example:
• separate tea and coffee drinking from meal times; consumption 1–2 hours later
will not inhibit iron absorption;
• consume dairy products (milk, cheese and other foods made from milk) as a b/n
meal snack, not at a meal time.

References
1. Williams Hematology 9th
Edition
2. Post Graduate Hematology 5th
Edition.
3. Principles and Practice of Pediatric Oncology 7th Edition.
4. Nelson Text Book of Pediatrics, 21st
Edition.
5. Up-to-date, 2022.
6. Clinical Hematology 5th
Edition.
7. WHO 2017, Nutritional Anemias tools for Effective Prevention Control.

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