Approach to anemia

G/HIWOT G.(MD,PEDIATRICIAN)
Anemia is defined as a reduction of the hemoglobin concentration
or red blood cell (RBC) volume below the range of values occurring
in healthy persons.

In practice, anemia is defined by reductions in HGB or HCT that is

more than two standard deviations below the mean for the age
and sex of reference population
Hematocrit (HCT) — The hematocrit is the fractional
volume of a whole blood sample occupied by red blood
cells (RBCs), expressed as a percentage.

Hemoglobin (HGB) — This is a measure of the

concentration of the RBC pigment hemoglobin in whole
blood, expressed as grams per 100 mL (dL) of whole
blood.
Hemoglobin, hematocrit, red blood cells in children 1-14 years of age, by age group and sex: the

Third National Health and Nutrition Examination Survey (1988-91)

Anemia is a significant global health problem affecting children and reproductive age women
Physiologic adjustments of anemia
Increased cardiac output
 Increased oxygen extraction (increased arteriovenous
oxygen difference)
 Shunting of blood flow toward vital organs and tissues.
 Concentration of (2,3-DPG) increases within the RBC
Increased EPO production
CLASSIFICATIONS OF ANEMIA
Anemia is not a specific entity but rather can result from any
of number of underlying pathologic processes.

To narrow the diagnostic possibilities, anemias may be

classified on the basis of their:

 morphology
 physiology
1.Physiologic classification

 Anemia may be classified in two broad categories based on

the reticulocyte count, which serves as a marker of whether
erythropoiesis is suppressed or active.
1. Disorders resulting in an inability to adequately produce red
RBCs (ie, bone marrow depression)
 generally associated with a lower than expected reticulocyte response.
(reticulogytopenia or normal rtic.count)

2.Disorders resulting in rapid RBC destruction (hemolysis) or RBC

losses from the body (bleeding) are
 generally associated with a robust reticulocyte response (reticulocytosis)
Absolute reticulocyte count = percent reticulocytes x red blood cell count/L

 The normal retic. percentage is approximately 1%, with an absolute

reticulocyte count of 25,000-75,000/mm3.

 during anemia, EPO production and the ARC rises.

The marrow can increase its output 2-3–fold acutely, with a maximum of 6-8–
fold in long-standing hemolysis.

The reticulocyte percentage can be corrected to measure the magnitude of

marrow production in response to hemolysis as follows:
Disorders of effective red cell
production(hypoproliferative)

1 . Marrow failure
a. Aplastic anemia
Congenital
Acquired
b. Pure red cell aplasia
Congenital: Diamond–Blackfan syn
Acquired:TEC
c. Marrow replacement
Malignancies
Myelofibrosis
2. Impaired erythropoietin production
a. Chronic renal disease
b. Hypothyroidism, hypopituitarism
c. Chronic inflammation
d. Protein malnutrition
3. Abnormalities of cytoplasmic
maturation
a. Iron deficiency
b. Thalassemia syndromes
c. Sideroblastic anemias
d. Lead poisoning
4. Abnormalities of nuclear maturation
a. Vitamin B12 deficiency
b. Folic acid deficiency
c. Thiamine-responsive megaloblastic
5. Primary dyserythropoieitc anemias
6. Erythropoietic protoporphyria
7. Refractory sideroblastic anemia
Disorders of increased red cell destruction or loss
1. Defects of hemoglobin
a. Structural mutants (eg. HbSS, HbSC)
b. Diminished globin production (eg. Thalassemias)
2. Defects of the red cell membrane
3. Defects of red cell metabolism
4. Antibody-mediated
Disorders of increased red cell destruction or loss
5. Mechanical injury to the erythrocyte
a. Hemolytic uremic syndrome
b.TTP
c. DIC
6. Thermal injury to the erythrocyte
7. Oxidant-induced red cell injury
8. Paroxysmal nocturnal hemoglobinuria
9. Plasma-lipid-induced abnormalities of the
red cell membrane
10. Acute/Chronic blood loss
11. Hypersplenism
2.Morphologic classification
 Anemias also may be classified according to RBC
morphology, reflected by indices of RBC
size (mean corpuscular volume, MCV)
hemoglobin content (mean corpuscular hemoglobin, MCH)
 hemoglobin concentration (mean corpuscular hemoglobin
concentration, MCHC)
Mean corpuscular volume — represents the mean value (in
femtoliters, fL) of the volume of individual RBCs in the blood
sample.
 Microcytosis is defined as an MCV values less than 2 SC below
the mean (or <80 fL in adults);
 macrocytosis is defined as an MCV values more than 2 SD above
the mean (or >100 fL in adults).
 MCV values within two standard deviations of the mean are
considered normocytic.
The MCHC is a calculated index (MCHC = HGB/HCT),
yielding a value of grams of HGB per 100 mL of RBC.
 the normal range (33 to 34 g/dL), indicate that cells are
normochromic, whereas values lower than normal indicate
the presence of hypochromia.
Increased MCHC (hyperchromic) –
dehydration and loss of membrane
Red cell distribution width — The red cell distribution width
(RDW) is a quantitative measure of the variability of RBC
sizes in the sample (anisocytosis).
 normal values generally are between 12 and 14 percent.
HISTORY AND PHYSICAL EXAMINATION
1.Demography (age and sex)
 Iron deficiency anemia
 Before 6 months: Prematurity, neonatal blood loss, maternal
anemia
 School age children: ongoing blood loss, malabsorption, or a

very poor diet

 Neonatal period include recent blood loss,
isoimmunization, congenital infection, or the initial
manifestation of a congenital hemolytic anemia
 Hemoglinopathies and thalassemia fetal – young
infancy
2. Severity and initiation of symptoms

Acute vs chronic anemia:

Either due to acute blood loss or acute hemolysis
 Symptoms often due to loss of circulating volume
Symptoms in chronic anemia due to lack of O2 carrying capacity
 Tolerated better due to compensatory mechanisms
3. Questions related to hemolytic episodes
4. Family history , race, and ethnicity Family members with
jaundice, gallstones, or splenomegaly should be identified.
Asking if family members have undergone cholecystectomy
or splenectomy (inherited hemolytic anemias)
5.Questions about possible blood loss
6. Underlying medical conditions(chronic infectious or
inflammatory conditions)
 eg, malaria, hepatitis, tuberculosis
 SLE ,IRA
6. Questions relating to diet (Type/quantity of milk)
7. The presence of pica (particularly pagophagia, the eating
of ice) is a useful clue to a diagnosis of lead poisoning
and/or iron deficiency
8. Birth history — including infant and mother's blood type
 any history of exchange or intrauterine transfusion
 history of anemia in the early neonatal period
 GA at birth is important, because premature infants
may have iron or vitamin E

9. Developmental milestones folats and cobalmine

deficiency

10.Maternal history in the first 6 month

 Drug ingestion
 Pregnancy/delivery complications
 Pica, nonfood product ingestion
 Anemic during pregnancy
11.Evidence of endocrinopathy
12.Evidence of liver disease
13.Easy bruising/blood loss
14.History of nematod infestations
Tachycardia suggests an acute process
Pallor
A normal heart rate suggests a more
chronic process
Jaundice points to a hemolytic process
Splenomegally
 Inherited hemolytic anemia
Malignancy
Acute infection
 Hypersplenism
Petechiae indicate multiple cell lineages are involved
Laboratory
The laboratory examination should begin with:
 CBC including RBC indices
 Reticulocyte count and RPI
 Peripheral blood smear
RBC indices
Enables classification of anemia
 microcytic
 normocytic or
 macrocytic.

 The lower limit for the MCV(<10 years) approximately 70 fL +

age in years
The upper limit for (>0.5 years) is 84 + 0.6 fL per year until the
upper limit of 96 fL
The red cell volume distribution width (RDW)
 reflects the variability in cell size
used as a measure of anisocytosis
The use of the RDW and the total RBC count to aid in
further differentiating between specific etiologies of
microcytic, normocytic, and macrocytic anemia
3.Asess the white blood cell (WBC) and platelet
counts
isolated anemia Vs pancytopenia
A leukoerythroblastic blood picture
normal bone marrow is replaced by tumor or other
diseases
Elevated WBC and/or platelet count
most often due to reactive processes
infection is the most common cause
iron deficiency anemia

autoimmune disorders

inflammatory bowel diseases

 hemolytic anemia

vitamin E deficiency
peripheral morphology: include assessment
of size, shape, and color (pallor), and the
presence of inclusions.

 Macrocytic,Normocytic,Microcytic
Central pallor:Excessive(Hypochromia) ,
Absence (spherocytosis)
Polychromasia with large cells
(reticulocytosis)
RBC size – A normal RBC should have the same diameter
as the nucleus of a small lymphocyte
Central pallor – The normal mature RBC is a biconcave disc. As a result, RBCs on the peripheral smear demonstrate an
area of central pallor, which, in normochromic RBCs, is approximately one-third the diameter of the cell
Peripheral morphology continued
 Distinctive abnormalities in shape
Red cell membrane disorders (eg spherocytosis,
stomatocytosis, or elliptocytosis)
 Hemoglobinopathies (eg sickle cell disease,
thalassemia).
Presence of inclusions
basophilic stippling (as seen in
thalassemia, lead poisoning)
Nucleated red blood cells
Normal only in the newborn
Indicative of a stressed marrow
The number and morphology of WBCs and platele
(Peripherally )
Toxic granulation suggests an acute inflammatory state
Hypersegmented neutrophils are characteristic of vitamin B12
and Folate deficiency
 Other investigations (stool, bilrubin, LDH etc)
 Iron studies
Physiological anemia of infancy
Normal newborn- High Hb level progressively declines up
to 8-12 wk -9-11g/dl.- Hypoxia stimulates Renal and
Hepatic oxygen sensors – erythropoietin production
increases.

Preterm- Hb decline is extreme & rapidly falls to 7-9 g/dl

by 3-6 wk of age.- Sampling for Lab tests. There are
relatively insensitive Hepatic oxygen sensors; as Renal
Oxygen sensors switch on at 40 wk of gestation.
Iron defeciency anemia
Most common hematologic disease of infancy and
childhood
More than 30% of world population affected
1mg of iron must be absorbed each day
Because <10% of dietary iron usually is absorbed, a
dietary intake of 8-10 mg of iron daily is necessary
Absorption is in the duodneum
Iron in human milk is highly bioavaliable 2-3 times more
than cow’s milk
Storage is enough till 6-9 months of age for term healthy
neonate
Why is Iron important?
Essential component of
hemoglobin and myoglobin
Component of certain proteins
important for respiration and
energy metabolism
Component of enzymes
involved in the synthesis of
collagen and some
neurotransmitters
Essential for normal immune
function
 Iron absorption
• 10% of dietary iron is
absorbed
• Absorption depends on:
-dietary iron content
- bioavailability (heme vs. non-
heme)
- mucosal cell receptor number
• Main absorption occurs in
duodenum

.
 Iron absorption
Heme (meat) >> non-heme iron
sources
 (30%-50% vs. <10%)
Ferrous sulfate >> ferric
sulfate
Enhanced by red meat,
ascorbic acid, breast milk
Diminished by vegetable fiber,
cow milk, egg yolk, tea,
phytates, phosphates (soda)
Risk factors for Iron Deficiency in Infants and Children

-Prematurity or low birthweight

-Exclusively breastfeeding beyond 4-
5 months without iron
supplementation
-Cows milk before 1 year
-Excessive milk intake
-Obesity
-Poverty/Low socioeconomic status
-Malnutrition
-Chronic illness or special health
needs
 Cows milk and iron deficiency
• Poor source of iron
• Poor absorption (5-10%)
• Reduces consumption of
other foods, especially with
overconsumption
• Can cause microscopic GI
bleeding

.
 Iron rich foods
Heme iron (better bioavailability)
 Meat (beef and turkey best)
 Shellfish
Non-heme iron (less bioavailability)
Breakfast cereal (iron fortified)
 Pasta (iron fortified)
 Beans and lentils
 Baked potato with skin
Foods that increase iron absorption
 Fruits, vegetables, meat, fish,
poultry, white wine

.
 Causes of Iron deficiency:
Blood Loss
•GI blood loss:
 -cow’s milk, IBD, esophageal
varices, ulcers, anatomic
lesions, parasitic infections,
polyps.
•Menorrhagia
•Epistaxis
 Iron Deficiency: Malabsorption
• Short gut
• Celiac disease
• Medications (GERD)
• Chronic Giardiasis
 Clinical manifestations
Pallor is the most important sign of iron deficiency
Irritability/ anorexia
Pagophagia
Easy fatigability
Decreased school performance
Exercise intolerance
Cardiac dilation/ CHF
 LABORATORY FINDINGS
Sequence of biochemical and hematologic events
occuring in IDA are:
A) BM hemosederin disappear( tissue iron)
( A serum ferittin will give an estimate if no inflammation)
B) Serum iron level decreases, iron binding capacity
(serum transferrin) increases but % saturation of
transferrin decreases
C) FEP accumulates
D) As IDA advances RBCS become smaller and HGB
decreases
E) Still with advacned deficiency; microcytosis,
hypochromia, poiklocytosis and increased RDW
Thrombocytosis/ Thrombcytopenia
The bone marrow is hypercellular, with erythroid
hyperplasia , no stanable iron
Stool occult blood in third of patients
 ddx
Thalassemia (RDW, iron studies RBC count)
Anemia of chronic illness (Fe, transferrin,TfR,
(ferittin))
Lead poisoning (FEP, basophilic stippling)
Sideroblastic anemia
 IRON α OR β ANEMIA OF
STUDY DEFICIENCY THALASSEMI CHRONIC
ANEMIA A DISEASE
Hemoglobin Decreased Decreased Decreased
Normal-
MCV Decreased Decreased
decreased
Normal-
RDW Increased Normal
increased
Normal- Normal-
RBC Decreased
increased decreased
Serum ferritin Decreased Normal Increased
Total Fe
binding Increased Normal Decreased
capacity
Transferrin
Decreased Normal Decreased
saturation
FEP Increased Normal Increased
Transferrin
Increased Normal normal
receptor
 Prevention of Iron Deficiency Anemia in Infants and Toddlers

• Breastfeeding for the first 6 months of life

• Iron fortified formula
• Iron fortified infant cereal beginning at 6
months of age
• Iron supplementation for preterm infants
• Iron supplementation for breastfeeding
infants at 4 months of age
• Avoid cows milk before 1 year of age
• Limit cows milk intake to 18-24 oz/day
after 12 months of age
 treatment
Important diagnostic and therapeutic feature
Ferrous salts (sulfate, gluconate, fumarate)
Oral preparations of these salts 4-6mg/kg of elemental
iron in three doses
If oral intake is intolerable IV dextran
Iron medication should be continued for 8 wk after
blood values are normal
Blood transfusion- if severe Hgb <4gm/dl or if infection or
CHF
Therapeutic response
TIME AFTER IRON
ADMINISTRATION RESPONSE
12–24 hr Replacement of intracellular
iron enzymes; subjective
improvement; decreased
irritability; increased appetite

36–48 hr Initial bone marrow response;

erythroid hyperplasia

48–72 hr Reticulocytosis, peaking at 5–7

days

4–30 days Increase in hemoglobin level

1gm/dl per wk(adequat respons
afyer 3wks of Rx 2gm/dl.
 Iron Deficiency-Treatment
Oral iron therapy
• Mild iron deficiency- 3 mg/kg/d
elemental iron in daily dose
• Moderate to severe- 6 mg/kg/d
elemental iron divided twice
daily
• Severe- consider PRBC
transfusion (Hgb <4 gm/dl) AND
oral iron

.
 Types of Oral iron
 Ferrous sulfate Carbonyl iron
 - 20 % elemental iron -100% elemental iron
 - well absorbed** -15 mg tab
 - 325 mg tab- 65 mg elemental -15 mg/1.25 ml
 -75mg/0.8 ml – 15 mg elemental -less absorption
 -15mg/ml- 15mg elemental
 Ferrous gluconate Iron polysaccharide

-12% elemental iron -100% elemental iron
 -300 mg tab- 36 mg elemental -100mg/5 ml, 150 mg tab
 -well absorbed
 Ferrous fumarate
 -33% elemental iron
 -200 mg tab- 66 mg elemental
 -chewable tab 33 mg
 -extended release tabs- poorer absorption
 -Iron sprinkles (developing countries)


.
Megaloblastic anemias
Megaloblastic anemia group of disorders caused by impaired
DNA synthesis.
RBCs are larger than normal at every stage of dev’t.
 maturational asynchrony b/n the nucleus (delayed nuclear
development) and cytoplasm of erythrocytes.
Myeloid and platelet precursors are also affected

 giant metamyelocytes and neutrophil bands are often present in

the bone marrow.
 There is associated thrombocytopenia and leukopenia
All are characterized by;
A. Ineffective erythropoesis
B. Macrocytes
C. Presence of hypersegemented neutrophiles
 Almost all cases of megaloblastic anemias are vit. B12 or
folate defeciency
Macrocytic anemia with hypersegmented neutrophil
Macro-ovalocyte in megaloblastic anemia
 Folic acid defeciency
Dietary folate and its absorption
Available in green vegetables, meet and liver.
Degraded by prolonged boiling
 H2O soluble
Absorption is in SI, mainly jejunum.
Body stores are limited megaloblastic anemia occur 2-3
months after folate free diet
 Structure:
Folic acid

•Made of three components.

•Folic acid derived from diet
is not biologically active.
•Once absorbed through the
duodenum it hydrolyzed,
reduced and methylated to Pterdine Amino benzoic acid Gultamic acid
form MTHF. (Poly Glutamic Acid)
•Other form THF
(biologically active).
 Absorption and metabolism

Diet Intestine

Poly glutamic acid Poly glutamate

Folate reductase
Glu

Re
Mono glutamate

du
ced
an
d
me
th
CH3THF

y la
ted
Methyl Tetrahydrfolate
 DNA
Synthesis cTHF
Glu
THF
Methionine
Homocysteine

CH3THF CH3THF

Tissue cell Circulation

 etiology
 Inadequate intake
 insufficient intake during increased requirements(pregnancy, periods of accelerated growth, and/or chronic hemolysis.
 Goat’s milk
 Malnutriton
 Maternal malnutrition
 Malabsorption
 chronic diharea ,
 chonic inflam.(chrone’s disease, celiac ds)
 Surgery
 Medication(phenytoin,phenobarb)
 Hereditary folate malabsorption (HFM) mutation of gene encoding carrier transporter
protien.
 Congenital dihydrofolate defeciency
 Functional methionine synthase deficiency
 Drug induced abnormality (Methotrexate) inhbits dihydrofolate reductase and prevents formation
THF.
 Clinical manifestations
Megaloblastic anemia
Peak age 4-7 months
Irritablity
Failure to gain weight
Chronic diarrhea
Hemorrhage in advanced cases
 Laboratory diagnosis of megaloblastic anemia

• CBC
Low hemoglobin level and elevated MCV.
• PB morphology
Macrocytosis, macroovalocytes and hyper segmented
neutrophils.
• Chemical testing
Serum folic acid Low (RC FA)
• BM
Hyper cellular BM.
Megaloblastic picture (large cells with increased RNA
per DNA unit.
 treatment
Folic acid 0.5mg-1mg/day for 3-4 weeks
Transfusions in severe anemia
Hematologic response occurs within 72 hrs
 Vitamin b12
Mainly animal source
Synthesized by microorganism
 The cobalamins are released by the acidity of the stomach
 Combine there with R proteins and intrinsic factor (IF);
Traverse the duodenum, where pancreatic proteases break
down the R proteins;
Absorbed in the distal ileum via specific receptors for IF-
cobalamin
In the plasma, cobalamin binds to a transport protein,
(TC-II), which carries the vitamin B12to the liver, bone
marrow, and other tissue storage sites
older children and adults have sufficient vitamin
B12stores to last 3–5 yr
Absorption and
transport of
vitamin B12
 an intermediate of the citric
Important for DNA synthesis,
acid cycle, porphyrin synthesis
nervous tissue and fat metabolism
in the liver (Heme synthesis)
 etiology
Inadequate vitamin B12 intake
Lack of IF
Impaired vitamin B12 absorption
Absence of transport protein
Surgery
 clinically
Weakness, fatigue, FTT, irritabilty
Pallor
Glossitis
Vomiting, diarrhea and icterus
Neurologic symptoms (can occur in isolation)
 Schilling test
Used to access vitamin B12 absorption
Give radioactive vitamin B12
Combines with IF
Little or none is excreted in urine
Then flushing dose 1mg of non radioactive cobalamine IM
after 2 hours
10-30% of previously absorbed radioacive B12 will appear in
urine within 24hr
Children with pernicious anemia usually excrete ≤2% under
these conditions
To confirm absence of IF
IF and radioactive B12
If this is abnormal then ileal dysfunction or bacterial
overgrowth
 TREATMENT
Parentral vitamin B12
Reticulocytosis 2-4 days