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Approach to Childhood Anemia. H. Tamary Hematology, Schneider Children’s Medical Center of Israel. Normal Hemoglobin and MCV Values in Term Infant. Hb MCV (g/dL)(fl) Day 119.0±2.2119 ±9.4 12 weeks11.3 ±0.988 ±7.9. Regulation of Erythropoiesis.

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Approach to Childhood Anemia

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Approach to childhood anemia

Approach to Childhood Anemia

H. Tamary

Hematology, Schneider Children’s Medical Center of Israel

Normal hemoglobin and mcv values in term infant

Normal Hemoglobin and MCV Values in Term Infant



Day 119.0±2.2119 ±9.4

12 weeks11.3 ±0.988 ±7.9

Regulation of erythropoiesis

Regulation of Erythropoiesis

Hemoglobin concentration different gestational age

Hemoglobin Concentration- Different Gestational Age

Globin synthesis in embryo fetus and adult

Globin Synthesis in Embryo, Fetus and Adult

Decline in fetal hemoglobin

Decline in Fetal Hemoglobin

Criteria for identifying children with low hemoglobin values

Criteria for Identifying Children with Low Hemoglobin Values



6ms –11 years<11

>11 male<13

>11 female <12

Etilogical classification of anemia i

Etilogical Classification of Anemia (I)

A. Blood loss

B. Excessive blood destruction

1. Intrinsic factors

a. Defects of membrane: spherocytosis, elliptocytosis

b. Defects of hemoglobin

  • Structural anomaly: HbS

  • Synthesis anomaly: thalassemia

Etilogical classification of anemia ii

Etilogical Classification of Anemia (II)

c. Enzymatic defect: G6PD deficiency, pyruvate kinase

2. Extrinsic factors

a. Immune mechanisms: Rh, ABO incompatibility, autoimmune hemolytic anemia

b. non-immune mechanisms: infections

Etilogical classification of anemia iii

Etilogical Classification of Anemia (III)

C. Decreased production

1. Deficiency of substance: iron, Vit B12, folic acid

2. Mechanical interference: malignant replacement

3. BM failure

a. Primary: aplastic anemia

b. Secondary: renal, liver disease

Etiological classification of neonatal anemia

Etiological Classification of Neonatal Anemia

  • A.Blood loss-fetal to fetal, feto-maternal, traumatic delivery

  • B.Increased blood destruction-Rh, ABO or minor blood group incompatibility, enzymopathy, hemoglobinopathy a-thalassemia

  • C.Decreased production-pure red cell aplasia

Anemia historical factors

Anemia Historical Factors

  • Age-Neonatal period initial manifestation of hemolytic disease, 6 m-iron deficiency, b-thalassemia

  • Ethnic group-Thalassemia syndromes, G6PD def

  • Diet- documented sources of iron

  • Drugs- oxidant-induced hemolytic anemia, drug induced aplastic anemia

  • Inheritance-family history of anemia, jaundice, gall stones

Anemia physical findings

Anemia Physical Findings

SkinHyperpigmentationFanconi Anemia (FA)

FaciesFrontal bossingThalassemiaProminence malarMajor

&maxillary bone


HandsAbnormal thumbFA

SpleenEnlargementHemolytic anemia, infection, leukemia

Features of ineffective erythropoiesis

Features of Ineffective Erythropoiesis

Fa congenital anomalies

FA Congenital Anomalies

Complete blood count

Complete Blood Count

  • Hemoglobin

  • MCV

  • WBC and differential count

  • PLT

  • RDW- red cell distribution width

  • CHr - hemoglobin concentration in reticulocytes

Microcytic anemias mcv 80fl

Microcytic AnemiasMCV<80fl

  • Iron deficiency anemia

  • Thalassemia syndromes

  • Chronic inflammation

  • Siderblastic anemias

  • Lead poisoning

Normocytic anemias mcv 80 90fl

Normocytic AnemiasMCV 80-90fl

  • Congenital hemolytic anemia

  • Acquired hemolytic anemia

  • Acute blood loss

  • Splenic pooling

  • Chronic disease

Macrocytic anemias mcv 90fl

Macrocytic AnemiasMCV>90fl

With megaloblastic bone marrow

  • Vitamin B12 deficiency

  • Folic acid deficiency

  • Hereditary orotic aciduria

    Without meglaoblastic bone marrow

  • Aplastic anemia

  • Pure red cell aplasia

  • Liver disease

  • Congenital Dyserythropoietic Anemia

Direct antiglobulin test coombs

Direct antiglobulin test (Coombs’)

Bone marrow aspiration

Bone Marrow Aspiration

Acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia

Bone marrow biopsy

Bone Marrow Biopsy


Aplastic anemia

Erythroid bm colonies

Erythroid BM Colonies

Iron deficiency anemia in children

Iron Deficiency Anemia in Children

Human hemoglobin

Human Hemoglobin

Distribution of iron in man

Distribution of Iron in Man

Cytochromes 3%

Myoglobin 10%

Ferritin & Hemosiderin 22%

Hemoglobin 65%

Nutritional iron deficiency

Nutritional Iron Deficiency

Increment of rbc mass as function of age

Increment of RBC Mass as Function of Age

Stages of iron depletion

Stages of Iron Depletion

Absorption of food iron

Absorption of Food Iron

Iron absorption in infants

Iron Absorption in Infants

Mental psychomotor development according to hb concentration

Mental &Psychomotor Development According to Hb Concentration

Prevention of nutritional iron deficiency anemia

Prevention of Nutritional Iron Deficiency Anemia

  • Encourage breast feeding for the first 6 months

  • Avoid cow’s milk at least for the first year of life

  • Iron fortified formula (12mg/l)

  • Solid food: cereals, meat

  • Oral iron 2mg/kg 4-12months

  • CBC: 9-12 months and 15-18 months

Iron doses for low birth weight infants starting at 1 month of age

Iron Doses for Low Birth Weight Infants Starting at 1 Month of Age

IronBirth weight





The tragedy of iron deficiency during infancy and early childhood

“The tragedy of iron deficiency during infancy and early childhood”

  • Brain injury as a result of iron deficiency caused by improper nutrition

  • Iron deficiency affects mental development and motor functioning

  • Reduced activity of iron-containing enzymes in CNS, appear to be irreversible

    Buchanan G, J of Ped 135:413, 1999

Nutritional iron deficiency1

Nutritional Iron Deficiency

  • No iron prophylaxis

  • No introduction of meat products

  • Increased tea consumption

Stages of iron depletion1

Stages of Iron Depletion

Iron depletion

Iron Depletion

  • Hb, MCV, RDW, CHr-Normal

  • SI, TIBC-Normal

  • Serum Ferritin- Low

Iron deficiency no anemia

Iron Deficiency – No Anemia

  • Hb, MCV- Normal

  • RDW- High

  • CHr- Low

  • Serum Ferritin- Low

  • Serum Iron – Low

  • TIBC- High

Iron deficiency anemia

Iron Deficiency Anemia

  • Hb-Low

  • MCV- Low

  • RDW- High

  • CHr –Low

  • Serum Iron –Low

  • TIBC – High

  • Serum Ferritin - Low

Iron deficiency biochemical markers

Iron Deficiency-Biochemical Markers

  • Serum iron concentration-

    Influencedby iron absorption from meals, infection, inflammation and diurnal variation

  • Total iron-binding capacity (TIBC)-Increases in iron deficiency.

    Decrease in malnutrition, chromic infection and cancer.

  • Ferritin-Correlates with total iron stores.

    Acute phase reactant

Iron deficiency serum transferrin receptor

Iron Deficiency- Serum Transferrin Receptor

  • Serum transferrin receptor- in iron deficiency there is increased number of receptors

    Unlike ferritin, increases in iron deficiency but not in chronic infection

Iron deficiency treatment

Iron Deficiency-Treatment

  • Elemental iron 5-6mg/Kg/d

  • Reticulocytosis in one week

  • After 1 month the Hb should increase by at least 1gr%

  • Iron therapy continued 2-3 months after Hb returned to normal

  • No improvement after a month other cause for iron deficiency

Etiologic factors in iron deficiency 1

Etiologic Factors in Iron Deficiency (1)

Increased physiologic requirements

  • Rapid growth

  • Menstruation

    Decreased iron assimilation

  • Iron-poor diet

  • Iron malabsorption: Celiac disease

Etiologic factors in iron deficiency 2

Etiologic Factors in Iron Deficiency (2)

Blood loss

  • Gastrointestinal bleeding

  • Milk induced enteropathy

  • Peptic disease

  • Inflammatory bowel disease

  • Parasite bowel infection

    Hemoglobinuria due to prosthetic valve

    Idiopathic pulmonary hemosiderosis

    Intense exercise

Thalassemia syndromes hemoglobinopathies

Thalassemia Syndromes & Hemoglobinopathies

  • -thalassemia

  • -thalassemia

  • Sickle cell anemia



Geographical distribution of thalassemia and hemoglobin disorders

Geographical Distribution of Thalassemia and Hemoglobin Disorders

Globin synthesis in embryo fetus and adult1

Globin Synthesis in Embryo, Fetus and Adult

B thalassemia location and type of mutations

b-thalassemia -Location and Type of Mutations

Clinical classification of b thalassemia

Clinical Classification of b-thalassemia

  • b-thalassemia trait

  • Homozygous b-thalassemia Thalassemia Major Thalassemia Intermedia

Thalassemia minor

-thalassemia minor

Differential diagnosis of microcytosis

Differential Diagnosis of Microcytosis

Iron deficiencyCarriers of Anemia  Thalassemia

Serum IronLowNormal



HemoglobinNormalHigh A2


Thalassemia minor hplc hb electrophoresis

-thalassemia Minor –HPLC Hb Electrophoresis

Hb A

Thalassemia carrier detection

-thalassemia Carrier Detection

  • Microcytic anemia

  • MVC <78fl, MCH<27pg

  • HbA2>3.5%

Thalassemia major

-thalassemia Major

Thalassemia major at diagnosis

Thalassemia Major at Diagnosis

Peripheral blood smear

Peripheral Blood Smear


Beta-thalassemia Homozygote

Homozygous thalassemia hb electrophoresis

Homozygous -thalassemia Hb Electrophoresis

Hb F

Decline in fetal hemoglobin1

Decline in Fetal Hemoglobin

Pathogenesis of b thalassemia major

Pathogenesis of b-thalassemia Major

Free excess of a-globin chains


Ineffective erythropoiesis

Severe anemia

Skeletal deformities

Increased iron absorption

Transfusion program suppression of ineffective erythropoiesis

Transfusion Program-Suppression of Ineffective Erythropoiesis

Clinical manifestations of iron overload

Clinical Manifestations of Iron Overload

  • Cardiac: arrhythmias, CHF

  • Endocrine: growth failure, delayed sexual maturation, hypoparathyroidism, hypothyroidism, DM

  • Skin: bronze discoloration

  • Liver: cirrhosis

Approach to childhood anemia

Important studies of Deferoxamine Therapy in ThalassemiaYearFinding1974IM therapy stabilize hepatic iron 197812h portable infusion for iron balance 1981Therapy reduces hepatic iron 1985Reduction of cardiac disease in compliant patients 1989Extended survival in young patients

Compliance with dfo treatment and survival

Compliance with DFO Treatment and Survival

Combination of l 1 and dfo

Combination of L1and DFO

  • L1 not as powerful as DFO

  • Two chelators given on the same day have additive affect on urine iron loss

Bmt in thalassemia

BMT in Thalassemia

Prognostic Criteria

  • Hepatomegaly

  • Liver fibrosis

  • Quality of iron chelation

    Prognostic Categories

  • Class I-none of the above

  • Class II One of the above

  • Class III two or three of the above

Btm class i

BTM Class I

Prevention of thalassemia

Prevention of -thalassemia

  • Carrier screening

  • Prenatal diagnosis

    CVS and DNA analysis

    Pre-implantation diagnosis (PGD)

    DNA extracted form fetal erythroblasts in maternal circulation

A thalassemia


A globin cluster

a-globin Cluster

A thalassemia abnormal hbs

a-thalassemia-Abnormal Hbs



Hb Bart’s

Hb H

Gene deletion in a thalassemia

Gene Deletion in a-thalassemia

Hydrops fetalis syndrome

Hydrops Fetalis Syndrome

  • Most Hb- Hb Barts, unable to deliver O2 to tissues

  • Tissue hypoxia & anemia

    Massively enlarged palcenta

    Heart failure, edema anasarca

    Interferes with organogenesis, -congenital malformations

    Extramedullay erythropoiesis

Hydrops fetalis syndrome1

Hydrops Fetalis Syndrome

Hemoglobin h disease

Hemoglobin H Disease

  • Genotype --/-a

  • On cord blood: 10-20% Bart’s hemoglobin

  • Moderate microcytic anemia

  • Hb electrophoresis 5-30% Hb H

A thalassemina trait

a-thalassemina Trait

  • Genotype: - -/aa, -a/-a

  • Hb electrophoresis on cord blood:

    2-10% Hb Bart’s

  • On adult blood: microcytic, with or without anemia

  • Diagnosis by exclusion of b-thalassemia minor & iron deficiency

A thalassemia silent carrier

a-thalassemia Silent Carrier

  • -a/aa

  • Hb electrophoresis on cord blood:

    traces to 2% Hb Bart’s

  • No anemia or microcytosis on adult blood

Deletions in the a globin gene cluster

Deletions in the a-globin Gene Cluster

Categories of a thalassemia mutations

Categories of a-thalassemia Mutations

Non deletion a thalassemia mutations

Non-deletion a-thalassemia Mutations





A thalassemia genotype spectrum

a-thal Trait





Hb H Disease




a-thalassemia Genotype-Spectrum

Strategy for a thalassemia multiplex pcr analysis

Strategy for a-thalassemia Multiplex PCR Analysis

Anemia of chronic infection

Anemia of Chronic Infection

Anemia of chronic infection1

Anemia of Chronic Infection

  • Serum Iron- Low

  • TIBC- Low

  • Serum ferritin- High

  • Reduced release of iron form macrophages and reduced intestinal iron absorption

Anemia of chronic disease

Anemia of Chronic Disease

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