Approach to Childhood Anemia

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Approach to Childhood Anemia

• H. Tamary
• Hematology, Schneider Childrens Medical Center
  of Israel

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Normal Hemoglobin and MCV Values in Term Infant

• Hb MCV
• (g/dL) (fl)
• Day 1 19.02.2 119 9.4
• 12 weeks 11.3 0.9 88 7.9

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Regulation of Erythropoiesis
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Hemoglobin Concentration- Different Gestational
Age
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Globin Synthesis in Embryo, Fetus and Adult
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Decline in Fetal Hemoglobin
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Criteria for Identifying Children with Low
Hemoglobin Values

• Age Hemoglobin
• (g/dL)
• 6ms 11 years lt11
• gt11 male lt13
• gt11 female lt12

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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

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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

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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

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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

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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

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Anemia Physical Findings

• Skin Hyperpigmentation Fanconi Anemia
  (FA)
• Facies Frontal bossing Thalassemia Prominenc
  e malar Major
• maxillary bone
• Eyes Microphthalmia FA
• Hands Abnormal thumb FA
• Spleen Enlargement Hemolytic anemia,
  infection, leukemia

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Features of Ineffective Erythropoiesis
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FA Congenital Anomalies
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Complete Blood Count

• Hemoglobin
• MCV
• WBC and differential count
• PLT
• RDW- red cell distribution width
• CHr - hemoglobin concentration in reticulocytes

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Microcytic AnemiasMCVlt80fl

• Iron deficiency anemia
• Thalassemia syndromes
• Chronic inflammation
• Siderblastic anemias
• Lead poisoning

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Normocytic AnemiasMCV 80-90fl

• Congenital hemolytic anemia
• Acquired hemolytic anemia
• Acute blood loss
• Splenic pooling
• Chronic disease

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Macrocytic AnemiasMCVgt90fl

• 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

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Direct antiglobulin test (Coombs)
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Bone Marrow Aspiration
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Acute Lymphoblastic Leukemia
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Bone Marrow Biopsy
Normal
Aplastic anemia
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Erythroid BM Colonies
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Iron Deficiency Anemia in Children
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Human Hemoglobin
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Bodys Iron Economy
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Distribution of Iron in Man
Cytochromes 3
Myoglobin 10
Ferritin Hemosiderin 22
Hemoglobin 65
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Nutritional Iron Deficiency
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Increment of RBC Mass as Function of Age
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Stages of Iron Depletion
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Absorption of Food Iron
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Iron Absorption in Infants
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Mental Psychomotor Development According to Hb
Concentration
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Prevention of Nutritional Iron Deficiency Anemia

• Encourage breast feeding for the first 6 months
• Avoid cows 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

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

• Iron Birth weight
• mg/kg/day (g)
• 4 1000
• 3 1000-1500
• 2 1500-2500

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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 135413, 1999

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Nutritional Iron Deficiency

• No iron prophylaxis
• No introduction of meat products
• Increased tea consumption

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Stages of Iron Depletion
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Iron Depletion

• Hb, MCV, RDW, CHr-Normal
• SI, TIBC-Normal
• Serum Ferritin- Low

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Iron Deficiency No Anemia

• Hb, MCV- Normal
• RDW- High
• CHr- Low
• Serum Ferritin- Low
• Serum Iron Low
• TIBC- High

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Iron Deficiency Anemia

• Hb-Low
• MCV- Low
• RDW- High
• CHr Low
• Serum Iron Low
• TIBC High
• Serum Ferritin - Low

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Iron Deficiency-Biochemical Markers

• Serum iron concentration-
• Influenced by 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

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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

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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

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Etiologic Factors in Iron Deficiency (1)

• Increased physiologic requirements
• Rapid growth
• Menstruation
• Decreased iron assimilation
• Iron-poor diet
• Iron malabsorption Celiac disease

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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

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Thalassemia Syndromes Hemoglobinopathies

• ?-thalassemia
• ?-thalassemia
• Sickle cell anemia

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?-thalassemia
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Geographical Distribution of Thalassemia and
Hemoglobin Disorders
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Globin Synthesis in Embryo, Fetus and Adult
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b-thalassemia -Location and Type of Mutations
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Clinical Classification of
b-thalassemia

• b-thalassemia trait
• Homozygous b-thalassemia Thalassemia
  Major Thalassemia Intermedia

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?-thalassemia minor
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Differential Diagnosis of Microcytosis

• Iron deficiency Carriers of Anemia ?
  Thalassemia
• Serum Iron Low Normal
• Transferrin High Normal
• Ferritin Low Normal
• Hemoglobin Normal High A2
• electrophoresis

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?-thalassemia Minor HPLC Hb Electrophoresis
Hb A
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?-thalassemia Carrier Detection

• Microcytic anemia
• MVC lt78fl, MCHlt27pg
• HbA2gt3.5

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?-thalassemia Major
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Thalassemia Major at Diagnosis
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Peripheral Blood Smear
Normal
Beta-thalassemia Homozygote
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Homozygous ?-thalassemia Hb Electrophoresis
Hb F
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Decline in Fetal Hemoglobin
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Pathogenesis of b-thalassemia Major
Free excess of a-globin chains
Hemolysis
Ineffective erythropoiesis
Severe anemia Skeletal deformities Increased iron
absorption
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Transfusion Program-Suppression of Ineffective
Erythropoiesis
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Clinical Manifestations of Iron Overload

• Cardiac arrhythmias, CHF
• Endocrine growth failure, delayed sexual
  maturation, hypoparathyroidism, hypothyroidism,
  DM
• Skin bronze discoloration
• Liver cirrhosis

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Important studies of Deferoxamine
Therapy in Thalassemia
Year Finding 1974 IM therapy stabilize
hepatic iron 1978 12h portable infusion for
iron balance 1981 Therapy reduces hepatic iron
1985 Reduction of cardiac disease in
compliant patients 1989 Extended survival
in young patients
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Compliance with DFO Treatment and Survival
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Combination of L1and DFO

• L1 not as powerful as DFO
• Two chelators given on the same day have additive
  affect on urine iron loss

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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

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BTM Class I
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Prevention of ??-thalassemia

• Carrier screening
• Prenatal diagnosis
• CVS and DNA analysis
• Pre-implantation diagnosis (PGD)
• DNA extracted form fetal erythroblasts in
  maternal circulation

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a-thalassemia
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a-globin Cluster
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?a-thalassemia-Abnormal Hbs
?
?
?
?
?2?2
?2?2
Hb Barts
Hb H
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Gene Deletion in a-thalassemia
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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

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Hydrops Fetalis Syndrome
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Hemoglobin H Disease

• Genotype --/-a
• On cord blood 10-20 Barts hemoglobin
• Moderate microcytic anemia
• Hb electrophoresis 5-30 Hb H

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a-thalassemina Trait

• Genotype - -/aa, -a/-a
• Hb electrophoresis on cord blood
• 2-10 Hb Barts
• On adult blood microcytic, with or without
  anemia
• Diagnosis by exclusion of b-thalassemia minor
  iron deficiency

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a-thalassemia Silent Carrier

• -a/aa
• Hb electrophoresis on cord blood
• traces to 2 Hb Barts
• No anemia or microcytosis on adult blood

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Deletions in the a-globin Gene Cluster
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Categories of a-thalassemia Mutations
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Non-deletion a-thalassemia Mutations
a2
aNco
aHph
aTSaudi
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a-thalassemia Genotype-Spectrum

• a-thal Trait
• --/aa
• -a/-a
• aTa/aa
• aTa/-a

• Hb H Disease
• --/-a
• aTa/aTa
• aTa/--

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Strategy for a-thalassemia Multiplex PCR Analysis
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Anemia of Chronic Infection
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Anemia of Chronic Infection

• Serum Iron- Low
• TIBC- Low
• Serum ferritin- High
• Reduced release of iron form macrophages and
  reduced intestinal iron absorption

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Anemia of Chronic Disease