Approach to Childhood Anemia

H. TamaryHematology, Schneider Children’s

Medical Center of Israel

Normal Hemoglobin and MCV Values in Term Infant

Hb MCV(g/dL) (fl)

Day 1 19.0±2.2 119 ±9.412 weeks 11.3 ±0.9 88 ±7.9

Regulation of Erythropoiesis

Hemoglobin Concentration- Different Gestational Age

Globin Synthesis in Embryo, Fetus and Adult

Decline in Fetal Hemoglobin

Criteria for Identifying Children with Low Hemoglobin Values

Age Hemoglobin(g/dL)

6ms –11 years <11>11 male <13>11 female <12

Etilogical Classification of Anemia (I)

A. Blood lossB. Excessive blood destruction

1. Intrinsic factorsa. Defects of membrane: spherocytosis, elliptocytosisb. Defects of hemoglobin

– Structural anomaly: HbS– Synthesis anomaly: thalassemia

Etilogical Classification of Anemia (II)

c. Enzymatic defect: G6PD deficiency, pyruvate kinase

2. Extrinsic factorsa. Immune mechanisms: Rh, ABO incompatibility, autoimmune hemolytic anemiab. non-immune mechanisms: infections

Etilogical Classification of Anemia (III)

C. Decreased production1. Deficiency of substance: iron, Vit B12,

folic acid2. Mechanical interference: malignant

replacement3. BM failure

a. Primary: aplastic anemiab. Secondary: renal, liver disease

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 thalassemia

• C. Decreased production-pure red cell aplasia

Anemia Historical Factors

• Age-Neonatal period initial manifestation of hemolytic disease, 6 m-iron deficiency, 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 FindingsSkin Hyperpigmentation Fanconi Anemia (FA)Facies Frontal bossing Thalassemia Prominence malarMajor

&maxillary boneEyes Microphthalmia FAHands Abnormal thumb FASpleen Enlargement Hemolytic anemia,

infection, leukemia

Features of Ineffective Erythropoiesis

FA Congenital Anomalies

Complete Blood Count

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

reticulocytes

Microcytic AnemiasMCV<80fl

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

Normocytic AnemiasMCV 80-90fl

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

Macrocytic AnemiasMCV>90fl

With megaloblastic bone marrow• Vitamin B12 deficiency• Folic acid deficiency • Hereditary orotic aciduriaWithout meglaoblastic bone marrow• Aplastic anemia • Pure red cell aplasia• Liver disease• Congenital Dyserythropoietic Anemia

Direct antiglobulin test (Coombs’)

Bone Marrow Aspiration

Acute Lymphoblastic Leukemia

Bone Marrow BiopsyNormal Aplastic anemia

Erythroid BM Colonies

Iron Deficiency Anemia in Children

Human Hemoglobin

Distribution of Iron in Man

Hemoglobin 65%

Cytochromes 3%Myoglobin

10%

Ferritin & Hemosiderin

22%

Nutritional Iron Deficiency

Increment of RBC Mass as Function of Age

Stages of Iron Depletion

Absorption of Food Iron

Iron Absorption in Infants

Mental &Psychomotor Development According to Hb Concentration

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 Birth weightmg/kg/day (g)

4 10003 1000-15002 1500-2500

“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 Deficiency

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

Stages of Iron Depletion

Iron Depletion

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

Iron Deficiency – No Anemia

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

Iron Deficiency Anemia

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

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

Iron Deficiency- Serum Transferrin Receptor

• Serum transferrin receptor- in iron deficiency there is increased number of receptorsUnlike ferritin, increases in iron deficiency but not in chronic infection

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)

Increased physiologic requirements• Rapid growth• MenstruationDecreased iron assimilation• Iron-poor diet• Iron malabsorption: Celiac disease

Etiologic Factors in Iron Deficiency (2)

Blood loss• Gastrointestinal bleeding• Milk induced enteropathy• Peptic disease• Inflammatory bowel disease• Parasite bowel infectionHemoglobinuria due to prosthetic valveIdiopathic pulmonary hemosiderosisIntense exercise

Thalassemia Syndromes & Hemoglobinopathies

-thalassemia-thalassemia

• Sickle cell anemia

-thalassemia

Geographical Distribution of Thalassemia and Hemoglobin Disorders

Globin Synthesis in Embryo, Fetus and Adult

-thalassemia -Location and Type of Mutations

Clinical Classification of-thalassemia

-thalassemia trait

• Homozygous -thalassemia Thalassemia Major Thalassemia Intermedia

-thalassemia minor

Differential Diagnosis of Microcytosis

Iron deficiency Carriers of Anemia Thalassemia

Serum Iron Low NormalTransferrin High NormalFerritin Low NormalHemoglobin Normal High A2electrophoresis

-thalassemia Minor –HPLC Hb Electrophoresis

Hb A

-thalassemia Carrier Detection

• Microcytic anemia• MVC <78fl, MCH<27pg• HbA2>3.5%

-thalassemia Major

Thalassemia Major at Diagnosis

Peripheral Blood SmearNormal

Beta-thalassemia Homozygote

Homozygous -thalassemia Hb Electrophoresis

Hb F

Decline in Fetal Hemoglobin

Pathogenesis of thalassemia Major

Free excess of globin chains

Hemolysis Ineffective erythropoiesis

Severe anemiaSkeletal deformities

Increased iron absorption

Transfusion Program-Suppression of Ineffective Erythropoiesis

Clinical Manifestations of Iron Overload

• Cardiac: arrhythmias, CHF• Endocrine: growth failure, delayed

sexual maturation, hypoparathyroidism, hypothyroidism, DM

• Skin: bronze discoloration • Liver: cirrhosis

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

Compliance with DFO Treatment and Survival

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

Prognostic Criteria• Hepatomegaly• Liver fibrosis• Quality of iron chelationPrognostic Categories• Class I-none of the above• Class II One of the above• Class III two or three of the above

BTM Class I

Prevention of -thalassemia

• Carrier screening

• Prenatal diagnosis

CVS and DNA analysis

Pre-implantation diagnosis (PGD)

DNA extracted form fetal erythroblasts in maternal

circulation

thalassemia

globin Cluster

thalassemia-Abnormal Hbs

22

Hb Bart’s

22

Hb H

Gene Deletion in -thalassemia

Hydrops Fetalis Syndrome

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

• Tissue hypoxia & anemiaMassively enlarged palcentaHeart failure, edema anasarcaInterferes with organogenesis, -congenital malformationsExtramedullay erythropoiesis

Hydrops Fetalis Syndrome

Hemoglobin H Disease

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

hemoglobin• Moderate microcytic anemia• Hb electrophoresis 5-30% Hb H

thalassemina Trait

• Genotype: • Hb electrophoresis on cord blood:

2-10% Hb Bart’s• On adult blood: microcytic, with or

without anemia• Diagnosis by exclusion of thalassemia

minor & iron deficiency

-thalassemia Silent Carrier

• Hb electrophoresis on cord blood: traces to 2% Hb Bart’s

• No anemia or microcytosis on adult blood

Deletions in the -globin Gene Cluster

Categories of -thalassemia Mutations

Non-deletion thalassemia Mutations

Nco Hph TSaudi

-thalassemia Genotype-Spectrum

thal Trait• --/• ---

Hb H Disease• --/-/--

Strategy for thalassemia Multiplex PCR Analysis

Anemia of Chronic Infection

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