approach to anemia in children dr. huda el faraidi pediatric hematology and bmt consultant

Approach to Anemia in Children

Dr. Huda El FaraidiPediatric Hematology and BMT

consultant

Objectives:

• To describe a practical approach to diagnose anemia in children.

• Definition of anemia• Over view of Erythropoeisis• Classification of anemia• Clinical Evaluation of anemia• Microcytic anemias• Normocytic anemias• Macrocytic anemias• Hemolytic anemias

Definition of Anemia:

• Anemia may be defined as a reduction in red blood cell (RBC) mass or blood hemoglobin concentration.

• In practice, anemia most commonly is defined by reductions in

one or both of the following:

Definition of Anemia:

• Hematocrit (HCT) :• The hematocrit is the fractional volume of a whole blood

sample occupied by red blood cells (RBCs), expressed as a percentage.

• As an example, the normal HCT in a child age 6 to 12 years is approximately 40 percent.

Definition of Anemia:

• 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.

• The normal value for HGB in a child age 6 to 12 years is approximately 13.5 g/dL

Definition of Anemia:

• The threshold for defining anemia is a HGB or HCT that is more than two standard deviations below the mean for the reference population.

• Normal ranges for HGB and HCT vary substantially with age, gender, and race.

Definition of Anemia:

• Physiologic definition: • Hemoglobin level too low to maintain cellular oxygen

demands.

• Practical definition:• Hb level 2SD below mean value for age, gender and

race.

Overview of Erythropoiesis:

3 Changes in Early Life:

1) Location

• Fetal erythropoiesis begins in the yolk sac at 3- 5

weeks of gestation.

• Normoblastic erythropoiesis takes place at 6 weeks

of gestation.

OVERVIEW OF Erythropoiesis:

• Blood formation takes place in the liver which is the

primary organ of hematopoiesis , spleen, thymus and LN

from the 3rd to the 6th months of gestation.

• The liver and the spleen continue to produce red blood

cells in the first week of postnatal life.

OVERVIEW OF Erythropoiesis

• Bone marrow hematopoiesis begins around the fourth

month of gestation and increases throughout intrauterine

development.

• After birth, further marrow volume expansion occurs.

OVERVIEW OF Erythropoiesis

• 2 ) Quantity:

• In utero EPO and fetal Hb levels are high due to intrauterine hypoxia.

• After birth oxygen saturation increases from 65% to 100% accompanied by a decrease in erythropoietin production

• Erythropoietin levels in term infants are lowest at one month and highest at two months of age.

OVERVIEW OF Erythropoiesis

• RBC production is at a minimum during the second week after birth and subsequently rises to maximum values at approximately three months.

• These changes in hemoglobin level typically reaches a nadir at six to nine weeks of age referred to as (physiologic anemia )

• Physiologic anemia occurs at 8 –10 weeks in term infants and 6-8 weeks in preterm infants due to the shorter life span of preterm RBCs

OVERVIEW OF Erythropoiesis

• The mean half-life of RBCs for term infants is 23.3 days, as compared with 16.6 days in preterm infants, and 26 to 35 days in adults.

OVERVIEW OF Erythropoiesis

• 3)Type

• During the 3rd trimester, gamma chain production diminishes, and beta chains increase, so Hb F goes down and Hb A goes up.

• By 3 months, Hb A overtakes Hb F.

• By 6 months of age, there is only trace gamma chain production, and thus very little Hb F.

OVERVIEW OF Erythropoiesis

Types of Hemoglobins:

NORMAL HEMOGLOBINS

• Hb F = α2γ2

• Hb A = α2β2

• Hb A2 = α2δ2 (normally up to 3% of adult Hb).

BETA CHAIN VARIANTS

• Hb C = α2βC2 (a variant of the β chain).

• Hb S = α2βS2 (a variant of the β chain).

• Hb D and Hb E (other variants of the β chain).

TETRAMERS

• Hb H = β4 (observed in α-thal)

• Hb Bart = γ4 (observed in α-thal)

Classification of Anemia:

1) Physiologic Classification

2) Morphologic Classification

Classification of Anemia:

1) Physiologic Classification:

• Anemia may be classified based on the reticulocyte count, which

serves as a marker of whether erythropoiesis is suppressed or active:

• N.B. (Absolute reticulocyte count = percent reticulocytes x red blood cell count/L)

Classification of Anemia:

Increased destruction and blood loss:

• These disorders are generally associated with active

reticulocyte response.

Decreased production:

• These disorders are generally associated with a lower

than expected reticulocyte response.

Increased destruction due abnormality of :

1) The Cell Membrane:

2) Haemoglobin

3) Enzymes

Classification of Anemia:

• Increased destruction or loss:• Hemolytic Disorders (Adequate retic response):

1) Problem Intrinsic to the Red Cell:

- Membrane defects: HS, HE, etc.

- Hemoglobin synthesis defect

(hemoglobinopathies) : sickle cell anemia, unstable Hb, and

thalassemia.

- RBC enzyme defects: 2,3 DPG, PKD,and G6PD

deficiency.

Classification of Anemia:

2) Problem Extrinsic to the Red Cell:

- Non-immune hemolysis: HUS, TTP, DIC, Burns, Wilson, Vit E def, etc.

- Immune hemolysis: autoimmune, isoimmune, drug-induced.

Classification of Anemia:

• Blood destruction continued:

- Infectious agents.

- Chemical: heavy metal, oxidant.

- Physical trauma as microangiopathy, thermal injury, and heart valve.

- Acute and chronic blood loss

Classification of Anemia:

• Decreased production:

- Nutritional: Fe, B12 , folic & ascorbic acid deficiency. - Bone marrow infiltration: Malignancy - Marrow failure syndromes (acquired and congenital). - Others: Osteopetrosis, Dyserythropoiesis.

Classification of Anemia:

2) Morphologic classification:

• Anemias may be classified according to RBC morphology, reflected by indices :

- RBC size (mean corpuscular volume, MCV).

- Hemoglobin content (mean corpuscular hemoglobin, MCH)

- Hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC).

- Red cell distribution width (RDW).

Classification of Anemia

• MCV (mean corpuscular volume):

• The only red cell index directly measured by the electronic counter.

• Reflects a quantitative defect in the production of Hb due to ↓ haem or globin synthesis .

• Categories anemias into microcytic, normocytic and macrocytic types.

• Value must be interpreted with age.

Classification of Anemia

• MCHC & MCH:

• Are calculate values & therefore less accurate.

• MCHC is a measurement of cellular hydration status; an increase is characteristic of spherocytosis.

Classification of Anemia

• RDW (Red cell volume distribution width):

• Reflects the variability in cell size and measures the degree of anisocytosis .

• Normal < 14.5

• ↑ in Fe deficiency anemia.

• Normal in thalassemia trait .

Classification of Anemia:

• Morphologic classification:

- Normochromic Normocytic

- Hypochromic Microcytic

- Normochromic Macrocytic

Microcytic Anemia:

Why are the cells small? Because there is inadequate production of hemoglobin.

Iron deficiency Thalassemia Lead poisoning Sideroblastic anemia Chronic inflammatory disease (usually normocytic but

can be microcytic)

Normocytic Anemia: Why are the cells normal sized? Because they are normal

cells with no enough production due to something impairing adequate marrow synthesis.

Anemia of chronic disease Chronic renal failure Transient erythroblastopenia of childhood Malignancy/marrow infiltration Other: HIV, HLH Anemia due to blood loss or hemolysis An unexplained normocytic anemia, inadequate retic

response should usually lead to consideration of a bone marrow exam.

Macrocytic Anemia:

Vitamin B12 deficiency:

Strict vegetarian diet, pernicious anemia, ileal resection,

abnormal intestinal transport, transcobalamin deficiency.

Folate deficiency:

Malnutrition, malabsorption, antimetabolites, chronic

hemolysis, phenytoin, septra, goat’s milk.

Macrocytic Anemia:

Marrow failure:

Myelodysplasia, diamond-blackfan, fanconi anemia,

aplastic anemia.

Other causes of macrocytosis:

Normal newborn, Hypothyroidism, Down syndrome,

chronic liver disease, drugs.

Massive Rticulocytosis.

Evaluating Anemia:

• History:

• Age: (iron def is rare before 6 month)

• Duration: acute or Chronic

• Diet: cow milk (iron), goat milk (folate), vegetarian (B12), favism, pica (iron def)

• Symptoms: pallor, exercise intolerance, headach,

excessive sleeping, poor feeding, and syncope, thyroid symptoms (cold intolerance, dry skin, thin hair, constipation).

• PMHx: Birth history, neonatal jaundice, any chronic illness , surgical history

Evaluating Anemia:

• Meds: septra, phenytoin, antimetabolites, AZT, , antimalarials (oxidant stress), penicillin (immune hemolysis).

• Allergies: eg Cow milk protein allergy.

• FamilyHx: ethnic background (thal, sickle, G6PD), anemia in siblings, sickle, thal, other red blood cell disorders, leukemia, G6PD, splenectomy, early age cholecystectomy, thyroid.

• Social Hx: nutrition, living conditions, (lead toxicity)

Evaluating Anemia: Physical Examination:

• Growth parameters (Weight, Height, Head circumference (increased in extramedullary hematopoiesis).

• Vital signs.

• Head: prominent skull bones

• Eyes: pallor, jaundice, blue sclera (iron), Fleischer rings (Wison)

Evaluating Anemia: Physical Examination:

• Mouth: bruises, gum swelling, glossitis (vitB12, iron), angular stomatitis (iron def), pharyngitis (infection), ulceration/mucositis (white cell disorders).

• Neck: lymph nodes (infection, infiltration), thyroid exam.

• Skin: petechiae, purpura, pallor, jaundice, café au lait macules.

• Hands: dactylitis (SCD), bone deformities (marrow failure syndromes).

Evaluating Anemia: Physical Examination:

• CVS: tachycardia, murmur, heart failure (anemia).

• Resp: distress, cyanosis.

• Abdo: hepatsplenomegaly (extramedallary hematopoesis, infiltration), tenderness, masses.

• Extremities: hemarthrosis, thrombosis.

Evaluation of anemia in children according to mean corpuscular volume

Evaluation of Anemia: Lab Studies

• A review of the peripheral smear is an essential part of any anemia evaluation.

The 3 most important tests are: - CBC: MCV, WBC, RBC, Platelets - Reticulocyte count - Peripheral blood smear

• The following features should be noted:

RBC size: Identify the patient with microcytosis or macrocytosis .

Evaluation of Anemia: Lab Studies

Evaluation of Anemia: Lab Studies

• Typical morphologic abnormalities:

• Sickle cells, as seen in sickle cell disease.• • Elliptocytes, as seen in congenital elliptocytosis .• • Stomatocytes, as seen in hereditary or acquired

stomatocytosis .

• Pencil poikilocytes, which can be seen in iron deficiency anemia or thalassemia.

Evaluation of Anemia: Lab Studies

• Target cells, as seen in the various hemoglobinopathies including thalassemia, in liver disease, and post-splenectomy.

• Bite cells, as seen in Heinz body hemolytic anemia.

Evaluation of Anemia: Lab Studies

Red blood cell indices:

MCV, MCH, MCHC , and RDW are an integral part of the evaluation of the anemic child.

White blood count and platelet count:

In the patient with anemia, the presence of leukopenia , neutropenia, and/or thrombocytopenia may signify abnormal bone marrow function or increased peripheral destruction of blood.

Evaluation of Anemia: Lab Studies

• For suspected IDA: serum iron, transferrin/TIBC, ferritin, soluble transferrin receptor.

• For suspected hemoglopenopathies (thal or sickle): Hb electrophoresis, Hb H prep.

• For suspected megaloblastic anemia: RBC folate, serum B12.

Evaluation of Anemia: Lab Studies

• For suspected hemolysis: LDH, haptoglobin, indirect hyperbilirubin , Direct Coomb’s (if positive, means autoimmune hemolytic anemia), G6PD assay, PK level, etc.

• If spherocytes seen on smear, test further with an osmotic fragility test or Flocytometry.

• Optional tests when indicated: • Examine stool and urine for blood loss (PNH)

Evaluation of Anemia: Lab Studies

• Role of bone marrow examination:

• Most useful in hypoproductive anemias.

• May be important to rule out malignant infiltration or

identifying dyserythropoietic anemia.

The Peripheral Blood Smear:Red Cell Morphology

Q. What are the differences between iron deficiency anemia and Thal trait?

1) In alpha thal, the iron studies (serum iron, TIBC, ferritin, and marrow stores) are normal.

2) In alpha thal, RDW is normal, in IDA it is high.

3) In alpha thal, the RBC count is increased, usually around 5, and the MCV is very low.

4)The Mentzer’s index (MCV/RBC) is >13 in IDA, and under 13 in thal trait.

Q. What are the differences between iron

deficiency anemia and Thal trait?

5) In IDA, platelets are often increased.

6) Hb electrophoresis is normal in both IDA and Alpha Thal.

7) Increased Hb A2 in Beta Thal.

Useful facts of childhood anemia:

• Reticulocyte count is very often not included in the CBC

• Macrocytic anemia is rare in childhood.

• In macrocytosis, it is prudent to determine if the ↑MCV is due to reticulocytosis.

• Many childhood anemias have a hereditary basis.

• Nutritional deficiency is extremely rare in infants who are fed on commercial formula or breastfed by mothers with an adequate diet or taking supplement.

Useful facts of childhood anemia:

• IDA is probably the most common cause of isolated anemia especially in children aged 1-5 years.

• In a patient with β thalassaemia trait & concomitant Fe deficiency, HbA2 level can be normal as Fe deficiency depresses δ globin synthesis; Hb electrophoresis should be repeated after Fe deficiency is corrected.

Useful facts of childhood anemia:

• Parvovirus is unique in its erythrotropic nature & striking affinity for erythroid precursors and produces transient erythroid marrow aplasia.

• It may cause a dramatic fall in Hb in patients who have chronic haemolysis with a shortened red cell survival – “aplastic crisis”.

Useful facts of childhood anemia:

• Reticulocyte count Reflects the rate at which new RBC are produced; normal < 1% after 3 months; at birth up to 10%.

• In anemic patients, the reticulocyte life span ↑ from 1 to 2-2.5 days.

• Absolute reticulocyte count or reticulocyte index more

accurately reflect the rate of erythropoiesis.

Bring home messages

• Symptoms of anemia in children may be non-specific.

• Nutritional history is important, especially in infants and

young children for possible iron deficiency .

• Family and neonatal history are important for possible inherited causes of anemia.

Bring home messages

• Associated physical and developmental abnormalities may provide useful clues for diagnosis (growth parameters, cutaneous or skeletal abnormalities, etc).

• A systemic approach should be adopted in laboratory investigations for the cause of anemia.

• Red cell indices and reticulocyte response remain the

most useful tools for evaluation of anemia.

Thank you for listening