1. Anemias in children

2. Anemia…
… abnormal low hemoglobin, hematocrit or RBC count, lower than the age-adjusted reference range for healthy children.

3. Anemia…
… abnormal low hemoglobin, hematocrit or RBC count, lower than the age-adjusted reference range for healthy children.

4. Etiologic classification
I Impaired red cell formation
A/ Deficiency
Decreased dietary intake
Increased demand
Decreased absorption
Increased loss
B/ Bone marrow failure
Failure of a single or all cell lines
Infiltration
C/Dyshematopoietic anemia
II Blood loss
III Hemolytic anemia
Corpuscular (membrane, enzymatic or hemoglobine defects)
Extracorpuscular (immune, idiopathic)

5. Diagnosis of Anemia Additionally: -bone marrow evaluation
detailed history
careful physical examination
peripheral blood smear
red cell morphology
MCV
RDW (red cell distribution width)
WBC and platelet morphology
Additionally:
-bone marrow evaluation
-additional testing

6. History
- Diet (iron , folate, vitB12 intake, onset of hemolysis after certain foods –e.g.,fava beans)
- family history (transfusion requirements of relatives, splenectomy, gallblader disease)
- environmental exposures (lead poissoning)
- symptoms (headache, exertion dyspnea, fatigue, dizziness, weakness, mood or sleep disturbances, tinnitis)
melena, hematemesis, abdominal pain- chronic blood loss

7. Physical Examination Pallor (skin, oral mucosa, nail beds)
Jaundice -hemolysis
tachycardia
tachypnea
orthostatic hypotension
venous hum
systolic ejection murmur
peripheral edema?
Splenomegaly?
Hepatomegaly?
Glossitis?
gingival pigmentation?
Adenopathy?
Facial, extremity examination

8. Peripheral Blood Components important
Peripheral Blood Components important! Different values dependent on age!
RBC
Hgb
HCT
MCV – 80 – 100 fl/L (a calculated value)
MCH
RDW
Reticulocyte Count

9. MCV for Characterize Anemia
(>85fl)
*Macrocytic
Normal newborn
Increased erythropoesis
Post splenectomy
Liver disease
Aplastic anemia
Megaloblastic anemia
Down S.
Obstructive jaundice
Low(<70 fl)
*Hypochromic/Microcytic
-Iron deficiency anemia
-Thalassemia
-Sideroblastic anemia
-Chronic infection
-Lead poisoning
-Inborn errors of Fe metabolism
-Severe malnutrition
-Copper deficiency

10. Normocytic Acute blood loss Infection Disseminated malignancy
Renal failure
Connective tissue disorders
Liver disease
Disseminated malignancy
Early iron deficiency
Aplastic anemia
Bone marrow infiltration
Dyserythropoietic anemia

11. Iron Deficiency Anemia
Causes
-Dietary deficiency
-Increased demand (growth)
-Impaired absorption
-Blood loss (menstrual problems)
Symptoms
GI: Anorexia, poor weight gain, pica, atrophic glossitis
CNS: fatigue, irritability
Cardiac: increased cardiac output, cardiac hypertrophy
Dry skin, thin hair, pallor, nail ridges

12. Iron Deficiency Anemia
*characteristics of peripheral blood smear
microcytic
hypochromic
*MCV and Hgb– decreased (Hgb<12g/L)
Ferritin – decreased (<13mg/dL)
TIBC - high
-Serum iron –decreased (N µg/dL)

13. Iron Deficiency Anemia
Treatment
oral iron supplementation: 4 - 6mg/kg/day of elemental iron
goal: to replace iron stores, not just circulating Hgb!
Reticulocytes- starts to rise in 3 -4 days,
Hbg- after 4- 5 days
After Hgb normalisation – continue Fe therapy 1-2 months to replace Fe stores
*Iron- rich foods: animal protein, green vegetables, iron fortified cereales
Folate, vit C

14. parenteral therapy (IM,IV)
indications
poor compliance
severe bowel disease
intolerance of oral iron
chronic hemorrhage
acute diarrhea disorder

15. Megaloblastic anemia
Presence the megaloblasts in the bone marrow and macrocytes in the blood
In > 95% occurs as a result of folate and vitamin B12 deficiency
Deficiencies of ascorbic acid, tocopherol, thiamine may be related to megaloblastic anemia
Dietary vitamin B12 (cobalamine) is required from animal sources (meat and milk)

16. Causes of vitamin B12 deficiency
I Inadequate dietary intake (<2mg/day) –malnutrition, veganism, maternal deficiency
II Defective vitamin B12 absorption
Failure to secrete intrinsic factor
Failure to absorption in small intestine
III Defective vitamin B12 transport
IV Disorders of vitamin B12 metabolism (congenital, acquired)

17. Folic acid deficiency
One of the most common micronutrient deficiences in the word (next to iron deficiency)
Component of malnutrition and starvation
Women are more frequently affected than men
Folate sufficiency prevents neural tube defects
Low mean daily folate intake is associated with twofold increased risk for preterm delivery and low infant birth weight

18. Causes of folic acid deficiency
Inadequate intake (method of cooking, special diet, goat’ milk)
Defective absorption (congenital or acquired)
Increased requirements (rapid growth, chronic hemolytic anemia, dyserythropoietic anemias, malignant disease, hypermetabolic state, cirrosis, post –BMT)
Disorders in folic acid metabolism (congenital, acquired)
Increased excretion

19. Clinical features of cobalamine and folate deficiency
Insidious onset: pallor, lethargy, fatigability, anorexia, sore red tongue and glossitis, diarrhea
History: similarly affected sibling, maternal vitamin B12 deficiency or poor maternal diet
Vitamin B12 deficiency: signs of neurodevelopmental delay, apathy, weakness, irrability, athetoid movements, hypotonia, peripheral neuropathy, spastic paresis

20. Megaloblastic Anemias: Clinical Findings
Anemia is slow to develop
Fatigue
Weakness
Yellow color
Weight loss
Glossitis

21. Megaloblastic Anemia: Lab Features: Hematology
Macrocytic, normochromic anemia
Increased MCH: due to large cell volume
Normal MCHC
RBC, HGB, Hct decreased
Granulocytes and Thrombocytes are affected as well.
Granulocytes are hypersegmented
Megakaryoctyes are abnormal resulting in thrombocytopenia

22. Megaloblastic Anemia: Lab Features: Peripheral blood
Triad of oval macrocytes, Howell-Jolly bodies and hypersegmented neutrophils
Anisocytosis, Poikilocytosis
RBC’s are fragile, lifespan is shortened and many die in the bone marrow which causes ↑ LDH

23. Megaloblastic Anemia: Lab Features: Misc
Bone marrow
Chemistries
Hypercellular with megaloblastic erythroid precursors
M:E ratio decreased
Vitamin B12
Folate
Methylmalonic acid (MMA)
Homocysteine
Lactic dehydrogenase(LDH)

24. Diagnosis
Red cell changes: Hgb usually reduced, MCV increased to levels 110 – 140fl., MCHC normal,
in blood smear many macrocytes and macro-ovalocytes, anisocytosis, poikilocytosis, presence of Cabot rings, Howell-Jolly bodies, punctate basophilia
White blood cell count reduced to 1500 – 4000/mm3, neutrophils show hypersegmentation (>5 lobes)
Platelets count moderately reduced (50,000 – 180,000/mm3)
Bone marrow: megaloblastic appearance
Serum vitamin B12 values lowered (normal 200 – 800 pg/ml)
Serum and red cell folate levels – wide variation in normal range; less than 3 ng/ml -very low, 3-5 ng/ml –low, >5-6 ng/ml normal, in red cell: ng/ml
Schilling urinary excretion test – measurement of intrinsic factor availability and absorption of vitamin B12

25. Treatment
Vitamin B12 deficiency Prevention in cases of risk of vitamin B12 deficiency Treatment 25 – 100µg vitamin B12 Folic acid deficiency Correction of the foliate deficiency ( µg/day) Treatment of the underlying causative disorder Improvement of the diet to increase folate intake

26. Macrocytic Anemia Megaloblastic Nonmegaloblastic
Abnormal DNA synthesis, usually due to vitamin B12 or folate deficiencies
Results in delayed nuclear development, causing the larger cells
Nonmegaloblastic
Mechanism not well defined
Increase in membrane lipids
Characterized by large erythrocytes( MCV> 100)

27. Megaloblastic Anemias
“Megaloblast”: large abnormal marrow erythocyte precursor
Group of disorders characterized by defective nuclear maturation caused by impaired DNA synthesis.
Nuclear replication is slowed down resulting in maturation delays, prolonging the premitotic interval
Results
Large nucleus
Increased cytoplasmic RNA
Early hgb synthesis

29. Megaloblastic Anemia: Causes of
Vitamin B 12 deficiency
Folate deficiency
Drugs
Myelodysplastic syndromes
Acute leukemia

30. Megaloblastic Anemias: Deficiency of Vitamin B12
Vitamin B12 (cyanocobalamin) deficiency
Inadequate dietary intake
B12 is found in food of animal origin: red meat, fish, poultry, eggs, dairy products

31. Megaloblastic Anemias: Deficiency of Vitamin B12
Malabsorption
Pernicious anemia
Caused by gastric parietal cell atrophy which causes decreased secretion of intrinsic factor (IF). IF is necessary for B12 absorption.
Atrophy due to immune destruction of the acid-secreting portion of the gastric mucosa
Onset is usually after age 40, primarily women
Affects people of Northern European backgrounds
Neurologic problems
Schilling test used for diagnosis

32. Schilling test Establishes the cause of vitamin B12 deficiency
Test performed in two parts
If parts one & two abnormal: Pernicious anemia
If part one only abnormal: malabsorption

33. B12 Malabsorption causes (con’t)
Gastrectomy
Blind loop syndrome
bacteria use up the B12
Fish tapeworm= Diphyllobothrium latum
completes for B12

34. Other Causes for B12 Deficiency
Drugs
Alcohol
Nitrous oxide
Antitubercular drug

35. Megaloblastic Anemia: Folic Acid (Folate) deficiency
Inadequate dietary intake
Poverty
Old age
Alcoholism

36. Megaloblastic Anemia: Folic Acid (Folate) deficiency
Malabsorption
Ileitis/Crohn’s disease
Tropical sprue
Blind loop syndrome
Nontropical sprue
Gluten-sensitive enteropathy
Childhood celiac disease

37. Megaloblastic Anemia: Folic Acid (Folate) deficiency
Increased requirement
Pregnancy
There is increased demand during pregnancy and should be supplemented prior to and during pregnancy. Deficiency during pregnancy can cause neural tube defects in utero.
Infancy
Hematologic diseases that involve rapid cellular proliferation such as sickle cell anemia

38. Megaloblastic Anemia: Folic Acid (Folate) deficiency
Drugs
Methotrexate (chemotherapy drug that is a folate antagonist)
Alcohol
Oral contraceptives
Long term anticoagulant drugs

39. Treatment of megaloblastic anemia
B12 deficiency
Vitamin therapy
Intramuscular or subcutaneous injections for pernicious anemia to bypass absorption throught the gut.
Folate deficiency

40. Non-Megaloblastic Anemia
MCV doesn’t go as high as in megaloblastic
Macrocytes are round NOT oval
No hypersegmented neutrophils
Leukocytes and platelets are normal
Jaundice, glossitis and neuropathy are absent

41. Non-Megaloblastic Anemia
Causes of
Chronic liver disease
Alcoholism (alcohol has toxic effect on RBC’s)
Stimulated Erythropoiesis

42. Anemia associated with liver disease
Causes of:
Blood Picture:
Blood loss
Alcoholism
Folate Deficiency
Impaired bone marrow response
Hemolysis
Target cells
Acanthocytes
Macrocytes
Hypochromia
Microcytosis

43. Anemia associated with:
Alcoholism:
Ethanol has a toxic effect on precursor cells.
Red cells are macrocytic
Stimulated erythropoiesis:
Increased EPO, adequate iron
Release of stress reticulocytes

44. Intravascular vs. Extravascular
•AHTR
•Severe burns
•Severe microangiopathy
•G6PD
•DIC
Extravascular
•AIHA
•DHTR
•Hemoglobinopathies
•HS
•Hypersplenism
•Live

45. -RBCs being made appropriately and then destroyed?
Anemia
•Use common sense, and think in global terms
-RBCs being lost?
•GI bleeding, menstrual loss (both often with Fe deficiency)
-RBCs being made appropriately and then destroyed?
•AIHA (elevated bili & retic, classic w/ hemolysis)
•Hypersplenism (?liver dz w/ portal hypertension)

46. •Fe deficiency – not enough substrate; low retic
Anemia
-RBCs not being made?
•Fe deficiency – not enough substrate; low retic
•Transient erythroblastopenia of childhood (TEC) – transient
marrow shut-off; zero retic
•Marrow infiltration (other counts likely to be affected)
•Aplastic anemia (WBC, plts also low; possible increased MCV)

47. -RBCs not being made correctly, thus being destroyed?
Anemia
-RBCs not being made correctly, thus being destroyed?
•Hereditary spherocytosis (elevated bili & retic)
-RBCs made with wrong Hgb/enzyme defect, thus hemolyzing?
•Sickle cell, thalassemia, G6PD

48. ABO/Rh incompatibility if newborn, congenital anemia, G6Anemia
if near 2 mos,
ABO/Rh incompatibility if newborn, congenital anemia, G6Anemia
•Similarly, think about what’s common, given the age and clinical presentation
-Infants <12mos
•Fe def is exceedingly RARE; think physiologic nadir PD def, α
thal trait, leukemia (unlikely to present w/ isolated anemia)

49. -Toddlers – many more possibilities
Anemia
-Toddlers – many more possibilities
•Fe def very common, TEC, Diamond-Blackfan Anemia, HS, previously
undiagnosed sickle cell, α thal trait, G6PD def, HUS, leukemia

50. -Later school age/adolescent
Anemia
-School age
•Fe def possible, HS, α thal trait, AIHA, HUS, leukemia, GI blood loss
-Later school age/adolescent
•Fe def common in menstruating ♀ (think twice about Fe def in males),
AIHA, GI blood loss, leukemia

51. Hemoglobin values vary with age
Hb (gm/dL)
Age
MCV=
Reticulocytes 3-7%
(cord blood)
Newborn
9.0 (term)
8.5 (low birth wt.)
9.5
10.0
2-3 months
3-6 months
6-12 months
Infancy
10.5
11.5
12-24 months
> 24 months
Child
12.0 (female)
13.5 (male)
> 13 years
Adolescence

52. -Diet, pica behaviors, living situation, family ethnicity & surgeries,
Anemia
•Use the entire history and physical to your advantage
-Diet, pica behaviors, living situation, family ethnicity & surgeries,
frequent moves, neonatal history, menstrual history, viral history, GI
blood loss, medications
-Vitals, color, organomegaly, nodes

53. -Indices (MCV, particularly in
Anemia
•Labs
-Hgb – how low?
-Indices (MCV, particularly in
comparison to Hgb, MCHC) and smear
-Retic count!

54. •Fe studies – Fe, TIBC, ferritin
Others as indicated
•Fe studies – Fe, TIBC, ferritin
•Bili
•Coomb’s
•Lead level
•Hgb electrophoresis
•Osmotic fragility

55. Differential Diagnosis of Anemia
•Divide into groups by size of cell (MCV)
Macrocytic
Normocytic
Microcytic
Newborn
Acute blood loss
Fe-def
Liver disease
Thalassemia
Hypothyroidism
Renal disease
Sideroblastic
Splenectomy
Infiltrated marrow
Lead toxicity
Trisomy 21
E TEC
Hgb
Reticulocytosis
Connective tissue
Inborn errors
Aplastic
Aplastic Anemia Anemia/MDS
Copper def.
Vit B12/Folat
Atransferrinemia

56. Differential Diagnosis of Anemia
Consider increased destruction versus decreased production based on reticulocyte count
Destruction
Production
Dietary(Fe,B12,Folate)
Aplastic Anemia
Diamond-Blackfan TEC
Bone Marrow infiltrate
Hemoglobin
Enzyme defects
Membrane defects
Immune-mediated

57. 19 mo old male noted by his grandmother to be pale and fussy
19 mo old male noted by his grandmother to be pale and fussy. Described as very picky, his diet is mainly string cheese, mac & cheese and milk. The child appears in no distress. He is slightly tachycardic with normal heart rhythm, no gallop, +systolic murmur, normal BP and good peripheral perfusion. CBC shows Hb=5.0 gm/dl, MCV 52fL, retic 1.6%. What is the most appropriate clinical management?
1) Refer immediately to the closest hospital for 10cc/kg PRBC transfusion.
2) Schedule a slow transfusion with 5cc/kg of PRBC then start supplementation with oral iron.
3) Start the patient on a daily children’s chewable vitamin with Fe.
4) Obtain nutrition consult and start oral Fe at 3-6 mg/kg elemental Fe daily.

58. 19 mo old male noted by his grandmother to be pale and fussy.
Described as very picky, his diet is mainly string cheese,
mac & cheese and milk. The child appears in no distress.
He is slightly tachycardic with normal heart rhythm, no gallop, +systolic
murmur, normal BP and good peripheral perfusion. CBC shows Hb=5.0 gm/dl,
MCV 52fL, retic 1.6%.
What is the most appropriate clinical management?
Refer immediately to the closest hospital for 10cc/kg PRBC transfusion.
2) Schedule a slow transfusion with 5cc/kg of PRBC then start supplementation with oral iron.
3) Start the patient on a daily children’s chewable vitamin with Fe.
4) Obtain nutrition consult and start oral Fe at 3-6 mg/kg elemental Fe daily.

59. Iron Deficiency Anemia
•Toddlers and adolescent females particularly susceptible
•Anemia of varying degree (can be severe), with low RBC and MCV and inadequate reticulocytosis (↓substrate)
•↓Fe, ↑TIBC, nl to ↓ferritin

60. Iron Deficiency Anemia
•Treat with oral iron
-3-6 mg elemental Fe/kg/day in divided doses
-325 mg qd-bid (adolescents)
•Recheck CBC, retic in 2-3 wks
•No change - ?compliance, wrong dx (thal trait)
•If no obvious dietary or menstrual hx to explain the Fe deficiency, rule out occult GI blood loss

61. Which of the following sets of labs are consistent with iron deficiency anemia?
1) ↑ RDW, ↓ RBC#, ↑ MCV
2) Normal RDW, ↑ RBC#, ↓ MCV
3) ↑ RDW, ↓ RBC#, ↓ MCV

62. Which of the following sets of labs are consistent with iron deficiency anemia?
↑ RDW, ↓ RBC#, ↑ MCV
Normal RDW, ↑ RBC#, ↓ MCV
↑ RDW, ↓ RBC#, ↓ MCV

63. Thal trait vs. Fe-deficiency
•Remember, in thalassemia trait, all red cells are very small (↓ ↓ MCV), but they’re all the same size (nl RDW), and there is no production problem (nl to ↑ RBC). There is marked discrepancy between Hgb value and MCV, whereas in Fe-def, these two values tend to go down at a similar rate.