1. Childhood Anemia: An Overview
Gao Ju MD, PhD
Professor of Pediatrics
Department of Pediatric Hematology/Oncology
West China Second University Hospital, SU

2. Major Items Essentials of Hematology: An Brief Review
Hematopoiesis  Hematological Features in Normal Children
Childhood Anemia: An Overview
Useful References and Websites

3. Fundamentals of Hematology

4. Cardiovascular system
Blood is the fluid circulating constantly in the closed cardiovascular system (CVS).
It consists of plasma  blood cells.
Blood cells in turn include red cells, white blood cells  platelets.
Cardiovascular system
platelet
red cell

5. Differs in cell morphology  functions
WBC includes neutrophils, lymphocytes, monocyte, eosinophils  basophil.
Differs in cell morphology  functions
neutrophils
monocytes
eosinophils
lymphocytes
basophils

6. Blood: plasma  “formed elements”-blood cells

7. Hematopoiesis: the process of producing mature blood cells, among which circulating red cells are essential to oxygen carrying to tissues.
Under normal physiologic conditions, the Production of blood cells (hematopoiesis) is kept in dynamic balance with the Destruction of blood cells (D=P).

8. Blood plays many important physiological functions
Blood plays many important physiological functions. Among them, oxygen transport is the most important, which is essential to our survival. This is specifically carried out by Hb, the most abundant protein in red blood cells.
300 million Hb molecules in a single mature circulating red cell, comprising 97% of red cell dry weight

9. Humans are strict aerobic animals
Humans are strict aerobic animals. We need oxygen for energy production and many other metabolic processes.
Two molecules of ATP is produced from 1 molecule of glucose via anaerobic glycolysis, but 34 molecules of ATP could be produced from 1 molecule of glucose via tricarboxylic acid cycle (Krebs cycle ) .
Mature red cells, anucleated and without mitochondria, are incapable of oxidative metabolism and destined to death up to their normal life span ( days)

10. Blood O2 content = [1.34  Hb (SaO2/100)] + 0.003PO2 = 20.8ml
Henry’s law : the amount of oxygen dissolved is proportional to the partial pressure.
For each mmHg of PO2 there is ml O2/dL (100ml of blood)
Blood O2 content = [1.34  Hb (SaO2/100)] PO2 = 20.8ml
For the sake of efficient oxygen transportation, there must be a vehicle to carry oxygen from the lungs to peripheral tissues, instead of direct dissolution of O2 in water (plasma).
Low oxygen solubility: oxygen dissolved in plasma could be as low as 0.13 mmol/L under maximal arterial oxygen partial tension. It could be as high as 8.6 mmol/L while bound to Hb under the same arterial oxygen partial tension—66-fold increase.
Poor oxygen diffusibility
In fact, 100 ml blood (Hct45%, equivalent of Hb15 g/L) can carry 20 ml of oxygen, while 100ml plasma can only carry 0.3 ml of oxygen.(60-fold difference)

11. Hb is JUST the right vehicle
Molecular structure (Hb is a allosteric enzyme)
The peculiar sigmoidal oxygen dissociation curve facilitates oxygen binding in lungs with higher oxygen tension, and promotes oxygen dissociation in peripheral tissues with lower oxygen tension.

12. Hematopoiesis  Hematological Features in Normal Children

13. Bone marrow, the organ of blood cell production
Low-power field
High-power field

14. Hematopoiesis in normal children
Two distinct stages：fetal  postnatal hematopoiesis
Fetal Hematopoiesis
Mesenchymal Hematopoiesis
Liver/Spleen Hematopoiesis
Medullary Hematopoiesis

15. Postnatal Hematopoiesis
Medullary Hematopoiesis
Hematopoiesis in all bones before 5 years of age (red marrow).
Yellow marrow increases gradually after 5-7 years.
Hematopoiesis primarily concentrates in flat bones and proximal ends of long bones.
Extra-Medullary Hematopoiesis
Happens in case of increased demand for hematopoiesis (e.g., hemolysis, bleeding).
Characterized by hepatosplenomegaly and presence of nucleated red cells in peripheral circulation.

16. Hb Switching during embryonic, fetal  postnatal life
Actually, there are only 6 Hb during ontogeny, just because that some globin chains are present at different time period during development.

17. Hematological features in normal children
RBCs and Hb
RBCs at birth: ( )1012/L
Hb at birth: g/L
2-3 months after birth(nadir: physiologic anemia)
RBCs 300 1012/L
Hb 110g/L
Reticulocytes
Within 3 days after birth: ( ) 1012/L
1 week after birth: ( ) 1012/L
1 month after birth: ( ) 1012/L
5 month after birth: same as that in adults

18. Types of Hb WBC count HbF at birth: 75%。 HbF at 4 month:20%。
HbF at 1 year of age:5%。
HbF at 2 years of age: 2%。
WBC count
At birth: WBC /l.
During infancy: 10000/l.
After 8 years of age: same as that in adult.
HbA(22): 95%~97%
HbA2(22): 2%~3%
HbF(22): 1%

19. WBC differential count- two cross-overs
At birth, neutrophil predominates.
The first cross-over occurs at 4-6 days after birth. Then， lymphocytes predominates during infancy (65%) and neutrophils account for 35%.
The second cross-over happens during 4-6 years of age. After that, neutrophils predominate again.
Platelete
(10-30) 109/L, same as that in adult

20. WBC differentials during childhood
4-6days
4-6 yrs
Lymphocyte
0.3
0.4
0.5
0.6
0.7
neutrophils
WBC differentials during childhood

21. Childhood anemia with different underlying diseases
Anemia: An Overview
Childhood anemia with different underlying diseases
-Illustrative photos

22. Definition of Anemia Literally, anemia means “without blood” .
Physiologically, anemia refers to any state of reduced red cell mass (RCM).
Clinically, anemia is defined as a reduction of RBC count, Hb concentration or hematocrit in unit volume of peripheral blood compared to a normal group (Keep in mind these are all measures of concentration).
According to WHO criteria, anemia is defined as Hb conc. lower than 95 percentile of norm.

23. Anemia is best defined by the decrease in the body's total red cell mass (RCM)

24. Functionally, anemia is best characterized by Hb concentration below normal, given the fact that Hb is the primary vehicle for oxygen transportation.
Practically, anemia is said to be present when Hb is lower than 110g/L for children aged 6 months to 6 years; or lower than 120 g/L for children aged 6-14 years at sea level , according WHO diagnostic criteria(1972)(lower than 95 percentile of normal values)

25. Normal Hb concentration at different ages

26. Red Blood Cells: Adult Reference Ranges
Measurement (units)
Men
Women
Hemoglobin (gm/dL)
Hematocrit (%), HCT
39-49
33-43
Red cell count (106/μL)
Reticulocyte count (%)
Mean cell volume (μm3), MCV
82-96
Mean corpuscular hemoglobin (pg), MCH
27-33
Mean corpuscular hemoglobin concentration (gm/dL) - MCHC
33-37
RBC distribution width, RDW

28. Summary
Anemia per se is NOT an independent disease entity，but rather a clinical syndrome , or constellation of clinical manifestations.
In order to diagnose anemia, there must be normal Hb reference values (gender-specific, age-specific, race-specific and region-specific), although they are arbitrary cutoff points with a 95% confidence interval.
Hb, expressed as g/L (concentration) is just a relative number. Its value is affected by many factors, such as measuring method, altitude, hemoconcentration and hemodilution.

29. Diagnostic criteria of anemia
WHO (1972)(at sea level)
6 month to 6 years of age: <110g/L
6-14 years of age: <120g/L
Neonates less than 7 days: <145g/L
There is a overlapping between Hb distribution curves in normal and anemic populations. 

30. Severity degrees of anemia
Mild: Hb g/L，RBC 3-41012/L
Moderate: Hb 60-90g/L，RBC 2-31012/L
Severe: Hb 30-60g/L，RBC 1-21012/L
Very severe: Hb <30g/L，RBC < 11012/L

31. Classification of anemia
Morphological classification
Emphasizes the importance of direct microscopic observation of red cells morphology.
May suggest a clue of anemia etiology.
Subdivides anemia into normocytic-normochromic, microcytic-hypochromic  macrocytic anemias, based on RBC indeces.

33. (Normocytic Normochromic Anemia)
（MCV=80-96；MCHC=33-35）
Acute bleeding
Hemolytic anemia
Extrinsic defects：immune and non-immune mediated.
Intrinsic defects：membrane, enzyme, globin.
Bone marrow failure syndromes
Aplastic anemia, pure red cell aplasia

35. (Normocytic Normochromic Anemia) （MCV<80fl；MCHC=330g/L)
Iron deficiency anemia, IDA
Thalassemia
Anemia of chronic disease，ACD
Sideroblastic anemia

36. Microcytic Hypochromic Anemia （MCV<80fl；MCHC <330g/L）

38. Macrocytic Normochromic Anemia
（MCV>96；MCHC=33-35）
Megaloblastic Anemia
Folate deficiency
Cobalamin deficiency
Combination of the above two
Non-Megaloblastic Macrocytic Anemia

39. Macroovalocyte in peripheral circulation
Megaloblastic nucleated red cells (megaloblast) sometimes could be seen

40. Neutrophil hypersegmentation of neutrophil nucleus：important clue to diagnosis and sometimes macrothrombocytes could be identified

41. Pathophysiological Classification
Fosters an understanding of the disease process in kinetic terms.
Reticulocyte count: most suitable starting point in kinetic approach
Reticulocytosis (Ret%2%-3%, or absolute Ret100,000/mm3
Ret counts are most helpful if extremely low (<0.1%) or  3% (100,000/mm3 total).
But anemia could be due to more than one mechanisms.

42. Pathophysiologically, there are TWO and JUST two mechanisms responsible for anemia development
Decreased RBC Production
Increased RBC Loss or Destruction

43. Water level in a reservior: an analogy
Inflow=Outflow
 Outflow
 Inflow
120g/L
60g/L
60g/L
Water level in a reservior: an analogy

44. Reduced RBC Production: Decreased Inflow
Bone marrow failure : aplastic anemia
Inadequate supply of hematopoietic materials
Impaired hemoglobin synthesis: IDA
Impaired DNA synthesis: folate/Cobalamin deficiency
Increased RBC loss or destruction: increased outlow
Loss( hemorrhage): acute v chronic; internal v external
Destruction (hemolysis): acute v chronic; intravscular v extravascular

46. Compensation to Anemia: An Analogy
Clinical manifestations
Compensation to Anemia: An Analogy
400km CD CQ
Task 60 p；loads 60p CQ
400km CD
Task 60 p；loads 30p CQ
400km CD
Task 60 p；loads 4p

47. Anemia can adversely affect multiple organ systems, with symptoms and signs occuring when oxygen carrying capacity of the blood is unable to meet the oxygen requirements of body tissues

48. The clinical presentations are determined by
The underlying disease leading to anemia
Hemolysis: jaundice and hemoglobulinuria
Iron deficiency: pica and CNS symptoms
VitB12 deficiency: motor and mental delay or regression
The degree and rapidity of anemia
Mild versus Severe
Acute versus Chronic
The adequacy of the body’s compensatory responses
Tachypnea, tachycardia, increases capillary pulsation
Right shift of the Oxygen-Dissociation curve

49. Compensatory mechanisms to anemia
Redistribution of blood flow
Skin vasoconstriction: pallor
Renal vasoconstriction
Diversion of blood to vital organs (heart, brain)
Hemodilution due to increased plasma volume in case of chronic anemia, with reduced viscosity and facilitated blood flow
Increased RBC DPG production and right shift of the oxygen-dissociation curve, and ease of Hb oxygen release in peripheral tissues

50. Opening of pulmonary and peripheral capillaries
Increased cardiac contractility and heart rate, with resultant cardiac output
Compensatory erythroid hyperplasia

51. Anemia: Stepwise Diagnostic Approaches
Is there anemia INDEED?
Pallor and other symptoms
Hb reduction
How about the degree?
Hb measurement
What is the underlying cause(s)?
Clinical presentations
Specific lab investigations

52. Diagnostic flowchart of anemia: an illustration
Anemia Diagnosis
Diagnostic flowchart of anemia: an illustration
In the majority of clinical circumstances, the definite diagnosis of anemia relies heavily on clinical reasoning  relevant lab investigations

53. Anemia: Therapeutic Principles
Etiological Therapy
Management of the underlying disease
Iron, folate or cobalamin supplementation
Symptomatic and supportive therapy
Component transfusion
Stem cell transplantation

54. Anemia: Summary
Anemia: Hb reduction in unit volume of peripheral blood compared to normal.
NOT independent disease entity.
Classifications:Morphological and pathophysiological.
Mechanisms: Decreased RBC Production or Increased RBC Loss or Destruction.
Diagnostic approach: Three-Steps.

55. Key Websites & References
Irvin JJ and Kirchner JT. Anemia in children. Am Fam Physician. 2001;64(8):1379－1386.
Understanding anemia, by Ed Uthman, MD,
Blood cells and the CBC.
Anemia: pathological consequences, classification and clinical investigation.

57. Atlas of hematology

58. BLOODLINE.net

59. Our Team-Pediatric Hematology/Oncology

60. Reach me if you have any questions
高举 Gao Ju, MD, PhD. Director. Pediatric Hematology/Oncology, West China Second University Hospital, Sichuan University Tel: (O)