Anemia

Hematology-Oncology Division –Child Health

Departement ,Medical School University of Sumatera
Utara

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 Anemia
Definition :
Reduction in hemoglobin concentration ,
hematocrit or number of red cells per cubic
millimeter . The lower limit of the normal
range is two standard deviations below the
mean for age and sex for normal population

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 Table 1. Normal red blood cell values in children

Hemoglobin (g/dl) MCV (fl)

AGE Mean - 2 SD Mean - 2 SD

Birth (cord blood) 16.5 13.5 108 98
1-3 days (capillary) 18.5 14.5 108 95
1 week 17.5 13.5 107 88
2 weeks 16.5 12.5 105 86
1 month 14.0 10.0 104 85
2 months 11.5 9.0 96 77
3-6 months 11.5 9.5 91 74
0.5-2 years 12.0 10.5 78 70
2-6 years 12.5 11.5 81 75
6-12 years 13.5 11.5 86 77
12-18 years, female 14.0 12.0 90 78
12-18 years, male 14.5 13.0 88 78
18-49 years, female 14.0 12.0 90 80
18-49 years, male 15.5 13.5 90 80

Hasting, C. Anemia , In: Hematology/oncology handbook, 2002HIS,2015

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Level  Hemoglobin  and  Hematocrit  (  WHO  2001  )  

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 Caused  :  
     
 1.Decreased  red  blood  cell  produc0on    
 2.Increased  red  blood  cell  destruc0on    
 3.Red  blood  cell  loss  

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                              Classification of Anemia

 Screening Hb CBC:
  ↓ MCV- MCH
Peripheral blood
  smear
Reticuloyte index
Microcytic,
Normocytic,
hypochromic
normochromic Macrocytic
MCV <80 fL
MCV 80-95 fL MCV >95 fL
MCH <27 pg
MCH ≥ 27 pg
Megaloblastic:
Iron deficiency anemia Hemolytic anemia vitamin B12 deficiency
Anemia chronic disease or folat
Thalassemia
Anemia due to bleeding Non-megaloblastic:
Anemia chronic alcohol, liver disease,
disease Renal disease myelodysplasia
Mixed deficiency Aplastic anemia
Lead poisoning
Bone marrow failure
Sideroblastic anemia

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 Microcytic Hypochromic
Anemia
1.  Iron  Deficiency  Anemia    (  IDA)  
2.  Thalassemia  minor/trait  
3.  Hemoglobin  C    and  E  disorders  
4.  Anemia  of  chronic  Diseases      (ACD  )  
5.  Lead  Poisoning  
6.  Sickle  Thallassemias  ,  Hemoglobin  SC  Diseases  
7.  Rare  microcy0c  diseases  
                                                                         Nelson Textbook of Pediatric,19 ed,2011  
th

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 Asses degree of Anemia

Mild Moderate Severe

(Hb > 10 g/dl) (Hb 7-10 g/dl) (Hb <7 g/dl)

History and physical examamination History, physical examination

Compatible with iron deficiency Iron studies

or (Hb electrophoresis)
Trial of oral iron 4-6 mg/kg/day Iron studies Family studies
Deficient
Dietary counselling (FEP, Fe/TIBC, %
Not transferin sat.)
Reticulocyte count at 1 week Hospitalization
Improved
Improved
Suggestive smear
Consider : Transfusion
Continue oral Fe Reticulocyte count
Iv or oral iron (if indicated)
3-6 months Stool guaiac

Blood loss (urinalysis, stool guaiac, Meckel’s Severe iron deficiency

scan) Hemogloinopathy/thalassemia
Red cell aplasia
Hemolysis (Coomb test, perpheral smear) (Hb electrophoresis, family
studies) Malignancies
Hemoglobinopathy/thalassemia
Lead toxicity Infection
Hb electrophoresis
Hemolytic anemia with illness/infection
Family studies
Thalassemia
Lead poisoning
Thalassemia β mayor, Hb H diseases
Iron studies, Iron malabsorption
Hemoglobinopathies
Oral iron challenge, consider parenteral iron
HIS,2015 Sickle cell 8
Hasting, C. Anemia , In: Hematology/oncology handbook, 2002 ; 2
 IRON DEFICIENCY ANEMIA

•  Definition :
–  Anemia resulting from lack of sufficient iron for
synthesis of hemoglobin.

•  Prevalence :
–  The most common cause of anemia worlwide
–  An estimated 30% of the world’s population :
•  4.5 billion ] anemic
•  500 – 600 million ]Iron def. anemia

–  Indonesia : 25 – 35% (aged 5 yrs)

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Causes  of  iron  deficiency  

Decresed    
iron  intake  

Decresed    
iron  
absorpEon  

Increased   Increased  
iron   iron  loss  
requiremets  

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 Impact    of  iron  deficiency  and  Iron  
Deficiency  Anemia  
 
1.Infant  :    adverse  neurodevelopmental  
outcome  and  cogni0ve  problem    
2.Impaired  motor  and  mental  development    in  
infants,  children  and  adolescents  
3.Decreased  work  capacity  ,  Behavior  and  
learning  problem  
4.Prolonged  IDA:  motor  and  cogni0ve  defects,  
inability  to  concentrate  ,lower  standardized  
math  scores  
Haas et al,2001
Graham-Mc Gregor et al,2001
11 11
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 Iron cycle

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Iron Status in Human Body

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Criteria of IDA by WHO :

1.  Hb concentration < normal (age dependent)

2.  Mean Hb concentration < 31% ( N: 32 - 35%)
3.  Serum iron < 50 Ug/dl (N: 80-180 ug/dl)
4.  Transferrin sat. < 15 (N: 20-50%)

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 Diagnostic Approach

•  Anamnesis
•  Physical examination findings
•  Laboratory examination

             

                 
 
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 History taking
•  Pallor,floppiness  :0me  of  onset  
•  Fa0gue,lethargy  
•  Poor  feeding  
•  Irritability  
•  Abdominal  pain  
•  Headache  ,dizziness  
•  Shortness  of  breath  
•  Arthralgia  
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 Clinical Manifestation
 
  §  Pica :
•  Pallor ,jaundice Phagophagia (compulsive
•  Tachycardia eating of ice)
Geophagia : interest in dirt
•  postural hypotensio consumption ]risk for
•  Anorexia parasitic infestation & lead
•  Angular stomatitis poisoning)
§  Ephitelial changes :
•  Glossitis
Koilonychia, atrophy of
•  Spoon nail lingual papil
 
§  Exercise intolerance
                                                                                                 
   Nathan  Oski,2003   §  Behavioral changes
   Lanzkowsky  P,2005              
     Glader  B,  2007                 §  Abnormal thermogenesis
§  Altered host response

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HIS,2015 19
Pale Conjunctiva and Pale Palmar Creases

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20
 LABORATORIUM FINDINGS

Red blood cells (RBCs)

•  Hb concentration : $
•  Chronic iron def. ] red cell indices (MCV, MCH,
MCHC) : $ parallels with Hb concentration
•  Reticulocytes : slightly #
•  Red cell morphology :
– Mild iron def. ] hypochromic, anisocytosis
– Chronic iron def. ] poicylocytosis (targets
cells, ovalocytes, mycrocytes & cell fragments)
•  RBCs survival : shortened

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 Thalassemia minor Iron Deficiency

Poikilocytosis Anisocytosis
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 TREATMENT  
1. Oral iron therapy
} Ferrous salt : adsorbed 3X better than ferric salts
} Ferrous gluconate, ferrous fumarate, & ferrous sucsinat :
well adsorbed but >> expensive
} Dose : 4 – 6 mgkg of elemental iron in three divided
doses.

2 .Parenteral iron therapy

Dose : weight (kg) x desired increment Hb (g/dl) x 2.5

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 …….. Treatment
•  Erythropoietin
–  Recombinant human erythropoietin (EPO) stimulates
proliferation & differentiation of erythroid precursors ]#
in heme synthesis.
–  A typical starting dose : 150 U/kg (3x a week) ] IV or
SQ

•  Transfusion therapy
–  Children with very severe anemia (Hb < 5 g/dl)
–  Blood is best given : packed red cells by a modified
exchange transfusion ] avoid expansion of the blood
volume.
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 Factors affecting iron absorption of nonheme
iron from the gastrointestinal tract

q Increased  absorp-on  
 Vit  C:  citrus,  tomatoes,  potatoes,    
 Solutes  
 Sugars  
 meat,  fish,poultry  
 Hydrochloric  acid  
q Decreased  absorp-on  
 Antacids  
 Pancrea0c  secre0ons  
 Hypochlorhydria  
 Phytates  
 Phosphates  
Blackwell,2006
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 …….. Treatment

Prevention

–  Encouragement of breast – feeding

–  Use of iron - fortified infant formulas after
weaning
–  The introduction of wholes cow’s milk to 1
years of age
–  Use of iron – fortified infant cereals & ascorbid
acid-rich foods at 4 – 6 months
–  Supplemental iron for preterm infants after the
first month.

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                                                                                                                                                                                …..PrevenEon  

Iron  supplemental:  
 
§  Exclusive breast feeding beyond 6 month : 1
mg/Kg/d
§  Low birth weight infants:
a. 1.5-2.0 kg : 2 mg/kg/day
b. 1.0-1.5 kg : 3 mg/kg/day
c. <1 kg : 4 mg/kg/day

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ANEMIA OF CHRONIC
DISEASE ( ACD )

         
Pediatrics  Departement  –  Medical  Faculty  
University  of  Sumatera  Utara  

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 Introduc0on    
Waxwell  Wintrobe  and  George  Cartwright,1940      
       pioneered  Anemia  of  chronic  disease  (ACD)  
       associated  with  chronic  inflamma0on    (chronic    
       infec0on,  rheumatologic  diseases),  malignancy  
   
1960,ACD  were  well  recognized  
     impaired  erythropoiesis  
     reduced  erythropoie0n  
     moderate  decrease  of  the  life  span  of  red  cells              

Lee RG.Wintrobe’s clinical hematology.9th,1993.840-51

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Anemia  of  Chronic  Disease    =  Anemia  of  inflammaEon    
=  HypoproliferaEve  anemia    
•  Mild  to  moderate  anemia  
•  Develops  during  the  first  1  to  2  months  of  illness      
Clinical  causes  :  infec0on,  inflamma0on,  trauma0c  or  
neoplas0c  diseases    
•  Persist  for  more  than  1  or  2  months    

Lee RG.Wintrobe’s clinical hematology.9th ed.1993.840-51

Fitzsimons EJ, Brock JH.BMJ 2001;322:811-2HIS,2015 32
•  Low  serum  or  plasma  iron  concentra0on  
•  Adequate  re0culoendothelial  iron  stores                                      
•  Cytokines  mediated  the  immune  or  inflammatory  
response  
•  Acute  or  chronic  immune  ac0va0on  
•  Resolves  when  underlying  disorders  is  corrected            

Fitzsimons EJ,Brock JH.BMJ 2001;32:811-2

Weiss G,Goodnough LT.N Engl J Med 2005;352:1011-23
Spivak JL.Oncology 2002;16:5-33 HIS,2015 33
 Underlying  causes  anemia  of  chronic  disease  
   1.  Chronic and acute infections :
  Pulmonary infections : abscesses, emphysema,
tuberculosis, pneumonia
  Infections : HIV, Hepatitis C
  Subacute bacterial endocarditis
  Pelvic inflammatory disease
  Osteomyelitis
  Chronic urinary tract infections
  Chronic fungal infections
  Meningitis
  Parasitic : malaria
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Causes…continued

2.  Malignant diseases :

Hodgkin, leukemia, lymphosarcoma, lung cancer,
breast cancer
4.  Autoimmune disease
Rheumatoid arthritis, systemic lupus
erythematosus, connective tissue disorder,
vasculitis, sarcoidosis, inflammatory bowel disease

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 Causes…con+nued  
 

4.  Congestive heart failure, ischemic heart disease

5.  Chronic renal disease and inflammations
8.  Chronic Rejection reaction after transplantation solid
organ
9.  Bleeding episodes, cobalamine deficiencies, folic acid
deficiencies, hyperspleenism, autoimmune hemolysis

Lee RG. Wintrobe‘s clinical hematology, 1993. h. 840-51

Spivak JL. Oncology 2002 Sep;16 (9 Suppl 10):25-33
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 Pathogenesis    
1.  Iron  homeostasis  disorder  (disturbances)  
2.  Failure  of  erytrhoid  progenitor  cells  
prolifera0on  
3.  Unresponsiveness  of  erythropoe0n  

Weiss G, Goodnough LT. NEJM 2005; 352:1011-23

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Pathophysiological Mechanisms Underlying Anemia Of Chronic Disease

Interferon

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Weiss G, Goodnough LT. NEJM 2005; 352:1011-23
 Clinical  findings  
•  Mild  symptom  (commonly)  
•  Fever  
•  Shivering  
•  Arthralgia  
•  Loss  of  body  weight  
•  Pale    
•  Headache  
•  Weakness  
•  Tachycardia    

Lee RG. Wintrobe‘s clinical hematology, 1993. h. 840-51

Weiss G, Goodnough LT. NEJM 2005; 352:1011-23
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 Serum  Levels  That  DifferenEate  Anemia  of  Chronic  Disease  from  
Iron-­‐Deficiency  Anemia  
Anemia of Iron
Variable chronic deficiency Combination
disease anemia
Iron Reduced Reduced Reduced

Transferrin Reduced to Increased Reduced

normal
Transferrin saturation Reduced Reduced Reduced

Ferritin Normal to Reduced Reduced to

increased normal
Soluble transferrin receptor Normal Increased Normal to
increased
Ratio soluble transferrin receptor to Low (<1) High (>2) High (>2)
log ferritin
Cytokine levels Increased Normal Increased

Weiss G, Goodnough LT. NEJM 2005; 352:1011-23

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 Treatment  
1.  Treat  the  underlying     Future  :  
disease    
•  Iron  chela0on  à  to  
2.  Blood  transfusion  
induce  endogen  
3.  Iron  therapy   erythropoie0n  
•  Controversial    
•  Hepcidine  
•  Oral  administra0on  à   antagonist  
bad  absorp0on  because  
down  regula0on  in   •  Cytokine  à  to  
duodenum   induce  
4.        Erythropoie0n   erythropoiesis  in  
inflamma0on  
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          MacrocyEc  anemia    

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 MacrocyEc  anemia    
MegaloblasEc   Non-­‐MegaloblasEc  
•  Folate  deficiency   •  Liver  disease  
•  Cobalamin  deficiency   •  Myelodysplasia  
•  An0folate  drugs   •  Re0culocytosis  
•  Cancer  chemotherapy   •  Hypothyroidism  
•  Alcoholism  
•  Chronic  obstruc0ve  
pulmonary  disease  (COPD)    

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 MEGALOBLASTIC
ANEMIAS
•  Definition :
–  Abnormalities of red blood cell (RBC) morphology and
maturation.
–  RBC : larger than normal & have open, dispersed
nuclear chromatin, an asynchrony between the
maturation of nucleus & cytoplasm.
•  Etiology :
–  Deficiency of folic acid
95%
–  Deficiency Vit. B12 ( Cobalamin )
–  Inborn errors of metabolism (rarely)
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HIS,2015
Megaloblastic anemia 45
32
Nucleated RBC of megaloblastic anemia

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Reticulocytes
 FOLIC ACID DEFICIENCY
•  Primary dietary source folic acid : fresh
uncooked fruits and vegetables
•  Green vegetables, fruits & animals organs.
•  Naturally : polyglutamed form & absorbed less efficiently
than the monoglutamate species (folic acid).
•  Folic acid : adsorbed in the small intestine
•  Megaloblastic anemia : occurs after 2 – 3 mo on a folate-
free diet.

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 ETIOLOGY
•  Inadequate folate intake
–  Alcoholism
–  pregnancy, growth in infants & chronic hemolysis
–  Lack of fresh fruits and vegetables .
•  Decreased folate absorption
–  Malabsorption due to chronic diarrheal states,
–  Inflammatory bowel diseases.
–  Extensive small bowel resection
–  Anticonvulsant drugs
–  Gluten sensitive enteropathy ( celiac sprue ) , tropical sprue

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 …….. Etiology

•  Hemodialysis
•  Antiepileptic drugs
•  Acquired and congenital disorders of folate
metabolism :
§  Megaloblastic anemia : congenital dihydrofolate
reductase deficiency
§  Drugs induced abnormalities in folate metabolism :
Anti folate drugs ( Methotrexate)

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 …….. Folic acid deficiency

CLINICAL MANIFESTATIONS

–  Megaloblastic anemia : the peak incidence at 4- 7 mo

of age.
–  Anemia, irritability, fail to gain weight adequately,
chronic diarrhea.
–  Hemorrhages from thrombocytopenia
–  Accompany : kwashiorkor, marasmus, or sprue.

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 …….. Folic acid deficiency

LABORATORIUM FINDINGS
–  Anemia is macrocytic (MCV > 100 fl)
–  Reticulocyte count : $
–  Neutopenia & thrombocytopenia
–  Neutrophils : large & hypersegmented nuclei
–  Serum folic acid : < 3 ng/ml (N 5 – 20 ng/ml)
–  Levels of iron & vit. B12 : N or #
–  LDH serum : #
–  Bone marrow : hypercellular

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 …….. Folic acid deficiency

TREATMENT

§  Diagnosis of folate deficiency is established :

•  Folic acid can be orally or parenterally
•  Dose : 0.5 – 1 mg/day
§  Specific diagnosis is in doubt :
•  Smaller dose : 0.1 mg/day for a week ]diagnostic test
§  Transfusion : severe anemia or child is very ill.
Folic acid therapy (0.5 – 1 mg.day) : should be
continued for 3 – 4 weeks untills hematologic
response (+).
–  Maintenace therapy with multivitamin (containing
0.2 folate) is adequate.
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 VITAMIN B12 DEFICIENCY
ANEMIA
VITAMIN B12 :
–  Derived from cobalamin in food ( mainly animal sources)
secondary to production by microorganism.
–  Obtained primarily from :
•  Animal proteins (ie, red meat, poultry, fish, eggs, and dairy)
•  Plants and vegetables lack the vitamin unless they have been
contaminated by soil microorganisms

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Absorption of vit. B12
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 …….. Vit. B12 deficiency

ETIOLOGY
}  Inadequate dietary intake of vitamin
} Extreme dietary restriction (strict vegetarians or
vegan)
} In children : breast-fed infants whose mothers are
vegans or pernicious anemia
}  Lack of IF (intrinsic factor) secretion by the stomach
} Congenital pernicious anemia
} Juvenile pernicious anemia
} Gastric surgey
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 …….. Etiology
–  Impaired intestinal absorption of IF cobalamin
•  Inflammatory diseases( regional enteritis or NEC)
•  Imerslund-Grasbeck Syndromes)
–  Absence of vitamin B12 transport protein
CLINICAL MANIFESTATIONS
–  Weakness, fatigue, failure to thrive, or irritability
–  Pallor, glossitis, vomiting, diarrhea, & icterus
–  Neurologic symptoms : parasthesias, sensory deficits,
hypotonia, seizures, developmental delay, &
neuropsychiatris changes.

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 ….. Vit. B12 deficiency

LABORATORIUM FINDINGS
–  Macrocytic anemia (MCV > 100 fl)
–  RBCs : prominent macroovalocytosis
–  Neutrophil : large & hypersegmented
–  Neutropenia, thrombocytopenia, simulating apalstic
anemia or leukemia
–  Serum Vit. B12 levels : < 100 pg/ml
–  Serum iron & folic acid : Normal / elevated
–  Seru LDH : #
–  Serum bilirubin levels : moderate elevations (2-3 mg/dl)
–  Methylmalonic acid in the urine : >>> (N 0 – 3.5 mg/
24hrs)

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 ….. Vit.B12 deficiency

TREATMENT
–  Prevention: total gastrectomy,ileal resection à
prophylactic vit.B12 should be prescribe
–  Parenteral administration of vit. B12 (1mg) ]
reticulocytes begin increase on 3 – 4 days
–  The physiologic requirment for vit. B12 : 1 – 5 µg/day
–  If evidence of neurologic involvement (+) : dose
1 mg/day (IM) for at least 2 weeks
–  Maintenance therapy : 100 µg /sc monthly

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