1

Study Notes on Anemia in Pediatrics (2014-2015)

by Remedios C. Ong, M.D.

Generalities on Anemia
I. Definition of anemia: (Chapter 441)
- Reduction in Hgb, Hct, or number of RBCs/mm3.
- Lower limit of normal range is set at 2 SD below the mean for age & sex of the normal
population.

II. Etiologic classification of anemia

Major mechanisms Subcategories Examples
of anemia
A. Inadequate RBC 1. “physiologic anemia”
production 2. Deficiency •  intake /  demand: Iron, folate, B12
•  absorption
•  loss
3. Inefficient • Thalassemia syndromes
erythropoiesis • Pb poisoning
• Chronic inflammation
• Anemia of renal origin
4. BM failure • single cell line
- congenital: Diamond-Blackfan anemia (DBA)
- acquired: Transient Erythroblastopenia of
childhood (TEC)
• multiple cell lines
- constitutional: Fanconi anemia
- acquired aplastic anemia: idiopathic or secondary
• BM infiltration: primary or secondary

B. Blood loss 1. Acute Hemorrhage

2. Chronic Occult GIT bleed from cow’s milk enteropathy or
hookworm disease
C. Sequestration Hypersplenism
D. Hemolytic 1. Corpuscular • defects in Hgb - Heme defect
anemias (HA) - globin defect:
 qualitative ( Sickle cell anemia)
 quantitative (thalassemias)
• defects in RBC cell membrane: spherocytosis
• defects in RBC metabolism: G6PD deficiency
2. Extracorpuscular • Immune
- isoimmune
- autoimmune:  idiopathic  secondary: SLE
• Nonimmune:  idiopathic  secondary

III. Classification of anemia based on RBC size. (See also table 441-1)

Microcytic Macrocytic Normocytic

1. IDA
a. nutritional
b. chronic blood loss
c. impaired absorption
2. Chronic Pb poisoning
3. Thalassemia syndromes
4. Chronic disease
a. infection
b. cancer
c. inflammation
5. Sideroblastic anemia
1. Vit B12 deficiency
2. Folic acid deficiency
3. Aplastic anemia
4. Diamond-Blackfan sydrome
(DBA)
5. BM infiltration
6. Liver disease
7. Hypothyroidism
8. Increased erythropoiesis as
in acute hemolysis
1. congenital HA
a. Hgb mutants
b. RBC membrane defects
c. disorder of RBC
metabolism
2. acquired HA
a. Ab-mediated
b. microangiopathic HA
c. secondary to acute infection
3. acute blood loss
4. splenic pooling
5. chronic disease (usually)
6. Renal disease
7. TEC

IV. Historical factors of importance in evaluating patients with anemia

A. Age of onset:
1. in neonatal period: recent blood loss
isoimmunization
congenital hemolytic anemias
infection
2. at 2 months: “physiologic anemia” though onset is earlier in preterm, DBA
3. at 3-6 months: congenital disorders of Hgb synthesis or Hgb structure, DBA
4. at 6-9 months: IDA, earlier in preterms, DBA
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B. Gestational & perinatal history

1. Intrauterine infections
2. complications during delivery
3. multiple birth
4. prematurity & NICU stay, blood extractions
5. isoimmune hemolytic disease
C. Gender: X-linked – G6PD, pyruvate kinase
D. Race:
1. ß-thalassemias – relatively more in whites
2. -thalassemias – more in black & yellow races
E. Ethnicity:
1. Thalassemia syndromes – Mediterranean origin
2. G6PD – Filipinos, Sephardic Jews, Greek, Sardinians, Kurds
F. Diet:
1. Type of milk formula, semisolids, diet
2. Sources of iron, Vit B12, folic acid, Vit E in diet
3. Pica, geophagia, or pagophagia : associated with IDA
G. Drugs:
1. Oxidant-induced hemolytic anemia (sulfas, antimalarials, etc)
2. Phenytoin  megaloblastic anemia
3. Drugs  aplastic anemia (chloramphenicol, antineoplastic agents)
H. Infections:
1. hepatitis  aplastic anemia
2. viral infections  pure red cell aplasia
3. Infection  hemolysis
4. Parasites  IDA
I. Family history of the following:
1. Anemia
2. Jaundice
3. Gallstones
4. splenomegaly
J. Diarrhea
1. small bowel disease with malabsorption of folic acid, B12
2. inflammatory bowel disease (IBD) & blood loss
3. exudative enteropathy, cow’s milk protein enteropathy
K. Other co-morbid conditions like heart problems, CTD, liver disease etc, commonly associated
with anemia.

V. PE findings as clues to etiology of anemias

Body parts Findings Possible etiology of anemia

Skin hyperpigmentation Fanconi aplastic anemia
Petechiae, purpura Autoimmune HA
Thrombocytopenia
HUS
Carotenemia IDA in infants
Jaundice HA, hepatitis, aplastic anemia
Cavernous hemangioma Microangiopathic HA
Ulcers on lower extremities S & C hemoglobinopathies, thalassemia
Face Frontal bossing, prominence of Congenital HA
malar & maxillary bones Thalassemia major
severe IDA
Eyes Microcornea Fanconi anemia
Cataracts G6PD deficiency
Galactosemia with HA in newborn period
Edema of lids Infectious mononucleosis
exudative enteropathy with iron deficiency
Renal failure
Blindness osteopetrosis
Mouth Glossitis Vit B12 & Fe++ deficiency
Angular stomatitis Fe++ deficiency
Hands Triphalangeal thumbs Red cell aplasia
Hypoplasia of thenar eminence Fanconi anemia
Spoon nails IDA
Spleen Enlargement Congenital HA
Leukemia, lymphoma
Acute infection
Portal hypertension
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VI. Evaluation of anemic patients: Special tests for suspected

hemolytic anemia (HA)
Special Tests for IDA • evidence for RBC breakdown
• Free erythrocyte protoporphyrin (FEP) - blood smear
• Serum Ferritin, TIBC - serum bilirubin
• Reticulocyte Hgb concentration - urinary urobilinogen
• Stool for occult blood - hemoglobinuria
• 99mTc pertechnetate scan for Meckel’s -  serum haptoglobin,
diverticulum if indicated. -  serum LDH
• Endoscopy (upper & lower GIT) if • evidence for RBC regeneration
indicated -  reticulocyte
- blood smear
- skeletal radiographs
• evidence for corpuscular HA
 membrane
- blood smear
Essential labs: - osmotic fragility test
• Hgb, Hct, RBC count  Hgb: electrophoresis
• RBC indices  Enzymes: enzyme assay
History • RDW
& PE • evidence for extracorpuscular HA
• platelet count (immune-mediated):
• WBC & differential count - antiglobin test (Coomb’s test)
• Reticulocyte count - ANA
• Peripheral smear

Other special tests: Special tests for suspected aplastic Special tests for suspected
• viral serology anemia or leukemia B12 or folate deficiency
• ANA, complement, CH50 • BM aspiration & biopsy – • BM exam
• BUN, Cr cytochemistry, immunologic • serum B12 level
• T4, TSH markers, chromosome analysis • serum folate level
• Tissue biopsy • skeletal radiographs • Schilling test

A. Red cell indices

Indices Formula Mean values Significance

MCV ___Hct x 10___ 90 + 9 fL Indicates red cell vol, micro-(< 80 fL) or

RBC (106/µL) macrocytosis (> 100 fL)

MCH __Hgb x 10___ 32 + 2 pg Measure of amount of Hgb per RBC

RBC (106/µL)

MCHC Hgb ÷ Hct 33 + 3% Measure of relative concentration of Hgb

B. Red cell distribution width (RDW): an index of distribution of red cell volume provided by
automated counter; mathematical representation of anisocytosis (cells of different sizes); increased
RDW suggests mixed population of cells commonly seen in IDA. It’s usually normal or low in
thalassemia trait.

C. Reticulocyte production index (RPI): Reticulocyte stage last 3-4 days & is the last stage of
development of RBC in the bone marrow (BM). Reticulocytes spend 3-3.5 days in the BM,
thereafter are exported to the circulation where they stay as reticulocyte for 1 day before becoming
mature RBC. Normally, 1% of reticulocytes are exported into the circulation to replace the 1%
senescent RBCs in the circulating pool of RBCs that are taken up by the RES. When there is blood
loss or increased hemolysis, young reticulocytes are exported prematurely into the circulation where
their count becomes higher. Thus, their maturation time in the BM becomes shorter & they stay
longer than 1 day as retic in circulation. But to assess the adequacy of BM response to the drop of
Hct, the reticulocyte count has to be correlated to the degree of anemia by using the ff formula.

RPI = actual reticulocyte count (%) x ___actual Hct___ x __1__

ideal Hct µ

µ = maturation time (days) of reticulocyte in the blood at the corresponding Hct level. See Table
below.
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Number of days of maturation for reticulocytes in the BM & blood

Hct Marrow normoblasts & Blood reticulocytes (days)
reticulocytes (days)
45 3.5 1.0
35 3.0 1.5
25 2.5 2.0
15 1.5 2.5

VII. Approach to the diagnosis of anemia by MCV & reticulocyte count.

Anemia

MCV

Normal
High Low

• folate deficiency • IDA

• B12 deficiency Reticulocyte Count • Thalassemia
• DBA • Pb poisoning
• aplastic anemia • ACD
• Preleukemia
• Immune HA
• liver disease

High Low
Bilirubin WBC & Platelet

Normal High

Low Normal Increased

Hemorrhage Hemolytic
anemia
• BM depression • pure red cell • infection
• Malignancy aplasia • ACD
• Aplastic anemia • Diamond-Blackfan
Coomb’s test - congenital • transient
- acquired erythroblas-
topenia of
childhood (TEC)

(-) (+)
Corpuscular Extracorpuscular
Corpuscular
• Hemoglinopathies • autoimmune
• Enzymopathies hemolytic anemia
• Membrane defects - primary
- secondary (CTD,
drug, isoimmune,
Extracorpuscular ABO, mismatched
transufions

• Idiopathic
• Secondary
- drugs
- infections
- microangiopathic
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I. Anemias due to inadequate / ineffective production:

Physiologic anemia: See Chapter 447

Iron Deficiency Anemia (IDA) Chapter 449
1. Epidemiology
• most common nutritional deficiency in children
• peak prevalence in late infancy & early childhood due to the following factors:
- rapid growth with exhaustion of gestational iron
- low levels of dietary iron
- complicating effect of cow’s milk esp with whole cow’s milk ingestion causing exudative
enteropathy
• 2nd peak is seen during adolescence due to:
- rapid growth & suboptimal intake
- menstrual loss in females
2. Dietary requirements:
• It is necessary to absorb 1 mg/day of iron for + iron balance. Since <10% of dietary iron is absorbed, a
dietary intake of 8-10 mg of iron daily is needed to maintain iron levels.
• Both breast milk & cow’s milk contain < 1.5 mg iron per 1000 calories. But the bioavailability of iron
in breast milk is > than in cow’s milk, 49 vs 10%. Breastfed infants absorb iron 2-3 x more efficiently
than when fed bovine milk.
3. Iron stores & onset of anemia:
• The newborn has 0.5 mg iron. As the high Hgb concentration falls in the 1st few months, recycled iron
are reclaimed & stored. These iron stores are sufficient for blood formation in the 1 st 6-9 months of
life in term infants. Stores are depleted sooner in preterm or LBW infants or those with perinatal loss.
Anemia from inadequate dietary iron occurs at 9-24 months and 3-4 months respectively in term &
preterm infants.
4. Stages of iron deficiency anemia:
- Prelatent: char by  in BM hemosiderin & serum ferritin
- Latent:  serum Fe++,  TIBC,  serum transferring receptors,  transferring saturation,  FEP
- Frank IDA: MCV, MCH, RBC,  RDW, poikilocytosis,  RPI
5. Causes of IDA:
 deficient intake: most common cause, esp during rapid growth period.
  demand with growth & in cyanotic heart disease
 blood loss
a. Perinatal blood loss
b. Postnatal GIT blood loss can be due to:
- primary IDA resulting in gut alteration with blood loss aggravating existing IDA; ~ 50% of
children with IDA have guaiac + stools. This is due to effects of iron deficiency on mucosal
lining.
- hypersensitivity to cow’s milk (?) due to heat labile protein leading to blood loss & exudative
enteropathy (leaky gut syndrome). This should be suspected under the following circumstances:
• consumption of ≥ 1 quart whole cow’s milk/day
• Iron deficiency associated with  serum protein, Cu++, Ca++, transferrin, immunoglobulins
(Ig) due to leakage
• IDA that is unexplained by LBW,  Fe++ intake or  growth rate
• poor response to Fe++ treatment
• return of GIT function & correction of anemia on stopping cow’s milk.
- anatomic gut lesions like Meckel’s diverticulum, polyps & those caused by allergic
gastroenteropathy, inflammatory bowel disease
- gastritis from ASA, NSAIDs, steroids
- intestinal parasites
- HSP
c. blood losses from other organs, ex. Idiopathic pulmonary hemosiderosis
 impaired absorption:
6. Effects of IDA
 GIT (the most common site of bleeding):
a. Anorexia – common & early symptom
b. Pica – pagophagia (ice), geophagia (sand)
c. Atrophic glossitis
d. Dysphagia
e. Esophageal webs (Kelly-Paterson Syndrome)
f.  gastric acidity
g. Leaky gut syndrome
- guaiac + stools: isolated
- exudative enteropathy
h. Malabsorption syndrome
- iron only
- generalized: xylose, fat, Vit A, duodenojejunal mucosal atrophy
i. Beeturia
j.  disaccharidases, esp. lactase
k. absorption of cadmium & Pb
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 CNS
a. Irritability
b. Fatigue &  activity
c. Conduct disorders
d.  mental & motor developmental test scores on Bayley scale that may be long lasting;  cognitive
performance
e.  attentiveness, shorter attention span   scholastic performance
 CVS
a.  in exercise & recovery CR & cardiac output
b. cardiac hypertrophy
c.  in plasma volume
 musculoskeletal system
a. deficiency of myoglobin & cytochrome C
b. impaired performance of a brief intense exercise task
c. physical performance in prolonged endurance work & rapid development of tissue lactic acidosis
d. radiographic changes in bone (widening of diploic spaces)  adverse effect on fracture healing
 Immunologic system: conflicting information as to the effects on immune system
 cellular changes
7. Lab findings & Diagnosis of IDA
  Hgb, Hct, RBC count & RBC indices
- MCV  & < normal for age late indicators of IDA
- MCH < 27.0 pg
- MCHC < 30%
- Reticulocyte Hgb concentration (CHr) is a sensitive indicator that falls within days of onset of Fe
deficient erythropoiesis
 RDW > 14.5%
-  MCV + widened () RDW – best screening test for IDA
 Blood smear: RBCs are hypochromic, microcytic, with anisocytosis & poikilocytosis. Basophilic
staining (basophilic inclusions represent aggregates of ribosomal RNA or denatured mitochondria)
maybe present but more common in thalassemia trait.
 Reticulocyte count usually normal unless associated with bleeding but RPI is 
  free erythrocyte protopophyrin (FEP): The incorporation of iron into protoporphyrin represents the
ultimate stage in the biosynthetic pathway of heme. Poor iron supply will result in accumulation of
FEP not incorporated into heme synthesis in the normoblast  release of RBCs into circulation with
high FEP levels. FEP is  in both IDA & PB poisoning but is much higher in the latter; it is normal in
- & ß-thalassemia minor.
 Serum ferritin reflects level of body iron stores & is usually low in IDA. However it is an acute phase
reactant so it can be normal in patients with IDA having infection, malignancy or chronic
inflammatory conditions.
 Serum Fe++ is usually  in IDA as well as in infection. It is no longer recommended by some authors
for diagnosig IDA because of wide circadian variations & wide normal variations.
  iron binding capacity &  iron saturation;  transferring receptor
 Therapeutic trial: The most reliable criterion of IDA is the response to an adequate therapeutic trial of
oral iron, ie. reticulocytosis peaking between 5th & 10th day of treatment followed by rise in Hgb
levels (0.25-0.4 g/dl/day or rise in Hct by 1%/day in the first 10 days of therapy, slower rise
subsequently
8. Further work-ups of patients with IDA:
- Pathogenesis of IDA must be established. If microcytic anemia is not found to be due to deficient iron
intake or thalassemia, or IDA is persistent despite adequate treatment, work up for occult blood loss
from GIT.
9. Differential diagnosis: See Table III
10. Treatment of IDA:
 Nutritional counseling & prevention:
- Maintain breastfeeding for at least 6 months.
- Use iron fortified infant formula until 1 y/o.
- Use iron fortified cereal from 6 months to 1 y/o.
- Provide supplemental iron for low-birth-weight infants
- Facilitators of iron absorption should be given: Vit C rich foods, meat, fish, poultry
- Inhibitors of iron absorption should be avoided: tea, phosphate, phytates common in vegetarian diets
 Oral iron medication:
- Ferrous iron preferred (Ferrous sulfate or gluconate etc) as ferric irons are poorly absorbed.
- Dose: 1.5 – 2 mg/Kg elemental irons tid (3-6 mg/Kg/day). FeSO4 is 20% elemental Fe by wt.
- Duration: Continue till 8 wks after Hgb level & RBC indices return to normal to reestablish Fe
stores
- Response to Fe therapy: see Table 449-4 in Nelson’s
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Megalobastic anemias (Chapter 448.2)

- Characterized by presence of megaloblast in the BM, & macrocytes in the blood.
- Etiology: > 95% of cases are due to folate & vit B12 deficiency. Other rare causes are due to inborn error
of metabolism
- There is maturational asynchrony between nucleus & cytoplasm of erythrocytes with delayed nuclear dev.

Common causes of megaloblastic anemias:

1. Vit B12 deficiency (Chapter 448.2)
 inadequate intake: food fads, veganism, malnutrition, poorly controlled PKU diet
 defective B12 absorption:
a. failure to secrete Intrinsic Factor: congenital deficiency or pernicious anemia
b. failure of absorption in small intestine:
- specific B12 malabsorption
- generalized malabsorption in intestinal disease
- competition for B12
 defective B12 transport
 disorders of B12 metabolism

2. Folic Acid Deficiency (Chapter 448.1): Next to iron, folate deficiency is one of the most common
micronutrient deficiencies worldwide.
 inadequate intake
- poverty, ignorance, faddism
- method of cooking (sustained boiling of food  40% loss of folate)
- goat’s milk feeding
- malnutrition
- special diets for PKU or maple syrup disease
- primaturity
 defective absorption
- congenital
- acquired
 increased requirements
- rapid growth
- chronic hemolytic anemia, esp. with ineffective erythropoiesis (thalassemia major)
- malignant disease
- hypermetabolic states
- extensive skin disease (psoriasis, exfoliative dermatitis)
- cirrhosis
- post-BM transplant
 disorders of folate metabolism both congenital & acquired
 increased excretion

Clinical features of cobalamin & folate deficiency:

• Both present insidiously with: lethargy, fatigability, anorexia, sore red tongue glossitis, episodic or
continuous diarrhea.
• Vit B12 deficiency presents with the following:
- developmental delay, apathy, weakness, irritability
- neurodevelopmental delay, loss of developmental milestones esp. with motor achievements
- Athetoid movements, hypotonia, loss of reflexes
- In older children, signs of subacute dorsolateral degeneration of the spinal cord: paresthesias in
hands or feet (peripheral neuropathy), difficulty in walking or use of hands, loss of vibration &
position sense with an ataxic gait & + Romberg’s sign
• Maternal folate deficiency: associated with neural tube defects, prematurity, fetal growth retardation &
fetal loss.

Laboratory diagnosis of cobalamin & folate deficiency:

• Red cell changes
- Hgb: 
- Red cell indices:  MCV, normal MCHC
- RDW 
- blood smears would show macrocytes
• WBC:  with hypersegmentation (nuclei > 5 lobes)
• Platelet: moderately 
• BM: megaloblastic
•  serum vit. B12 level
•  serum folate level

Treatment of B12 deficiency & response:

• Monthly IM injection of B12 probably for life
• In B12 responsive megaloblastic anemia:
- beginning BM reversal to normoblastic cells within 6º, complete in 72º
- level of alertness & responsiveness improve within 48º; developmental delays may catch up in
several months in young infants, but permanent neurologic sequelae often occur.
-  reticulocytes begins on 3rd -4th day of treatment
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*Note: Prompt hematologic responses are also obtained with the use of oral folate but this is
contraindicated in B12 deficiency because folate has no effect on neurologic manifestations &
may even precipitate or accelerate their development.

Treatment of folate deficiency:

• Before folate is given, it is necessary to exclude B12 deficiency.
• Treatment dose: 100-200 mcg (µg) of folic acid per day for several months until a new population of
RBCs has formed.
• Treat underlying cause
• Response to treatment:
- within 1-2 days: appetite improves, with return of sense of well-being
-  in reticulocytes, WBC & platelets in 2-4 days, peaking at 4-7 days
- normalized Hgb & Hct in 2-6 wks
- megaloblastic changes  within 24-48º

Review on Structure of Hemoglobins:

- Hgbs are each made up of iron containing heme + the protein moiety globin.
- Each Hgb is a tetramer made up of 2 pairs of polypeptide chains with each chain having a heme group
attached. 2 pairs of alleles on chromosome 16 are responsible for the genetic information for the structure
of -cahin. The ß,  &  genes are closely linked on chromosome 11.
1. fetal Hgb (Hgb F): 
2. adult Hgb (HgbA): 22
3.adult HgB (g
Hgb H: ß4
Bart’s Hgb: 
From infancy > 6 months old to adulthood: Hgb A = 95-97%, Hgb A2= 2.3-4% HbgF=1-2%

Thalassemias Syndromes: (Chapter 456.9)

Genetic disorders in globin chain production with wide array of genetic defects & corresponding diversity
of clinical syndrome characterized by  ineffective erythropoiesis &   hemolysis
1. Clinical syndromes:
a. -thalassemias: due to deletion of 1 or more of the 4 genes (2 each on chromosome 16) for -globin
synthesis; common among those of Southeast Asian & African ancestry.
 -Thalassemias Gene defect Phenotypic expression
Silent carrier deletion of 1 gene Normal
-thalassemia trait deletion of 2 genes Normal features with mild anemia; with 
MCV & MCH, often mistaken for IDA but
will not respond to iron therapy.
Hb Constant Spring Abnormal (non-deletional) Moderate –severe microcytic hypochromic
-chain variant produced anemia
in small amounts +Hepatosplenomegaly
mimicking deficiency of More severe than HgbH disease
gene May require intermittent transfusion &
splenectomy
HbH (ß4) deletion of 3 -chain Mild anemia with  MCV & MCH,
resulting in marked  of  Mild splenomegaly
chain synthesis Transfusion usually not required; generally
milder than ß-thalassemia major.
Hydrops fetalis deletion of all 4  globin No normal adult (22) or fetal Hgb (22);
genes usually death in utero

b. ß-thalassemias: due to point mutations in one or both of the 2 globin genes (on chromosome 11);
occurs predominantly in children of Mediterranean, Southern & Southeast Asian ancestry.
ß-thalassemias Gene defects Phenotypic expression
ß-thalassemia trait ß0 or ß+* heterozygote  Hgb & MCV, normal RDW, asymptomatic,
ß-thalassemia Homozygous or doubly Milder anemia than thalassemia major; not
intermedia heterozygous transfusion dependent.
ß-thalasssemia ß0  no detectable ß-chain  MCV, nucleated RBCs; transfusion
major synthesis due to absent ß- dependent
chain mRNA.
*ß0 thalassemia: no detectable ß-cahin synthesis
ß+ thalassemia:  ß-chain synthesis due to  or nonfunctional ß-chain mRNA

Pathogenesis of homozygous or doubly heterozygous ß thalassemias:

- variable reduction of ß-chain synthesis
- relative -globin chain excess (4) resulting in intracellular precipitation of insoluble -chains
-  but ineffective erythropoiesis with  RBC precursors prematurely destroyed due to -chain
excess
-  RBC lifespan; variable splenic sequestration
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2. Clinical & lab features of ß-thalassemia syndromes: There is a spectrum of clinical severity due to
variability in the severity of the fundamental defects. The ß-thalassemia major presents with the
following:
• FTT early childhood; growth retardation, delayed puberty
• Anemia:  MCH, MCV,  reticulocytosis but  reticulocyte production index;
• blood smear: target cells, nucleated RBCs, extreme anisocytosis, contracted RBCs, polychromasia, +
normoblasts
•  RBC life span
•  Hgb F (22) in ß-thalassemias
• jaundice, gallstones
• hepatosplenomegaly, hypersplenism
• Thalassemia facies: Maxilla hyperplasia, frontal bossing, flat nasal bridge, exposure of upper central
teeth;
• + hair on end appearance on skull x-rays due to widening of diploic spaces; fractures; osteoporosis
• leg ulcers, skin bronzing
3. Complications/ sequelae of moderate – severe cases:
• chronic anemia if undertransfused
• chronic transfusion  hemosiderosis & hemochromatosis if not compliant with chelation therapy
• endocrine disturbances
• liver cirrhosis  liver failure
• cardiac failure from myocardial iron overload
• bony deformities & osteoporosis
4. Management:
• Stem cell transplantation from an HLA-identical sibling is the treatment of choice
• gene therapy: under study
• hypertransfusion to maintain a pretransfusion Hgb between 10.5- 11.0 g/dL
• chelation therapy: deferoxamine, deferasirox
• splenectomy in patients with hypersplenism; prophylactic penicillin after splenctomy
• supportive care:
- folic acid among patients on low transfusion regimens
- vaccinations: Hepa B for all patients, polyvalent pneumococcal, meningococcal & Hib vaccines
should be given at least 2 wks before splenctomy
- endocrine & cardiac & osteroporosis interventions if needed
- cholecystectomy for gallstones;
- genetic counseling & antenatal diagnosis when indicated

Common or important conditions presenting with bone marrow

failure:

Diamond-Blackfan syndrome (Chapter 442): a rare pure red cell aplasia predominantly of infancy &
childhood resulting from an intrinsic hematopoietic cell defect in which erythroid progenitors and
precursors are highly sensitive to death by apoptosis.
1. Clinical features:
• autosomal dominant, possible autosomal recessive, some sporadic
• median age at presentation of anemia is 2 months (2-6 months)
• platelets & WBC are usually normal
• physical anomalies occur in ~ 50% of patients (head, face, hand & upper extremities, heart, kidneys)
with craniofacial being most common, short stature in 30%.
• normal karyotype
• no hepatosplenomegaly
• + malignant potential
2. Diagnostic criteria:
• usually macrocytic anemia
• reticulocytopenia despite  EPO
• normocellular marrow with selective paucity of erythroid precursors
• supportive criteria includes increased fetal Hgb, increased erythrocyte adenosine deaminase (eADA)
3. Treatment:
• PRBC transfusion
• prednisone
• stem cell transplantation

Transient Erythroblastopenia of childhood (TEC): (Chapter 444): most common acquired red cell aplasia
in children
1. Pathophysiology:
• usually preceded by nonspecific viral illness 1-2 months prior to TEC
• IgG & IgM Ab & T cells developed vs virus also binds to erythroid progenitor epitopes
• Occurs in previously healthy children 6 mo – 3 y/o, with most older than 1 y/o at onset.
2. Onset between 6 months & 4 y/o
3. Labs:
• Hgb 
• 0% reticulocytes
• normal or  WBC, normal or  platelets
• BM: absence of red cell precursors
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4. Prognosis:
• Spontaneous recovery within wks to months, with majority within 1 month
5. Treatment: PRBC transfusion if necessary

Anemia of chronic disease (ACD) Chapter 445.1

1. Pathophysiology:
- associated with chronic systemic diseases (infection, inflammation, CTD) which lead to release of
inflammatory cytokines IL-1. IL-6, TNF which lead to release of IFN- & IFN- which cause anemia
- anemia also partly from erythrophagocytosis by activated macrophages
- blunted response to EPO despite  EPO with  RBC lifespan
- Fe++ sequestration in macrophages +  GIT absorption
2. Labs:
- often with leucocytosis
- often normochromic & normocytic occasionally hypochromic & microcytic esp if with IDA
- serum  Fe++ without  in TIBC; low to normal transferrin level,  serum ferritin

Anemia of renal disease (Chapter 445.2)

- usually normocytic
- Due to  EPO production, absolute &/or functional Fe deficiency from chronic blood loss & disturbance
in Fe metabolic pathway

Aplastic Anemia: (Chapter 463)

1. A physiologic & anatomic failure of the BM characterized by a marked  or absence of blood forming
elements in the BM & peripheral pancytopenia; hepato- splenomegaly & lymphadenopathy are not
characteristic
2. Types:
 Congenital (Fanconi anemia): rare autosomal recessive (occasionally X-linked) inherited BM failure
syndrome generally associated with multiple congenital anomalies (café au lait, short stature, skeletal
anomalies, microcephaly, ear & eyes’ abnormalities, renal & cardiac anomalies, etc.
- cells are hypersensitive to chromosomal breakage caused by DNA cross-linking agents, ionizing
radiation
- hematologic dysfunction usually presents with macrocytosis, followed by thrombocytopenia 
progressive pancytopenia & severe aplastic anemia, terminating in myelodysplastic syndrome
(MDS) & AML.

 Acquired aplastic anemia:

• Pathophysiology:
- Direct toxicity on BM precursor cells induced by radiation, chemotherapy, benzene, or drug
metabolites.
- Immune-mediated: Exposure to an inciting Ag, cells & cytokines (esp IFN-F secreted by
T cells) of the immune system destroy stem cells in the BM  pancytopenia . Both IFN- & TNF
are potent inhibitors of both early & late hematopoietic progenitor cells & inducers of apoptosis
by activation of Fas receptors on hemopoietic stem cells.
• Classification
- Idiopathic: ~70% of cases
- Secondary: due to drugs, chemicals, toxins, irradiaton, infections, immunologic disorders, MDS,
hypoplastic preleukemia etc.
• Clinical features: onset often insidious
- anemia  pallor, easy fatigability, weakness & anorexia
- thrombocytopenia  petechiae, easy bruising, epistaxis, bleeding into GIT & GUT
- leucopenia   susceptibility to infections & oral ulcerations which respond poorly to antibiotics
- hyperplastic gingivitis is also a symptom of aplastic anemia
• Laboratory work-ups & findings:
- anemia: normo- or macrocytic, normochromic
- reticulocytopenia
- leucopenia: granulocytes < 1500/mm3
- thrombocytopenia: platelet < 30,000/mm3
- slightly or moderately fetal Hgb
- BM: marked depression or absence of hematopoietic cells & replacement by fatty tissue-
containing reticulin cells, lymphocytes, plasma cells & tissue mast cells; BM culture for
infectious agent
- other work-ups to rule out secondary aplastic anemia
• Severe aplastic anemia:
- granulocyte count < 500/mm3
- platelet < 20,000/mm3
- reticulocyte count < 40,000/mm3
• Treatment of severe aplastic anemia:
- Allogeneic BM or hematopoietic stem cell transplant is best.
- If transplant is not feasible: ATG, Cyclosporine A, methylprednisolone, growth factors like G-
CSF, GM-CSF
- Prevent infection
- Treat infection aggressively
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Bone Marrow Infiltration: (Chapter 463)

Causes:
1. Nonneoplastic:
A. Storage diseases: Gaucher’s, Newmann-Pick, Cystine storage disease
B. Osteopetrosis
C. Langerhans cell histiocytosis
2. Neoplastic
A. Primary: leukemia
B. Secondary: neuroblastoma, non-Hodgkin’s & Hodgkin’s lymphoma, Wilm’s tumor, Retinoblastoma,
Rhabdomyosarcoma

Hemolytic Anemias: Chapter 451

- Characterized by premature RBC destruction leading to  RBC survival of < 120 days & reticulocytosis
1. Clinical features suggesting a hemolytic process:
- Ethnicity, family history of anemia, gallstones, jaundice
- Persistent / recurrent anemia associated with reticulocytosis
- Anemia unresponsive to hematinics
- Intermittent bouts or persistent indirect hyperbilirubinemia
- Splenomegaly
- Hemoglobinuria
- + multiple gallstones
- Chronic leg ulcers
- Development of anemia or hemoglobinuria after exposure to certain drugs
- Cyanosis without cardiorespiratory distress
- Polycythemia
- Dark urine due to dipyrroluria
2. Causes of hemolytic anemias due to corpuscular & extracorpuscular defects: See page 1
3. Laboratory findings of hemolytic anemia consist of the following investigations:
a. Evidence of  RBC survival & accelerated Hgb catabolism
- Signs of extravascular hemolysis
•  B1
•  fecal & urinary urobilinogen
•  rate of CO production
• hepatosplenomegaly

- Signs of intravascular hemolysis

•  plasma Hgb
• Hemoglobinuria
• Hemosiderinuria (sloughing of iron laden tubular cells into urine)
•  or absent plasma haptoglobin
•  plasma methemalbumin (albumin bound to heme) & methemoglobin (oxidized free plasma
Hgb)
b. Evidence of  erythropoiesis
- reticulocytosis up to 10-20%
-  MCV due to  reticulocytes &  RDW as Hgb levels fall
-  normoblasts in the peripheral blood
- erythroid hyperplasia
- morphologic abnormalities: sickle cells, target cells, basophilic stippling, irregularly contracted
cells (schistocytes), & spherocytes

Hemolytic anemias due to corpuscular defects:

1. Prototype of membrane defect: Hereditary spherocytosis (Chapter 452)
- autosomal dominant in ~ 75%, most common inherited abnormality of RBC membrane
- pathogenesis: membrane instability due to dysfunction or deficiency of a red cell skeletal protein
(ankyrin, spectrin)   tendency to spherocytosis  progressive loss of membrane lipid & surface
area  sphering   RBC deformability  sequestration in spleen
- labs: anemia,
  MCV,  MCHC & RDW, reticulocytosis
 (-) Coomb’s test
 Blood smear: microspherocytes, hyperdense cells, polychromasia
 + osmotic fragility test;  survival of 51Cr-labeled RBCs &  splenic sequestration
- Clinical features: early onset anemia, jaundice, splenomegaly,
- Diagnosis: from blood smear, FH, and  RPI
- Treatment:
• splenectomy after 5 -6 y/o, but immunize first vs encapsulated organisms & given penicillin
prophylaxis
• folic acid 1 mg daily
- Complications:
• aplstic crisis esp. from parvovirus B19 infection
• gallstones
• exercise intolerance
2. Prototype of enzyme defect: G6PD deficiency (Chapter 457.3)
- X-linked recessive, fully expressed in hemizygous males & homozygous females
 12

- pathogenesis: RBC G6PD activity falls rapidly & prematurely as the red cells age  
NADPH/NADP ratio  oxidation of Hgb & -SH groups in membrane impaired RBC integrity
esp. on exposure to oxidant drugs, oxidizing chemicals, fava beans & infections
- Clinical features: Acute self-limiting hemolytic anemia with hemoglobinuria with normal Hgb
between episodes; Heinz bodies in circulating cells, blister cells, fragmented cells & spherocytes, with
reticulocytosis.
- May present in neonatal period with hemolysis & hyperbilirubinemia
- Severe G6PD deficiency caused by certain enzyme variants may present with chronic nonspherocytic
hemolytic anemia
- G6PD assay: assay maybe normal if done soon after a hemolytic episode because young cells have
higher enzyme content.
- Treatment: avoidance of triggers, if indicated PRBC transfusion, genetic counseling

3. Prototype of Hgb defect: thalassemias

Hemolytic anemias due to extracorpuscular defects:

Causes Examples
A. Isoimmune • Hemolytic disease of the newborn
I • Incompatible blood transfusion
M B. Auto-  idiopathic • warm Ab
M immune • cold Ab
U • cold- warm Ab (Donath-Landsteiner)
N  secondary • infections: viral & bacterial
E • drugs & chemicals
• hematologic disorders: leukemias, lymphomas, lymphoproliferative
disorders etc
• immunopathic disorders: CTD, immune deficiency states
• tumors
A. Idiopathic
N B. Secondary • infections: viral, bacterial, parasites
O • drugs & chemicals
N • hematologic disorders: leukemia, aplastic anemia, megaloblastic
I anemia, hypersplenism, pyknocytosis
M
• microangiopathic hemolytic anemia: TTP, HUS, burns, post-cardiac
M
U surgery, etc,
N • miscellaneous: Wilson’s disease, hypersplenism etc.
E

Autoimmune hemolytic anemia (AIHA )associated with warm Abs: Chapter 458
1. Pathogenesis:
• Exact mechanism: unclear, viral or drug Ags may trigger Ab production which may cross-react with
RBC Ags; or infectious agents or drugs can alter RBC membrane leading to production of Abs directed
vs the altered RBC Ags.
• IgG Abs are most commonly responsible for AIHA in children
• Abs are directed against one of the Rh erythrocyte Ags in > 70%
• IgG Ab’s maximal activity at 37ºC (warm-Ab induced HA)
2. Clinical & lab features:
• sudden onset of pallor, jaundice, dark urine, can be severe & life threatening
• splenomegaly
•  Hgb, reticulocytosis, occasionally with  WBC & platelets
•  osmotic fragility
• + direct Coomb’s test
• hyperbilirubinemia,  haptoglobin, hemoglobinuria,  urinary urobilinogen
3. Management:
• transfuse with washed PRBCs from compatible donor
• corticosteroid: high dose
• IVIG 5 g/Kg (dose greater than that in ITP)
• cytotoxic & immunosuppressive (cyclosporine A) agents
• splenectomy for selected patients
• monoclonal Abs directed vs B cells, ie. rituximab
• plasmapheresis

Autoimmune hemolytic anemia (AIHA) associated with cold Abs:

1. Pathogenesis:
• often associated with IgM Abs which are cold agglutinins that are directed vs Ags of the I/i system,
common in Mycoplasma associated hemolysis.
• hemolysis is usually triggered by cold temperatures.
• requires complement activation
2. Clinical features are similar to those in warm autoimmune hemolytic anemia; less common in children
3. Management:
• treat underlying cause
• transfusion may be necessary
• usually self-limited
• corticosteroids less effective than in warm autoimmune HA
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References used:
1. Lanzkowsky, P. Manual of Pediatric Hematology & Oncology, 4 th edition, Elsevier
Academic Presss, MA., USA, 2005
2. Kleigman, R. et al (ed). Nelson Textbook of Pediatrics, 19th ed. Elsevier Sanders,
Philadelphia, USA, 2012