Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
of the Blood
Jocelyn C. Banatao, MD
Pediatric Hematology-Oncology
Hematopoietic System
Hematopoiesis in the human embryo:
Process by which cellular elements of the blood
are formed
3 anatomic stages:
1. Mesoblastic: occurs in the extraembryonic
structures (yolk sac)
- begins bet the 10th and 14days of gestation
2. Hepatic - 6-8 wk of gestation
- by 10-12 wk extra embryonic hematopoiesis
essentially ceased
- the liver is the predominant erythropoietic
organ through 20- 24 wk of gestation
3. Myeloid – hepatic production diminishes
during the second trimester while bone
marrow (myeloid) hematopoiesis increases
• Red cell life span of the Fetus and Neonate
- highest hematocrit during a person’s lifetime
occurs at birth
- lowest occurs about 10 wk later
- 120 days life span
Physiologic Anemia of Infancy
• At birth, normal FT infants have higher Hb
levels and larger RBC than do older children
and adults
• 1st week of life – progressive decline in Hb
level begins and persists for 6-8 weeks
- In healthy term infants – Hb 10g/dl
Premature: 3-6 wk of age (Hb 7-9 g/dl)
Treatment:
- FT infants: no treatment needed
- Premature: transfusion may be needed in
infants with poor weight gain, respiratory
difficulties, abnormal heart rate
Anemia
• Reduction of the hemoglobin concentration or
RBC volume below the range of values
• Normal hemoglobin and hematocrit vary
substantially with age and sex, racial
differences
• Global health problem affecting children and
reproductive age women
Approach to Anemia in Children
• Anemia - defined as a reduction in red blood
cell (RBC) mass or blood hemoglobin
concentration
RETICULOCYTOPENIA
Iron deficiency Anemia Low serum Fe, dec MCV, dec Hgb
Iron supplementation
RDW increased
Mentzer index (MCV/RBC) > 13
RETICULOCYTOPENIA
Lead poisoning Inhibits enzymes involved in heme synthesis
Reduction of intracellular iron
Prognosis:
- high risk for myelodysplastic syndrome, acute myeloid
leukemia, colon Ca, genital cancer
Overall Survival rate - 75% at age 40
- 87% for those maintained on steroids
- 57% for transfusion-dependent patients
Mortality Rate - 67% treatment related
- 22% DBA related malignancy and severe Aplastic Anemia
2. Pearson Syndrome
- Rare mitochondrial disorder
- Presents with hypoplastic anemia
- Appears in the neonatal period - macrocytic,
neutropenia and thrombocytopenia
- Hemoglobin F is elevated
- Multiorgan involvement (FTT, exocrine pancreas
dysfunction, liver and renal tubular defects,
malabsorption)
Treatment: supportive (PRBC transfusion)
Acquired Pure Red Cell Aplasia
1. Transient Erythroblastopenia of Childhood (TEC)
- MC acquired red cell aplasia in children
- Severe transient hypoplastic anemia occurs mainly in
previously healthy children (6 mo and 3 yr of age)
- Most of the children are older than 12 mo at onset
- Only 10% are > 3 yr of age
- Incidence: 4.3 cases/100,000
- TEC follows a viral illness, although no specific virus
has been consistently implicated
- Temporary suppresion of erythropoiesis results in
reticulocytopenia and moderate to severe normocytic
anemia.
- PC are normal or elevated
- MCV is normal for age
- Hb F is normal before the recovery phase
- All children recover within 1-2 months
Treatment:
- RBC transfusion may be necessary for severe anemia
- Corticosteroid is of no value
Anemia of Chronic Disease and Renal
Disease
Mild to moderate normocytic, normochromic,
hypoproliferative anemia associated with a decreased
serum iron and low transferrin saturation
Etiology:
- decreased red cell life span, impaired erythropoiesis
and increased utake of iron in the RES
Pathophysiology:
- Elevation of cytokines (interleukin-1) - may increase
the macrophage’s ability to ingest and destroy
erythrocytes
Laboratory Findings:
- Hemoglobin – 6-9g/dl
- normochromic, normocytic
- Absolute Reticulocyte Count (ARC) are normal or low,
and leukocytosis is common
- The serum iron level is low, without the increase in serum
transferrin that occurs in IDA
Diagnostic feature: low serum iron, low-to-normal iron-
binding protein (serum transferrin), serum ferritin level
may be elevated, BM has normal cellularity, CBC precursors
are decreased or adequate, marrow hemosiderin may be
increased, and granulocutic hyperplasia may be present
Treatment:
• Treat the underlying disorder
• Transfusion raise the hemoglobin
concentration temporarily but are rarely
indicated
• Erythropoietic stimulating agents (ESA) – eg:
recombinant human erythropoietin: increase
hemoglobin level and improve activity and
well-being
Anemia of Renal disease
Anemia – normocytic and ARC is normal or low
Etiology:
- decreased EPO production by the disease
kidneys
- IDA as a result of chronic blood loss (blood
sampling, dialysis and surgery)
- disturbance in iron metabolic pathway
Laboratory finding:
- anemia is hypoproliferative, normocytic and
normochromic
- EPO and ARC are low
- White cell and PC are normal
- Ferritin low if with concomittant IDA and
high if with inflammation
Treatment:
- oral iron therapy
- IV iron therapy if on maintenance
hemodialysis
- ESA – mainstay of treatment
Megaloblastic Anemias
1. Folic acid deficiency
Folate - Essential for DNA replication and cellular
proliferation
- humans cannot synthesize folate and
depends on dietary sources (green
vegetables, fruits and animal organs)
Peak incidence: 4-7 months
Etiology:
- Inadequate folate intake: malnutrition
- Decreased folate absorption: chronic diarrhea
- Acquired and congenital disorders of folate
metabolism or transport
- Hereditary folate malabsorption (HFM)
- Drug induced abnormalities in folate
metabolism: methotrexate, pyrimethamine
Clinical Manifestation:
- Anemia
- Irritability
- Chronic diarrhea
- Poor weight gain
- Hemorrhages in severe cases
Lab findings:
- Macrocytosis (MCV >100fL)
- Reticulocyte count (RC): low
- (+) nucleated RBC with megaloblastic morphology
- Neutropenia and thrombocytopenia (long
standing and severe cases)
- Bone marrow is hyercellular with erythroid
hyperplasia
- Large, abnormal neitrophilic forms with
cytoplasmic vacuolations
• Folic acid – NV 5-20 ng/ml (def <3 ng/ml)
• RBC folate are better indicator of chronic
deficiency
• Normal RBC folate level- 150-600 ng/ml of
PRBC
• Serum level of lactate dehydrogenase (LDH) –
marker of ineffective erythropoiesis is
markedly elevated
Treatment:
- Supplement (0.5-1.0 mg/day)
- Hematologic response within 72h
2. Vitamin B12 (cobalamin) deficiency
Clinical manifestations
- Weakness
- Lethargy
- Feeding difficulties
- FTT, Irritability
- Pallor, glossitis, vomiting, diarrhea,and icterus
- Neurologic findings: paresthesia, sensory deficits,
hypotonia, seizure, developmental delay,
developmental regression
Laboratory findings:
- macrocytic, macro-ovalocytosis of the RBCs
- Hypersegmented neutrophils
- Neutropenia and thrombocytopenia in advanced cases
- Vit B12 low, serum methylmaonic acid and
homocystein are elevated
- Serum iron and folic acid are normal or elavated
- LDH increased
- Sensitive index: excessive methylmalonic acid in the
urine (N 0-3,5 mg/24h)
Treatment:
- Supplemental therapy – 1-3 ug/day
Iron deficiency Anemia
- 30% global incidence if IDA (majority in
developing countries)
- US - 9% of children ages 12-36 mo are iron
deficient
Clinical manifestations:
- Pallor (not usually visible until Hb falls to 7-8g/dl)
- Hb <5g/dl: irritability, anorexia, lethargy, systolic
flow murmur
Nonhematologic systemic affects
- impaired neurocognitive function in infancy
- there is association of IDA and later, possibly
irreversible, cognitive defects
- PICA
- Pagophagia – desire
Indicators of IDA
1. Hemoglobin (g/dl)
Cut-off values: <11.0 for non hispanic ages 0.5-4
yr
- When used alone, it has low specificity and
sensitivity
- Use age specific normal values
2. Mean Corpuscular Volume (MCV) (um3)
- <70 from 6-24 mo
- a reliable, but late indicator of IDA
- Low values can be a result of thalassemia and
other causes of microcytosis.
3. Serum ferritin (ug/L)
- In all age groups in the presence of infection < 30
- Most useful laboratory measure of iron stores and
helps identify ID
- Low value of SF is diagnostic for IDA in a patient with
anemia
- Is an acute phase reactant that increases in many acute
or chronic inflammatory conditions independent of
iron status
- Combining SF with measurement of C-reactive protein
(CRP) helps to identify false-negative SF
4. Reticulocyte hemoglobin content (CHr)
- In infants and young children <27.5, in adults
<28.0
- Sensitive indicator that falls within days of
onset of iron deficient erythropoiesis and is
unaffected by inflammation
- False normal values can occur when MCV is
increased in thalassemia
5. Serum transferrin receptor (sTFR)
- Varies with assay and with patient’s age and
ethnic origin
- This soluble receptor is upregulated in Iron
Deficiency (ID) and is found in increased
amounts in serum. Increased during enhanced
erythropoiesis.
6. Transferrin saturation
- < 16%
- It is inexpensive, but its use is limited by
diurnal variation in serum iron and by many
clinical disorders that affect transferrin
concentrations including in inflammatory
conditions
7. Erythrocyte zinc protoporphyrin (ZPP)
(umol/mol heme)
- A useful screening test in field surveys,
particularly in children, in whom
uncomplicated ID is the primary cause of
anemia
- Lead poisoning can increase values
8. Hepcidin
- <10 ng/ml
- Extremely elevated in anemia of inflammation
and suppresed in IDA
Laboratory studies Differentiating the most common Microcytic
Anemias
Study IDA Alpha or beta Anemia of chronic
Thalassemia disease
Hb Decreased Decreased Decreased
MCV Decreased Decreased Normal - Decreased
RDW Increased N/ increased Normal-Increased
RBC Decreased Normal-increased Normal-Decreased
Serum ferritin Decreased Normal
Total Fe binding Increased Normal Decreased
capacity
Transferrin saturatio Decreased Normal Decreased
– CLUE:
+ previous surgery or dental procedure without bleeding
complications à unlikely to have congenital bleeding
disorder
Family History
Important bec most children have not encountered
severe hemostatic challenge
• Ask about
– Previous surgical procedures/dental extractions
– Transfusions
– Menstrual and obstetric histories
• 20% of girls with menorrhagia from menarche have
congenital bleeding disorder
Type of Bleeding
• PLATELET disorder (or VWD)
– Mucosal Membrane bleeding
• Gingival hemorrhage,
• epistaxis
• menorrhagia
– Petechiae
– Bruising
Type of bleeding
• Coagulation factor deficiencies ( eg.
Hemophilia)
– Deep muscle bleeding
– Joint bleeding
Time of onset
• Acute (over days to weeks)
– Acquired disorder
• ITP
• Vitamin K deficiency
• Chronic
– Congenital disorder
• VWD
• Coagulation factor deficiencies
Time of Onset
• Congenital Coagulation disorders
– At birth
• During circumcision
– In the first months of life
• With immunizations
– When they become mobile
• Experience mild trauma
Purpura 2mm – 1 cm
Petechiae < 2mm
Hematoma
Ecchymoses > 1 cm
Laboratory Evaluation
• Initial lab tests
– CBC with platelet
– PTT (intrinsic)
– PT (extrinsic)
Lab Evaluation
• PT
– Prothrombin time
– Tests Extrinsic pathway: Factors VII, V, X, II, I
– Plasma + thromboplastin (commercial TF) +
Calcium à measure time to clot
– Normal: 10 to 16 seconds; INR < 1.2
Lab Evaluation
• aPTT
– activated Partial Thromboplastin Time
– Measures intrinsic pathway: Factors XII, XI, IX,
VIII, X, V, II, I
– Activating surface (e.g. silica) + plasma à
activates factor XII à measure time to clot
– Normal 25 to 45 seconds
DDX, based on initial screen
↑PT ↑ PTT ↑ PT,PTT
Normal plt, Normal plt, Normal plt
PTT PT
Early Liver Dx F VIII def Vit K Def
Vit K Def (hemophilia or Liver Disease
VWD)
F VII Def Massive Transfusion
Warfarin
F IX, XI Oral anticoagulant
F XII def
PT inhibitor (F II, V, X or
PTT inhibitor fibrinogen def)
DDX based on initial screen
↑ PTT, PT and All normal Platelet
low plt dec
DIC VWD ITP
Liver Dysfxn Platelet fxn d/o Infection
Mild factor def (VIII, CVD
IX, XI, XIII ) Early BM
Fibrinolytic defect failure
Collagen Disorder CAMT,
TAR,BSS
Vitamin C def
WAS, GPS
• VWF
– 0.20 u /ml (0.5 – 1.5 u/ml)
Von Willebrand Disease
• Most common inherited bleeding disorder (Prevalence: 1% -
by lab def’n; only 10% symptomatic)
• vWF assay
– Definitive test
3/ male
• 2 day history of petechiae and purpura over
lower extremities later extending to trunk
• Otherwise well and playful
• No other abnormal physical examination
findings except for skin bleeding
• Previous immunizations and circumcision
without cxs
3 / female
• CBC
– Hb 114 WBC 11 x 109 Plt 25,000
• PT Act 100% INR 1.0
• PTT 32.5 secs (normal)
↑ PTT, TT All normal Platelet dec
Normal PT,
platelet