Diseases

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

• Hematocrit (HCT) − fractional volume of a whole blood

sample occupied by RBCs, expressed as a percentage
• Hemoglobin (HGB) − measure of the concentration of
the RBC pigment hemoglobin in whole blood, expressed
as grams per 100 mL (dL) of whole blood.
Mean Corpuscular Volume (MCV) Normal: 80-100
(microcytic, normocytic, macrocytic) Age: lower limit 70 + age in years
upper limit 84 + age in years

Reticulocyte count Normal: 0.5% - 1.5%

- provide information on the rate of or 0.005 – 0.015
RBC production
Absolute reticulocyte count Normal: 40,000 – 100,0000
= RBC (n x 1012) x retic % x 1000

Corrected reticulocyte count Normal: 0.5 – 1.5

= Retic % x Hct pt / 0.45
 Anemia
2 broad classes of anemias
1. Red cell loss or destruction – increased retic
- e.g. hemolysis, blood loss
2. Dec red cell production – decreased retic
e.g. aplastic, iron deficiency
 Macrocytosis
RETICULOCYTOPENIA
Bone marrow Failure Aplastic Anemia
- MCV inc bec of production of stress rbc’s Fanconi anemia
Diamond- Blackfan Anemia
Megaloblastic anemias Folic acid deficiency
Vitamin 12 deficiency
Drug-induced Alcohol
Cotrimoxazole
Methotrexate
Hypothyroidism

RETICULOCYTOSIS
Thalassemia Major
RETICULOCYTOPENIA
Iron deficiency Anemia
Thalassemia trait
Microcytosis
Profound anemia
Hepatosplenomegaly
Jaundice
Growth retardation
Low serum Fe, dec MCV, dec Hgb
Iron supplementation
RDW increased
Mentzer index (MCV/RBC) > 13
Disorder in globin syntehsis
(+) poikilocytosis (+) basophilic stippling
RDW normal
Mentzer index (MCV/RBC) < 13
 Microcytosis

RETICULOCYTOPENIA
Lead poisoning Inhibits enzymes involved in heme synthesis
Reduction of intracellular iron

Sideroblastic Anemia Failure to incorporate iron into heme

Chronic Disease Renal disease, chronic liver disease, hypothyroidism

Increased Ferritin level
 Normocytic Anemia
RETICULOCYTOSIS
Hemolysis
RBC membrane defect
RETICULOCYTOPENIA
Chronic Disease Kidney disease, liver disease, malignancy
TEC (Transient Erythroblastopenia of Transient immune reaction against
Childhood) erythroid progenitor cells
Anemia after toxin ingestion or viral
illness
 History and Physical examination
• Family history of anemia
• Splenomegaly, jaundice
• Early age onset of gallstones
• Clinical findings do not become apparent until
the hemoglobin level falls to <7-8g/dl
Clinical features:
- pallor, sleepiness, irritability, decreased
exercise tolerance
- flow murmur
- weakness, tachypnea, shortness of breath on
excertion, tachycardia, cardiac dilatation and
high output failure
 Laboratory Studies
• Hemoglobin, hematocrit and red cell indices,
WBC, differential count, platelet, Retic count
and peripheral blood smear
Anemias of Inadequate Production
1. Congenital Hypoplastic Anemia (Diamond-
Blackfan Anemia)
- Rare congenital bone marrow failure syndrome
that usually becomes symptomatic in early
infancy
- 90% recognized in the 1st year of life
- Normochromic, macrocytic, reticulocytopenia
and insufficient or absent RBC precursors in
otherwise normally cellular bone marrow
- 50% have extrahematopoietic anomalies
• Etiology:
- Mutation of RPS19 gene(25%), ribosomal
protein gene (50-70%)
Epidemiology:
- 7:1M live births
- Autosomal dominant disease
Clinical manifestations
- Profound anemia by 2-6 months of age
- 25% anemic at birth and hydrops fetalis occurs
rarely
- 92% diagnosed within the first year of life
- 50% have congenital anomalies (>1 anomaly
in 21% of individuals with DBA)
Treatment:
a. corticosteroid: mainstay of therapy (80%
response rate)
- 2 MKD initial dose
- 0.5 MKD or 1 MKD every other day
- Hemoglobin goal of >9g/dl
Response: increase in RBC precursors in the bone
marrow in 1-3 wk after therapy
- Normal Hb can in 4-6 weeks
b. Hematopoietic stem cell transplantation
- curative
- human leukocyte antigen (HLA) matched sibling donor in < 9
yr of age or younger

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

FEP Increased Normal Increased

Transferrin Receptor Increased Normal Increased

Reticulocyte Decreased Normal Normal-Decreased

hemoglobin
concentration
 Differential diagnosis of microcytic Anemia that
fails to respond to oral Iron
1. Poor compliance (true intolerance of Fe is uncommon)
2. Incorrect dose or medication
3. Malabsorption of administered iron
4. Ongoing blood loss (GI, menstrual and pulmonary)
5. Concurrent infection or inflammatory disorder inhibiting the response to iron
6. Concurrent vitamin B12 or folate deficiency
7. Diagnosis other than IDA
- thalassemia
- hemoglobins C and E disorders
- anemia of chronic disease
- lead poisoning
- Sickle Thalassemia
- iron refractory IDA (IRIDA)
- rare microcytic anmeia
Prevention:
- Breastfeeding should be encouraged
- Supplemental iron at 4 months
- Routine screening (Hb and Hct) is done at 12
onths of age, or earlier if at 4 months of age
the child is at risk for IDA
Treatment:
- 3-6 mg/kg elemental iron
- Max dose 150-200 mg of elemental iron daily
- Parenteral iron – used when malabsorption is
present
- Dietary counseling
- Repeat CBC 4 weeks after initiating therapy
- Duration: 2-3 months after blood values
normalize to reestablish iron stores
- Blood transfusion:
 Response to Iron Therapy in IDA
Time after iron administration Response to iron therapy in IDA
12-24h Replacement of intracellular iron enzymes
Subjective improvement
Increased irritability
Increased appetite
36-48h Initial bone marrow response
Erythroid hyperplasia
48-72h Reticulocytosis, peaking at 5-7 days
4-30 days Increase in Hb level
1-30 days Repletion of stores
 Hemolytic Anemias
Hemolysis – premature destruction of RBC
Anemia results when the rate of destruction
exceeds the capacity of the marrow to
produce RBCs
 Site of RBC Destruction
1. Intravascular Hemolysis
- Occurs when the RBCs are destroyed within
the blood circulation
CM: fever, chills, tachycardia and backache
Lab evaluation:
- hemoglobinemia, hemoglobinuria and
hemosidenuria
2. Extravascular Hemolysis
- Most common
- Occurs when RBCs are removed from the blood
circulation by tissue macropahges, primarily in
the spleen.
CM: jaundice, splenomegaly
Lab: haptoglobulin levels are normal or slightly
decreased
- unconjugated hyperbilirubinemia is present
 Cellular Defects
MEMBRANE DEFECTS
1. Hereditary Spherocytosis
- cytoskeletal protein defects
- often involve vertical interactions of
spectrin ankyrin, protein 3
Lab test:
- spherocyte on blood film
- negative coomb’s test eliminates immune
hemolysis
 - increases incubated osmotic fragility
- abnormal cytoskeletal protein analysis
Treatment:
- if Hb > 10g/dl and reticulocyte count <10%:
none
- if severe anemia, poor growth, aplastic crisis,
and age <2yr: transfusion
- folic acid, 1 mg qd
- splenectomy
 Guidelines for Splenectomy
1. Severe HS
2. Frequent hypoplastic or aplastic crisis
3. Poor growth or cardiomegaly
• Not recommended for mild HS
• Should be performed after the age of 6 yr
• Vaccines for encapsulated organism (H.
Influenza type b, pneumococcus,
meningococcus) 14 days before splenectomy
2. Hereditary Elliptocytosis
defect: cytoskeletal protein defects
- often involves horizontalinteractions of
spectrin, protein 4.1 and glycophorin C
Lab test:
- elliptocytosis on blood film
- RBC’s mildly heat-sensitive
- abnormal cytoskeletal protein analysis
Treatment:
- mild types: no treatment
- chronic hemolysis: transfusion and
splenectomy
3. Hereditary Pyropoikilocytosis
- cytoskeletal protein defects
- homozygous or double heterozygous
abnormality in horizintal interactions of alpha
spectrin
Lab test:
- extreme variation in RBC size and shape
- thermal sensitivity- fragmentation at 45 ‘C for
15 mins
Treatment:
- transfusion and splenectomy
- folic acid 1mg qd
4. Hereditary Stomatocytosis
Defect: cytoskeletal protein defects
- decreased protein 7.2b (1 subset)
- abnormal RBC cation and water content
Lab test: stomatocytes on blood film
Treatment: splenectomy should be avoided
- folic acid 1 mg qd
5. Paroxysmal Norturnal Hemoglobinuria
Defects: primary acquired marrow disorder
- RBC’s unusually sensitive to complement-
mediated lysis
Lab Test:
- decreased WBC CD55 and CD59 or decreased
CD59 by flow cytometry
- marrow aspirate and biopsy to assess celularity
- decreased decay-accelerating factor
PNH
Treatment:
• Folic acid 1 mg qd
• Mild cytopenia: no treatment
• Chronic hemolysis and other cytopenia:
prednisone, qd initially
• Iron for secondary iron defciency
• Anticoagulation
• Marrow transplant for pancytopenia
 Enzyme deficiency
1. Pyruvate Kinase defciency
Defect: decreased or abnormal enzymes
Lab test: pyruvate kinase assay
Treatment:
- severe anemia with symptoms, poor growth
and age <2 yr: transfusion
Treatment:
- splenectomy: age > 6yr, but earlier if
necessary
- folic acid, 1 mg qd
2. G6PD deficiency
- A type: age-labile enzyme
- Mediterranean type: no enzyme activuty in
circulating RBC’s
Lab test: G6PD assay
Treatment:
- avoid oxidant stress to RBCs
- transfusion if acute anemia is symptomatic
 Extracellular Defects
1. Autoimmune
a. “warm” antibody
- Accounts for approx 70% of AIHA
- Alteration in membrane surface antigen (Rh)
or abnormal response of B lymphocytes,
causing autoantibody formation
- “molecular mimicry” to viral antigen
Lab test:
- spherocyte on blood film
- positive direct antiglobulin (coombs) test to IgG
“warm” antibody or anti C3d directed against
RBCs
- positive indirect Coombs test and antibody
detectable in plasma
- thermal amplitude 35-4-’C
- some complement (C3b) may be detected on
RBCs
• direct Coombs test is positive, a visual
indication that antibodies (and/or
complement proteins) are bound to the
surface of red blood cells.
 Indirect Coomb’s Test
• It detects antibodies against RBCs that are
present unbound in the patient's serum. In
this case, serum is extracted from the blood
sample taken from the patient.
Treatment:
- if Hb >10g/dl and retic count <10%: none
- severe anemia may require transfusion;
prednisone, 2 mg/kg/24h
- IVIG
- Rituximab
- splenectomy
- immunosuppresive
- folic acid, 1 mg/24 hr if chronic
2. “cold” antibody or IgM autoantibody
- Directed againts I/I antigen system
- Lab test: agglutination or rouleaux on blood
film
- (+) direct Coombs test to complement (C3b)
Traetment:
- if Hb >10g/dl and retic count <10%: none
- Severe anemia might require transfusion
- Avoid exposure to cold
- If severe: Rituximab
- Prednisone is less effective
- Plasmapheresis
- Splenectomy is not useful
- Folic acid
 Hemoglobinopathy
• Thalassemia – refers to disorders associated
with defective synthesis of α- or β-globin
subunits of hemoglobin HbA
• (α2; β2), inherited as pathologic alleles of one
or more of the globin genes located on
chromosomes 11 (β) and 16 (α).
Pathophysiology:
• decreased Hb production and red blood cell (RBC)
survival
• In severe β-thalassemia, ineffective
erythropoiesis (IE) results in expanded marrow
cavities that impinge on normal bone and cause
distortion of the cranium, and of facial and long
bones.
• extensive lymphadenopathy and
hepatosplenomegaly.
Work-up and evaluation :
• CBC with reticulocyte count: hypochromic,
microcytic anemia, reticulocytosis
• Leukopenia and thrombocytopenia (may develop
with hypersplenism)
• Blood smear: target cells and nucleated red cells,
extreme anisocytosis, contracted red cells,
polychromasia
• Haemoglobin electrophoresis
• Note: screen parents and siblings
Beta Thalassemia
1. Βeta Thalassemia Minor (trait) – 1 normal β globin allele
and 1 β globin thalassemic allele
Anemia: mild (microcytic and hypochromic, hct > 30%, RBC
higher than normal, normal RDW )
• Hemoglobin electrophoresis: HbA 90 to 95, HbA2 normal or
increased (up to 7 to 8%)
• HbF increased in 50% patients (1 to 3)
• PBS: target cells, dacryocytes, reticulocyte count are
normal or slightly increased, overt hemolysis is not present
• Clinical manifestation: asymptomatic
2. Beta Thalassemia Intermedia – symptomatic
beta thalassemia who do not require transfusion
(NTDT) during at least the first few years of life
• Genotype: β+/β+ and others
• MCV: low
• Anemia: moderate
• Hemoglobin electrophoresis: HbA2 normal or
increased (up to 7 to 8%), HbF increased in
approximately half of patients
Clinical manifestations: bone marrow expansion,
hepatosplenomegaly and chronic haemolytic
anemia
Complications: increased absorption of dietary
iron leading to iron overload
- complications of chronic hypoxia (high
cardiac output, increased pulmonary vascular
resistance, pulmonary hypertension and heart
failure)
3. Beta Thalassemia Major – diagnosed at 6 to 12 months of
age
• Genotype: β0/β0
• MCV: low
• Anemia: hgb as low as 3 to 4 g/dl (markedly hypochromic,
microcytic red cells)
• Haemoglobin electrophoresis: HbA absent; only HbA2 and
HbF are elevated
• PBS: extreme hypochomia and poikilocytosis,
predominance of microcytes, tear drop and target cells,
• inclusion bodies – Heinz bodies (precipitates of alpha globin
within the red cells)
• CBC - high WBC, normal PC, reticulocyte count
is low
• Severe hemolytic anemia: increased indirect
bilirubin and LDH and reduced or absent
haptoglobin
• Clinical manifestations: pallor, irritability,
growth retardation, hepatosplenomegaly, and
jaundice
 α-Thalassemia
1. Silent carrier α-thalassemia: deletion of one
α-globin gene
• Genotype: αα/α-
• MCV: Normal limit (NL)
• Anemia: none
• Haemoglobin electrophoresis: normal, < 3%
Hb Barts at birth
2. Minor (α-Thalassemia trait): deletion of two
α-globin genes
• Genotype: α α/- - or α -/α –
• MCV: low
• Anemia: Mild
• Hemoglobin electrophoresis: normal; 3to 8%
Hb Barts at birth
3. Hb Constant Spring: abnormal α-chain variant produced in
very small amounts, thereby mimicking deficiency of the
gene
4. HbH disease: deletion of three α-globin genes resulting in
significant reduction of α-chain synsthesis,
• mild to moderate microcytic hypochromic anemia with Hb
levels 8-10 g/dL.
• Genotype: α -/--
• MCV: low
• Anemia: moderate
• Hemoglobin electrophoresis: 5 - 30% HbH present in adults;
20 – 40% Hb Barts at birth
5. Major (Hydrops fetalis): deletion of all four- α-
globin genes; no normal adult or hbF
production
• Genotype: --/--
• MCV: low
• Anemia: fatal
• Hemoglobin electrophoresis: Hb Barts, Hb
Portland, and HbH present; HbA, HbF, and
HbA2 are absent
Sequelae:
1. Hyperplastic marrow - bone marrow
expansion with cortical thinning
• Bony abnormalities - abnormal facies,
prominence of malar eminences, frontal
bossing, depression of bridge of the nose, and
exposure of upper central teeth
• Skull radiographs – hair-on-end appearance
(widening of diploic spaces)
2. Increased iron absorption and iron overload
(from blood transfusion and increased GI
absorption of iron)
• Fibrosis/cirrhosis of the liver
• Endocrine disturbance (DI, hypothyroidism,
hypogonadism, hypoparathyroidism,
hypopituitarism)
• Skin hyperpigmentation
• Cardiac hemochromatosis (arrhythmia and
cardiac failure)
3. Hypersplenism
• Shortened red cell life
• Leukopenia and thrombocytopenia
Management :
Transfusion therapy: Hemoglobin <7g/dl (on at
least 2 measurements)
• Poor growth
• Development of other complications (eg.
pulmonary hypertension, extramedullary
hematopoiesis)
• Goal: maintain pretransfusion level > 9-9.5 g/dl
• 10-15 cc/kg packed leukodepleted red cells q 3-5
weeks
 Diet recommendation
Nontransfused thalassemia patients (NTDT)
1. Low-iron diet, avoid iron-fortified cereals and other
products and excessive consumption of red meat
(beef, lamb and pork, liver), sea food such as sardines
and mussles
2. The calcium, present in milk, cheese and yogurt and
cream decreases the absorption of meat iron
3. Wheat bran, maize, oats, rice and soy decrease iron
abdorption while food rich in vitamin C increase iron
absorption
4. Drinking black tea/coffee with meals is recommended
to reduce iron absorption from food
For transfused patients on chelation therapy:
• low-iron diet is unnecessary and may decrease
the quality of life.
• The amount of iron absorbed in 1 unit of
blood pRBC (200mg) far outweighs the
amount of iron from a 3 – ounce steak (5 mg)
 Iron Chelation
Indications:
• Cumulative transfusion load of 120 ml/kg or
greater
• Serum ferritin persistently >1000 ng/ml
• LIC >5-7 mg/g dry weight
Common chelators:
• Deferiprone
• Deferoxamine
• Deferasirox
 Splenectomy:
Indications:
1. Calculated annual transfusion requirement is
200 to 220 mL RBCs/kg per year
2. Hematocrit of 70% - equal to 250-275 mL/kg
per year of packed RBCs with a hematocrit of
60%
Supportive care:
• Immunization 2 weeks before or 2 weeks after
splenectomy (ideally 4-6 weeks prior to
splenectomy)
• pneumococcal, meningococcal vaccines and
conjugated Hib vaccines. Pneumococcal
vaccine repeated in 5 years
» Influenza vaccination yearly
» antimicrobial prophylaxis :
 PANCYTOPENIAS
Reduction below normal values of all 3
peripheral blood lineages: leukocyte, platelets
and erythrocytes
 Inherited Pancytopenia
1. Fanconi Anemia
- Autosomal recessive inheritance
History:
- Skeletal and renal malformations
- LBW, pancytopenia
- Family history with bone marrow failure (MDS,
AML)
- Thumb and radial malformation
- Hyperpigmented skin lesions
- Short stature
- MDS, AML, squamous cell carcinoma at young
age, renal and cardiac malformation
- Microcephaly and hypogonadism
Genes inactivated:
- FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE
- Encode proteins known to protect genome from
excessive damage induced by crosslinking agents
Screening and diagnostic tests:
- Chromosomal breakage analysis (in response to
mitocin C or diepoxybutane)
- Gene sequencing
2. Dyskeratosis Congenita
- Intrauterine growth retardation
- Developmental delay
- Short stature
- Family history of MDS, AML. Marrow failure
- Abnormal finger nails or toenails
- Mucocutaneous triad: reticulate skin
pigmentation of upper body, mucosal
leukoplakia, nail dystrophy
- Head and neck cancer or pulmonary fibrosis
Genes inactivated:
- Autosomal recessive
- DKC1, TERC, TINF2, NOLA2 and NOLA3
- These genes encode proteins known
participate in maintenance of telomeres
Treatment:
- Quantitative analysis of telomere
- Gene sequencing
3. Schwachman-Diamond Anemia
• Pancreatic insufficiency
• Low birth weight
• Metaphyseal dyostosis, initial neutropenia and
delayed development
PE:
- Short stature, abnormal thorax
Genes:
- SBDS autosomal recessive marrow clonal
expansion in 15%
Screening:
- CT (fatty infiltration of pancreas)
- Gene testing
- May evolve to myelodysplasia or leukemia
- Absence of pancreatic lipomatosis, fecal fat
 ACQUIRED PANCYTOPENIA
1. Aplastic anemia
Etiology - Radiation, drugs and chemicals
• Predictable: chemotherapy, benzene
• Idiosyncratic: chloramphenicol, antiepileptic, gold
• Viruses: CMV, EBV, Hepatitis
• Pregnancy
• Marrow replacement: leukemia, myelodysplasia
• Autoimmune: increased circulating activated T
lynphocytes producing cytokines that suppress
hematopoiesis (interferron-Y)
Hallmark:
- Peripheral pancytopenia
- Hypoplastic or aplastic BM
Severe AA: 2 or more cell line components have
become seriously compromised
- ANC <500/mm3
- PC <20,000/mm3
- Retic count <1%
- Bone marrow biopsy: moderately or severely
hypocellular
Moderate AA
- ANC 500-1,500
- PC 20,000-100,000/mm3
- RC <1%
Clinical Manifestations:
- anemia, leukopenia and thrombocytopenia
Treatment:
- Supportive care and treat underlying BM failure
- Allogeneic hematopoietic stem cell
transplantation(HSCT) – 90% long term survivals
Complications:
- life-threatening bleeding
- Infection due to protracted neutropenia
Prognosis:
- Spontaneous recovery rarely occurs
- If left untreated, severe pancytopenia has an
overall MR of 50% within 6 months
- 75% overall with infection and hemorrhage being
the major causes of mortality and morbidity
Clinical Evaluation
of Bleeding patient
• What is abnormal bleeding?
– Epistaxis
• unrelieved by 15 minutes of pressure
– Menstrual periods
• > 7 days
• associated with clots, saturation of pads or frequently
stained clothing
– Bleeding from dental procedures
• Lasting beyond day of procedure
• Requiring a blood transfusion
 Detailed History
• What is abnormal bleeding?
– Ecchymoses
• size or character inconsistent with trauma

– 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

* Factor XIII deficiency

• Good initial hemostasis à followed by persistent oozing (failure to form a
firm clot)
 Detailed History
• Liver disease
– Decreased production of coagulation factors
– Thrombocytopenia sec to splenic sequestration
• Malabsorption
– Impaired Vit K absorption
• Renal disease
– Abnormal platelet function
• Otherwise well
– ITP
– Congenital bleeding disorders
 Physical Examination

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

CAMT = Congenital Amegakaryocytic Thrombocytopenia

TAR – Thrombocytopenia with Absent Radius
WAS = Wiskott Aldrich Syndrome
GPS = Gray Platelet Syndrome
 26 / M
• Epistaxis and easy bruising
• Needs dental extraction
• Strong family history of bleeding
• Labs
– CBC Normal
– PT Normal
– PTT 39.3 (23 – 33 secs)
DDX, Normal plt, Normal PT prolonged
PTT,

• Dec Factor VIII

due to
– Hemophilia A
– VWD
• Dec Factor IX, XI,
XII
• Lupus
anticoagulant or
other coagulation
factor inhibitors
– Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)

– VWF : 1.2 u/ml (0.5 – 1.5 u/ml)

 HEMOPHILIA
• Essentials
– Factor VIII (or IX ) deficiency
– X-linked or spontaneous mutation (1/3)
– Bruising, soft tissue bleeding, hemarthrosis
– Prolonged PTT + dec factor VIII (or IX) levels
 HEMOPHILIA
• Most common severe congenital bleeding
disorder
• Prevalence
– Hemophilia A (Factor VIII)
• 1 / 10,000 males
– Hemophilia B (Factor IX)
• 1 / 50,000 males
 HEMOPHILIA- Lab findings
• Prolonged PTT
• Normal PT, Normal platelet
• Dx is confirmed by Factor Assay
– dec F VIII ( with normal VWF ) =
Hemophilia A
– dec F IX = Hemophilia B
 HEMOPHILIA –
severity classification
• Factor VIII
– reported in units / ml ( 1 unit/ml = 100% factor activity)
- Normal range: 0.5 – 1.5 U/ml (50 – 150%)
- Classification
- Severe (60% of cases) : < 1% factor VIII (spontaneous
bleeding)
- Moderate : 1 - < 5%
- Mild : 5 – 40 % ( only with trauma and surgery)
 HEMOPHILIA- S/Sx
• Severe Hemophiliacs
– Usually initial presentation in 1st 2 years of
life ( severe bruising and joint bleeds)
– 40 – 50% present in the 1st month of life
– 1-4% present in the neonatal period (birth
trauma)
 HEMOPHILIA
• Mild or Moderate hemophiliacs
– Boys
• Trauma related bruising or bleeding
• Excessive bleeding following surgery or dental
extraction
– Girls ( carriers )
~ Often with Factor VIII < normal
• Mild bruising or bleeding
• Heavy menstrual periods
 16 / female
• Easy bruising
• Heavy Menses
• Epistaxis (in childhood)
• Gum bleeding
• Inc bleeding with dental extraction
• No previous BT
• Iron supplement in the past
• Family History
– Maternal grandmother and mother with
epistaxis and heavy menses
– 3 brothers and 2 sisters normal
• Hb 114
• Platelet 300 (150 – 450)
• PT : normal
• PTT : normal 32.5 (23.5 – 33.5)
↑ PTT, TT All normal Platelet dec
Normal PT,
platelet

Heparin CAMT, TAR,BSS

VWD
WAS, GPS
Platelet fxn d/o
ITP
Mild factor def (VIII, IX, XI,
XIII ) Infection
Collagen Disorder CVD
Early BM failure
Vitamin C def
• VIII
– 0.48 u /ml (0.5 – 1.5 u/ml)

• 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)

• Quantitative or Qualitative deficiency of vWF

• Easy bruising / epistaxis from childhood / menorrhagia

 Von Willebrand Factor
• Protein in plasma
• Function
- Glues platelets to damaged endothelium
- Binds and protects Factor VIII
 vWD- S/Sx
• Increased bruising and excessive epistaxis
• Prolonged bleeding with trauma or surgery
• Menorrhagia
– Significant menorrhagia from menarche should
prompt investigation for congenital bleeding
disorders (commonly VWD)
 vWD-Labs
• Initial screen:
- PT normal
- PTT sometimes prolonged
> in type 3 (factor VIII dec)
- Platelet sometimes dec
> in types 2 and 3
• Most of the time: PT, PTT, platelet --- all NORMAL
• Blood type ‘O’ – normally lower vWF
VWD
• Bleeding time - prolonged

• Platelet function analyzer – prolonged closure time

• 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

Heparin VWD CAMT, TAR,BSS

Platelet fxn d/o WAS, GPS
Mild factor def (VIII, IX, XI, ITP
XIII )
Infection
Collagen Disorder
Vitamin C def CVD
Early BM failure
 Immune Thrombocytopenic Purpura
• Production of autoantibodies against patient’s
platelets
• Acute onset of bleeding (petechiae and
bruising)
• History of recent viral infection of
immunization
• Peak in toddler and early school age years
 Immune Thrombocytopenic Purpura
• All normal except decreased platelets
• Majority recover normal counts within 2
months; 80% within 6 months
Stages:
• Newly diagnosed ITP – within 3 months from diagnosis
• Persistent ITP – between 3-12 months, includes
patients who have spontaneous remission or whose CR
at the end of the first therapy is not maintained
• Chronic ITP - lasting more than 12 months
• Refractory ITP – two criteria:
» lack of response after splenectomy or have relapsed thereafter
» a bleeding risk that needs treatment.
Natural History (Remission)
• 37%: 1-6 months
• 16%: 6-12 months
• 24%: 24 months
Necessary evaluation: no need for further tests if with
typical history, PE, CBC with Peripheral blood smear

• the presence of abnormalities in the history, PE, or

CBC and PBS should be further investigated (e.g.
BMA or other appropriate investigations, before the
diagnosis of ITP is made
Clinical manifestations:
- May occur after viral infections or live virus
vaccination
- Mucosal bleeding (hematuria, hematochezia,
menometrorrhagia or epistaxis)
- Rarely develop severe bleeding: ICH (<1%),
epistaxis, hemoptysis, GI bleeding
Management:
• To achieve a platelet count (PC) that is
associated with adequate hemostasis rather
than a normal PC
• The decision to treat should involve a
discussion with the patient and consideration
of severity of bleeding, anticipated surgical
procedure, medication side effects, and
health-related quality of life
Children:
• IVIg (0.8-1g/kg) single dose or a short course
corticosteroid (CST) should be used as first-
line treatment
• IVIg should be used instead of CST if a more
rapid increase in platelet is required
• Anti-D may be considered for first- line
therapy in Rh+ non-splenectomized children
Supportive care:
• Restrict physical activities – no contact sports
• Avoid NSAIDS, aspirin
• Soft diet
• Antifibrinolytic agents
• Monitor menstrual bleeding –
antifibrinolytics, hormonal therapy if needed
• Parental education
 Kasabach-Meritt Syndrome
Giant hemangioma with localized intravascular
coagulation causing thrombocytopenia and
hypofibrinogenemia
Inside the hemangioma there is platelet
trapping and activation of coagulation with
fibrinogen consumption and generation of
fibrin degradation products
Treatment:
- Propanolol
- Surgical excision
- Laser
- Alpha interferon
- vincristine
 Congenital Thrombocytopenic
Syndromes
Wiskott-Aldrich Syndrome (WAS)
- Thrombocytopenia with tiny platelets
- Eczema
- Recurrent infection as a consequence of immune
deficiency
- X-linked disorder (point mutation on WAS gene)
- Bone marrow: normal number of
megakaryocytes
- Treatment: splenectomy, Hematopoietic stem cell
transplantation is curative