Download Hematology and Oncology (K)

HAEMATOLOGY AND ONCOLOGY
General outline
 General haematology
 Approach to the child with anaemia
o Nutritional anaemia
o Aplastic anaemia
o Acute haemolytic anaemias
o Chronic haemolytic anaemias (Thalassemia)
 Approach to the bruised child
o Idiopathic thrombocytopenic purpura
o von Willebrand disease
o Haemophilia
 Blood Product Transfusion
 Childhood Cancers
 Leukaemia
 Lymphoma
 Oncologic emergencies
 Brain Tumours
 Neuroblastoma
 Other Tumours – Wilm’s Tumour (Nephroblastoma), Liver Tumours, Retinoblastoma, Soft Tissue
Sarcomas, Bone Tumours
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General Haematology
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Haematological values change with age
o Fetus lives in hypoxic environment (excellent “parasite”)
o In children  FBC either central line/finger prick not accurate for platelets as it may coagulate
and give lower reading
 High Hb
 High HbF (HbF has higher affinity for O2)
@birth HbF (all gone by 1 yr), HbA, HbA2
o Postnatal “shock” (too much oxygen!)
 Red cell production shut down
 Hb falls to nadir at 6-8 weeks
 Switch from HbF to HbA
 Other changes E.g. MCV
o Gestational age aggravates differences
o Affects interpretation of normal values
 Hb level
 MCV
 HbF (as indicator of β-thalassaemia)  ↑proportion > 1 yr old = inherited disorder of Hb
pdtn
Microcytosis as indicator of iron deficiency or thalassemia
o MCV is more sensitive indicator of iron deficiency than Hb level
o Normal MCV level varies with age
o High at birth, falls rapidly
 Nadir at 12 months
o Rule of thumb
 Lower limit of MCV = 70 + Age (in years)
 E.g. In 3-year-old child, MCV of <73 is low
Serum ferritin levels are the best indicator of iron deficiency
Main site of hematopoiesis in fetal life  liver
Postnatal  bone marrow
Blood vol: Term infant: 80ml/kg
Pre term: 100ml/kg
Hb types in newborns & adults
o Newborn:
 HbF 74%
 HbA 25%
 HbA2 1%
o Adult/ Children>1 yr:
 HbA 97%
 HbA2 2%
Kristy’s Paediatric Hematology and Oncology Notes
Approach to anaemia
Definition
 Reduction in the RBC mass or blood Hb concentration
 Useful to know the normal values for the population; for the value to be abnormal it should be 2SD below
the mean
 Normal values at different ages
o Neonate < 14g/dl
o 1-12 mths < 10g/dl
o 1-12 yrs < 11g/dl
 Stores of Fe, folic acid, vit B12
o Adequate in term babies
o Pre term adequate but lower @ birth and depleted more quickly, therefore deficiency @ 2 - 4
months if supplementation is not given
Age
Hb (g/dl)
RBC
WBC
Birth
14 - 21.5
3.7-6.5
10.0-26.0
2 weeks
13.4-19.8
3.9-5.9
6.0-21.0
2 months
9.4-13.0
3.1-4.3
6.0-18.0
6 months
11.1-14.1
3.9-5.5
6.0-17.5
1 year
11.3-14.1
4.1-5.3
6.0-17.5
2-6 years
11.5-13.5
3.9-5.3
5.0-17.0
6-12 years
11.5-15.5
4.0-5.2
4.5-14.5
12-18 years (F)
12.0-16.0
4.0-5.2
4.5-13.0
12-18 years (M)
13.0-16.0
4.5-5.3
4.5-13.0
→ Preterm babies have a steeper fall in Hb to 6.5 - 9g/dl @ 4-8 weeks chronological age
Physiological classification of anaemia
Kristy’s Paediatric Hematology and Oncology Notes
Kristy’s Paediatric Hematology and Oncology Notes
Morphological classification of anaemia
MCV
- Low in Fe Def
- Raised in Folic acid
def
Kristy’s Paediatric Hematology and Oncology Notes
History
1. BIODATA
 Age – Fe deficiency common in infants
 Sex – X-linked traits e.g. G6PD deficiency
 Ethnicity- thalassemias common in Mediterranean and Middle East
2. CURRENT HISTORY
 Severity and initiation of symptom – Because of the body's compensatory abilities, patients with chronic
anemia may not be as symptomatic as patients with acute anemia with similar hemoglobin values. Prior
episodes of anemia may indicate inherited forms, whereas anemia in a patient with previously
documented normal blood counts suggests an acquired etiology.
 Questions relating to hemolytic episodes – Specific questions regarding changes in urine color, scleral
icterus, or jaundice associated with the symptoms of anemia should be asked. Hemolytic episodes that
occur only in male family members may indicate the presence of a sex-linked disorder, such as G6PD
deficiency.
 Prior therapy or anemic episodes – Prior anemic episodes, duration, etiology, and resolution, as well as
all prior therapy for anemia, should be reviewed. Patients with haemoglobinopathies resulting in the
production of small (microcytic) and pale (hypochromic) RBCs, such as HbE or the various thalassemias,
may have a history of treatment on multiple occasions for an erroneous diagnosis of iron deficiency
anemia, in which the RBCs are also hypochromic and microcytic.
 Questions about possible blood loss – Specific questions related to bleeding from the gastrointestinal
tract, including changes in stool color, the identification of blood in stools, and history of bowel symptoms,
should be reviewed. Teenagers may have excessive menstrual losses without realizing it, and, therefore,
information regarding the menstrual history including duration of periods, flow, quantitation and saturation
of tampons or pads, should be obtained.
Kristy’s Paediatric Hematology and Oncology Notes
3. PAST MEDICAL HISTORY
 Chronic underlying infectious or inflammatory conditions
 Intestinal worm infections
 Travel to/from areas of endemic infection
 Recent illnesses
4. PRIOR DRUG OR TOXIN EXPOSURE
 Prior medications
 Toxin exposure
 History of oxidant-induced haemolysis
 Type and duration of homeopathic or herbal medications (risk for exposure to lead and other toxins)
 Environment, housing, paint exposure, cooking materials, and use of poorly glazed ceramic pots in order
to evaluate for possible lead exposure.
5. DIETARY HISTORY
 Iron content in the diet and to a lesser degree, folate and B12 content.
 Type of diet, type of formula (if iron fortified), and age of infant at the time of discontinuation of formula or
breast milk
 Amount and type of milk
 Symptoms consistent with pica may aid with the diagnosis of lead poisoning and/or iron deficiency
6. BIRTH HISTORY
 Infant and mother's blood type
 History of exchange or intrauterine transfusion, and a history of anemia in the early neonatal period
Gestational age at birth is important, as premature infants may have iron or vitamin E deficiencies
resulting in anemia.
 The presence of jaundice or need for phototherapy may signify the presence of an inherited hemolytic
anemia.
7. DEVELOPMENTAL MILESTONES
 Parents should be asked questions to determine if the child has reached age-appropriate developmental
milestones.
 Loss of milestones or developmental delay in infants with megaloblastic anemia may signify abnormalities
in the cobalamin pathway.
8. FAMILY HISTORY
 Family history of anemia
 Asking if family members have undergone cholecystectomy or splenectomy may aid in the identification of
additional individuals with inherited hemolytic anaemias.
 Race and ethnic background are helpful in guiding the workup for haemoglobinopathies and
enzymopathies. For example, thalassemia syndromes are more common in individuals of Mediterranean
and Southeast Asian descent; Hemoglobin S and C are most commonly seen in Black populations.
Physical examination
 Skin, mucosae – pallor, dryness, purpura
 Hands – koilonychias, palmar crease pallor
 Facies – skull bossing, maxillary hyperplasia
 Eyes – jaundice, pallor
 Mouth – glossitis, cheilosis, ulcers
 Heart – tachycardia, functional murmurs, CCF
 Lungs – breathlessness
 Abdomen – hepatosplenomegaly
 PR – bleeding, occult blood
 Others – lymphadenopathy
Investigations
1. HAEMATOLOGIC
 Hb
 HCT
 RBC indices: MCV, MCH, MCHC
 Leucocyte count
 Retic count
Kristy’s Paediatric Hematology and Oncology Notes
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Platelet count
ESR
Peripheral blood film
2. URINE ANALYSIS
 Appearance : Color, pH, clarity, specific gravity
 Test for protein, bence jones protein
 Bilirubin, uribilinogen
 Occult blood
 Microscopic examination
3. STOOL ANALYSIS
 Appearance : color, consistency
 Occult blood
 Examination for ova, parasites
4. BIOCHEMICAL ANALYSIS
 Urea, electrolytes and creatinine
 Bilirubin, direct and indirect
 Protein
 Serum Fe, TIBC, ferritin
5. SPECIAL TESTS
 Hb typing/Coombs’ test, G6PD, autohemolysis test, haptoglobin etc.
Anemia in the newborn
1. Reduced red cell pdtn (Rare)
 Congenital infection by parvorirus B19
 Congenital red cell aplasia (Diamond-black fan anemia)
} both cause red
} cell aplasia
2. ↑Red cell destruction (hemolytic anemia)
 Immune. (hemolytic disease of the newborn)
- Antibodies against blood grp antigens
- *Anti-D (rhesus)
mother always -ve for antigen
- Anti-A
and baby +ve.
- Anti-B
mother makes Ab & cross
- Anti-Cell
placenta
- Positive direct Coombs test
 Red cell membrance disorders (hereditary spheroaytosis)
 Red cell enzyme disorders (G6PD)
 Abnormal Hb
→ x clinically present
→ tested positive on Guthrie Test
3. Blood loss
 Feto-maternal hemorrhage (occult bleeding into mother)
 Twin-to-twin transfusion (bleeding into twin)
 @ delivery eg. placenta abruption
Hb low
RBC look normal
reticulocyte low
bilirubin normal
↑ reticulocyte count
↑ unconjugated bilirubin
severe anemia
↑ reticulocyte
normal bilirubin
4. Anemia of prematurity
 Inadequate erythropoietin pdtn
 ↓ red cell lifespan
 Frequent blood sampling while in hospital
 Iron & folic acid def (after 2-3 mths)
Kristy’s Paediatric Hematology and Oncology Notes
Nutritional anaemia
Epidemiology
 Iron deficiency anaemia is the most common nutritional deficiency in children in the world.
o Main causes:
1. Inadequate intake
 Common in infants as a lot is needed for ↑ in blood vol & growth
 May be due to delay of introduction of mixed feeds > 6 mths
2. Malabsorption
3. Blood loss
 However, in Singapore, Fe deficiency anaemia less common as society becomes more affluent
 Occurs most requently in children 6 months to 2 years old (MCQ)
o <6 months: Assume breast fed – still has a good natural store of iron. Additional iron stores given
transplacentally
o From 4 months onwards, the natural iron store starts to drop – give iron supplement.
Clinical manifestation
 Iron deficiency anaemia (IDA) is a microcytic, hypochromic, hypoproductive state
o Low MCV, low MCH
o Other causes of low MCV → βthal trait/ α thal trait/ Anemia of chronic disease.
 Mostly asymptomatic
 Some p/w severe anemia: lethargy, pallor, irritability, cardiomegaly, poor feeding, & tachypnea
 May present as part of a complex medical problem including
o GI blood loss
look for these if Hx/examination points to
o Malabsorption syndromes e.g. Celiac disease
non-dietary cause or if failure to respond to
o Chronic inflammatory diseases
therapy in compliant patients
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Other manifestations of Fe deficiency
o Neurodevelopmental: impaired psychomotor and/or mental development, subtle auditory and
visual dysfunction.
o Immunity: increased risk for progression of infection
o Exercise capacity: decreased work capacity (iron is an essential cofactor for enzyme-driven
aerobic metabolism)
o Thrombosis: IDA has been reported to be associated with cerebral vein thrombosis
Principles of diagnosis
 Hb concentration < 11.0 g/dL combined with a low serum ferritin.
o N.B.: Serum ferritin is an acute phase reactant, with serum levels increasing in liver disease,
infection, inflammation, and malignancy  pt with Fe deficiency and a concomitant
inflammatory disease may have a "falsely" normal ferritin concentration.
 Ix: FBC, PBF, reticulocyte count
 Children with a hypochromic microcytic anemia generally are treated with iron, and further evaluation is
performed only if the response is inadequate
 A more complete evaluation for IDA is indicated at presentation in children with complicated medical
histories, which would include serum iron, ferritin, total iron-binding capacity, and transferrin saturation
Test
Fe deficiency
Thalassemia
Anaemia of Chronic
Disease
Hb
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MCV
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~/
RCW
N
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~/
TIBC
N
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Transferrin
N
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S ferritin
N
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 After diagnosis of IDA, take a careful dietary history, screen for lead poisoning, stool OB x 3
Principles of management (Fe absorption increases when taken with vit C rich foods)
 Prevention of Fe deficiency in infants
o Encourage breastfeeding exclusively for first 4-6 months, thereafter, consider adding iron-fortified
cereals
o For breastfed preterm or low-birth-weight infants, begin iron supplementation (1 to 2 mg/kg per
day; maximum 15 mg) at one month and continue until 12 months
Kristy’s Paediatric Hematology and Oncology Notes
o
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For infants younger than 12 months of age who are not breastfed or are partially breastfed, use
only iron-fortified formulas
o At age six months, encourage one feeding per day of foods rich in vitamin C (i.e. citrus fruits and
juices, cantaloupe, strawberries, tomatoes, and dark green vegetables)
o After age six months, or when developmentally ready, considering introducing pureed meats,
which increase the absorption of non-heme iron
o Avoid low iron formulas or cow's milk until age 12 months
o Children aged 1-5 yrs should consume no more than 600-720 mL of milk/day. They should also
consume an adequate amount of iron-containing foods to meet daily requirements  red meat/
liver/ kidney/ beans/ nuts & seeds/ dark green veg
o 1 yr old requires 8mg/day
Sources:
Breast milk (low content but 50% absorbed)
Infant formula
 Cow's milk (higher [Fe] but only 10% absorbed)
 Solids
Tx of Fe def anemia  dietary advice & oral iron therapy
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Oral therapy
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 Sytron (Sodium iron edetate)/Niferex (polysaccharide iron complex)
 Continue until Hb normal, then for another 3 mths to replenish iron stores
o Ferrous sulfate (3 mg/kg, OM/BD x 4/52) should produce a rise of greater than 1 gm/dL in
patients with iron deficiency
o Potential causes for recurrent or refractory IDA include: Compliance issues, intolerance to meds,
ongoing GI blood loss (parasite, Meckel’s diverticulum, ulcers, or other anatomic maladies),
chronic inflammatory disease, incorrect diagnosis, pulmonary hemosiderosis
Parenteral therapy
o Reserved for patients with severe, persistent anemia who have proven intolerance to oral
supplements, malabsorption, or poor compliance to oral therapy
o 2-3% risk for anaphylaxis, some cases of which resulted in death.
Blood transfusion
o Transfusion therapy is rarely necessary (children reach Hb 2-3 g/dl very gradually & can tolerate
it) for severe IDA, even with Hb of 4 to 5 gm/dL.
o Transfusions reserved for patients in distress (heart rate greater than 160/min, respiratory rate
greater than 30/min, lethargy, not feeding well) and should be used with caution (transfusion
volumes of 5 mL/kg over three to four hours) to avoid inducing heart failure.
Follow-up
Aplastic anaemia
Overview
 Aplastic anemia (AA) is a rare disorder characterized by pancytopenia and hypocellular bone marrow due
to injury to or loss of pleuripotent haematopoietic stem cells.
 AA can result from either inherited or acquired causes.
 The incidence is triphasic, with one peak in childhood at 2-5 yrs (due to inherited causes), and two peaks
in adulthood, 20-25 yrs and the majority of pt presenting beyond 55 to 60 years of age (due to acquired
causes)
 Causes of inherited AA
o Fanconi anaemia
o Dyskeratosis congenital
o Shwachman-Diamond syndrome
o Amegakaryocytic thrombocytopenia
 Causes of acquired AA
o Idiopathic
o Cytotoxic drugs and Radiation
o Idiosyncratic drug reaction
 Chloramphenicol, Gold, NSAID, Sulfonamides, Antiepileptic
o Toxic chemicals
o Viral infections
 Parvo B19, HIV, EBV
o Immune disorders
o SLE, graft VS host disease
Kristy’s Paediatric Hematology and Oncology Notes
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3 Main causes
o Congenital red call aplasia (Diamond-Black fan anemia)
o Transient erythroblatopenia of childhood
o Parvovirus B19 (only causes red cell aplasia in children with inherited hemolytic anemia and not
in healthy children)
Diagnostic Clues
 Low reticulocyte count despite ↓Hb
 Normal bilirubin
 Negative direct antiglobulin test (Coombs test)
 Absent red cell precursors on BM exam
Clinical presentation
 Thrombocytopenia: hemorrhagic manifestations
 Progressive anaemia: Fatigue and pallor
 Neutropenia: Fever, mucosal ulcerations, and bacterial infections
 Some of the inherited disorders of AA often are a/w characteristic congenital malformations and/or extrahaematologic manifestations
Disease
Fanconi anaemia
Manifestations
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly
Hypogonadism
Short Stature
Dyskeratosis congenital
Reticulated or mottled hyperpigmented rash
Nail dystrophy
Mucosal leukoplakia
Diamond-blackfan anemia
(Rare; fam Hx in 20%)
 Present at 2-3 mths, some @birth
Symtoms of anemia
Short stature
Some
Abnormal thumbs
Transient erythroblastopenia of
childhood
(TEC)
Usually triggered by viral infection
Always recovers in a few weeks
tx by oral steroids
(monthly red cell
transfusion for those
unresponsive to
steroids)
No fam hx/ congenital
anomalies/ RPS
mutation
Principles of diagnosis
 Bone marrow aspiration and biopsy. Characteristic findings of AA include:
o Hypocellular with a decrease in all elements
o Marrow space is predominantly composed of fat cells and marrow stroma
o Malignant infiltrates or fibrosis are absent.
 Evaluation for possible precipitating factors or causes of AA
o FHx of cytopenias and h/o exposure to medications or toxin
o Physical examination looking for dysmorphic features or signs of other causes of pancytopenia
such as infections, malignancies, or rheumatologic disorders.
o Serologic testing for viruses associated with AA (HIV, CMV, EBV, Parvo, HSV)
o Serum folate and B12 levels
o Tests for specific causes of AA such as diepoxybutane (DEB) screening for chromosomal
breakage in lymphocytes to detect Fanconi anemia
Principles of management
 Haematopoietic cell transplantation from a HLA-matched sibling donor is the treatment of choice for
severe and very severe acquired aplastic anemia.
 Intensive immunosuppressive therapy if a HLA-matched sibling donor is not available (antithymocyte
globulin, cyclosporine, prednisone and recombinant human G-CSF or GM-CSF)
Kristy’s Paediatric Hematology and Oncology Notes
Hemolytic anaemia
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↓ red cell lifespan due to ↑ red cell destruction in the circulation (intravascular hemolysis) or in
Liver/spleen (extravascular hemolysis)
Normal red cell lifespan: 120 days
BM pdtn ≈173000 x106 RBC/day
Hemolysis: RBC survival ↓ by a few days BUT BM can ↓ pdtn by 8X, therefore only leads to anemia when
BM no longer able to compensate
Immune hemolytic anemia (rare in kids but more in neonate)
Mainly due to intrinsic abnormalities of RBC
1. Red cell membrane disorders (hereditary spherocytosis)
2. Red cell enzymes disorders (G6PD)
3. Hemoglobinopathies (β thal major, sickle cell)
Hemolysis for ↑ red cell breakdown leads to:
 Anemia
 Hepatosplenomegaly
 ↑ blood levels of conjugated bilirubin
 Excess urinary urobilinogen
Diagnostic Clues
1. ↑ reticulocyte count (polychromasia on PBF)
2. Unconjugated bilirubinemia, ↑urinary urobilinogen
3. Abnormal appearance of RBC on PBF
4. Direct antiglobulin test (positive if immune causes)
5. ↑RBC precursor in BM
Bone Marrow Failure
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Aplastic anemia
Rare. Reduction/ absence of all 3 main lineage → peripheral pancytopenia
Inherited/ idiopathic/ Aquired [Virus (hepatitis), drug (sulphonamides/chemo), toxins (benzene/glue)]
Partial/complete
May begin with failure of one lineage & progress to all 3
Clinical presentation
→ anemia due to ↓ red cell number
→ infection due to ↓ WBC number
→ bruising & bleeding due to thrombocytopenia
1. Inherited aplastic anemia (All rare)
1. Fanconi Anemia
o Most common form
o AR
o Majority have congenital anomalies
 Short stature
 Abnormal radii & thumbs
 Renal malformations
 Microphthalmia
 Pigmented skin lesions
o
o
o
Either present with this/ signs of BM
failure (5-6 yrs old)
Neonates:
 Normal FBC
 ↑ chromosomal breakage of peripheral blood lymphocytes → identify affected
fam/antenatal
Affected children: High Risk of death from BM failure OR transformation to leukemia
Tx: BM transplant
2. Shwachman - diamond syndrome
 AR
 BM failure & pancreatic exocrine failure & skeletal abnormalities
 Most: mutations in SBDS gene → used to identify/prenatal diagnosis
 ↑ risk of transforming to leukemia
Kristy’s Paediatric Hematology and Oncology Notes
Acute haemolytic anaemia: G6PD deficiency
Case: A previously well 2-year-old black male child is treated with sulfonamide. Two days later, he develops
fever, back pain, dark urine, and anaemia. Blood smear shows fragmented erythrocytes.
Case: A 3-year-old boy is admitted with a history of fever for 1 day, pallor noted the past few hours and red urine,
which did not sediment on standing for a few hours.
Hemolysis  predominantly intravascular
Definition
 Enzyme defect of hexose monophosphate (HMP) pathway resulting in hemolysis when exposed to
stresses such as infection or certain drugs
 G6PD is essential for preventing oxidative damage to Red cells
Epidemiology
 Higher incidence in black, Middle Eastern and Mediterranean populations
 Most common hemolytic enzymopathy
 X-linked Recessive
Pathogenesis
 X-linked recessive, affected males are more vulnerable to oxidant injury
 Carrier females are asymptomatic except for those with a high proportion of enzyme-deficient RBCs (due
to unfavourable lyonisation)
 G6PD catalyzes the conversion of G-6-P to 6-phosphogluconate, in the first step of the pentose
monophosphate shunt in which the co-factor, NADP is reduced to NADPH.
 This is vital for maintaining gluthatione in the reduced state (GSH)
 GSH is the major intracellular anti-oxidant.
 When G6PD-deficient RBCs are exposed to oxidant stress, there is oxidation of Hb producing
denaturation and Heinz body formation.
 Oxidation of the membrane leads to polypeptide aggregates producing rigidity and less deformability
 This leads to entrapment and destruction of RBCs in the spleen – Splenic macrophages ‘bite out’ RBCs
 Sources of oxidant stress
o Drugs: antimalarials, sulphonamides, nitrofurantoin, aspirin and Vit K derivatives
o Toxins
o Infections: trigger release of toxic radicals from phagocytes
Clinical features
 History
o Episodic intravascular hemolysis secondary to oxidant stress
 Drugs: Acute and of variable clinical severity [KIDS W G6PD SHDNT TAKE THESE]
 Aspirin (high dose)
 Sulfonamides (co-trimoxazde..)
 Ciprofloxacin
 Antimalarials (primaquine, quinine, chloroquine)
 Nitrofurantoin (abx)
 Fava beans (“Favism”)/ Naphthalene (mothballs)
 Infection
*List of drugs that children with G6PD shouldn’t take
o Patients develop haemolysis after a lag period of 2-3 days
o Neonatal jaundice (usually)
1st 3 days of life
 Most common cause of severe NNJ needing exchange transfusion.

Physical Examination
o Spontaneous chronic nonspherocytic hemolytic anaemia
 Usually a/w fever, malaise & passage of dark urine Hb & urobilinogen present
 Hb falls rapidly and may be <5 g/dl in 24-48 hrs
o Jaundice, dark urine
o Splenomegaly
Kristy’s Paediatric Hematology and Oncology Notes
Diagnosis
 Reduced G6PD activity in RBCs may be misleadingly elevated during hemolytic crises due to ↑ [G6PD]
in reticulocytes
 Anaemia, Heinz bodies, and bite cells on peripheral smear
 Reticulocytosis
B/w episodes, almost all will have:
 Elevated serum bilirubin and LDH
- Completely normal bood picture
 Decreased serum haptoglobin
- No jaundice
 Hemoglobinuria
- No anemia
Investigations
 Based on the typical association of haemolysis with a triggering agent
 “Bite” cells are seen on the blood smear and cresyl blue staining shows Heinz bodies
 Qualitative and quantitative measurement of G6PD activity confirm the diagnosis; however the level may
be falsely high during or soon after a hemolytic episode
Principles of management
 Avoid precipitating drugs
 Supportive care, blood transfusion and counseling and education to prevent further episodes of
haemolysis.
 Generally self limiting as the bone marrow produces more RBCs
 Advice about signs of acute hemolysis (jaundice, pallor, dark urine)
Management
 Admit
 Removal of oxidant stressor
 Oxygen
 Transfusion of packed RBC if
o Hemodynamic instability
Rarely required
o Hb <6g/dL
o Ongoing hemolysis
Acute haemolytic anaemia: Sickle cell disease
3 main forms of sickle cell disease & the sickle cell trait
1. Sickle cell anemia (HbSS)
a. Homozygous for HbS
b. No HbA
2. HbSC disease (nearly normal Hb, less painful crisis than HbSS)
a. HbS from one parent
b. HbC from the other
c.
Therefore no HbA
May develop proliferative retinopathy in adolescence (check eyes), prone to osteonecrosis of hip
& shoulders
3. Sickle β thalassemia
a. Hbs from one parent
b. β thal trait from other
Most no HbA
4. Sickle trait
a. Hbs from one parent
b. Normal β globin gene from other
c. 40% of Hb is HbS
d. No sickle cell disease, but carriers
Asymptomatic
Epidemiology
 Highest incidence in Africa, where it confers a slight protective effect against Plasmodium falciparum
malaria
 Worldwide, it is the commonest form of familial haemolytic anaemia
 Locally, it is rare
 Prognosis  premature death
 50% with severe form die < 40 yrs
Kristy’s Paediatric Hematology and Oncology Notes
Pathogenesis
 Autosomal recessive
 Mutation in the gene encoding β–globin chain, Single amino acid substitution: substitution of valine for
glutamic acid at the 6th amino acid position of the β–chain produces HbS
 Heterozygous (sickle trait) – does not result in any clinical problem
 On deoxygenation, HbS molecules undergo gelation/crystallisation (a change in physical state), distorting
the RBCs, which assume a characteristic crescentic, sickle shape.
 Outcome of sickling
o Dysfunctional sickled RBCs are removed by mononuclear phagocytic cells, resulting in chronic
extravascular anaemia
o Sickled RBCs cause microvascular obstruction and results in ischemic tissue damage
→ worsened by low O2 tension, dehydration and cold
Clinical features
 History
o In homozygotes, symptoms of anaemia manifest after 6th month of life, after HbF depletes
o Prone to infections
Physical examination
 Splenomegaly
Kristy’s Paediatric Hematology and Oncology Notes
Complications
 Splenomegaly  autosplenectomy
 Vascular congestion and thrombosis can affect any organ
 Ischemia of the bone marrow  necrotic marrow can give rise to fat emboli  travel to the lung to cause
“acute chest syndrome”
 Stroke
 Aplastic crisis: due to parvovirus infection causing temporary cessation of erythropoiesis
 Gallstones
Investigations
 FBC: severe anaemia in homozygotes
 Reticulocytosis
 LFT: hyperbilirubinaemia
 X Ray: In the skull, appositional new bone formation results in a “crew-cut” appearance
 Hb electrophoresis
Tx of acute crises
 Pain  oral/IV analgenes
 Good hydration  oral/IV
 Abx
 O2
 Exchange transfusion for acute chest syndrome, priapism, stroke
Tx of chronic
 Hydroxyurea
Principles of management
 Prophylactic treatment (daily oral penicillin against encapsulated) against pneumococcal infections, Hib,
Irep pneumonia, meningococcius
 Hydroxyurea: increases levels of HbF which inhibit sickling
 Daily folic acid
 minimise exposure to cold, dehydration, excessive exercise, undue stress/bypoxia
Kristy’s Paediatric Hematology and Oncology Notes
Chronic haemolytic anaemia: Thalassemia*
History (must know Hx taking!)
- Ask about the 4Cs of chronic disease  course, control, compliance, complication
1. DEMOGRAPHICS
 Age
 Gender
 Ethnicity (Malays – HbE β-thalassaemia; Chinese – HbH disease)
 Date of admission
 Drug allergies
2. PRESENTING COMPLAINT/HISTORY OF PRESENTING COMPLAINT
 Reasons for current admission – Consider:
o Visit to drug therapy centre for regular blood transfusion, otherwise stable and well
 Admission for elective surgery, e.g. splenectomy, cholecystectomy – premature bilirubin gallstone
formation and biliary tract infection – due to the increased turnover of bilirubin in chronic haemolysis
o Symptoms of disease complications, e.g. cardiomyopathy, CCF, DM, worsening anaemia,
jaundice
o May also be for causes not directly related to thalassaemia
3. PAST MEDICAL HISTORY
 Diagnosis
o Age of diagnosis, when was it diagnosed
o Initial presentation
o Where it was diagnosed, investigations done
Usually presents at 6-12 months of age with increasing pallor, FTT, jaundice. But also may be
antenatal diagnosis
o How was the diagnosis made
o Which type of thalassemia
 β / HbE β: thal major/ thal minor
 HBH disease (Hemoglobin H)
 HBH/ Hb constant spring mutation (Hb CS) Both are alpha thalassemia
o Molecular mutations
o Blood group
 Course and control
o Treatment history
 Age at 1st transfusion
 How often are transfusions needed per year? (__ units per __ weeks)
 What is the pre-tx Hb level? Baseline Hb levels
Any transfusion reactions – requires premedications? Leucocyte filter? During allogenic blood transfusion a
person receives large number of allogenic donor leukocytes and these are recognized as foreign cells by the
recipient immune system which leads to several adverse reactions.
 Need for special blood products (wash/ leukodepleted/ specific antibodies – HIA card)
o Iron Chelation therapy
 Age when chelation therapy was started (Desferal/L1)
 Current chelator
 Route of administration (PO/SC)
 Dose and frequency
 Who administers therapy
 Correct technique, knowledge of self administration
o Other medications, e.g. Folate, Vit C, B-complex, Thyroxine (for short stature), penicillin (post
splenectomy), ask for drug allergies too.
 Compliance
o Blood transfusion: who brings them to the therapy centre
o Iron chelation therapy: compliance and side effects that affect compliance
 Complications
o Kids usually get pale and tired just before their next transfusion is due  anemia
o Of the disease
 Hyperbilirubinemia (jaundice, gallstones  need for cholecystectomy)
 Extra-medullary erythropoiesis (splenomegaly  splenectomy  complications of
splenectomy e.g pneumococcal vaccinations)
o Of the treatment
 Blood transfusion:
Kristy’s Paediatric Hematology and Oncology Notes




Acute complications (transfusion rxns: signs of rash, fever, anaphylaxis)
Blood products associated infections: Hep B, Hep C, HIV
Chronic complications (mainly due to iron deposition in organs)
o Pituitary gland
 Short stature – compare with siblings, compare with
classmates
 Delayed puberty (no increase in LH and FSH)
 Hypogonadism
o Thyroid gland
 Hypothyroidism
 Compliance to L-thyroxine
o Parathyroid gland
 Hypoparathyroidism
 Hypocalcemia causing muscle cramps/spasms,
numbness around lips, fingers, petechiae
 Osteoporosis & its management  recent BMD,
DEXA score, on biphosphates? PO/IV,compliance?
o Heart
 Cardiomyopathy
 Ask about symptoms of CCF/ arrhythmias
 Investigations done for CMP
o Cardiac MRI done before? Results?
o Cardiology assessment? Treatment for CCF/
CMP?
o Liver
 Chronic liver disease  symptoms and follow up with
specialist

o Pancreas
 Test for diabetes
 Management of diabetes
 Iron chelation:
 Audiology screening and ophthalmology assessment (due to toxicity of iron
chelating agents)
Other medical history
o Hospitalizations (other than for PCT – “packed red blood cells transfusion”), reasons. Previous
surgeries, e.g. splenectomy (ask abt date, and all the vaccinations: pneumococcal, HiB, pen V
prophylaxis, complications), cholecystectomy.
o Birth
o Immunizations
o DA
4. FAMILY HISTORY
 Parent’s genetic status, do they know if they are carriers? Consanguinity?
 Any siblings affected? If so, on treatment?
 Any genetic counseling before?
 Family tree!
5. SOCIAL HISTORY
 Disease impact on the child
o Schooling:
 Which stream, level
 Academic performance
 Amount of school missed
 Behaviour, conduct
 Able to take part in PE?
o Body image, pubertal anxieties (in teens)
 Disease impact on family
o Financial considerations (cost of desferal + pump). In Singapore, desferal costs $3.60/vial
(500mg), 2 vials per day needed, most people use it on alternate days
o Social support available, support groups
 Understanding of disease
o Perception of disease
Kristy’s Paediatric Hematology and Oncology Notes
o
Compliance with medications
6. SUMMARY
My patient is a (age/race/gender) who has (β-thal major/HbE β-thal/HbH etc.), who is:
 Transfusion dependent (or not)
 Clinically thalassaemia major/intermedia
 Ongoing problems/issues include: ________ (& reason for hospitalization is ________)
Physical examination
1. INSPECTION
 Bronzed skin (iron deposits)
 Short stature
 Peripheral cyanosis (heart prob so decrease in blood flow so blood in peripheries stay there longer and
tissue take up O2 longer)
 Deformities due to pathological fractures
 PCT, O2, IV line
 Thalassaemic facies – frontal bossing, maxillary hypertrophy, malocclusion of teeth
 Pallor
 Jaundice
2. ABDOMEN
 Desferal (used in iron overdose to bind iron) scars (pigmented, round, no lipodystrophy)
 Surgical scars (open/laparoscopy)  cholecystectomy/ splenectomy
 Hepatomegaly (secondary to extramedullary erythropoiesis/Fe deposition + splenomegaly
 Stigmata of chronic liver disease
3. CHEST (look for CCF signs)
 Apex beat displaced?
 Bilateral creps
 Pedal edema
 Systolic ejection murmur in severe anemia
 Flow murmur
 In CCF?
4. ENDOCRINE
 Signs of hypothyroidism
o Pale, dry skin, slow DTR (deep tendon reflexes)
 Screen visual acuity
 Delayed/ absent sexual characteristics (E.g. lack of axillary/ pubic hair)  offer, may not be allowed to
examine in the exam
 Tanner staging, if patient allows it.
5. WISHLIST
 Patient’s height and weight and plot it on a growth chart
Case presentation
The history is taken from the patient/ parent. My patient, (name), is a __ year old (gender) who has (type of
thalassemia), who is transfusion dependent/ transfusion independent. The patient is adequately/ inadequately
transfused. Clinically, the patient is iron overloaded/ not overloaded. His current issues are:
a. Medical issues, acute & chronic (E.g. CCF secondary to severe anemia as evidenced by bilateral
creps heard in both lung bases and pedal edema, chronic liver disease secondary to iron deposition)
b. Psychosocial issues (school performance, financial concerns)
In the management of this patient I would like to: _____
Introduction
A spectrum of diseases characterised by the reduced or absent production of one or more globin chains (alpha or
beta, predominantly), resulting in a disruption of the ratio between alpha and non-alpha chains.
Clinically the thalassaemias vary from asymptomatic with mild anaemia (thal minor) to transfusion-dependent (thal
major) to forms not compatible with life (Hb Bart’s).
Kristy’s Paediatric Hematology and Oncology Notes
HAEMOGLOBIN TYPES AND THEIR COMPONENTS
Haemoglobin is composed of 2 alpha-globin subunits and 2 non-alpha-globin subunits
 In adults the predominant form of haemoglobin is HbA  2 alpha- and 2 beta-globin subunits.
 In children, predominant form is HbF  2 alpha and 2 gamma subunits
o Production of β globin only increases after birth (switch from HbF to HbA from 3-6 months)
Adult
blood:
HbA
α2β2
HbA2 α2δ2
HbF α2γ2
(96-98%)
Fetal
blood:
(1.5-3.2%)
(0.5-0.8%)
α2γ2
(age depd)
HbA2 α2δ2
(age depd)
HbF
Epidemiology
 Carrier rate of thalassaemia in Singapore
o β-thalassaemia:
2%
o HbE:
6% (among Malays)
o -thalassaemia:
6.2%
 0 - 3.0%
 + - 3.2%
(Chinese tend to carry α0 mutation)
Population
+
0
E
+
0
Overall (n = 1032)
3 (0.29%)
12 (1.16%)
17 (1.65%)
32 (3.10%)
17 (1.65%)
Chinese (n = 485)
0 (0%)
11 (2.27%)
1 (0.21%)
9 (1.86%)
17(3.51%)
Malays (n = 334)
2 (0.6%)
1 (0.3%)
16 (4.19%)
14 (4.19%)
0 (0%)
Indians (n = 213)
1 (0.47%)
0 (0%)
0 (0%)
9 (4.23%)
0 (0%)
Pathophysiology
 Chain imbalance
o E.g. in -thalassemia, there is an excess of -chains in the RBC precursors, which aggregate
together to form a very unstable and nonfunctional molecule
 Ineffective erythropoiesis
o RBC precursors proliferate prodigiously (leading to marrow expansion) but the hemoglobin
produced is ineffectual
 Hemolysis
o Typical extramedullary hemolysis is seen only if the Hb is sufficiently stable to be released into
the blood (seen in HbH disease, but not -thalassemia major)
Clinical features
1. THALASSAEMIA MAJOR
Commonly, two features define thalassaemia major:
1.Transfusion dependence; and
2. Early age of onset. Almost all thal major patients have beta-thalassaemia and not alpha-thalassaemia.
Transfusion dependence:
 Thal major patients require regular blood transfusions for severe haemolytic anaemia, usually once every
3-4 weeks, and they will be very symptomatic if not transfused.
 Thal intermedia patients who receive transfusions when they are symptomatic or when their Hb level is
low, which is usually less frequent than required in thal major patients.
 Thal minor patients do not require transfusions.
Age of onset:
 Beta-thal major usually presents at 3 to 6 months of age with the decline in production of foetal
haemoglobin (HbF-alpha2/gamma2) declines and HbA (alpha2/beta2) becomes the predominant
haemoglobin.
 Beta-thal intermedia usually presents later than 18 months of age. However, there are also thal major
patients who present late and are still transfusion-dependent.
 Alpha-thal intermedia patients usually present at birth or soon after birth, as alpha chains are needed for
both foetal and adult haemoglobin.
Kristy’s Paediatric Hematology and Oncology Notes
In summary:
 Thalassaemia major is a clinical presentation where the patient has severe symptomatic anaemia with
onset usually within 1 year of life, requiring regular, frequent blood transfusions.
2. THALASSEMIA INTERMEDIA
Symptomatic thalassaemia but not requiring transfusion at least during first few years of life, and patients are
able to survive into second decade of life without chronic hypertransfusion therapy.
3. THALASSEMIA MINOR
Usually asymptomatic, mild MCHC anaemia; may have slight splenomegaly. Not transfusion dependent.
Other features
 Chronic haemolytic anaemia
o Pallor
o Jaundice (“lemon-yellow” jaundice of unconjugated hyperbilirubinaemia)
o Decreased effort tolerance – fatigue, postural giddiness, SOB, chest pain, palpitations
o Decreased growth (due to increased caloric requirements of erythropoiesis, and also endocrine
effects of iron overload)
o Cardiac dilatation and failure if untreated (rarely untreated nowadays)
 Extramedullary haematopoiesis
o Skeletal changes secondary to expansion and invasion of erythroid bone marrow which widen
the marrow spaces and attenuate the cortex
 Frontal bossing
 Maxillary hypertrophy
 “Hair-on-end” radiographic appearance of skull bones due to widening of diploic spaces
o Hepatomegaly
 Later in life, iron overload results in liver cirrhosis
o Splenomegaly
 Look for scar of splenectomy – no palpable spleen
 Splenomegaly may result in hypersplenism – worsens anaemia or causes decrease in
other cell lines.
 Fe overload from chronic hypertransfusion
 Iron overload from chronic hypertransfusion
o Cardiac haemosiderosis – sterile pericarditis, arrhythmias (both supraventric-ular and
ventricular), end-stage restrictive cardiomyopathy leading to cardiac failure
 Fatal arrhythmias are a common cause of death in teen years
o Liver cirrhosis
o Endocrine and metabolic complications
 Hypogonadism, growth retardation
 Diabetes (iron deposition in pancreas)
 Hypothyroidism
 Increased cell turnover – hyperuricaemia + gouty arthropathy
 Aplastic crisis from Parvovirus B19 infection
 Osteoporosis occurs even in well-chelated and well-transfused patients, though cause is not well known
o Contributory factors: genetic abnormalities, vitamin D deficiency (aetiology in thal unknown),
failure to progress normally through puberty (due to hypogonadism)
 Premature bilirubin gallstone formation and biliary tract infection
o Due to the increased turnover of bilirubin in chronic haemolysis
Possible causes of jaundice in thalassemia patients
 Aplastic crisis/haemolytic crisis
 Gallstones
 Infections (Hep B, CMV, EBV etc.)
 Cirrhosis
 Other unrelated causes i.e. autoimmune, drugs etc.
Kristy’s Paediatric Hematology and Oncology Notes
Laboratory features
1. FULL BLOOD COUNT
 Anaemia
o Microcytic (lower limit of MCV is [70 + age] up to 8yrs old, after which it is 78)
o Hypochromic
o Hb level:
>9g/dL: mild;
7-9g/dL: moderate;
<7g/dL: severe
o Other cell lines may be affected by hypersplenism – leucopaenia, thrombocytopaenia
2. PERIPHERAL BLOOD FILM
 Microcytic hypochromic RBCs
 Anisocytosis (cells of different size)
 Poikilocytosis (cells of different shape)
 Target cells (also called Mexican hat cells – RBCs lose their biconcave configuration) – not
pathognomonic of thal
 Evidence of intravascular haemolysis – fragments
 HbH inclusion bodies on Brilliant Cresyl Blue stain seen in alpha thalassaemias – HbH disease and
alpha-thal-1
(HbH is a tetramer of beta-globin chains due to the excess of beta-globin in the RBC)
3. OSMOTIC FRAGILITY
 Decreased fragility (as cells are less full as compared with normal RBCs)
 In contrast, osmotic fragility is increased in hereditary spherocytosis as surface area to volume ratio is
very low – volume cannot expand any more
4. HAEMOLYSIS MARKERS
 Reticulocyte count high
 LDH elevated
 Haptoglobins level low
5. LIVER FUNCTION TESTS
 Elevated bilirubin – unconjugated (indirect bil)
 Liver enzymes may be deranged in cirrhosis secondary to iron overload
6. Hb ELECTROPHORESIS
 In beta-thal:
o HbA2 will be elevated to 3.5-7% (normal <3%)
o Increased HbF % (greater increase in beta-thal major than beta-thal-minor)
o Decreased HbA %
 In alpha-thal
o Decreased HbA, HbA2, and HbF
o HbH band seen in HbH thal
7. GENOTYPING
 Deletion mutation in alpha-thal – most commonly the Southeast Asian mutation in Singapore
 Point mutation in beta-thal
8. SERUM FERRITIN
 Sign of iron overload – serum ferritin will be increased
 Start iron chelation therapy when serum ferritin reaches 1000mcg/L
Kristy’s Paediatric Hematology and Oncology Notes
Genetics and correlation with phenotypic features
-THALASSEMIA
- Healthy ppl have 4  globin genes
There are 2 genes encoding for the alpha-globin chain on chromosome 16, making four alleles for the alphaglobin chain. In Asian populations, alpha thalassaemia commonly results from a deletion of one or more of the
alpha-globin genes; there are thus 4 possible genotypes:
(1) Alpha-thal-2 (one mutant allele: αα/α-) ( thal trait)
 Essentially asymptomatic, and no anaemia
 Silent carrier
 FBC, peripheral blood smear, and Hb electrophoresis are largely normal
 A few fine inclusion bodies with BCB
 There may be slight hypochromia and/or microcytosis seen
 Detection by
 Exclusion (family screening)
 Genotyping
 Diagnosis:
o FBC: normal
o Hb electrophoresis: normal
o HbH inclusion: negative
o DNA analysis: -α/αα or αcsα/αα
(2) Alpha thal-1 (2 mutant alleles: αα/-- or α-/α-) ( thal trait)






Also called alpha-thal minor
Features
o Similar phenotype to beta-thal minor – mild MCHC anaemia not requiring transfusion (may not
even have anemia)
o Asymptomatic
PBF shows few coarse HbH inclusion bodies on BCB stain
Hb electrophoresis is normal – no HbH band seen
Phenotypic features are slightly worse in patients with the ‘cis’ configuration (αα/--) compared to the ‘trans’
configuration (α-/α-)
Diagnosis:
o FBC: microcytic anemia. Hb (9-12) MCV <80
o Hb electrophoresis: normal
o HBH inclusion: positive
o Serum iron: normal
o DNA analysis: --/αα or –α/-α
(3) HbH disease (3 mutant alleles: α-/--)
 Clinically thal intermedia phenotype
 Common in Chinese (Rare in Malays and Indians)
 Moderate anaemia (Hb 7-10g/dL), occasionally transfusion dependent
 Haemolytic anaemia starts in the foetus, and newborns with HbH will usually be anaemic and jaundiced,
occasionally with hydrops
 Clinical features are similar to beta-thal intermedia – patients are not dependent on chronic transfusion
support in the first decade of life but may require it in the second or third decades
 Moderate pallor, jaundice (lemon yellow) and splenomegaly
 Laboratory features
o Microcytosis
o Reticulocytosis
o Osmotic fragility decreased
o Obvious target cells
o PBF shows many HbH inclusion bodies on BCB stain – “golf-ball” appearance
o Hb electrophoresis shows a fast moving HbH band
 Diagnosis:
o FBC: moderate microcytic anemia; Hb 6-10; MCV<70
o HBH electrophoresis: decreased HbA2, HbH 10-15%
o HBH inclusive: Positive
o Serum iron: normal
o DNA analysis: --/-α or --/αcsα
Kristy’s Paediatric Hematology and Oncology Notes
(4) Bart’s hydrops (4 mutant alleles: --/--) ( thal major)








Not compatible with life
Deletion of all 4 α-globin genes, No HbA (α2β2) produced
Seen solely among Chinese
Hb Bart’s is a tetramer of gamma-globin chains in the foetus, which cannot deliver oxygen to tissues due
to an extremely left-shifted oxygen dissociation curve, resulting in massive tissue ischaemia. Hydrops
foetalis occurs due to high output cardiac failure, and the foetus usually dies in the late second to midthird trimester, or dies soon after birth.
An aggregate of 4γ chains (name after St Bart’s Hospital in London)
More common in Asia since the ‘cis’ form of alpha-thal-1 is more common in Asia than in Africa – two
alpha-thal-1 parents have a 25% chance of having a child with Bart’s hydrops
Only survivors  monthly intra-uterine transfusion + monthly lifelong transfusion
Diagnosis:
o FBC: severe anemia Hb<3
o Hb electrophoresis: Hb Bart’s (gamma 4)
o DNA analysis: --/--
Constant spring mutation (HbCS)
 Hb Constant Spring is a mutation in the alpha-globin gene that results in the conversion of the stop codon
into a codon coding for an amino acid, thus lengthening the alpha-globin chain by 31 amino acids.
 The resultant longer alpha-globin chain is functional and relatively stable; however, the precursor mRNA
is markedly instable as a result of this mutation and is rapidly degraded, with the end result that only 1-5%
of the normal production of alpha-globin from the gene is achieved.
 Clinically, HbCS heterozygotes are similar to alpha-thal-2 patients, and homozygotes similar to alpha-thal1
 Compound heterozygotes may occur: HbCS/α- (thal minor phenotype); HbCS/-- (thal intermedia);
HbH/HbCS (thal intermedia)
-THALASSEMIA
The gene for the beta-globin chain is situated on chromosome 11. Mutations causing beta-thalassaemia are
commonly point mutations, and result in two types of defect: (i) β o mutations result in absence of production of
beta-globin; and (ii) β+ mutations result in decreased production of beta-globin.
Both result in ↓HbA.
Severe reduction in β-globin and disease severity depends on amount of residual HbA and HbF pdtn.
Autosomal recessive trait.
Additionally, there is a mutation called HbE, which is prevalent among the Malay population; this mutation involves
a single-base substitution that results in the substitution of lysine in place of glutamate as the 27th amino acid in
the beta-globin chain. This mutation produces an additional abnormal splice site – 65% of the pre-mRNA is
spliced at this site and the resulting mRNA is not translatable and highly unstable, while only 35% of the premRNA is spliced normally. The normally spliced mRNA produces a beta(E) globin that is relatively stable, but the
overall rate of production is only 35% of normal due to the abnormal splicing. The HbE gene thus results in a mild
form of the thal minor phenotype in heterozygotes.
Patients with beta-thal can either be heterozygous or homozygous, or compound homozygotes:
(1) Beta-thal trait [50% slight ↑ in HbF (1-3%] or beta-thal minor (ββ+ or ββo)
 2% of Singapore population. Usually asymptomatic.
 Clinically thal minor trait with mild MCHC anaemia
 PBF may show target cells
 Osmotic fragility decreased
 Hb electrophoresis shows elevated HbA2 (most diagnostic feature) of 3.5 to 7% (Normal is <3%); but
normal HbA2 does not rule out beta-thal trait because some forms have normal
HbA2
 10-15% may have asymptomatic slight hepatomegaly
 Diagnosis:
o FBC: microcytic anemia Hb 9-12, MCV <80
o Hb electrophoresis: HbA2 increased, HbF increased (RBC usually ↑)
o HBH inclusion absent
Kristy’s Paediatric Hematology and Oncology Notes
o
o
Serum iron: normal (diff from Fe def: ↓ serum ferritin)
Mild ↓ in MCH (18-22) & MCV (60-70)
(2) Beta-thal major (βoβo or β+β+) (most severe form)
 Condition is fatal w/o regular blood transfusions
 Cooley’s Anaemia
 Phenotype as described above – transfusion dependent, onset within 1 year of life (3-12 months).
Jaundice, FTT/growth failure
 Severe anaemia
o Hb averages 3-4g/dL for severe genotypes (βo/βo)
 Homozygous β+ patients are less severely affected than homozygous β o patients as they are still able to
produce some amount of beta-globin – some may be thal intermedia as opposed to thal major
 Iron overload leads to cardiomyopathy and endocrinopathies and
death during teens
 Frontal bossing, maxillary hyperplasia
o Extramedullary hemopoiesis
 prevented by transfusion
 if no transfusion, Hepatosplenomegaly, bone marrow
expension
 Skull X-ray: Hair-on-end appearance
 Diagnosis:
o FBC: severe microcytic anemia; Hb<6; MCV<60; WBC &
platelets normal
o Hb electrophoresis: no HbA, increased HbA2 and HbF
o HBH inclusion: negative
o Serum ferritin: normal
 Tx aim
o Hb > 10g/dl to reduce growth failure & prevent bone deformation
(3) Compound beta-thal (β+βo or HbE/β+ or HbE/βo)
 Defined by combination of genotypic and phenotypic features
o Genotypic – Homozygous β-thalassemia mutations (e.g. β+/ β+)
o Phenotypic – Moderately severe anaemia, but transfusion independent
 Rare locally
 HbE and beta-thal mutation compound homozygotes usually present with thal intermedia
 β+β0 patients are usually thal major
(4) Hemoglobin E – A Structural Hemoglobinopathy
 Caused by exonic mutation creating alternative splice site in β-globin gene
 4% incidence in Malays
 Both heterozygotes and homozygotes are asymptomatic
 Problem is co-inheritance with β-thalassemia mutation
Kristy’s Paediatric Hematology and Oncology Notes
Clinical correlation between genotypes and phenotypes
-THALASSEMIA
PHENOTYPE
Bart’s hydrops
Hydrops foetalis
Thal major
βoβo
β+ βo
β+β+ (mostly major but can be
intermedia)
HbE/βo (mostly intermedia but can
be major)
HbH
HbH/HbCS
HbH with αα /--
-THALASSEMIA
Thal intermedia
HbE/β+
HbF/ β+
HbCS homozygote
Alpha-thal-1
(αα/-- or α-/α-)
Thal minor
Alpha-thal-2 (αα/α-)
HbCS heterozygote
Thal minima
ββo
ββ+
HbE homo/heterozygote
Treatment
1. BLOOD TRANSFUSION
 Aims
o Maintain a good quality of life
o Prevent marrow hyperplasia
 For patients with thal intermedia or thal major
 Frequency depends on severity – thal major requires transfusions once every 2-3 weeks while thal
intermedia is less frequent
 Age when transfusions were started also varies – usually within first year of life for thal major, later in life
for thal intermedia
(Ask patient/parent if he/she knows his/her usual pre-transfusion Hb)
 Transfusion reactions
o Can be reduced by methods such as using leucocyte filter during transfusion, or giving pretransfusion medications e.g. hydrocortisone
o If filter and meds not effective – transfuse washed cells (WBCs removed from packed cells) but
more expensive, and need to do GXM for patient 2 days before each transfusion
Give folate in thalassemia intermedia as there is increased demand from active bone marrow for folate (high
turnover).
2. CHELATION THERAPY
 Usually started when serum ferritin reaches about 1000mcg/L – about 2-3 years old in thal major patients
where transfusion is started at 6 months of age
 Increases lifespan by decreasing iron deposition in various organs especially heart
 Choices available:
A. Desferrioxamine/Deferoxamine (Desferal)
 Traditional iron chelator
 Administered via slow subcutaneous infusion pumps at night (over 6-8 hrs for maximal effect) –
40mg/kg over 8-10 hrs, 6 days a week
 Side effects: ototoxicity and ophthalmotoxicity – need to monitor vision and hearing; also
anaphylaxis
 Problems with compliance common as it has to be injected – parents may not be able to cope
Kristy’s Paediatric Hematology and Oncology Notes
B. Deferiprone (Ferriprox or L1 [trial name])
 Given orally, TDS – absolutely stress need to be compliant
 Deferiprone has been found to be better in decreasing cardiomyopathy from iron overload
compared to desferrioxamine – used when patients start to have bad iron deposition in the heart
 Not proven to be comparable to desferrioxamine as monotherapy – most patients are on combined
therapy with both desferrioxamine and deferiprone
 Limitations: high cost; 0.5% risk of agranulocytosis – need to check FBC weekly for first year after
starting
C. Deferasirox (Exjade)
 Relatively new drug, side effects not well known, and extremely expensive
 Oral tablet taken once per day
 Not known yet whether it is good in preventing cardiomyopathy

Monitoring
o FBC if giving deferiprone
o Serum ferritin
o LFTs (for cirrhosis resulting from iron overload)
o MRI T2 star for heart and liver once yearly (monitor iron deposition)
3. SPLENECTOMY
 Indication for splenectomy: Increase in the red cell transfusion requirement by 50 % or more over one
year
 Can decrease requirements for red cell transfusion though effect is transient
 Should receive vaccinations against encapsulated bacteria before splenectomy (H. influenzae, Strep
pneumoniae, Neisseria meningitidis)
 Advice to seek medical attention early in case of infections
 Prophylactic penicillin (long-term therapy)
4. CHOLECYSTECTOMY
 For biliary stones causing problems/symptoms
5. SCREENING, PREVENTION AND TREATMENT OF OSTEOPOROSIS
 Bone mineral density studies for screening starting in adolescence
 Regular physical activity
 Avoidance of smoking
 Adequate zinc, calcium, vitamin D intake
 Blood transfusions to inhibit excessive bone marrow expansion
 Adequate chelation
 Potential use of agents to inhibit osteoclast activity – calcitonin, bisphosphanates
6. SCREENING FOR ENDOCRINOPATHIES
 Close monitoring of pubertal development and referral for appropriate endocrinological treatment for
Hypogonadism
 Screening for diabetes – early diagnosis and good control
 Screening for hypothyroidism
 Follow up investigations: Ca/Mg/PO4 (for hypoPTH), thyroid function tests, blood sugar level, urine
glucose, OGTT
 Yearly assessment of growth and pubertal status: bone age; if >14 years old, tests to screen
hypothalamus-pituitary-gonadal axis e.g. testosterone/oestrogen, LH, FSH
7. HAEMATOPOIETIC STEM CELL TRANSPLANTATION
 Only definitive treatment
 Increasing evidence for benefit in patients with severe beta thalassaemia
 Good prognostic factors for HCT: no or minimal hepatomegaly (<2cm), no portal fibrosis, adequate
chelation therapy (90% probability for cure)
 Liable candidates include siblings. However it is difficult to find siblings who do not have the disease.
(Need full HLA matching)
 If bone marrow is transplanted from thal-minor sibling to thal-major sibling, there will be conversion from
thal-major to thal-minor.
 Higher risk of rejection in thal patients as they have different antigens due to multiple transfusions.
 Therefore transplant most ideal when patient is still very young
Kristy’s Paediatric Hematology and Oncology Notes
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Pregnant mothers are not ideal donor candidates as foetus is considered a ‘foreign body’.
No need for immunosuppressants in bone marrow transplantation as the immune system of the recipient
is being completely replaced.
Since a new marrow is being transplanted, the immune cells would have to be educated again – this
means that all previous vaccinations would have to be administered again. Normal immunity takes almost
18 months to return.
A young child has a higher success rate for bone marrow transplantation as they have:
o Lesser antigens
o Lesser dormant infections
o Lesser exposure to environmental pathogens
In theory, foetal transplants (in utero) would be most useful.
Unrelated – marrow, cord blood
Screening and antenatal diagnosis
1. SCREENING FOR THALASSEMIA CARRIER STATUS IN PREGANCY
 FBC done in all mothers in first trimester
 Further investigation if Hb is low (<11g/dL) and MCV is also low (<85fl)  perform Hb electrophoresis
2. GENETIC COUNSELING
 For thalassaemia carrier who wants to have family
 Main aim is to prevent birth of babies with β-thalassemia major
 All mothers screened for thalassemia trait
 Husbands screened too if wife positive
 If parents want to have a normal baby, do IVF to generate multiple embryos, do single cell analysis at
blastocyte stage, and select for normal embryos (pre-implantation genetic diagnosis).
 If both parents are heterozygous for β thal  ¼ risk
2. ANTENATAL DIAGNOSIS
 National Thalassemia Registry in Singapore was set up to facilitate antenatal screening. Now we barely
get a new thal-major per year.
 Both husbands and wives genotyped
 If one or both of the parents are known thal carriers,
o Perform chorionic villus sampling in first trimester (11-13 wks) to test for gene defect of
thalassaemia.
o If patient/mother presents later in pregnancy, may use amniocentesis.
 PCR or DNA-DNA hybridization to detect homozygous -thalassemia in infants (Bart hydrops fetalis).
 If detected early, fetus can be preserved by intra-uterine transfusions and early delivery. Newborn
would have to be on lifelong monthly transfusions thereafter.
 Termination of pregnancy offered if baby is homozygous
Kristy’s Paediatric Hematology and Oncology Notes
Chronic haemolytic anaemia: Hereditary spherocytosis
Epidemiology
 Most common cause of hereditary haemolytic anaemia in people of Northern European (caucasians)
heritage (1 in 5000)
 Rare locally
Pathogenesis
 AD inheritance in 75%. (25% sporadic, new mutation)
 Affects membrane protein spectrin, ankyrin or band3
 RBC loses part of membrane as it passes through the spleen  spherocytes (SA:V ratio)
 Spherocytes less deformable than normal RBC therefore destroyed in microvasculature of spleen
Clinical Features (often suspected because of fam Hx)
 Asymptomatic
 Cardinal features of
o Anaemia (mild: 9-11g/dL) (50%)  Hb may fall transiently during infections
o Jaundice (10-15%)
 Develop in childhood but maybe intermittent
 Severe hemolytic jaundice @ 1st few days of life
o Splenomegaly (mild to moderate) (10-15%)
 Depends on rate of hemolysis
 Aplastic crisis
o Clinical course may be punctuated by aplastic crises: transient cessation of RBC production
o Triggered by parvovirus infections
o Because of the shortened lifespan of the RBCs, even a short period of failure of erythropoiesis
results in rapid worsening of anemia
o Self-limited in most cases
o May require blood transfusions (1-2 over 3-4 wks when RBC provided)
 Gallstone disease  due to ↑ bilirubin excretion
Investigations
 FBC: anaemia
 PBF: spherocytes; PBF is diagnostic
 Pseudohyperkalaemia: K+ leakage as blood is cooled
  Osmotic fragility (more specific test but usually not needed)
 Must do direct coombs to exclude autoimmune hemolytic anemia a/w spherocytes in the absence of fam
Hx of hereditary spherocytsis.
Management
 No treatment available
 When they present, we need to prevent complications of haemoglobinuria by hydrating patient and
encouraging diuresis.
 Give folate supplements.
 Cholecystectomy may be needed in patients with gallstone disease.
 If patient requires cholecystectomy, perform splenectomy at same sitting for convenience.
 Splenectomy is beneficial because the major site of destruction is removed.
o Only indicated for poor growth/troublesome symtoms of anemia
o Deferred until > 7 yrs old due to rises of post splenectomy sepsis
 Administer vaccination against meningococcus, pneumococcus and Hib and possible penicillin
prophylaxis life-long.
Southeast Asian Ovalocytosis (Stomatocytic Elliptocytosis)
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Common among aborigines in Malaysia and Papua New Guinea
Also seen in Malays
Autosomal dominant
2 gene mutations in Band 3 protein (on RBC membrane)
Clinically asymptomatic
Protects against malaria
Kristy’s Paediatric Hematology and Oncology Notes
Approach to the bruised child
History
1. PRESENTING COMPLAINT – NATURE OF BLEED
 When did the bruising start?
 Duration – bleeding tt stops and recur quickly → Coagulopathy
 Preceding/Precipitating event - Trauma, surgery, dental procedure
 Onset – Acute bleeds  Acquired disorder
– Bleeding since birth  Congenital disorder and progression
– Temporal relation to prepitating event
(i) Immediately after/ during trauma  platelet
(ii) Delayed bleeding (hrs)  Coagulopath
 Site – Superficial: skin, mucosa (nasal, gingival)  Platelet
– Deep: joint, muscle  Coagulopathy
– Hematemesis, Menorrhagia, Hematuria, Hematochezia, Melena
 Size – Petechiae, purpura  Platelet
– Echymoses  Coagulopathy
 Extent/ Severity of bleed
o CNS intracranial hemorrhage (↑ICP/ SOL): nausea, vomiting, headache, weakness
o Symptomatic Anemia: postural giddiness, pallor, fatigue, chest pain, SOB, palpitations,
 Search for Etiology
o Thrombocytopenia (petechiae or purpura)
 Infections: Fever, RN, cough, ST, vomiting, diarrhea
 Leukaemia / aplastic anaemia: LOA, LOW, fatigue, increased frequencies of falling sick,
bone pain
 SLE: Malar rash, discoid rash, ulcers, joint pain, chest pain, frothy urine, haematuria,
hallucination, depression, seizures
 Chronic liver disease  hypersplenism: jaundice, liver problem, abdominal pain /
distension
o Coagulopathy (ecchymoses or purpura)
 Haemophilia, vWD
 Liver disease
2. PAST MEDICAL HISTORY
 Previously Diagnosed Bleeding disorder (eg Hemophilia, ITP)
o Age
o Presentation
o Investigations
o Management and treatment in hospital
o Long term Mx: Medication, precautionary measures
o Follow up: frequency, compliance
o Previous admissions
3. DRUG HISTORY
 Aspirin, NSAIDs  Anti-platelet
 Warfarin  Vit K inhibitor
 Anti-convulsants  Thrombocytopenia
 Penicillin
 Procainamide  Lupus anticoagulant
4. FAMILY AND SOCIAL HISTORY
 Family tree
o Male relatives affected (Hemophilia, X-linked Recessive trait)
o Female relatives - Menstrual and Obstetric Hx
Kristy’s Paediatric Hematology and Oncology Notes
Physical examination
 Skin OE: Telangiectasia, Petechiae, Purpurae, Ecchymoses, Hematoma
 Mucosae OE: Nasal (Epistaxis), Gingival
 Muscle and Joint OE: Intramuscular Bleed, Hemearthrosis
Joint contractures ( chronic hemearthroses)
 Signs of anemia: Pallor , ↑ HR, ↓BP, Systolic flow murmurs
 Others: Mouth ulcers, skin rash
 Abd OE: Hepatosplenomegaly
Exclude non-accidental injury (NAI) when atypical sites for bruise e.g. armpit
Investigations
Thrombocytopenia: platelets < 150 x 109/L (worry about cerebral hemorrhage)
 Severe: <20 x 109/L (risk of spontaneous bleed)
 Moderate: 20-50 x 109/L (Risk of excess bleeding during ops/trauma but low risk of spontaneous)
 Mild: 50-150 x 109 (Low risk of bleeding unless major trauma/op)
Neonates  All clotting fators low except factors & fibrinogen
1. FULL BLOOD COUNT AND PERIPHERAL BLOOD FILM
 ↓Hb (significant blood loss)
o Normocytic normochromic: blood loss anemia
o Microcytic: prolonged blood loss
o Pancytopenia (↓Hb, ↓TWC, ↓Plts)
 BM failure
 BM infiltration (Leukemia, Lymphoma)
o Platelet count ↓
 Quantify Thrombocytopenia [< 150x109/ L]
o Platelet morphology-size
 Large plts - ITP, Bernard- Soulier Syndrome
 Small plts - Wiskott-Aldrich Syndrome
Kristy’s Paediatric Hematology and Oncology Notes
2. BLEEDING TIME (BT)
 Primary hemostasis screen (time to form platelet plug)
o ↑ BT + Normal Platelet count
 Platelet function disorder (qualitative)
 von- Willebrand disease
 Fibrinogen disorders (Afibrinogenemia, Dysfibrinogenemia)
3. COAGULATION PROFILE
 PT/ aPTT
 Secondary hemostasis screen (time for coagulation cascade to form fibrin clot)
 ↑ PT : Extrinsic + Common Pathway (Fx 1, 2, 5, 7, 10)
o INR = Pt / Control PT N 1.0 - 1.1
 aPTT : Intrinsic + Common Pathway (Fx 1, 2, 5, 8, 9,10, 11, 12)
o Factor deficiency
o Factor inhibitor
o Heparin contamination
o Circulating anticoagulants
4. MIXING STUDIES
 Dy/dx Factor deficiency and Factor Inhibitor
 Follows abnormal PT/ aPTT
 Normalizes = Factor Deficiency
 Persistence = Factor Inhibitor
5. FACTOR ASSAY
 Quantify Factor deficiency – Factors 8, 9, 11 (Fxs tt cause bleeding)
6. THROMBIN TIME (TT)
 Time to clot when thrombin is added to plasma
 ↑ TT
o Quantitative Fibrinogen Disorder : Afibrinogenemia
o Qualitative Fibrinogen Disorder : Dysfibrinogenemia
7. FIBROGEN MEASUREMENT
 Quantitative Fibrinogen Disorder : Afibrinogenemia
 Qualitative Fibrinogen Disorder : Dysfibrinogenemia
8. PLATELET AGGREGATION STUDIES
9. D-DIMERS
 Test for fibrin degradation pdts.
10. LFT, RENAL PANEL
Normal Hemostasis
1. Coagulation factors
a. Produced by liver (inactive)
b. Activated by tissue factor in vessel injury
2. Coagulation inhibitors
a. Either in plasma/bound to endothelium
b. Necessary to prevent widespread coagulation
3. Fibrinolysis
a. Limits fibrin deposition @ site of injury due to plasmin activity
4. Platelets
a. Vital
b. Aggregate @ sites of vessel injury to form the 1o plug which is stabilised by fibrin
5. Blood vessels
a. Initiate & limit coagulation
b. Intact: prostaglandin 12 & NO  promote vasodilation & inhibit aggregation
c. Damaged: tissue factor * procoagulants (collagen & VWF)
Kristy’s Paediatric Hematology and Oncology Notes
d. Inhibitors of coagulation on the endothelial surface (thrombomodulin, antithrombin, proteins) to
modulate coagulation
Intrinsic
121198105 thrombin
Ca2+
Extrinsic
TF710thrombin
Diagnostic Approach
a. Identify features in presentation
b. Initial lab tests
c. Special inx to characterise/exclude impt conditions/def
1. Bleeding Tendency
FBC
Differential count
Peripheral blood film
Neutropaenia
Pancytopaenia
Anaemia
Aplastic Anaemia
Malignancy eg leukaemia
Infection
Hypersplenism
Intravascular haemolysis
Look for red cell fragmentation
DIVC
Sepsis
HUS
Isolated thrombocytopenia
Autoimmune haemolysis
Look for spherocytes, macrocytes
DCT Positive
DCT Negative
Autoimmune diseases
Evans syndrome
Drug-induced
IMS, HIV
Marrow function
Check reticulocyte count
2. Isolated Thrombocytopaenia
Kristy’s Paediatric Hematology and Oncology Notes
3. Autoimmune Thrombocytopaenia
4. Abnormal Coagulation
 Acquired disorders
→ Vit K def
→ Liver disease
→ ITP
→ DIC
Management of acute haemorrhage in bleeding diathesis
 Check ABCs and ensure vitals are stable
o Tachycardia  loss of ~ 1L of blood
o Postural drop in BP  loss of ~1.5L of blood
o Hypotension  loss of ~ 2L of blood
o Peripheral shutdown  cold, clammy limbs
o Delayed capillary refill >3s
o Anaemia
 Assess and identify the site of bleeding
 Apply pressure to bleeding site
 Insert 2 large bore IV catheters and send blood for FBC, U/E/Cr, PT/PTT and GXM.
 Infuse 20ml/kg of N/S over 20 mins (up to 3x)  if till refractory, consider inotropes.
Kristy’s Paediatric Hematology and Oncology Notes
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Correct coagulopathy
o Fresh frozen plasma (10-20ml/kg)
o Cryoprecipitate
o Factor VII/IX infusions
o Desmopression – stimulates Factor VII and vWF
o Antifibrinolytics (tranexamic acid, epsilon amino caproic acid)
Analgesia for pain relief
Once acute bleeding has been managed, evaluate with history, physical examination and investigations to
ascertain type of bleeding disorder.
Specific Treatment (with regards to underlying etiology)
o Factor replacement therapy
o Coagulopathy - haemophilia
Kristy’s Paediatric Hematology and Oncology Notes
Etiology of bleeding diathesis in children [causes of purpura (nonblanching rash)/easy bruising]
Pathogenesis
 Platelet vs Coagulopathy
o Platelet bleeding
 Petechiae, purpura
 Bleed during trauma
o Coagulopathy
 Joint bleed, large bruise, intramuscular bleed
 Delayed bleeding i.e. hours after injury
1. VASCULAR CAUSES
 Causes
Congenital
Acquired
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Hereditary Hemorrhagic Telangiectasia
Rare disorders: Ehlers – Danlos, Marfan
HSP
Infections i.e. meningococcaemia
Scurvy
CT disorders - Ehler- Danlos Syndrome congenital
Clinical features
o Not usually severe
o Skin and mucous membrane bleeding (easy bruising, petechiae, ecchymoses)
Investigations
o Screening tests normal
2. PLATELET CAUSES
 Causes
Thrombocytopenia (qualitative) (Platelet count reduced)
Fanconi’s Anemia
Decreased Production
Congenital
Wiskott- Aldrich Syndrome
Chromosomal Trisomy 13, 18, 21
Marrow Failure- Aplastic anemia
Acquired
Marrow Infiltration- Leukemia, Lymphoma
Drug-induced
Severe Iron deficiency
ITP
Increased Consumption/
Immune
Post-infectious (Dengue hemorrhage)
Destruction
Drug-induced
Post- transplant
Post-transfusion
Autoimmune ( SLE)
Hyperthyroidism
Alloimmune neonatal thrombocytopenia
DIVC (disseminated intravascular
Non-immune
coagulation)
Hemolytic anemia and Thrombocytopenia
Hemolytic Uremic Syndrome
Thrombotic Thrombocytopenia
Congenital heart disease
Giant hemanglomas (Kasabach-Merritt
syndrome)
Sequestration Hypersplenism
Hyporthermia
* Neonatal Thrombocytopenia Neonatal Alloimmune Thrombocytopenia
Neonatal Autoimmune Thrombocytopenia
Congenital Viral Infections (TORCHeS)
Birth Asphyxia
Sepsis
Congenital heart disease
Respiratory distress syndrome
Prematurity
Kristy’s Paediatric Hematology and Oncology Notes
Congenital
Acquired
Platelet function disorders (qualitative – platelet count normal)
Bernard -Soulier Syndrome
Glanzmann disease/glanzmann thromboasthenia (Rare)
Myeloproliferative disorders
Drug-induced (Aspirin)
Cardiopulmonary bypass
Uraemia
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Clinical features
o Petechiae, purpura
o Bleed during/ immediately after trauma
o Superficial bleeds: Skin, mucosal (epistaxis, gum bleeds)
o Severe cases  intracranial hemorrhage**, severe GI hemorrhage, hematuria

Investigations
o Platelets count: ↓
o Platelet morphology (size):
 Large plts - ITP, Bernard- Soulier Syndrome
 Small plts - Wiskott-Aldrich Syndrome
3. COAGULOPATHY
 Extrinsic pathway (Factors 1, 2, 5, 7, 10)
 Intrinsic pathway (Factors 1, 2, 5, 8, 9,10, 11, 12)
 Common pathway (Factors 1, 2, 5, 10)
Hemophilia A, B, C
A - Factor 8 deficiency
B - Factor 9 deficiency
C - (rare, affecting Ashkenazi Jews)
Von- Willebrand Disease
Severe - Factor VIII deficiency in
addition to
Platelet dysfunction
Vitamin K deficiency
Factor 2< 7< 9< 10
- ↓intake,
- ↓ absorption
- ↓ utilization
- Vit- K antagonist - Warfarin
Chronic Liver Disease
Factors 2, 5, 7, 9, 10
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Clinical features
o Joint bleed, large bruise, intramuscular bleeds
o Delayed bleeding
o More in boys
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Investigations
o PT↑ (Extrinsic Factor 7)
o APTT  (Intrinsic Factors 8, 9, 11, 12)
o Mixing studies - Normalization (vs Persistence = Function Inhibitor)
o Factor Assays (8, 9, 11)
o Thrombin time ↑
o Fibrinogen (factor 1) measurement
(Above 2 are gibrinogen disorders - Afibrinogenemia, dysfibrinogenemia)
Kristy’s Paediatric Hematology and Oncology Notes
Idiopathic thrombocytopenic pupura (ITP)/immune thrombocytopenia
Case: A 15-year-old girl presents with a history of easy bruisability and multiple petechial hemorrhages over her
body for the past 7 months. These symptoms worsen when she goes for her gymnastics class. Her full blood
count showed WBC 4.5x104/L, Hb 11.4g/dL and platelets 20x109/L.
Dx: Chronic ITP
Epidemiology
 Commonest cause of thrombocytopenia in childhood
 Mechanism not established, usually due to destruction of circulating platelets by antiplatelet lgG
autoantibodies
Etiology and Pathogenesis
 Preceded by viral infection
 Ab binds to platelet membrane→ Splenic destruction of Ab -coated platelets
 Rarely secondary to autoimmune disease – SLE
Classification  severe bleed uncommon, despite platelets usually being <10 x 10 9 /L
 Acute ITP (80%)
o 1-4 wks after viral illness (VZV, Measles, EBV, vaccinations
o Self-limiting; resolves in 2-4 wks
o Cf : petechiae, purpura, ecchymoses, epistaxis, hematuria, GI bleed, CNS bleed
 Chronic ITP (20%)
o Age: 2-10 yrs old
o Thrombocytopenia ≥ 6 mths
o Usually in children > 10 yrs (MCQ)
o Progression from Acute → Chronic in 5-10% ] ↑ risk of intracranial bleed
o Exclude underlying autoimmune causes – SLE
o Exclude congenital causes in younger kids, eg. Wiskott-Aldrich or Bernard-Soucier Syndrone
o Exclude Platelet production disorder
 BM exam
 Exclude acute leukemia/aplastic anemia
 Esp if atypical signs such as: anemia, neutropenia, hepatosplenomegaly, marked
lymphadenopathy
Investigations
 FBC
o Plt ↓
 BM exam
o Megakaryocytes  / N
 Sometimes compensatory mechanism (if clinical features are characteristic/no other
abnormalities ONLY platelets low/no intention to treat  DON’T do BMA
 Autoantibodies
o Antiplatelet IgG
o Antiplatelet IgM
Management
 Acute ITP
o Most can just manage at home, don’t need admission. No need tx even if <10 x 10 9/L unless
evidence of major bleed/persistent minor bleed.
o Precautionary measures : Avoid rough sports, trauma
o Platelet transfusions for acute life-threatening bleeding  raise platelets for only a few hours
o Controversial (if plt < 20,000 or bleeding): IVIG, Oral corticosteroids, Anti-D Ig ] all have
significant side effects
o Platelet count ≥30000 and minor purpura can be managed as outpatient
o Excellent prognosis, 90% resolution
o BM aspirate if before Rx, or if suspicious
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Chronic ITP (mainly supportive, drug tx! persistent bleed affecting life)
 Regular SLE screen. Thrombocytopenia predate development of autoantibodies.
o Intermittent courses of oral steroid, IVIG, splenectomy (induces remission in 70%)
 Must check bone marrow. Steroids can mask ALL  compromise prognosis
Kristy’s Paediatric Hematology and Oncology Notes
von Willebrand disease
Platelet Dysfunction
Congenital Causes
Bernard-Soulier Syndrome (AR)
Glanzman Thrombasthenia (AR)
Gray platelet syndrome (alpha granule deficiency)
Von Willebrand disease (vWD)
Acquired Causes
Myeloproliferative disease
Cardiopulmonary bypass
Uraemia
Drug inhibition e.g. NSAIDs, aspirin
Epidemiology
 Most common congenital bleeding disorder
 Autosomal dominant (AD), variable expression
Etiology and Pathogenesis
 vWF synthesized in vascular endothelial cells and megakaryocytes
 Function of vWF
o Platelet adhesion and aggregation
o Factor 8 carrier - prevents Factor 8 breakdown
o Quantitative or Qualitative vWF defect
 Deficiency of the vWF:Ag
 3 Types
o Type 1: Quantitative deficiency  80% of all vWD, mild disease  often not diagnosed till
puberty/adulthood
o Type 2: Qualitative deficiency  Variable severity
o Type 3: Complete absence of vWF  Severe disease
Clinical features
 Mild ≈ Platelet Disorder
 Severe ≈ Coagulopathy
Bruising excessive, prolonged bleed after surgery mucosal bleed
(epistaxis.menorrhagia)
Investigation
 Ristocetin cofactor
 vWF Ag - ELISA
 Factor 8c Assay
 Multimeric analysis
 PT: normal
 aPTT: normal/↑
 Factor 8: C : ↓/ normal
 VWF antigen: ↓
 RiCoF: ↓
 Ristocetin - induced platelet aggregation: abnormal
 VWF multimers: variable
Management
 Depends on Type
o Type 1: DDAVP/ Desmopressin  stimulates endogenous release of vWF
o Type 2: DDAVP, vWF , Factor 8 concentrate
o Type 3: vWF, cryoprecipitate
 Seldom used. As it has not undergone viral inactivation.
o Avoid:
 IM injection
 Aspirin
 NSAIDs
Kristy’s Paediatric Hematology and Oncology Notes
Disseminated Intravascular Coagulation
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Disorder characterised by coagulation pathway activation leading to diffuse fibrin deposition in the
microvasculature and consumption of coagulation factors
Common causes:
o Severe sepsis
o Shock due to circulatory collapse
Most likely activated by extrinsic pathway
Predominant clinical feature:
o Bruising
o Purpura
o Hemorrhage
Inx:
o No reliable single test.
o Suspected if the following co exist
1. Thrombocytopenia
2. Prolonged PT
3. Prolonged aPTT
4. ↓ fibrinogen
5. ↑ fibrinogen degradation pdts
6. D-dimers
7. Microangiopathic hemolytic anemia
o May have
 ↓ anticoagulants
 ↓ protein C & S
 ↓antithrombin
Mx:
o Tx underlying cause
o Fresh frozen plasma
o Cryoprecipitate
o Platelets
Kristy’s Paediatric Hematology and Oncology Notes
Haemophilia - most common severe inherited coagulation disorders
Definition and epidemiology
1. HAEMOPHILIA A
 Haemophilia A is a factor VIII deficiency
 Reduced or absent factor VIII activity
 X-linked recessive d/o, 30% spontaneous mutation rate
 1 per 5000 male births
Hallmark of disease 
recurrent bleeds into
joints & muscles 
crippling arthritis
2. HAEMOPHILIA B (Christmas disease)
 Haemophilia B is a factor IX deficiency.
 1 per 30 000 male births.





Clinically it is not possible to distinguish between them.
Both are X-linked recessive conditions.
Over 60% of cases have a positive family history; 30% are spontaneous mutations.
Diagnosis is based on raised aPTT, factor VIII or IX assay and DNA analysis
The latter allows prenatal and carrier diagnosis as well.

Women can have haemophilia
o Lyonization of the normal X chromosome, Turner syndrome (
o Turner syndrome (XO)
o Father with hemophilia and mother as a carrier
o vW type 2 N (Normandy)
Clinical features
 Severity and frequency of bleeding complications are a reflection of the amount of factor VIII or factor IX
present.
 Severity grading by factor levels
o <1%
Severe
Presents young (end of 1 yr or crawl & walk)
Spontaneous bleeds – haemarthrosis, haematomas, haematuria


o
1-5%
o
5-30% Mild
Moderate
No spontaneous bleeding unless
Severe trauma (e.g. 6 yo child with 2 previous episodes of bleeding
Lead largely normal life
Bleed after surgery (e.g. prolonged oozing aft dental extraction)
Some female carriers, who have 30-50% of normal levels of these factors may present clinically with
gynaecological or obstetric haemorrhage.
Age-related presentation
o Birth to 4 weeks:
Bleeding following circumcision
CNS haemorrhage
o 4 to 6 months
Large haematomas after IM injections
Palpable subcutaneous ecchymoses
o 6 to 24 months
Gingival haemorrhages when teething
Bleeding from oral mucosa
Increased palpable bruises, with commencement of walking
o 3 to 4 years
Joint and muscle haemorrhage
becomes problematic
Kristy’s Paediatric Hematology and Oncology Notes
Severity
Clinical Manifestation
Factor 8
Mild
Epistaxis
Moderate
Intramuscular/
Hemearthrosis
Dental/ Gingival bleed
Hematuria
Local pressure 20 mins
Nasal packing
Anti-fibrinolytic Tx (prevent clots from
breaking down)
20 U/kg if fails
30 U/kg if fails
20 U/kg
30 U/kg
Severe
Life-threatening
Haemarthrosis
Intramuscular bleed
Epistaxis
Dental bleed
Hematuria
CNS hemorrhage
20 U/kg
Factor 9
30 U/kg
Bed rest
Prednisolone if fails
Iliopsoas
50 →25 U/kg (2
80→40 U/kg (2
wks)
wks)
CNS, GIT hemorrhage
50 → cont
80→ cont
infusion→
infusion→
maintenance (2
maintenance
wks)
(2wks)
- Initial first aid - Immobilize joint, Ice pack
- Early aggressive tx - Prevent rebleed
- Fx level 30-40%
- Early aggressive tx - Prevent cx ( Jt contracture)
- Fx level 30-40%
- Initial first aid
- Pressure on ant nares 20mins, head down-chin on chest
- Nasal packing
- Desmopressin, Anti-fibrinolytic Tx if refractory
Desmopressin : synthetic analogue of vasopressin
releases Fx 8 and vWF
IV/ intra-nasal
Anti-fibrinolytic Tx : Tranexemic acid
- Factor Replacement Tx if refractory
- Good dental hygiene and dental care
- Always give Factor replacement with Regional nerve block
- Anit-fibrinolytic Tx
- Bed rest, Increased fluid intake
- Avoid Anti-fibrinolytic Tx
- Immediate aggressive tx
- Fx level 80-100%
- No LP
Complications
 Haemarthrosis
o Results in destructive arthritis, joint instability and ankylosis
o Commonest joints affected are knees, followed by elbows, ankles and shoulders
 Neurological problems
o ICH – one of the commonest causes of death, survivors may have severe neurological deficits
o Haemorrhage into vertebral canal – rare, 75% are extra-medullary and 25% are intra-medullay,
presents with severe neck or back pain followed by ascending paralysis.
o Peripheral nerve compression – external compression or traction from IM bleeds; commoner
nerves affected and relevant muscles: femoral (iliopsoas), ulnar and median (forearm flexors),
sciatic (glutei)
 Life threatening haemorrhages
o Retropharyngeal – usually associated with pharyngitis, presents with dysphagia, drooling; can be
diagnosed on lateral neck X-ray
o Retroperitoneal – can have loss of large volume of concealed blood; may be spontaneous or from
trauma; diagnosed by CT scan or ultrasound.
Kristy’s Paediatric Hematology and Oncology Notes
History
1. PRESENTING COMPLAINT
 Reason for current admission
2. PAST HISTORY
 Initial presenting symptoms, diagnosis (when, where, how), subsequent management, progress of
disease, hospitalization details
 Complications of disease (above) or its treatment (i.e. HIV, HBV, HCV)
 Previous elective surgery or dental procedures (their management and outcome)
 Outpatient clinics attended (where, how often)
 Past treatments used (i,e, Factor VIII, desmopressin, PT, cryoprecipitate)
 Age when parents started administering factor VIII
 Age of self-administration
 Recent change in symptoms or management
3. CURRENT STATUS
 Average number of bleeds per year, common sites involved, any common precipitants, treatment
required, usual outcome, where usually managed, who gives infusions
 Ongoing symptoms of joint disease, neurological disease, immunocompromised state, liver disease and
management of disease.
 Management of bleeds away from home.
4. SOCIAL HISTORY
 Diseae impact on patient
o Avoidance of participation in sports
o Absenteeism
o Poor self-esteem
 Disease impact on parents
o Marriage stability
o Fears for future
o Financial considerations
o Modification of holiday plans
 Disease impact of siblings
o Sibling rivalry, hostility
o Genetic implications for girls
 Social supports
 Coping
o Who attends with patient
o Confidence with management
o Degree of understanding of disease
o Expectations for the future
o Understanding of prognosis
 Assess to local doctor, paediatrician and hospital ?
5. FAMILY HISTORY AND GENETIC ASPECTS
 Other boys with haemophilia
 More children planned
 Prenatal diagnosis
6. IMMNUNIZATION
 Routine
 Associated bleeding
 Hepatitis B
Physical examination
1. GENERAL INSPECTION
 Position patient standing, expose
 Vital signs: HR, RR, BP, SpO2, pain
 Parameters: weight, height, OFC
 Skin: bruises, anaemia
 Joints: swelling, posture, foot drop
Kristy’s Paediatric Hematology and Oncology Notes

Eyes: pallor, jaundice
2. DIRECTED EXAMINATION FOR COMPLICATIONS
 Full joint examination, for evidence of arthropathy
 Full neurological examination for any evidence of ICH, IVH or peripheral nerve lesions or late HIV
encephalopathy
 Generalized lymphadenopathy, oral candidiasis, herpes infections, parotid swelling or OIs for HIV
seropositive patients
Investigations
 aPTT prolonged but other bleeding profiles may be normal
 Factor 8:C decreased
Management
1. RECOMBINANT FACTOR VIII OR IX INFUSIONS
 Given as prophylaxis (given to children with severe conditions to reduce risk of joint damage) OR after
injury OR prior to surgery *
Regular infusions 8-12hrly for factor 8,
 Mild injury  sufficient to raise factor levels to >30% normal
12-24hrly for factor 9 OR continuously
 Major surgery  necessary to raise it to 100% normal



Complications  antibodies to factor VIII/IX (give v large dose,
immunosuppression, give recombinant factors)
 transfusion transmitted infections: HIV, Hep-B,
Hep-C.
Parents usually taught to give replacement therapy at home (2 – 3x / week)
2 units/kg raises level by 1%  need to raise to 30% if normal for minor cases, 100% for surgery &
maintained at 30-50% for 2 weeks.
2. DESMOPRESSION (DDAVP)  only Hemophilia A. not B.
 Synthetic analogue of vasopressin which raises factor VIII level up by up to 5-fold in normal subjects, and
7-fold in some mild haemophiliacs, but has no effect in patients with severe disease.
 Best for use in controlled situations such as elective minor surgery.
3. ANTI-FIBRINOLYTICS
 Epsilon-aminocaproic acid and tanexaminic acid have been used for oral bleeding and tooth extractions.
 Not recommended in haemarthrosis or haematuria as in both its use may be associated with excessive
fibrin deposition, possibly causing joint or renal damage respectively.
4. CRYOPRECIPITATE
 Protein precipitate of fresh frozen plasma, rich in factors VIII and XIII and fibrinogen.
 On average it contains 100 units of factor VIII per bag and is normally derived from a single donor.
5. FRESH FROZEN PLASMA (FFP)
 Contains all the clotting factors.
 Use is limited by its volume – 10 to 15ml/kg being the usual dosage
 Harvested from one donor, FFP is used for factor IX deficiency or mild haemophilia
6. PROTHROMBINEX
 Used for factor IX deficiency, this concentrate contains factors II, IX and X.
7. CORTICOSTEROIDS
 Has been used for haematuria
Issues in management
1. TREATMENT OF ACUTE HAEMORRHAGE
 Control of specific bleeding problem
 Analgesia
 Restoration of normal function
2. COMPLICATIONS OF MEDICAL TREATMENT  Avoid IM injections, Aspirin, NSAIDs
 Analgesic abuse
 HIV infection
 Hepatitis
Kristy’s Paediatric Hematology and Oncology Notes


Ab to FVIII/FIX
- In 5-20%
- Reduce/completely inhibit
- Require very high dose to bypass inhibition
Vascular access
- Peripheral veins may be difficult to cannulate
- Central venous access  infected/thrombosed
3. CHRONIC PROBLEMS
 Neurological sequelae
 Joint destruction
4. SPECIFIC DISCUSSION ARES
 Home management
 Sport
 Immunization
 Dental extractions
 Elective surgery
 Factor VIII antibodies
 Genetic counselling
 Progress- recombinant factor VIII, daily prophylaxis, genetic engineering (gene insertion therapy)
Blood Product Transfusion




Uncommon to use whole blood
Component therapy
Cellular components
o Red cells, platelets, granulocyte
Plasma components
o Fresh frozen plasma
o Cryoprecipitate
o Factor concentrates
Red Cell Concentrates
 Rx of anaemia, haemorrhage
 Hb conc 18-20g%
 10-15mL/kg over 2-3h will increase Hb by 3-5g%
 Each unit of red cell conc ~200-350mL
Platelet Concentrate
 Random platelets – from 1 unit of blood
o 1 unit per 10kg of body weight incr 30000/uL
 Pheresed platelets
o From 2-3L of pheresed blood
o Equivalent to 4-6 random platelets
 Transfuse at 10mL/kg/hr
Cryoprecipitate
 From fresh frozen plasma
 Contains: Fibrinogen, Factor VIII and XII, Fibronectin
Coagulopathy
 Fresh frozen plasma 10mL/kg
 Infuse at 10mL/kg/h
 No need radiation or leucodepletion
 6-8hrly replacement
Special Requests
 Leucodepleted blood products
o Leucocyte filters
o Reduce HLA alloimmunisation
o Chronic transfusion expected
o Decrease CMV transmission
 Irradiated blood products
o BMT, neonate, immunodeficiency
Kristy’s Paediatric Hematology and Oncology Notes
o
Reduced T1/2 of red cells
Problems
 Most common complication is post-transfusion hemolytic reaction (MCQ)
 Infections
 Syphilis
 HBV, HCV
 HIV
 CMV
 Testing: VDRL, HbsAg, antiHBV core Ab, anti-HCV
Most Important!
 Correct labelling of blood products
 Prepare blood forms and labels
 Check and prepare tubes and label immediately
 Check name of patient and ask their blood group
 Wrong blood product can kill 
Thrombosis in children




Uncommon, ~ 95% of venous thromboembolic events are due to underlying hypercoagulable conditions
Congenital prothrombotic disorders (thrombophilias)

Protein C def
]
Protein S def
] AD inheritance  homozygotes very rare  life threatening thrombosis
Antithrombin def
]
with widespread hemorrhage & purpura fulminans
Factor V Leiden
 heterozygotes predisposed to thrombosis in 2nd to
Prothrombin gene G20210A mutation
3rd decade of life
Acquired disorders:

Catheter-related thrombosis
DIC
Hypernatremia
Polycythemia
Malignancy
SLE
Must diagnose and not miss it!

Screening tests be done for:
1. Any child with unanticipated/extensive venous thrombosis, ischemic skin lesions/neonatal
purpura fulminans
2. Any child with positive fam Hx of purpura fulminans
Kristy’s Paediatric Hematology and Oncology Notes
Child with petechiae or purpura
* Positive glass test, Non blanching rash*
Non-thrombocytopenic
1. Henoch-schȍnlein purpura (HSP)
 Lesions confined to buttocks, extensor surfaces of legs & arms
 Swollen painful knees & ankles
 Abdominal pain
 Hematuria
 Ask about testicular pain/swelling
2. Sepsis
 Meningococcal/viral
 Fever, septicemia, meningitis, toxic looking
 If suspected, give parenteral penicillin immediately
 Tx: Ceftriaxone
3. Trauma
 Accidental/non-accidental
4. Other causes (rare)
Thrombocytopenia
1. Immune thrombocytopenia (ITP)
 Age: 2-10 yr old
 Widespread petechiae, purpura, superficial bruising
 Exclude Acute lymphoblastic leukemia & aplastic anemia
- Clinical features
- FBC, PBF
BMA only if platelets low, atypical clinical features, not on steroid tx
 Acute, benign, self limiting (80%)
 Tx: controversial. Only if bleeding
2. Leukemia
Clinical features:
- Malaise
- Bone pain, refusal to walk
- Infection
- Pallor
- Hepatosplenomegaly
- Lymphadenopathy
 Blood count
- Low Hb
- Blasts on PBF
- Confirmed with bone marrow
3. Disseminated Intravascular Coagulation (DIC)
 Critically ill
- Severe sepsis
- Shock
- Extensive tissue damage
4. Other causes (uncommon)
Kristy’s Paediatric Hematology and Oncology Notes
Childhood Cancers
Epidemiology
 2nd most common cause of death in <15y/o
 1 in 600 develop cancer before the age of 15 in developed countires
 About 100 new cases diagnosed each year in Singapore
Types












Childhood cancers
#1: Leukemia
#2: Brain tumors
Leukaemia (affects all ages peak in early childhood)
Lymphomas – Hodgkin: peak in adolescence & early adulthood
CNS / Spinal
Neuroblastoma & Wilms tumour (almost always ≤ 6 yrs old)
Germ cell tumours
Retinoblastoma
Renal tumours
Hepatic tumours
Bone tumours - adolescence & early adulthood
Soft tissue sarcoma
Carcinomas
Others
Appropriate Terminology
Leukaemia
Lymphoma
Blastoma
Sarcoma
Carcinoma
Malignancy arising from marrow elements
From lymph nodes, more mature in terms of
differentiation compared to leukaemia
Resemble fetal tissue. Neuroblastoma,
Nephroblastoma, Retinoblastoma.
Soft tissue / mesenchymal origin
Epithelial tissue origin
Predisposing Factors
Kristy’s Paediatric Hematology and Oncology Notes
Clinical Approach
 History
o Lethargy, effort tolerance
o Bleeding tendency
o Infection / fever
o Bone pain
o Abdominal swelling
o Neck swelling
o Antenatal
o Chickenpox, vaccination
o Consequences of disseminated disease (BM infiltration)
o Consequences of pressure from a man on local structures/tissue
 Physical Examination  can be localised mass
 Investigations
o General
o Diagnostic
o Radiology
 Locate solid tumor +/- metastases via u/s, Xray, CT, MRI
 Nuclear medicine imaging (identify bone/bone marrow disease)
 MIBG Scan
o Tumor markers
 ↑ urinary ratecholamine excretion: neuroblastoma
 ↑ a-fetoprotein: germ cell/liver tumor and monitor tx response.
 Management
o General (Oncologic emergencies)
o Definitive
o Education / Social
Haematologic Malignancies
 Types – more restricted pattern compared to adults
o Leukaemias
 ALL
 AML
Prognosis
 Children > teens
& young adults
Kristy’s Paediatric Hematology and Oncology Notes
o
 CML
Lymphomas
 Hodgkin’s Disease
 Non-Hodgkin’s Lymphoma
 Only high grade
Tx:
Chemo, radiotherapy, surgery
Chemotherapy
Combined or monotherapy
 Routes
o PO, IV, IM, SC, IT
 Access
o Peripheral, indwelling central line (Hickman’s, Port-A-Cath)
 Side effects
o General
 Nausea, vomit, mucositis, hair loss, myelosuppression
o Specific
Uses of chemo:
1. 1o curative tx (ALL)
2. Control 1o/metastatic disease before definitive local tx (surgery/radio)
3. Adjuvant tx to deal with residual/ eliminate presumed metastases after surgery
Late Effects of Radiotherapy
 Some role in tx for certain Ca
 Risk of damage to growth
 Difficult to provide adequate protection of normal tissues and for careful positioning & immobilisation of pt
during tx
 Endocrinopathies
o Growth failure
o Thyroid deficiency
o Sex hormone disorders
 Neurocognitive sequelae
o Decreased intellect or learning disabilities
o Behavioural and adjustment problems
 Second Malignancies
o Thyroid cancers
o Meningiomas, gliomas, sarcomas
o Lymphoproliferative disease
Surgery
 Initial: restricted to biopsy
 Otherwise to remove residual after chemo/radiotherapy
Supportive Care & Side Effects of treatment
 Short-term side effects (Chemo)
o Bone marrow suppression
 Anemia
 Thrombocytopenia & bleeding
 Neutropenia  infection
o Immuno suppression
 Infection
o Gut mucosal damage
 Infection
Kristy’s Paediatric Hematology and Oncology Notes
o
o
o
 Undernutrition
Nausea/vomiting
 Undernutrition
Anorexia
 Undernutrition
Alopecia

Fertility preservation
o Surgically moving a testis/ovary out of the radiotherapy field
o Sperm banking (offer to all boys mature enough)

Venous access
o Multiple venepunctures for blood sampling & IV transfusions  central venous catheter
Infection
- Fever & neutropenia
o Admit promptly for cultures & blood spectrum Abx
- Opportunitic
o Pneumocystis jiroveci (esp leukemia)
o Disseminated fungal (aspergillosis/candidiasis)
o Coagulase negative staph (central venous catheter)
- Viral usually not worse than normal except: measles & varicella (life threatening)
o Immuglobulin administration
- Live vaccines contraindicated up to 1 yr after chemo
Bone marrow suppression
- Anemia  blood transfusion
Gastrointestinal damage, nausea, vomiting & nutritional compromise
- Mouth ulcers, common & painful
- Chemoagents
o Usually nauseating/induce vomiting
o Partially prevented by anti-emetics
- Chemo-induced gut mucosal damage
o Diarrhea
o ↑ risk of gram -ve infection
Drug specific SE
- Doxorubicin  cardiotoxicity
- Cisplastin  deafness & renal failure
- Cyclophosphamide  hemorrhagic cystitis
- Vincristine  neuropathy
 Unpredictable extent careful monitoring during tx & sometimes even after tx
Lymphomas
 Malignancies of lymphoid system that occurs outside the marrow at lymph node, spleen, thymus, MALT
 Characterised and defined by a combination of:
1. Morphology (histo)
2. Immunophenotype (cell surface markers)
3. Molecular signatures (translocation)
4. Clinical features (presentation & clinical course)
 Clinical features
1. Enlarging masses, painless @ sites of nodal tissue
2. Compression & infiltration of hollow organs
 Pain
 Obstruction
 Perforation (esp in GIT)
3. Interfere with normal organ fxn
 Solid organs (liver, bone marrow, kidney)
 Insufficiency esp, if extensively replaced by malignant cells
Kristy’s Paediatric Hematology and Oncology Notes
4. Systemic symptoms
 Fever
 Weight loss (>10% of body weight in 6 mth)
 Night sweats
 Ann Arbour Staging System
 More useful in guiding Hodgkin's (contiguous spread) vs NHL (x contiguous spread)
 Sub groups:
a  Asymptomatic
b  Symptomatic (unexplained weight loss >10% in 6mths +/- Fever +/- night sweats)
 Stages (best is I, worst is IV)
i.
Single LN group/contiguous LN or same side of diaphragm
ii.
2 or more LN groups/lymphatic tissue on same side of diaphragm
iii.
Involvement of lymphatic tissue on both side of diaphragm
iv.
Involvement of extra nodal tissues (bone marrow, liver, lung, skin ….)
Tx: multi-agent chemo
80% survive
1. Non-Hodgkin's Lymphoma (6th most common in males, 9th in females)
 2 kinds:
i.
Aggressive (proliferation ↑↑ >> death rate of tumor cells)
}
- Usually localised at presentation
} good response to treatment beause
- Shorter natural hx, median survival ≤ 2 years
} chemotherapy target cell cycle
- Curable
}
- Childhood symphomal are of this kind
}
- All cancers except: Follicular lymphoma, MALT Lymphoma & CLL/SLL
Natural Hx =
ii.
Indolent (low proliferation with low death rate)
development of
- Widespread at diagnosis
disease w/o tx
- Median survival > 5 yrs, longer natural Hx
- Incurable unless
→localised or marrow ablation with some type of stem cell transplant
 Mainly B-cell lymphomas → Diffuse B-cell lymphoma (31%0
Follicular lymphoma (22%) + (14;18) nce2; lgH
Mantle cell lymphoma (6%) + (11;14) Cyclin D1, lgH
Burkitt lymphoma (3%) + (8;14) c-myc; lgH
 Diffuse large B cell lymphoma
 Disease of adults and children; median age 64
 Rapidly enlarging masses (nodal: waldeyer's ring; extra-nodal: spleen, liver, GIT, skin, bone, brain)
 ~ 40% curable with aggressive chemo/stem cell transplant
 Aggressive lymphoma
 Cell of origin: germinal centre B cell
 + (14,18) [same as follicular]
 Immunodeficiency associated large B cell lymphoma (FBV infected neoplastic B cells)
 1o effusion lymphoma (KSHV infection) → present as malignant ascetic/pleural effusion
 Burkitt's lymphoma (1/3 of all childhood lymphoma)
 Cell of or-gin: germinal centre B-cell
 3% of lymphomas
 Aggressive
 a/w EBV
 Localisation in jaw
 70-80% children & 40% adults curable
 t(8;14) → result in upregulation of myc oncogene
 Starry sky pattern
 Follicular lymphoma (2nd most common lymphoma overall)
 Disease of adults (>40 yr old)
 Usually widely disseminated at presentation including bone marrow
 Incurable unless bone marrow transplant
 Responds to gentle chemo but will relapse
 *Indolent*
 Presents at painless lymphadenopathy
Kristy’s Paediatric Hematology and Oncology Notes



May transform to more aggressive forms → DLBCL, BL
t(14;18)(q32, q21)
Cell of origin: germinal centre B-cells
2. Hodgkin's Lymphoma
- Clinical features → painless lymphadenopathy (usually Neck)
→ larger & firmer than benign lymphadenopathy
→ long hx: several mths
→ systemic (uncommon): [with fever, pruritus, sweating] B symptoms
 A group of lymphoid neoplasms characterised by presence of neoplastic reed-sternburg cells amongst other
differences from NHL
 Cell of origin: altered B cell
 Classical HL (4 types)
(Lymphoid neoplasms with Reed Sternburg cells & an inflammatory non-neoplastic background, esp
eosinophils)
- CD15+, CD 30+
- Negative for other B-cell markers & CD 45 (common leukocyte antigen)
1.
2.
3.
4.
Nodular sclerosis (most common) } 70% 5 yr survival
Mixed cellularity
}
Lymphocyte rich (90% 5 yrs survival)
Lymphocyte depleted (20% 5 yr survival)
 Non Classical HL (Nodular lymphocyte predominant HL)
 Popcorn cell (lymphocytic & histiocytic variant cell)
 CD20+, BCL 6+
 CD15-, CD30 Contiguous spread, painless lymphadenopathy
 Overall cure rate 80%
 30% → EBV found in RS cells
 INX
 LN biopsy
 Radiological assessment
 BM biopsy
Stage and determine Tx
LEUKEMIAS
 Malignancies primarily disorders of bone marrow
 No solid masses unless infiltrate organs
 Widespread involvement of bone marrow
 Large number of tumor cells circulating in peripheral blood. *Can be diagnosed by peripheral blood film
 Tend to have increased hemorrhagic tendencies
 Leading cause of death (cancer) in children < 5 yo; 7th most common form of cancer death overall
 Originate in bone marrow → subsequently overgrow normal bone marrow cells → replace normal
hypercellularity (many cell types) with monotony
 Spill from bone marrow to blood → seen in large numbers
 Acute leukemias
- Symptoms from suppression of normal marrow fxn
o Anemia with fatigue
o Fever due to infection
o Bleeding due to thrombocytopenia
o Bone pain (BM infiltration)
o Malaise, anorexia
o Reticulo-endothelial infiltration → hepatosplenomegaly, lymphadenopathy
o Other organ infiltrate (rare @ diagnosis, usually @ relapses
→ CNS: headache, vomit, nerve palsy
Kristy’s Paediatric Hematology and Oncology Notes
→ Testes: enlargement
- Fatal within weeks if left untreated
- Present with immature blast cells (high N:C ratio, primitive looking, prominent nucleclus) in PBF
 Chronic leukemia
- Non specific symptoms
o Fatigue
o Weight-loss
o Anemia
o Abnormal sensation in abdomen due to splenomegaly
- Usually live longer even if untreated
- A/w more mature & well differentiated cells in PBF
1. Acute Lymphoblastic Leukemia (ALL) (80%)
 Rare, peak incidence 2-5 yr old
(Females better prog)
- Common ALL antigen (CALLC) positive → good prog.
 Cell of origin: precursor B/T cell
 t(9;22) → Bad prognosis
t(12;21) → Good prognosis
Peripheral white counts (low = good prog)
Age:
2-10: good
<2 or >10: bad!
1-10: @ risk
 Clinical features: depressed marrow
Bone pain generalised lymphadenopathy
(Mass effects if infiltration)
CNS effects due to meningeal involvement (Headache, vomiting, nerve palsies)
 Chemo: (2-3 yrs of tx)
WBC < 20 000: standard risk
WBC > 50 000: high risk
2. Acute myelogenous leukemia (AML)
 Cell of origin: precursor hematopoietic cell
 Affects adults & kids
 Caused by acquired oncogene mutations that impede differentiation, leading to accumulation of immature
myeloid blast cells in marrow
 Rapidly fatal w/o tx
 Similar clinical features as ACC
 Chemo: ~ 6 mths of tx
3. Chronic lymphocytic leukemia (CLL)
 Cell of origin: peripheral B cells
 Approx. 1/3 Of All Leukemia
 *Indolent*
 Disease of the elderly (~65 yo)
 Rare to have chromosomal translocations
 Poor prognosis if
o Lack of somatic hypermutation
o Deletion of 11q & 17p
 Clinical features:
o Asymptomatic
o Non specific (LOA, Low, fatigability)
o Generalised lymphadenopathy
o Hepatosplenomegaly
o Leukopenia/leukocytosis
o Transformation to DLBCL in some
4. Chronic myelogenous leukemia (CML) (rare)
Kristy’s Paediatric Hematology and Oncology Notes
 Cell of origin: myeloid cell
 Disease of middle age but in some children & young adults
 t(9;22)
philadelphia chromosome, encodes B(l-AB:
Tyrosine kinase
 Clinical features
o Indolent chronic phase (4-6 urs)
o Progress to accelerated & acute blast phase (6-18mth)
o Treat with imatinib mesylate (tyrosine kinase inhibitor)
Investigation
1. FBC, PBF
 Most abnormal with low Hb, thrombocytopenia & circulating leukemic blast cells
2. Bone marrow biopsy
 Essential to cfm diagnosis
 Identify immunological & cytogenic characteristics to give useful prognosis
3. Chest Xray
 mediastinal mass  T cell disease
Tx for ALL
1. Remission induction
o tx of anemia first
o Additional hydration and allopursinol to protect renal fxn against effects of rapid cell lysis
o Remission  eradication of blasts and restoration of normal marrow fxn
o 4 weeks of combination chemo  95% remit
2. Intensification
o A block of intensive chemo  consolidate remission
o Improve cure rates BUT risk of toxicity
3. CNS
o Cytotoxic drugs poorly penetrate CNS
o Intrathecal administration for prevention of CNS relapse
4. Continue therapy
o Modest intensity up to 3 yrs from diagnosis
o Co-trimoxazole prophylaxis  prevent pneumocyitis jaraveci
5. Tx of relapse
o High dose chemo
o Usually with total body eradication and BM transplant
Oncologic emergencies
1) HYPERLEUCOCYTOSIS SYNDROME
 High WBC count causing sludging of cells in circulation – ALL, CML, AML
 At risk when WBC > 100 000/uL
 Brain – decrease conscious state
 Pulmonary – decreased oxygenation, cyanosis
 Treatment: hydration, leucophoresis, start chemotherapy
2) TUMOUR LYSIS SYNDROME
Case: A child with a known history of ALL suddenly crashes.
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Metabolic derangement resulting from rapid death of malignant cells
Must have 2 important factors
o High tumour burden
o Highly sensitive tumour – ALL, AML, NHL
Hyperkalaemia – hydration, no K+ supplements, K+ binders
Hyperuricaemia – hydration, alkalinization, allopurinol, uricozyme to convert into allantoin
Hyperphosphataemia – phosphate binders
Hypocalcaemia (MCQ) – if symptomatic, partial correction
3) NEUTROPAENIC FEVER
Kristy’s Paediatric Hematology and Oncology Notes
Case: A 3-years-old boy with acute lymphoblastic leukaemia recently completed induction chemotherapy 1 week
ago. He now has a fever of 39oC. He is lethargic and mottled. His peripheries are cold and his capillary refill time
is 4s. His heart rate is 150/min and his blood pressure is 70/30mmHg.
Dx: Neutropaenic Septic Shock
Definition
 Fever
o
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Single oral/axillary temperature >38.5°C or oral/axillary temperature >38° C measured twice in 4
hours or persisting for one hour.
Neutropaenia
o Absolute neutrophil count (ANC) <500 cells/mm 2 or ANC<1000 cells/mm2 with an expected
decrease in counts
Risk stratification
Diagnostic evaluation
Treatment algorithm
Kristy’s Paediatric Hematology and Oncology Notes
Kristy’s Paediatric Hematology and Oncology Notes
Brain Tumours
→Almost always 1o
→60% infratentorial (below brain, above cerebellum)
Most common solid tumor in children
Case: An 18-month-old boy who had achieved good walking ability was noted to have unsteady gait in the past 2
months. This was associated with increasing lethargy and poor appetite. During the clinical examination, a
focused neurological examination possible for this age was performed.
Clinical Features - usually a/w ↑ ICP
 Usually presents with headache and vomiting in the morning (MCQ)
 Unsteady gait / Ataxia
 Nystagmus
 Cranial nerve signs
o Visual field impairment
o Diplopia
o Facial paralysis
o Hearing loss
 Papilloedema
 Focal neuro deficit depending on tumor site
 Spinal tumors (1o/ mets)
→ present with back pain, peripheral weakness of arms/legs, bladder/bowel dysfxn
*Persistent backpain in children → MRI!
Kristy’s Paediatric Hematology and Oncology Notes
Types
 Astrocytoma (40%)
→ benign to highly malignant (glioblastoma multiforme)
 Medulloblastoma (20%)
→ arise midline of posterior fossa
→ can seed through CNS via CSF
→up to 20% will have spinal mets @ diagnosis
 Ependymoma (8%)
→similar to medulloblastoma
 Craniopharyngioma (4%)
→developmental tumor from squamoul remnant of rathke pouch
 Brainstem glioma (6%)
Special Problems
 Blood-brain barrier limits chemotherapy
 Developing brain is vulnerable to toxicity of therapy
 Proximity of tumours to vital structures precludes extensive surgery
 Tendency to spread within neuraxis
DON’T do LP w/o neurosurgical advise if any suspicion of ↑ICP
Investigation
 MRI brain with contrast: Look for mass lesions in brain / cerebellar region
o Enhanced mass lesion
o Hydrocephalus
Classification
supratentorial
--------------------------------------infratentorial
Location: 2/3 above and 1/3 below tentorium
Sites and Symptoms
 Posterior fossa – limited space, disrupt CSF flow
o Vomiting, increased ICP
o Motor tract involvement – cranial nerve, long tracts
 Supratentorial
o Seizures – focal seizures
o Deterioration in school performance
o Hormonal defects – central precocity, diabetes insipidus
Therapy
 Surgical excision → usually first tx → aim to tx hydrocephalus, tissue diagnosis & maximum resection
→ Some sites unsafe (eg brainstem)
o Resectability
 Radiotherapy
o Toxicity
 IQ drop
Kristy’s Paediatric Hematology and Oncology Notes
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 Endocrinopathy
 Growth failure
Chemotherapy
o Prolong survival
o Increase cure rates
Factors affecting Prognosis
 Resectability
 Age
 Metastases
 Chemosensitivity
Cerebral Salt Wasting Syndrome (MCQ)
 Rare endocrine condition featuring hyponatremia (low blood sodium concentration) and dehydration
 In response to trauma/injury or the presence of tumors in or surrounding the brain
 This form of hyponatraemia is due to excessive renal sodium excretion resulting from a centrally mediated
process
Kristy’s Paediatric Hematology and Oncology Notes
Neuroblastoma (most malignant tumor of neural crest tissue origin)
- Spontaneous regression sometimes occur in very young infants
Case: Flank mass, 10cm extending to left hypochondrium, moves with respiration.
Epidemiology
 3rd most common solid tumour of childhood (<5 yr old)
 Neural crest origin (in adrenal medulla & sympathetic nervous system)
 Affects infants & preschool
o 50% younger than 2 year old
o 30% younger than 1 year old
Pathogenesis
 NB is a small, round blue cell tumour with varying degrees of neuronal differentiation
Clinical Features
 Arise from the sympathetic outflow – abdomen, adrenals and retroperitoneal sympathetic ganglia
commonest
 Infants tend to have localized NB in the cervical or thoracic region, whereas older children tend to have
disseminated abdominal disease
 Primary sites
o 70% abdominal primary → presentation: tumor mass often large & complex cross midline,
envelope major vessels & LN
→ most tend to have abdominal mass but 1o can be anywhere along
sympathetic chain from neck to pelvis
 50% adrenal medulla
 50% extra-adrenal tissues
o Thoracic tumours, posterior mediastinum (20%)
 Horner’s syndrome
o Head and neck tumours (10%)
o Epidural (dumbbell) tumours – cord compression
o Paravertebral tumors may invade intervertebral foramen & cause spinal cord compression
 Paraneoplastic syndrome
o Opsoclonus-myoclonus = “Dancing eyes, dancing feet”
 Metastasis
o Bone marrow – anaemia
o Bone (pain)
o Orbit (peri-orbital bruising)
o Liver (hepatomegaly)
o Lymph nodes
o Hypertension
o Irritability
o Skin (blueberry muffin)
o > 2 yr old
- Symptoms mainly from mets
o * Bone pain
o BM suppression → malaise
→ weight loss
Diagnosis
 Typicaly a mass is seen on CT or MRI
 95% of cases have elevated tumour markers, most often homovanillic acid (VMA) and vanillylmandelic
acid (VMA) in the urine
 MIBG (metaiodobenzylguanidine) radioisotope scan for detecing small primaries and metastases
 Stage 4s – infantile form, self-limited with good prognosis
 ↑ urinary catecholamines
Therapy → immunotherapy & long term 'maintenance' tx with differentiating agents for high risk disease
 Surgery (w/o mets → surgery alone)
 Chemotherapy (mets; high dose therapy with autologous stem cell rescue, surg & radiotherapy)
 Transplant (Stage 4, Nmyc amplification)
o HD chemo with autologous bone marrow transplant
Kristy’s Paediatric Hematology and Oncology Notes
Prognosis
 Age & stage
→ >1 yr usually present with advanced stage
 Over expression of N-myc oncogene
 Evidence of deletion or chr (des1p)
 Gain of material on Chr 17q in tumor cells
Risk of relapse is high
Cure for kids with mets a little
>30%
Poor prognosis
Presentation of Neuroblastoma
Common
Less Common
Pallor
Paraplegia
Weight loss
Cervical Lymphadenopathy
Abdominal Mass Proptosis
Hepatomegaly
Periorbital bruising
Bone pain
Skin nodules
Limp
Other Tumours – Wilm’s Tumour (Nephroblastoma), Liver Tumours, Retinoblastoma,
Soft Tissue Sarcomas, Bone Tumours
Wilm’s Tumour
(Nephroblastoma) → from embryonal renal tissue
 Most common renal tumor
 Triad
o Abdominal mass (D/D)
o Abdominal pain
o Haematuria (10%)
 Hypertension (25%)
 Associated abnormalities (WAGR)
o Aniridia (absent iris)
o Genitourinary tract abnormalities
o Mental retardation
INX:
-
80% < 5yr old
Rarely > 10 yr old
u/s +/- CT/MRI
Must look for Lung mets!
Fxn of contralateral kidney
Mx
-
Good prog
Chemo + nephrectomy
Relapse → poor prog
Clinical features
→ large abdominal mass
→ otherwise well
→ uncommon:
 Abdo pain
 Anorexia
 Anemia (hemorrhage into mass)
 Hematuria
 HTN
Kristy’s Paediatric Hematology and Oncology Notes
Liver Tumours - rare, pain also rare
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Hepatomegaly ± Jaundice - abdo distension/mass
Raised AFP (age-specific normogram)
2 types
o Hepatoblastoma (65%) → almost always ↑ α-fetoprotein
 Most common, most can be cured
 Infants & young children
o Hepatocellular carcinoma (25%) → worse prognosis
 Rare, older
 HBV, HCV
Mx
o Chemo & surg
o Sometimes: Liver transplant
Retinoblastoma (malignant tumor of retinal cells)
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30% familial, rare but accounts for 5% of visual impairment in kids
Tumour suppressor gene RB1, chromosome 13, dominant inheritance
Knudson’s 2 hit hypothesis: genetic & somatic mutations
95% diagnosed before 5y/o (most 1st 3 yrs)
Young children may be bilateral (all bilateral → hereditary, 20% unilateral → hereditary)
Need continued follow-up until 7y/o
→ Increase risk of 2nd malignancy (sarcomas) among survivors of hereditary retinoblastoma
Clinical Features
o Leukocoria: “White eye reflex” or “Cat’s eye”
o Strabismus (squint)
o White eye reflex and squint in children must be referred for ophthalmic assessment
Most confined to globe at diagnosis
o MRI & examine with anesthetic
o Usually multifocal tumors
Metastases late
Tx: cure & preserve vision
o Dont biopsy
o Enucleation of eye may be needed in severe case
o Chemo (esp for bilateral) followed by laser tx to retina
Soft Tissue Sarcomas
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Rhabdomyosarcoma (most common soft tissue sarcoma in childhood)
Sites
o Head and neck (cause proptosis, nasal obstruction, bloody nasal discharge)
 Orbit, nasopharyngeal, and middle ear tumours
o Genitourinary tract
 Bladder & prostate
} dysuria, urinary obstruction, scrotal mass,
 Vaginal and uterine
} bloodstain vaginal discharge
o Extremity
o Metastatic (lung, liver, bone, BM)
- Poor prognsis
- 15% @ diagnosis
Prognosis (overall cure rate ~ 65%)
o Orbit – excellent
o GU tract – good
o Extremity, retroperitoneal, metastatic – poor
Mx (depend on age)
o Multimodality
o 1o surgical resection → usually unsuccessful
Kristy’s Paediatric Hematology and Oncology Notes
Bone Tumours (@ diagnosis → bone pain but otherwise well)
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2 main types
o Osteogenic sarcoma (more common)
} male
o Ewing’s sarcoma (more in young kids) } predominance
Age
o Adolescents (rapid bone growth). Malignant: rare before puberty
Clinical
o Persistent & localised pain and swelling (Must do Xray). Most common site → limbs
o Metastases to lungs
o Red-herring
Inx
o Xray then MRI & bone scan
o Chest CT for lung mets
o BM sampling to exclude BM involvement
Mx
o Chemo before surg
o Amputation
o Ewing: radiotherapy
Long Term Survivors of childhood CA
 > 50% will have residual problem as a consequence of the disease/tx
 All survivors require long term f/u which continues even in adulthood
 Some issues faced:
 Poor/asymmetric growth (radiation to pituitary/bone)
 Infertility
 Sexual dysfxn (gonodal radiation/alkylating chemo agent)
 Risk of 2nd CA
 Specific organ dysfxn (nephrectomy for Wilms)
 Neuropsychological (brain surg/cranial irradiation < 5 yrs)
Palliative Care
 Most parents prefer home care
 Pain control & symptomatic relief
Kristy’s Paediatric Hematology and Oncology Notes
Kristy’s Paediatric Hematology and Oncology Notes