HAEMATOLOGY

Anemia:
1. Definition: hg% < 2 standard deviations below the mean for age with
2. Classification of anemia:
I.
Etiologic classification
i. 1. Impaired RBC production
ii. 2. Excessive destruction
iii. 3. Blood loss
ii. Ii. Morphologic classification
i. 1. Macrocytic anemia
ii. 2. Microcytic hypochromic anemia
iii. 3. Normochromic normocytic anemia
iii. Types of RBCs
1.Normocytic
2.Microcytic
3. Macrocytic
IRON D EFICIENCY ANAEMIA
1. Normal daily iron requirement:
1. 1 mg /day is the daily requirement
2. Only 10% is absorbed from the gut
3. Hence 10 mg is the daily requirement
2. Causes so iron deficient anemia:
30% of world population is anemic
Newborn:
1. Early cord clamping < 2 mts.
2. Blood sampling
Infants:
1. Milk has less iron
2. Lack of cereal diet
3. Cows milk allergry
4. Peptic ulcer
5. Meckels diverticulitis
6. Rectal polyp
7. Hemaangioma
8. Chronic diarrhea
Adolescents:
1. Growth spurt
2. Menstrual loss
3. Iron chelators- eg. Tea
4. Iron deficient food- faddism
5. Peptic ulcer
6. Hook warm
7. Helicobacter pylori infection of stomach
3. Symptoms:
1. Chronic anemia is compensated
2. Acute or severe anemia: symptoms develop
3. Pallor
4. Tiredness, easy fatigability and irritability

5. Generalized muscle weakness

6. Phagophagia and pica
7. School failure
8. Loss of hair
9. Cardiac de compensation
4. Physiological anemia of infancy:
1. Fetus lives in sterile condition and less need for wbc
2. Lives in hypoxic condition and hence need for RBCs more
3. Site of production of RBC from fetus to nb:
a. Yolk sac (mesoblastic erythropoiesis)
b. Liver (hepatic erythropoiesis)
c. Bone marrow ( myeloid erythropoiesis)
4. Normal values in NB:
1. Newborn:
I.
Pcv: 45-65%
II.
Reti. Count: 2-8%
III.
Hb: 16-18gm%
2. 6-8 weeks (Physiological anemia of infancy)
i. Hb: 10 gm%
ii. Pcv 30%
3. Causes of physiological anemia:
i. Decreased RBC life span
ii. Decreased eryhtropoietin
iii. Rapid increase in body weight
5. Lab tests:
1. HB%
2. Pcv
3. Serum ferritin
4. Serum iron
5. Iron binding capacity
6. Blood smear study
7. Stool occult blood
8. Bone marrow
6. Differential diagnosis of Microcytic hypochromic anemia:
1. Iron deficiency
2. Hemoglobinopathies
a. Thalassemia ( and )
b. Hemoglobin Lepore
c. Hemoglobin H
d. Hemoglobin E
3. Disorders of heme synthesis caused by a chemical
a. Lead
b. Pyrazinamide
c. Isoniazid
4. Sideroblastic anemias
5. Chronic infections or other inflammatory states
6. Malignancy
7. Hereditary orotic aciduria

8. Hypotransferrinemia:
a. Congenital
b. Acquired:
1. hepatic disorders;
2. malignant disease,
3. protein malnutrition (decreased transferrin synthesis),
4. nephrotic syndrome (urinary transferrin loss)
9. Copper deficiency
10. Inborn error of iron metabolism
Congenital defect of iron transport to red cells
7. Lab diagnosis:
1. Iron deficiency anemia:
1. Blood smear: Hypochromic microcytic red cells, confirmed by
RBC indices:
2. MCV less than acceptable normal for age
3. MCH less than 27.0 pg
4. MCHC less than 30%
5. Wide red cell distribution width (RDW) greater than 14.5%
6. Free erythrocyte protoporphyrin: elevated
7. Serum ferritin: decreased
8. Serum iron and iron binding capacity
9. Decreased serum iron
10.Increased iron-binding capacity
11.Decreased iron saturation (16% or less)
2. Lab: Differential Diaosis:
No
2
4
5

Disease
- and thalassemia trait
-thalassemia (or
thalassemia major)
-thalassemia trait

Hb H disease
-another form of thalassemia
The anemia of
chronic disease
(ACD) and infection
Lead poisoning

Lab findings
RDW (Red cell distribution width) is elevated in iron
deficiency and normal in - and -thalassemia trait
Pronounced erythroblastosis and severe hemolytic
component
normal results of iron studies (including ferritin),
normal levels of Hb A2and Hb F, and a normal
hemoglobin electrophoresis
Hb H is readily identified by hemoglobin
electrophoresis.
Normocytic,

Coarse basophilic stippling of the RBCs often is

prominent. Elevated blood lead, and urinary
coproporphyrin levels are seen

8. Treatment of iron deficiency anemia

1. Oral administration of simple ferrous salts (e.g., sulfate, gluconate,
fumarate) provides inexpensive and satisfactory therapy.
2. A daily total dose of 46 mg/kg of elemental iron in 3 divided doses;
abdominal discomfort can be minimized by administering iron with food
3. A parenteral iron preparation (iron dextran): response to parenteral iron
is no more rapid or complete than that obtained with proper oral
administration
4. Milk consumption should be limited to 500 mL (1 pint)/24 hr

5. Iron fortification:
a. Iron deficiency can be prevented in high-risk populations by
providing iron-fortified formula or cereals during infancy.
6. Adolescent girls:
a. Iron deficiency in adolescent females secondary to abnormal
uterine blood flow loss is treated with iron and hormone therapy
7. Response to treatment:
a. Within 7296 hr after administration of iron to an anemic child,
peripheral reticulocytosis is noted followed by a rise in the
hemoglobin level, which may increase as much as 0.5 g/dL/24 hr.
Iron medication should be continued for 8 wk after blood values
are normal.
8. Blood transfusion: In general, severely anemic children with
hemoglobin values <4 g/dL should be given only 23 mL/kg of packed
cells at any one time (furosemide also may be administered as a
diuretic).
9. Prevention and Nutritional Counseling:
1. Maintain breastfeeding for 6 months
2. Use an iron-fortified (612 mg/L) infant formula until 1 year of age
3. Restrict milk to 1 pint/day.
4. Use iron-fortified cereal from 6 months1 year.
5. Evaporated milk or soy-based formula should be used when irondeficiency is due to hypersensitivity to cows milk.
6. Provide supplemental iron for low birth weight infants: 2-3 mg/kg/day
7. Facilitators of iron absorption such as vitamin C-rich foods (citrus,
tomatoes and potatoes), meat, fish and poultry should be included in
the diet
8. Inhibitors of iron absorption such as tea, phosphate and phytates
common in vegetarian diets should be eliminated.
HEMOLYTIC ANEMIAS
1. General Features of Hemolytic anemia:
1. RBC life span is short
2. RBC count falls gradually due to chronic hemolysis
3. Erythropoietin level increases
4. Increased RBC production5. Erythroid hyperplasia of marrow
6. Extramedullary erythropoiesis in spleen and liver and flat bones.
7. Reticulocytes in peripheral smear
8. Reticulocytes:
1. Nonnucleated immature erythrocytes contain nuclear remnants
of RNA and the cell is known as a reticulocyte. To detect the
presence of this RNA, the red cells must be stained while they
are still living. This process is called supravital staining. With
supravital staining, the RNA appears as a reticulum within the
red cell.
2. The stains used are Methylene Blue or Brilliant Cresyl Blue

3. Under oil immersion magnification, count the number of

reticulocytes in 5 fields of 200 RBCs.
4. Reticount is expressed as % RBCs
5. Reticount of 1% of RBC is normal
6. Elevated in:
Hemolytic anemia
Acute Blood loss
For short period after correction of deficiency of:
Iron
B12
Folic acid
2. Other evidences of hemolysis
1. Indirect hyperbilirubinemia
2. Increased serum lactic dehydrogenase
3. Increased urinary and fecal urobilinogen
4. Bilirubin gall stones
5. Decreased hemophexin and haptoglobin which get bound to Heme
6. Increased free Hb- pink plasma
7. Carbon monoxide is released from Hb and appear in expired air
8. Aplastic crisis during certain infections like parvo virus
3. Classification of Hemolytic anemia:
1. Cellular: mostly inherited except paroxysmal nocturnal hemoglobinuria
1. Membrane defect- spherocytosis
2. Enzyme defect- G6PD; pyruvate kinase
3. Hemoglobin defect :
1. Quantitative deficiency of globin chains:
1. eg. Thalasemias
1. a thalasemia: alpha chains are less
2. b thalasemia: beta chains are less
2. Qualitative defect in globin chains:
1. eg. Hb S, C, E
2. Extracellular: mostly acquired except abetalipoproteinemia with
acanthocytosis
1. Antibody factors1. Autoimmune: SLE
2. Isoimmune: Rh, ABO
2. Plasma factors- abetalipoproteinemia, toxins
3. Mechanical factors- hemolytic uremic syndrome
HEREDITARY SPHEROCYTOSIS: Membrane defects:
1. Etiology:
a. autosomal dominant and, less frequently, as an autosomal recessive
disorder.
2. Pathology:

a. abnormalities of spectrin or ankyrin, which are major components of

the cytoskeleton responsible for RBC shape.
b. The loss of membrane surface area without a proportional loss of cell
volume causes sphering of the RBCs
c. The decreased deformability of the spherocytic RBCs impairs cell
passage from the splenic cords to the splenic sinuses hence destroyed
prematurely in the spleen.
d. Splenectomy markedly improves RBC life span and cures the anemia.
3. Clinical features:
a. In the newborn and may present as anemia and hyperbilirubinemia
b. Some children remain asymptomatic into adulthood, but others may
have severe anemia, with pallor, jaundice, fatigue, and exercise
intolerance.
c. The spleen is usually enlarged, and pigmentary (bilirubin) gallstones
may form as early as age 45 yr.
d. Children are susceptible to aplastic crisis, primarily as a result of
parvovirus infection
4. Laboratory findings:
1. Evidence of hemolysis includes reticulocytosis and indirect
hyperbilirubinemia.
2. The hemoglobin level usually is 610 g/dL, but it can be in the
normal range.
3. The reticulocyte percentage often is increased to 620%,
4. The spherocytes are smaller in diameter and appear hyperchromic
on the blood film as a result of the high hemoglobin concentration.
The central pallor is less conspicuous than in normal cells.
Spherocytes may be the predominant cell or may be relatively
sparse, depending on the severity of the disease, but they usually
account for >1520% of the cells when hemolytic anemia is
present.
5. Erythroid hyperplasia is evident in the marrow aspirate or biopsy.
6. Osmotic Fragility Test:
a. The presence of spherocytes in the blood can be confirmed
with an osmotic fragility test.
b. The RBCs are incubated in progressive dilutions of an isoosmotic buffered salt solution.
c. Exposure to hypotonic saline causes the RBCs to swell, and
the spherocytes lyse more readily than biconcave cells in
hypotonic solutions.
d. This feature is accentuated by depriving the cells of glucose
overnight at 37C, known as the incubated osmotic fragility
test.
e. This test is abnormal in immune and other hemolytic
anemias.
f. A normal test result also may be found in 1020% of patients.
7. Molecular diagnosis also is possible. Most patients have familyspecific private mutations that can be detected by DNA analysis.
Management:
1. Anemia is treatd by blood transfusion

2. Splectomy is the cure

THALASEMIAS
1. Thalassemia Syndromes:
1. Thalassemias are genetic disorders in globin chain production with
varying degrees of ineffective hematopoiesis and increased hemolysis.
2. There are four genes for -globin synthesis ( HBA1 gene and HBA2
gene two on each chromosome 16). Most -thalassemia syndromes are
due to deletion of one or more of the -globin genes rather than to
point mutations
2.
There are two HBB genes for -globin synthesis(chromosome 11); thalassemias are due to point mutations in one or both of the two -globin
genes.
2.
EPIDEMIOLOGY:
1. 3% of the world's population carries genes for -thalassemia, and in
Southeast Asia, 510% of the population carries genes for thalassemia
3. PATHOPHYSIOLOGY:
1. Gene mutations leading to decreased production of globin chains either
alpha or beta with variable severity is the basic defect
2. In thalassemia inadequate -globin production leads to decreased
levels of normal hemoglobin (Hb A), and an imbalance in - and globin chain production

3. In bone marrow:

1. Thalassemic mutations disrupt the maturation of red blood cells,

resulting in ineffective erythropoiesis in the following way:
2. In -thalassemias, there is an excess of -globin chains and less
of - and -globin chains;
3. Excess -globin chains have tendancy to join with eacfh other to
form -globin tetramers (4)
1. -globin tetramers (4) again have affinity to enter red cells with
intracellular precipitation of insoluble -chains. They interact
with the young red cell membrane and shorten red cell survival,
leading to hemolysis.
2. This in turn leads to anemia and a compensatory increase in
erythroid production and expansion of bone marrow.
3. When the -globin chains are produced in less amounts there is
relative increase in the production of and -globin chains for
which the genes are normal.
4. Now there is plenty of , and -globin chains, leading to an
elevated Hb F (22) and Hb A2(22) in -thalassemia.
5. In RBCs:
1. thalassemia:
1. Low levels of Hb A
2. More Hb F
3. More Hb A2
2. thalassemia:
1. More Barts Hb (4) and Hb H (4)

2. HbF can is less and hence death in fetal period is

common.
4.

5.

Demographics:
i.
Found most frequently in the Mediterranean, Africa, Western and
Southeast Asia, India and Burma
ii.
Distribution parallels that of Plasmodium falciparum
iii.
Abnormal Hb in RBC leads to resistance to malaria and while
people with normal gene die of malaria epidemics those with
abnormal genes survive.
Thalassemia types:
1. - thalassemia:
1. There are four genes for -globin synthesis (two on each
chromosome 16).
2. Most -thalassemia syndromes are due to deletion of one or
more of the -globin genes rather than to point mutations.
3. Types:
1. Silent trait: deletion of 1 -globin gene
2. -thalassemia trait: deletion of 2 -globin genes
3. Hb h disease: deletion of 3 -globin genes
4. - thalassemia major: deletion of all 4 -globin genes
causes profound anemia during fetal life, resulting in
hydrops fetalis
2. Beta thalasemia:
1. Most -thalassemias are due to point mutations in one or
both of the two -globin genes in chromosome 11.
2. -Thalassemia
1. 0 Thalassemia: No detectable -chain synthesis due
to absent -chain gene
2. + Thalassemia: Reduced -chain synthesis due to
reduced or non-functional -chain gene
3. -Thalassemia: - and -chain genes deleted
4. E-Thalassemia: Hemoglobin E (lysine-glutamic acid at
26) combined with -thalassemia mutation. May be 0
or 1.
5. Hb Lepore: a fusion globin due to unequal crossover of
the - and -globin genes (the globin is produced at a
low level because it is under -globin regulation).
1. Clinical types:
1. Major - homozygous
2. Minor (trait) - heterozygous
3. Intermedia: combination of -thalassemia mutations
(0/+, 0/variant, E/0)
3. Hereditary persistentce of fetal hemoglobin (HPFH).
Thalassemia Major- Cooleys anemia:

1. Pathogenesis
1. Variable reduction of -chain synthesis

2. Relative -globin chain excess

3. ineffective erythropoiesis and rbcs are prematurely destroyed;
4. Shortened red cell life span
2. Clinical:
1. A spectrum of clinical severity (major, minor and intermedia)
2. Failure to thrive in early childhood
3. Anemia
4. Jaundice, usually slight;
5. Gallstones
6. Hepatosplenomegaly, which may be massive;
7. Hypersplenism
8. Bone abnormalities:
i.
Abnormal facies,
ii.
prominence of malar eminences,
iii.
frontal bossing,
iv.
depression of bridge of the nose and
v.
exposure of upper central teeth
vi.
Skull radiographs showing hair-on-end appearance due to
widening of diploic spaces
vii.
Fractures due to marrow expansion and abnormal bone
structure
viii.
Generalized skeletal osteoporosis.
9. Growth retardation, delayed puberty, primary amenorrhea in females
and other
10. Endocrine disturbances secondary to chronic anemia and iron
overload
11. Leg ulcers
12. Skin bronzing.
13. If untreated, 80% of patients with beta thalassemia major die in the
first decade of life.
14. With current management, the life expectancy has dramatically
increased.Patients now reach the fifth decade of life and are expected
to live even longer.
1. Complications:
1. Chronic anemia may lead to CCF
2. Iron overload Due to repeated red cell transfusions and increased
absorption of dietary iron.Even in carefully managed patients, the
following complications may develop:
I.
Endocrine disturbances (e.g., growth retardation, pituitary failure
with impaired gonadotropins, hypogonadism, insulin-dependent
diabetes mellitus, adrenal insufficiency, hypothyroidism,
hypoparathyroidism)
II.
Cirrhosis of the liver and liver failure (exacerbated if concomitant
hepatitis B or C infection is present)
III.
Cardiac failure due to myocardial iron overload (often associated
with arrhythmias and pericarditis may occur)
IV.
Osteopenia and osteoporosis are common and the risk is directly
proportional to
V.
Pulmonary hypertension (tricuspid regurgitant jet velocity
greater than 2.5 m/s) occurs in both -thalassemia major and -

thalassemia intermedia. Splenectomy may exacerbate this risk,

particularly in patients who are not regularly transfused.
Causes of Death
1. Congestive heart failure.
2. Arrhythmia.
3. Sepsis secondary to increased susceptibility to infection postsplenectomy.
3. Lab findings
1. Elevated HbF and A2 in Hb electrophoresis
2. Severe anemia <5 gm%
3. Few reticulocytes <8%
4. Numerous nucleated RBCs
5. Leukopenia and thrombocytopenia (with hypersplenism).
6. Blood smear Microcytosis, target cells and nucleated red cells,
extreme anisocytosis, polychromasia, punctate basophilia,
circulating normoblasts.
7. Unconjugated bilirubin increased
8. Elevated serum ferritin
9. Saturation of transferrin
10.Erythroid hyrplsia of marrow
11.Osmotic Fragility Test:
i. RBCs are incubated in varying concentrations of a
hypotonic solution of sodium chloride (NaCl) at 37oC
ii. Normal cells begin to haemolyse at NaCl concentrations of
approximately 0.50%
iii. In positive test lysis is usually completed by 0.4-0.5%,
starting at higher NaCl concentrations
12.Cellulose Acetate Hb Electrophoresis: HbS band seen
4. Imaging : X Ray skull: hair on end appearance
5. Treatment:
1. Transfusion Therapy:
1. Indications for initiation of regular red cell transfusions include:
i. Hemoglobin level ,7 g/dl (on at least 2 measurements)
ii. Poor growth
iii. Facial bone changes
iv. Fractures
v. Development of other complications (pulmonary
hypertension, extramedullary hematopoiesis, etc.).
2. The goal of transfusions is to maintain a pretransfusion hemoglobin
greater than 99.5 g/dl.
3. Typical programs involve transfusion of 1015 cc/kg of packed
leukodepleted red cells. Blood should be matched for ABO, C, E and
kell antigens to reduce the risk of alloimmunization (some centers
perform extended red cell antigen matching).
4. Post-transfusion hemoglobin falls roughly 1 g per week,
necessitating transfusions every 34 weeks.
5. Transfusions result in:
i. Maximizing growth and development

6.

7.

8.

9.

ii. Minimizing extramedullary hematopoiesis and decreasing

facial and skeletal abnormalities
iii. Reducing excessive iron absorption from gut
iv. Retarding the development of splenomegaly and
hypersplenism
v. Reducing and/or delaying the onset of complications (e.g.,
cardiac involvement).
Iron overload and toxicity in thalassemia result from:
i. Multiple blood transfusions
ii. Increased gut absorption of iron (more important in thalassemia intermedia).
Monitoring Iron Overload
i. Serum ferritin
ii. Liver iron concentration (LIC); iron concentration >15 mg/g
dry weight of liver is associated with an increased risk of
cardiac disease and death. Methods to measure LIC include:
1. MRI: R2 methodology
2. Superconducting quantum interference device
(SQUID): highly specialized equipment available in few
centers worldwide
3. Liver biopsy: the gold standard, but invasive.
4. Cardiac iron measurment by T2* MRI.
Chelation Therapy:
i. To maintain a safe level of body iron burden:
ii. Chelation therapy typically is not used in children younger
than 2 years old and is often deferred until age 3 to 4 years.
iii. Indications for chelation therapy:
1. Serum ferritin level persistently 1,000 ng/ml
2. Liver iron concentration 57 mg/g dry weight.
iv. Chelating agents:
1. Deferoxamine must be administered as a
subcutaneous infusion over 824 hours. Audiological
and ophthalmological toxicities are more common. 25
50 mg/kg/day
2. Deferasirox is supplied as orally dispersible tablets,
which are dissolved in a glass of water or apple juice
and administered 1/2 hour before meals. Studies have
shown efficacy similar to that of deferoxamine.
Gastrointestinal disturbances including abdominal
pain, nausea, vomiting and diarrhea and liver and renal
toxicity are common. 2040 mg/kg/day
3. Deferiprone: Oral; 75 mg/kg/day; Three times a day;
Gastrointestinal disturbances;btransaminase
elevations; agranuloctyosis/ neutropenia; arthralgia
Splenectomy:
i. Indications:
1. Persistent increase in blood transfusion requirements
by 50%
2. Annual packed cell transfusion requirements in excess
of 250 ml/kg/year

3. Ferritin greater than 1,500 ng/ml or increased hepatic

iron concentration)
4. Evidence of severe leukopenia and/or
thrombocytopenia.
ii. Precaution with vaccination:
1. polyvalent pneumococcal
2. meningococcal vaccine
3. Haemophilus influenza vaccine
4. Following splenectomy, prophylactic penicillin 250 mg
bid is given
10. Supportive Care:
i. Folic acid is not necessary in hypertransfused patients; 1 mg
daily orally is given to patients on low transfusion regimens.
ii. Hepatitis A and B vaccination should be given to all patients.
iii. Cholecystectomy should be performed if symptomatic
gallstones are present.
11.Genetic counseling and antenatal diagnosis (when indicated) should
be carried out using chorionic villus sampling or amniocentesis.
2. Follow up of patients with thalassemia includes:
1. Monthly:
i. Complete blood count
ii. Complete blood chemistry (including liver function tests,
BUN, creatinine) if taking deferasirox
iii. Record transfusion volume.
2. Every 3 months:
i. Measure height and weight
ii. Measure ferritin (trends in ferritin used to adjust chelation);
iii. Perform complete blood chemistry, including liver function
tests.
3. Every 6 months:
i. Complete physical examination including Tanner staging,
monitor growth and development, dental examination.
4. Every year:
i. Cardiac function echocardiograph, ECG,
ii. Endocrine function (TFTs, PTH, FSH/LH, fasting glucose,
testosterone/ estradiol, FSH,
iii. Opthalmological examination and auditory acuity Viral
serologies (HAV, HBV panel, HCV (or if HCV1, quantitative
HCV RNA PCR), HIV)
iv. Bone densitometry
5. Other measures:
i. Hydroxyurea has been demonstrated to increase Hb F
production and mean hemoglobin levels in patients with
thalassemia
ii. Decitabine is another fetal hemoglobin-inducing agent that is
currently being studied in thalassemia.
6. Hematopoietic Stem Cell Transplantation
7. Gene Therapy
i. Research is underway on methods of inserting a normal globin gene into mammalian cells. Ultimately, the aim is to

insert the gene into stem cells and utilize these for stem cell
transplantation.
- THALASSEMIA
1. The major syndromes resulting from decreased -chain synthesis
a. Deletion of 1 gene: silent carrier
b. Deletion of 2 genes: Thalassemia trait
c. Deletion of 3 genes: Hb H disease-4
d. All 4 absent: Thalassemia major- hydrops fetalis
2. Hemoglobin H disease is clinically milder than homozygous -thalassemia
and usually does not require regular red cell transfusions.
3. Hemoglobin levels may fall with intercurrent illnesses and patients may
require transfusion at such times.
4. Hemoglobin H Constant Spring tends to produce a more severe
phenotype; some patients may require chronic red cell transfusion
therapy.
5. Hydrops fetalis is not compatible with life and presents with intrauterine
or neonatal death, though some babies have survived with fetal packed
red blood cell transfusions when antenatal diagnosis was made.
6. These patients should continue on hypertransfusion regimens and be
treated like -thalassemia major, or treated with allogeneic stem cell
transplantation.
SICKLE CELL DISEASE
1. Hb S:

1. In Hb S, thymine replaces adenine in position 6 of chain due to

mutation.
2. The result is glutamtic acid is replaced by valine forming Hb S.
3. In sickle cell disease hemoglobin S replaces both beta-globin subunits
in hemoglobin. In sickle cell trait, just one beta-globin subunit in
hemoglobin is replaced with hemoglobin S.
4. Autosomal recessive (autosomal co-dominant trait); the gene is
prevalent among tribal population in Maharashtra, Madhya Pradesh,
Orissa, Andhra Pradesh, Gujarat and to a lesser extent in Tamil Nadu,
Karnataka, Kerala and Uttar Pradesh.
5. Homozygotes (two abnormal genes, SS), red cells contain 75%
hemoglobin S (Hb S).
6. Heterozygotes (one abnormal gene), sickle cell trait, have red cells
containing 2045% Hb S
2. Pathophysiology:
1. Sickle cells are prematurely destroyed, causing hemolytic anemia
2. Intravascular hemolysis reduces nitric oxide (NO) bioavailability
3. NO normally regulates vasodilation, causing increased blood flow and
inhibits platelet aggregation. Thus, reduced NO bioavailability is
thought to contribute to vasoconstriction and platelet activation

4. Increased red cell adhesion reduces flow rate in the microvasculature,

trapping red cells contributing to vaso-occlusion

5. Sickle cells increase blood viscosity, which also contributes to vasoocclusion

6. Sickle red cells may damage the endothelium leading to production of
inflammatory mediators. Ischemiareperfusion also causes
inflammation
9. Hemolysis and NO depletion are thought to play an important role in
priapism, leg ulcers and pulmonary hypertension, while viscosity/vasoocclusion is thought to be more central in the pathophysiology of vasoocclusive pain and acute chest syndrome;
3. Hematology
1. Anemia moderate to severe in SS and S-0 thalassemia, milder with
SC or S1 thalassemia.
2. Reticulocytosis.
3. Neutrophilia common.
4. Platelet count often increased.
5. Blood smear sickle cells (not in infants or others with high Hb F)
increased polychromasia, nucleated red cells and target cells
6. Erythrocyte sedimentation rate (ESR) low (sickle cells fail to form
rouleaux).
7. Hemoglobin electrophoresis hemoglobin S migrates slower than
hemoglobin A.
4. Acute Complications:
1. Infections:
i. Children with sickle cell anemia have:
1. Deficient levels of serum opsonins of the alternate
complement pathway against pneumococci.
2. Increased risk for infection with encapsulated organisms,
such as Streptococcus pneumonia, and Haemophilus
influenzae type B
ii. Human parvovirus B19:
1. Acute infection with parvovirus B19 is usually associated
with red cell aplasia (aplastic episode),
7. Vaso-occlusive pain event (VOE): The cardinal clinical feature of sickle cell
anemia is pain from vaso-occlusive episode. The pain is due to tissue
ischemia.
1. Dactylitis:
iii. Dactylitis, often referred to as hand-foot syndrome, often
presents with symmetric swelling of the hands and/or feet
2. Bone pain:
iv. More common after age 3 years.
v. Often involves long bones, sternum, ribs, spine and pelvis.
3. Abdominal pain:
vi. Caused by microvascular occlusion of mesenteric blood supply
and infarction in the liver, spleen, or lymph nodes that result in
capsular stretching.
4. Acute chest syndrome:
vii. Acute chest syndrome (ACS) is the most common cause of death

viii. symptoms include fever, chest pain, tachypnea, cough,

hypoxemia and wheezing

ix. Caused by infection (Mycoplasma, Chlamydia, Streptococcus

pneumonia and Parvovirus B19) infarction and/or fat
embolization.
8. Neurologic complications (Stroke):
x. children with sickle cell anemia may have either overt or silent
strokes, respectively, before their 18th birthday.
xi. The most common underlying lesion is intracranial arterial
stenosis or obstruction, usually involving the large arteries
9. Priapism
1. Priapism is an involuntary painful penile erection lasting
longer than 30 minitues
2. Priapism often occurs due to venous outflow obstruction.
3. Treatment
i.
Treatment involves aspiration of the corpus cavernosum
followed by irrigation with a dilute (1:1,000,000)
epinephrine solution. A dilute solution of phenylephrine,
an alpha adrenergic agent, rather than epinephrine, has
also been utilized in some centers
ii.
Prevention of priapism
a. Pseudophedrine, 3060 mg orally at bedtime
b. Hydroxyurea appears to have promise
10.Splenic sequestration:
1. Large numbers of sickled red blood cells become trapped in the spleen, causing it to
suddenly enlarge.

2. This condition Highest prevalence between 5 and 24 months of age

3. Treatment:
a. Normal saline bolus of 1020 cc/kg
b. Red cell transfusion.
11.
Transient pure red cell aplasia
i. Cessation of red cell production that may persist for 714 days
with profound drop in hemoglobin (as low as 1g/dl)
ii.
Almost invariably associated with parvovirus B19 infection
12.Cardiovascular system
a. Cardiomegaly is found in most patients and left ventricular hypertrophy
b. Pulmonary hypertension in some children
13.Pulmonary
a. Pulmonary fibrosis
b. Asthma Prevalence appears to be higher in children with SCD
14.Kidney
a. Gross hematuria,
b. Papillary necrosis,
c. Nephrotic syndrome,
15.Liver and biliary system:
a. Chronic hepatomegaly
b. Increased serum glutamic-oxaloacetic transaminase (SGOT) and
serum glutamic pyruvic transaminase (SGPT)
c. Cholelithiasis
16. Bones

a. expansion of the marrow cavity,

b. Avascular necrosis (AVN): The most common cause of AVN of
the femoral head is sickle cell disease.
17. Skin: Cutaneous ulcers of the legs occur over the external or internal
malleoli.
18. Retinopathy: sickle retinopathy is common in all forms
19. Ears : Up to 12% of patients have high-frequency sensorineural hearing
loss
20. Adenotonsillar hypertrophy giving rise to upper airway obstruction is
seen in 18%.
21. G&D: the height and weight are significantly delayed. Delayed sexual
maturation
22. Functional hyposplenism: spleen undergoes progressive fibrosis
(autosplenectomy)

5. Diagnosis
a. In utero: mutation analysis of DNA prepared from chorionic villus biopsy
or fetal fibroblasts
b. During newborn period: The diagnosis of sickle cell disease can be
established by electrophoresis
c. Laboratory Findings:
a. Baseline hemoglobin level of 710 g/dL.
b. The baseline reticulocyte count is elevated markedly.
c. The anemia is usually normocytic or macrocytic, and the
peripheral blood smear typically shows the characteristic sickle
cells as well as numerous target cells.
d.

6. Prognosis

Sickling Test: A drop of patients blood is mixed with sodium

metabisulphate (a reducing agent that deoxygenates blood) and
examined under a microscope after 30min to see sickled RBCs.

1. 85% survive to 20 years of age.

2. Causes of death include:
1. Infection (sepsis, meningitis) with a peak incidence between 1 3 years
2. Acute chest syndrome/respiratory failure
3. Stroke (especially hemorrhagic) and
4. Organ failure including heart, liver and renal failure.
7. Management:
a. Infection:
i. Because of a marked incidence of bacterial sepsis and meningitis
and fatal outcome under 5 years of age, all children with sickle cell

b.

c.

d.

e.

disease should receive oral penicillin / erythromycin prophylaxis

starting by 34 months of age.
Immunization:
i. Routine childhood immunizations including conjugate H. influenza.
The pneumococcal, hepatitis B, Meningococcal and Influenza virus
vaccine should be given as per schedule.
Transfusion therapy:
i. Red cell transfusions play an important role in management.
ii. Transfusion therapy is used to prevent acute and chronic
complications of sickle cell disease. Indication: hemoglobin level
falls below 6 g/dL.
Augmentation of HbF:
a. Hydroxyurea (HU) is the most commonly used drug for Hb F
modulatory therapy
b. Butyrates are short chain fatty acids that raise Hb F levels through
modulation of histone acetylation
Successful stem cell transplantation cures sickle cell disease
HODGKIN DISEASE

1. Epidemiology:
1. The two broad categories of lymphoma, Hodgkin disease and nonHodgkin lymphoma (NHL), have different clinical manifestations and
treatments.
2. Lymphoma is the third most common cancer in children
3. Hodgkin disease accounts for about 5% of cancers in persons
younger than 15 yr of age and for about 15% in persons 15-19 yr of
age.
4. Males predominate in patients younger than 10 yr of age at
diagnosis, with roughly equal gender incidence in adolescence.
5. Three forms of Hodgkin disease have been identified in
epidemiologic studies:
a. A childhood form ( 14 yr of age),
b. A young adult form (15-34 yr of age),
c. An older adult form (55-74 yr of age).
2. Etiology:
1. The role of Epstein-Barr virus (EBV) is supported by serologic studies
and the frequent presence of EBV genome in biopsy material.
2. Pre-existing immunodeficiency, either congenital or acquired,
increases the risk of developing Hodgkin disease.
3. A genetic predisposition or a common exposure to the same
etiologic agent could account for an apparent increased risk in twins
and first-degree relatives ranging from 3- to 7-fold
3. Pathogenesis:
a. The Reed-Sternberg cell, a large cell (15-45 m in diameter) with
multiple or multilobulated nuclei, is considered the hallmark of
Hodgkin disease, although similar cells are seen in infectious
mononucleosis, NHL, and other conditions.
b. There is general agreement that the Reed-Sternberg cell arises from
germinal center of B-cells in most cases.

4.

5.
6.

7.

c. An infiltrate of apparently normal lymphocytes, plasma cells, and

eosinophils surround the Reed-Sternberg cell
d. The four major histologic subtypes are: Rye classification
i. lymphocyte predominant,
ii. nodular sclerosing,
iii. mixed cellularity, and
iv. Lymphocyte depleted.
Origin and spread:
a. Arise in lymphoid tissue and spreads to adjacent lymph node areas
in a relatively orderly fashion.
b. Hematogenous spread also occurs, leading to involvement of the
liver, spleen, bone, bone marrow, or brain
Cause for fever:
a. Cytokines from Hodgkin tissue
b. Immune suppression:
Clinical Manifestations:
a. Painless, firm, cervical, or supraclavicular lymphadenopathy is the
most common presenting sign.
b. Inguinal or axillary lymphadenopathy sites are uncommon
c. An anterior mediastinal mass is often present
d. Clinically detectable hepatosplenomegaly is rare.
e. symptoms and signs:
i. Airway obstruction,
ii. Pleural or pericardial effusion,
iii. Hepatocellular dysfunction,
iv. Bone marrow infiltration (anemia, neutropenia, or
thrombocytopenia).
v. Nephrotic syndrome is a rare but recognized manifestation
vi. Unexplained fever, weight loss and night sweat.
vii. Pruritus, lethargy, anorexia, or pain that worsens after
ingestion of alcohol
viii. Varicella-zoster infections in about 30% of cases
Diagnosis:
a. Formal excisional biopsy is preferred over needle biopsy
b. Modified Ann Arbor Staging System for Hodgkin
Disease:
STAGE I: Involvement of a single lymph node region
STAGE II: Involvement of two or more lymphoid regions on the
same side of the diaphragm;
STAGE III: Involvement of lymph node regions on both sides of
the diaphragm,
STAGE IV Diffuse or disseminated involvement
A or B, based on the absence or presence, respectively, of
systemic symptoms of fever and/or weight loss
Bulky disease, based on mediastinal mass larger than one third
thoracic diameter;
b. A complete blood cell count (CBC) identifies abnormalities due to
bone marrow
involvement.

c. Erythrocyte sedimentation rate (ESR), serum copper determination,

and serum ferritin levels are of some prognostic significance
8. Treatment:
a. Consists of radiotherapy combined with chemotherapy
b. The chemotherapy regimens in current use are:
i. COPP:
1. Cyclophosphamide
2. Oncovin (vincristine)
3. Procarbazine, and
4. Prednisone
ii. ABVD:
1. Adriamycin(doxorubicin
2. Bleomycin,
3. Vinblastine, and
4. Dacarbazine
iii. A minimum of six cycles of chemotherapy was given with
significant cumulative
iv. Toxicity, includes:
1. Second malignancies,
2. Sterility, and cardiac and
3. Pulmonary dysfunction.
c. Radiotherapy:
i. Extended-field radiation therapy
9. Relapse:
a. Patients who suffer relapse after initial treatment usually respond to
additional chemotherapy or radiation or both.
b. Those who never achieve remission or who suffer relapse after an
initial remission of less than 12 mo after chemotherapy have a
poorer prognosis
10.Prognosis:
a. Most treatment programs result in disease-free survival rates of
more than 60%, with overall cure rates greater than 90% in those
with early stage disease and more than 70% in more advanced
cases.
Non Hodgkin Lymphomas
1. Introduction:
a. Non-Hodgkin lymphoma (NHL) results from malignant clonal
proliferation of lymphocytes of T-, B-, or indeterminate cell origin.
2. Four histologic subtypes are recognized:
a. Burkitt lymphoma (BL), constituting 40%
b. Lymphoblastic, usually of T-cell origin; 30%
c. Diffuse large B-cell lymphoma (DLBCL), constituting 20%; and
d. Anaplastic large cell lymphoma (ALCL), accounting for 10%
3. Pathogenesis:
a. EBV infection has a major role in the pathogenesis of Burkitt
lymphoma.
b. Congenital or acquired immunodeficiency also predisposes to the
development of NHL.
c. pesticide exposure as a possible risk factor
d. Chromosomal translocations are specific for some histologic
subtypes

4. Clinical Manifestations:
a. NHLs are rapidly growing tumors and can cause symptoms based
on size and location.
b. Manifests as gastrointestinal, bone marrow, and central nervous
system (CNS) involvement.
c. Site-specific manifestations include:
i. Painless, rapid lymph node enlargement;
ii. Cough, superior vena cava (svc) syndrome,
iii. Dyspnea with thoracic involvement;
iv. Abdominal (massive and rapidly enlarging) mass,
v. Intestinal obstruction,
vi. Intussusception-like symptoms,
vii. Ascites with abdominal involvement;
viii. Nasal stuffiness,
ix. Earache, hearing loss, tonsil enlargement with Waldeyer ring
involvement;
x. and localized bone pain (primary or metastatic bone
involvement)
d. Three important clinical manifestations:
i. SVC syndrome secondary to a large mediastinal mass
ii. Acute paraplegias secondary to spinal cord compression
iii. Tumor lysis syndrome (TLS) secondary to severe metabolic
abnormalities, including hyperuricemia, hyperphosphatemia,
hyperkalemia, and hypocalcemia from massive tumor cell
lysis
5. Work up:
a. Bilateral bone marrow aspiration and biopsies;
b. Lumbar puncture with CSF cytology, cell count and protein;
c. Chest x-ray; and neck, chest, abdominal, and pelvic CT scans, PET
scan and bone scan (optional), and head CT scan (optional).
d. The tumor tissue tested by flow cytometry for immunophenotypic
origin (T, B, or null) and cytogenetics (karyotype).
e. fluorescent in situ hybridization (FISH) or quantitative RT-PCR for
specific genetic translocations, T and B cell gene rearrangement
studies,
f. Elevated levels of serum lactic dehydrogenase (>500 U/L) correlate
with tumor mass
6. The St. Jude staging system defines tumor extent, which is important for
designing treatme.
a. Stage I applies to localized disease,
b. Stage II to regional disease
c. Stage III to extensive disease, and
d. Stage IV to disseminated (CNS and/or bone marrow) disease.
7. DD:
a. Head and neck lymphadenopathy should be differentiated from
infectious nodal etiologies;
b. Mediastinal masses from Hodgkin and germ cell tumors;
c. Abdominal involvement from Wilms tumor, neuroblastoma, and
rhabdomyosarcoma;
d. Bone marrow involvement from lymphoblastic leukemia
8. Treatment and Prognosis:

a. The primary modality of treatment for childhood and adolescent

NHL is multiagent systemic chemotherapy and intrathecal
chemotherapy.
b. Surgery is used mainly for diagnostic and/or biologic specimens and
staging but rarely is used for debulking large masses.
c. Radiation therapy is rarely, if ever, used, except in special
circumstances such as CNS involvement in LL or occasionally BL,
acute SVC, and acute paraplegias.
d. Common regimens include COPAD (cyclophosphamide, vincristine,
prednisone and doxorubicin or COMP (cyclophosphamide,
vincristine, methotrexate, 6-mercaptopurine and prednisone).
e. Advanced disease usually is treated by 46 mo of multiagent
chemotherapy
f. Intrathecal chemotherapy is administered to moderate to advanced
disease in all subtypes of childhood and adolescent NHL and may
include intrathecal methotrexate, hydrocortisone, or Ara-C
9. Prognosis:
a. The prognosis is excellent for most forms of childhood and
adolescent NHL.
b. Patients with localized disease have a 90100% chance of survival,
and patients with advanced disease have a 6095% chance of
survival.
LEUKEMIAS
Definition
1. A group, of malignant diseases in which a genetic abnormality in
hematopoietic cells gives rise to clonal proliferation of maliganat cells:
2. Classification:
I.
Acute leukemias constitute 97% of all childhood leukemias and consist
of the following types:
i. Acute lymphoblastic leukemia (ALL) 75%
ii. Acute myeloblastic leukemia (AML), also known as acute
nonlymphocytic leukemia (ANLL) 20%
iii. Acute undifferentiated leukemia (AUL) ,0.5%
iv. Acute mixed-lineage leukemia (AMLL).
II.
Chronic myeloid leukemias constitute 3% of all childhood leukemias
and consist of:
i.
Philadelphia chromosome positive (Ph1 positive) myeloid
leukemia
ii.
Juvenile myelomonocytic leukemia (JMML).
4. Leukemias are common malignancy in pediatrics; 41% of all malignancies
< 15 years; 4.1 % per 100 000 children annually
ACUTE LYMPHOBLASTIC LEUKEMIA ALL
1. Epidemiology:
1. ALL 77%; AML 11%; CML 2-3%; rest unclassified
2. Age: 2-6 years; More in males
3. Higher incidence in:
a. Down

b.
c.
d.
e.
n.
o.

Bloom
Fanconi
Turner
Klinefilter
Ataxia telangiectasia (Immune deficiency)
100% monozygotic; 50% in dizygotic twins

2. Etiology
1. Unknown
2. Radiation : in utero, diagnostic, therapeutic
3. Epstein Barr virus?
4. Advanced maternal age
5. Alkylating agents
6. Benzene
3. Pathogenesis:
a. Malignant transformation of a single clone of cells belonging to
lymphoid series due to a genetic damage to DNA;
b. This is followed by proliferation of affected clone
c. Chromosomal translocation: e.g: Philadelphia Chromosome t (9;22)
d. Surface markers:
i. 85% are derived from B cells
ii. 15% from T cells
4. ALL Morphologic Classification - The French-American-British (FAB) Cooperative
Working Group
L 1: Lymphoblats: 85%
1. Small cells
2. High nucleus-to-cytoplasm ratio
3. Indistinct nucleoli
4. Cytoplasm is scanty
L 2: Lymphoblast - 14 %
1. Larger, often in a more
2. Heterogeneous population, with a
3. Lower nucleus-to-cytoplasm ratio
4. Prominent nucleoli
L3 Lymphoblasts 1 %
1. Heterogeneous group of cells
2. Deeply basophilic cytoplasm
3. Prominent cytoplasmatic vacuolization.
5. Philadiphia chromosome
1. The ABL gene on chromosome 9 is mistakenly transferred to
chromosome 22 and attaches to the BCR gene.
2. This creates a new fusion gene called BCR-ABL which leads to leukemic
process.
7. Clinical features
1. General Systemic Effects
1. Fever (60%).
2. Lassitude (50%).
3. Pallor (40%).
2. Hematologic Effects Arising from Bone Marrow Invasion

1. Anemia causing pallor, fatigability, tachycardia, dyspnea

and sometimes congestive heart failure.
3. Neutropenia causing fever, ulceration of buccal mucosa and
infection.
3. Thrombocytopenia causing petechiae, purpura, easy
bruisability, bleeding from mucous membrane and sometimes
internal bleeding (e.g., intracranial hemorrhage).
4. Clinical Manifestations Arising from Lymphoid System Infiltration
1. Lymphadenopathy sometimes presents with bulky
mediastinal lymphadenopathy causing superior vena cava
syndrome. More common in T-cell leukemia in adolescents.
2. Splenomegaly.
3. Hepatomegaly.
5. Clinical Manifestations of CNS Invasion
1. Signs and symptoms of raised intracranial pressure
2. focal neurologic signs such as hemi paresis, cranial nerve
palsies, convulsions,
3. cerebellar involvement ataxia,dysmetria, hypotonia,
hyperflexia)
4. Hypothalamic syndrome (polyphagia with excessive weight
gain, hirsutism and behavioral disturbances)
5. Diabetes insipidus (posterior pituitary involvement)
6. Chloromas of the spinal cord (very infrequent in ALL) may
present with back pain, leg pain, numbness, weakness,
BrownSequard syndrome and bladder and bowel sphincter
problems
7. CNS hemorrhage
6. Genitourinary Tract Involvement:
1. Testicular Involvement: painless enlargement of the testis.
2. Ovarian Involvement: Occurs very rarely.
3. Priapism: Occurs rarely. It is due to leukemic infiltrates or by
the coagulation of the platelet-rich leukemic blood in the
corpora cavernosa.
7. Renal Involvement
1. Occasionally may present with hematuria, hypertension and
renal failure.
8. Gastrointestinal Involvement
1. The most common manifestation is bleeding.
2. Infilotrayion of cecum, giving rise to typhlitis.
9. Bone and Joint Involvement
1. Bone pain is one of the initial symptoms
2. X ray: Transverse metaphyseal radiolucent bands
10.Skin Involvement: Besides signs of bleeding maculopapular skin
infiltration often of a deep red color (leukemia cutis) can be observed;
11.Cardiac Involvement: leukemic infiltrates and hemorrhage of the
myocardium or the pericardium.
12.Lung Involvement: Large mediastinal mass in adolescent boys with T
cell leukemia
Diagnosis
1.
Blood count
a. Hemoglobin: Moderate to marked reduction.

b. Normocytic; normochromic red cell morphology.

c. White blood cell count: Low, normal, or increased
d. Blood smear: Blasts are present on blood smear. When the white
blood cell (WBC) count is greater than 10,000/mm3, blasts are
usually abundant.
e. Eosinophilia is seen uncommonly in children with ALL; 20% of
patients with AML have an increased number of basophils
f. Thrombocytopenia: 92% of patients have platelet counts below
normal.
2. Bone marrow:
a. Bone marrow is usually replaced by 80100% blasts.
b. Megakaryocytes are usually absent.
c. Leukemia must be suspected when the bone marrow contains
more than 5% blasts.
d. Lymphoblast: The hallmark of the diagnosis of acute leukemia is
the blast cell, a relatively undifferentiated cell with diffusely
distributed nuclear chromatin, one or more nucleoli and
basophilic cytoplasm. Special bone marrow studies, which help
in detailed cell classification, include the following:
e. Special bone marrow studies, which help in detailed cell
classification, include the following:
a. Histochemistry
b. Immunophenotyping
c. Cytogenetics.
3.
X-Ray:
1. Chest radiograph: Mediastinal mass in T-cell leukemia.
2. X ray long bones:
a. Periosteal elevation
b. Growth arrest lines
4. Blood chemistry: Increase in LDH, uric acid, liver function tests,
immunoglobulin levels.
5. Cerebrospinal fluid: Chemistry and cells. Cerebrospinal fluid findings
for the diagnosis of CNS leukemia require:
1. Presence of more than 5 WBCs/mm3
2. Identification of blast cells on cytocentrifuge examination.
6. Coagulation profile: Decreased coagulation factors that frequently
occur with AML are: hypofibrinogenemia, factors V, IX and X.
7. Cardiac function: Electrocardiogram (ECG) and echocardiogram.
8. Immunologic screening: Serum for immunoglobulin levels, C3 and
C4.
9.
Abd.Us:
1. Kidney infiltartion
2. Intra abdominal lymphadenopathy
9. Classification of ALL: Acute leukemia is classified based on:
1. Morphologic characteristics,
2. Cytochemical features,
3. Immunologic characteristics and
4. Cytogenetic and molecular characteristics.
5. The World Health Organization has developed a new classification of
ALL based on cytogenetic and molecular characteristics
a. Morphologic classification:

1. Morphologic subtyping of the various forms of ALL used to be done

according to the French-American-British (FAB) classification. The FAB
classification:
o

ALL-L1: small uniform cells

ALL-L2: large varied cells

ALL-L3: large varied cells with vacuoles (bubble-like features)

2. The recent WHO International panel on ALL recommends that this

classification be abandoned, since the morphological classification has

no clinical or prognostic relevance. It instead advocates the use of the
immunophenotypic classification mentioned below.
b. Immunophenotyping:
1. Blast cells are classified by determining the surface markers of the
abnormal lymphocytes, called immunophenotyping.
2. There are 2 main immunologic types: pre-B cell and pre-T cell.
3. The mature B-cell ALL (L3) is now classified as Burkitt
leukemia/lymphoma (BL).
4. Phenotypically, surface markers show that about 85% of cases of ALL
are derived from progenitors of B cells, about 15% are derived from T
cells, and about 1% are derived from B cells.
5. Subtyping helps determine the prognosis and most appropriate
treatment in treating ALL.
c. Cytogenetic classification:
1. With current methods, more than 90% of cases of childhood ALL
demonstrate cytogenetic (chromosomal) abnormalities either in
number (ploidy) or structure.
2. Ploidy: abnormal number of chromosomes in blast cells:
1. Approximately 40% of cases are pseudodiploid;
2. Another 40% are hyperdiploid
3. Fewer than 2% of cases are hypodiploid (fewer than 45
chromosomes).
3. Structural abnormalities in blastcells:

1. Among the structural abnormalities, translocations are the most

common and occur in 40% of cases.
13. D.D:
1. Chronic infections by Epstein-Barr virus (EBV) and cytomegalovirus
(CMV), cause lymphadenopathy, hepatosplenomegaly, fevers, and
anemia.
2. Prominent petechiae and purpura suggest a diagnosis of immune
thrombocytopenic purpura.
3. Significant pallor could be caused by autoimmune hemolytic anemias,
or aplastic anemia.
4. Fevers and joint pains, with or without hepatosplenomegaly and
lymphadenopathy, suggest juvenile rheumatoid arthritis (JRA). Serum
LDH levels may help distinguish JRA from leukemia, as the LDH is
usually normal in JRA.
5.

An elevated WBC count with lymphocytosis is typical of pertussis;

however, in pertussis the lymphocytes are mature, and neutropenia is
rarely associated.

14. Prognostic Factors:

1) The disease is invariably fatal without treatment.
2) Favourable prognostic factors are:
1. Age 1 to 10 yrs;
2. Female child
3. WBC count < 25,000/L
4. French-American-British (FAB) L1 morphology
5. hyperdiploid ALL
5. t (12;21) translocation
6. No CNS disease at diagnosis
7. Good speed of response to treatment
3) Unfavourable factors
1. Age < 1 year.
2. Mature T cell ALL
3. A leukemic cell karyotype with chromosomes that are normal
in number but abnormal in morphology (pseudodiploid)
4. Translocations involving 11q23
5. Hypodyploid ALL
6. Presence of the Philadelphia: t(9;22)
7. Increased age in adults
8. B-cell immunophenotype
9. The presence of CNS disease at diagnosis:

10.

Minimal residual disease (MRD) present at the end of

consolidation therapy
4) Risk groups
1. Standard (low) risk:
a. Children aged 1 to 10 years
b. White blood cell count of less than 50,000/mL at
diagnosis.
c. Generally includes two-thirds of pre-B ALL patients,
have a 4-year event-free survival of 80%.
2. High risk:
a. Children younger than 1 year or older than 10 years
b. White blood cell count of 50,000/ml or more at
diagnosis
c. Chromosomal abnormalities such as t(9;22) or t(4;11),
d. Have a 4-year event-free survival of 65%.
15. Treatment:
1. Supportive care:
a. Correction of dehydration and anemia
b. Treatment of sepsis
c. uric acid nephropathy are prevented by allopurinol 10 mg/kg/day in
divided doses together with a fluid intake of 23 L/m2/day.
d. Live vaccines are contraindicated; inactivated vaccine should be
employed
e. Psychosocial support of child and family
2. Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia:
a. International standard protocols for treatment of Leukemias:
1. Childrens Cancer and Leukaemia Group (CCLG),
2. Children's Cancer Group (CCG)
3. Paediatric Oncology Group (POG).
4. Recently, these two groups have joined together to form the
largest group - Children's Oncology Group (COG).
5. There are many ongoing trials
6. Most favorable and successful trial will later become a standard
protocol
b. Goals of treatment:
1. To induce a clinical and hematologic remission
2. To maintain remission by systemic chemotherapy and
prophylactic CNS
therapy
3. To treat the complications of therapy and of the disease
c. Dfinitions:
1. A complete remission is defined as:
1. Complte regression of symptoms including CNS
2. A normal blood count, with minimal levels of 500/mm3
granulocytes, 75,000/ mm3 platelets and 12 g/dl
hemoglobin with no blast cells seen on the blood smear
3. A moderately cellular bone marrow with a moderate
number of normal granulocytic and erythroid precursors,

d.

e.

f.

g.

h.

together with adequate megakaryocytes and less than

5% blast cells.
2. Relapse is defined by the appearance of any of the following:
1. Progressive repopulation of blasts in excess of 5%,
2. More than 25% blasts in the bone marrow and 2% or
more circulating lymphoblasts
3. Leukemic cell infiltration in CNS or gonads (biopsy
proven)
Therapy for Standard-Risk ALL: Treatment duration is 2.5 years. The 6year event-free survival for this protocol was 86.6% with an overall
survival of 97.2%.
1. The 4 general phases of chemotherapy for ALL include:
1. Induction of remission:
2. Post remission consolidation or intensification:
3. CNS prophylaxis:
4. Maintenance:
Remission induction:
1. Treatment is for 4 weeks
2. Weekly vincristine : 1.5 mg/m2/iv
3. Prednisolone 40 mg/m2/oral/divided dose or oral
dexamethasone for 28 days (6 mg/m2/day in three divided
doses),
4. L-Asparaginase 10 000 U/m2/IM biweekly or a single dose of a
long-acting, pegylated asparaginase
5. Daunomycin weekly for high risk cases
6. For T-cell ALL, intravenous cyclophosphamide may be added
during induction.
CNS prophylaxis:
i. Triple intrathecal therapy e.g.for 2 yr old child; Weekly for 6
weeks followed by every 2 months for 2 years
a. Methtrexate
10 mg
b. Hydrocortisone
10 mg
c. Cytosine arabinoside
10 mg
ii. CNS irradiation: craniospinal irradiation for high risk groups
Consolidation (1 month):
a. Oral 6-mercaptopurine (75 mg/m2/d on days 128 of
consolidation),
b. IV vincristine (1.5 mg/m2 on day 1) and
c. Age-adjusted intrathecal methotrexate on days 1, 8 and 15
for patients without CNS disease at diagnosis.
Maintenance (girls, 20 months; boys, 32 months):
1. Dexamethasone (6 mg/m2/day on days 0 to 4, 28 to 32 and
56 to 60),
2. oral mercaptopurine (75 mg/m2/day on days 0 to 83),
3. IV vincristine (1.5 mg/m2 on days 0, 28 and 56),
4. weekly oral methotrexate (20 mg/m2 beginning on day 7 of
each course) and age-adjusted intrathecal methotrexate on
day 0 of each course

16. Prognosis
1. 5 year survival is 80% with aggressive therapy
2. Minimal residual Disease:
a. Refers to the burden of leukemic cells at end of induction
b. It has a prognostic value
c. High MRD at the end induction suggests a poor prognosis
3. Other treatment options:
a. Bone marrow transplant
b. Stem cell transplant

1.
2.
3.
4.
5.

ACUTE MYELOGENOUS LEUKEMIA (AML)

Incidence: 11 % of childhood leukemia
Etiology:
1. Ionizing radiation
2. Alkylating agents
3. Syndromes:
1. Trisomy 21
2. Fanconi Anemia
3. Bloom syndrome
4. Diamond-Blackfan syndrome
5. Neurofibromatosis Type I
4. Children who live near nuclear power plants or high-voltage power
lines
5. The risk of AML was slightly increased in people who smoked
compared with those who did not smoke.
6. Antecedent hematologic disorders that predispose patients to AML
include:
Aplastic anemia,
Myelofibrosis,
Paroxysmal nocturnal hemoglobinuria
Polycythemia vera
myelodysplastic syndrome
Epidemiology
1. Acute myeloid leukemia affects all races nearly equally.
2. Male and female distributions are nearly equal
3. More in the first year of life and the incidence increases in adulthood
Pathogenesis
1. Acute myeloid leukemia is most commonly associated with the
development of fusion genes resulting from chromosome translocations.
2. Multiple genetic mutations are required for the complete leukemic
transformation.
Clinical features
1.
Hemorrhage due to thrombocytopenia
2.
Fever due to infections
3.
Infiltration may manifest as adenopathy, hepatomegaly and
splenomegaly.

4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.

Mediastinal mass may cause symptoms of respiratory insufficiency or

superior vena cava syndrome
Abdominal masses obstruct the GI or urogenital tracts.
Nodules of myeloblasts, called chloromas, in the skin, orbit, CNS or any
other organ.
Monoblastic leukemia is often associated with gingival hyperplasia
Weight loss and cachexia are unusual
Bone pain is less common in patients with acute myelocytic leukemia
Compression fractures cause back pain and dysfunction of the lower
extremity
Elevated intracranial pressure,
Visual complaints.
Involvement of cranial nerves, most often the facial nerve and the
abducens nerve
Intracranial hemorrhage
Splenomegaly is sometimes massive
Typhlitis can mimic signs of appendicitis
Severe anemia may lead to congestive heart failure.
Skin nodules are firm, raised, and often bluish-purple in colorblueberry muffin

Work up
1. Anemia is usually normocytic
2. Platelet counts are less than < 20,000/l
3. WBC counts may be decreased or elevated.
4. Hyperleukocytosis with WBC counts of more than >100,000/l
5. Primitive granulocyte or monocyte precursors are observed on
peripheral smears.
6. Numbers of mature neutrophils are usually diminished.
7. Serum uric acid and lactic dehydrogenase levels are elevated
8. Serum muramidase (lysozyme) levels are increased
9. Evidence of disseminated intravascular coagulation
10.Auer rods:
1. Auer rods (thin, needle-shaped eosinophilic cytoplasmic
inclusions) in blast cells
2. Auer rods can be seen in the blasts of acute myeloid leukemia
3. They are composed of fused lysosomes and contain peroxidase,
lysosomal enzymes
Imaging:
1. Chest radiography to rule out mediastinal masses
2. Metaphyseal bands at the distal femurs
Bone marrow: hyperplastic marrow with monotonous sheets of leukemic
blasts.
FAB classification:

Treatment:
The
Oncology Group
Induction

M0

Minimally differentiated acute

myeloblastic leukemia

M1

Acute
myeloblastic
without maturation

M2

Acute myeloblastic leukemia, with

granulocytic maturation

M3

Acute
(APL)

M4

Acute myelomonocytic leukemia

M4e
o

Myelomonocytic together
bone marrow eosinophilia

promyelocytic

leukemia,

leukemia

with

Children's
(COG):
M5
Acute monoblastic leukemia
Remission:
Acute erythroid leukemias
M6
2 cycles of
induction
M7
Acute megakaryoblastic leukemia
therapy with
M8
Acute basophilic leukemia
infusions of
daunomycin, cytosine arabinoside, etoposide (ADE therapy).
Maintenance:
sequential cycles of chemotherapy are administered by using
combinations of :
1. Cytosine arabinoside and etoposide,
2. Mitoxantrone and cytosine arabinoside, and, finally,
3. High-dose cytosine arabinoside with L-asparaginase.
Supportive:
1. Marrow transplant
2. Stem cell transplant
3. Transfusion support
4. Management of Hyperkalemia and hyper phosphatemia with
associated hypocalcemia
5. Broad-spectrum antibacterial, antiviral, and antifungal antibiotics;
Classification of Platelet Disorders
Congenital:
1. May-Hegglin anomaly
2. Wiskott-Aldrich syndrome
Acquired
1. Thrombocytopenicquantitative platelet deficiency
1. Autoimmune or idiopathic thrombocytopenia purpura
2. Thrombotic thrombocytopenia purpura
3. Cytotoxic chemotherapy
4. Drug-induced (eg, quinine, quinidine, gold salts,
trimethoprim/ sulfamethoxazole, rifampin
5. Disseminated intravascular coagulation

2. Nonthrombocytopenic - qualitative or functional platelet

defect:
1. Drug-induced (eg, aspirin, NSAIDs, penicillin, cephalosporins)
2. Uremia
3. Alcohol dependency
4. Liver disease
Thrombocytopenia
The normal platelet count is 150 to 450 109/L.
Thrombocytopenia refers to a reduction in platelet count below 150
109/L.
Causes of thrombocytopenia include:
(1) Decreased production on either a congenital or an acquired basis,
(2) Sequestration of the platelets within an enlarged spleen or other
organ,
(3) Increased destruction of normally synthesized platelets either on an
immune or a nonimmune basis.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
The most common cause for acute onset of thrombocytopenia in an
otherwise well child is (autoimmune) idiopathic thrombocytopenic purpura
(ITP)
Etiology
1 to 4 wk after exposure to a common viral infection, a small
number of children develop an autoantibody directed against the
platelet surface.
A preceding history of a viral illness is described in 50-65% of cases
of childhood ITP
Virtually every common infectious virus has been described in
association with ITP, including Epstein-Barr (EBV) and HIV.
Clinical Manifestations
1. previously healthy 1-4 yr old child who has the sudden onset of
generalized petechiae and purpura
2. bleeding from the gums and mucous membrane may be present
3. The physical examination is normal other than the finding of
petechiae and purpura
4. Splenomegaly is rare
5. Spontaneous resolution of their ITP will occur within 6 mo.
6. Less than 1% of cases develop intracranial hemorrhage
7. 10 to 20 percent of children who present with acute ITP go on to
develop chronic ITP. ( >6 mo duration)
Laboratory Findings
1. platelet count < 20 109/L
2. The hemoglobin may be decreased if there have been profuse
nosebleeds or menorrhagia
3. white blood cell (WBC) count, and differential count should be normal
4. The bone marrow: normal granulocytic and erythrocytic series with
normal or increased numbers of megakaryocytes

5. An antinuclear antibody (ANA) test is positive in adolescents with ITP

who may go in for chronic ITP
6. HIV studies should be done in at-risk populations, especially sexually
active teens.
7. Platelet antibody testing is seldom useful in acute ITP.
8. A Coombs test should be done if there is unexplained anemia to rule
out Evans syndrome (autoimmune hemolytic anemia and
thrombocytopenia
9. Bleeding time
a. The bleeding time assesses the function of platelets and their
interaction with the vascular wall.
b. A blood pressure cuff is applied to the upper arm and inflated to
40 mm Hg for children and adults.
c. After the incision with the bleeding time device, blood is blotted
from the margin of the incision at 30 sec intervals until bleeding
ceases.
d. Although each laboratory must establish its own normal range,
bleeding usually stops within 4-8 min.
Differential Diagnosis
a. Drug-dependent antibodies,
b. Splenic sequestration
c. Aplastic processes such as fanconi anemia
d. Hemolytic-uremic syndrome,
e. Disseminated intravascular coagulation
f. Autoimmune thrombocytopenia may be an initial manifestation of
SLE, HIV, or lymphoma
g. Wiskott-aldrich syndrome: young males; low platelet counts,
eczema and recurrent infections
Treatment
a. Platelet transfusion in ITP is contraindicted unless life-threatening
bleeding is present
b. Intravenous immunoglobulin (IVIG). IVIG in a dose of 0.8-1 g/kg/day
1-2 days
c. 1-4 mg/kg/24 hr for 2-3 wk of prednisolone appear to induce a more
rapid rise in platelet counts
d. IV Anti- D Therapy 50 g/kg have demonstrated a rise in platelet
count
e. Splenectomy
a. Indications:
a. The older child (4 yr) with severe ITP that has lasted
longer than 1 yr (chronic ITP)
b. whose symptoms are not easily controlled with therapy
c. life-threatening hemorrhage (intracranial hemorrhage)
b. Splenectomy is associated with a lifelong risk of overwhelming
post-splenectomy infection caused by encapsulated organisms

c. Before splenectomy the child should receive pneumococcal

vaccine, and after splenectomy he or she should receive
penicillin prophylaxis for a number of years
Disseminated Intravascular Coagulation
(Consumptive Coagulopathy)
Consumption of clotting factors, platelets, and anticoagulant proteins.widespread
intravascular deposition of fibrin leading to tissue ischemia and necrosis, a
generalized hemorrhagic state, and hemolytic anemia
Etiology
a. Hypoxia, acidosis, tissue necrosis, shock, and endothelial damage, may
trigger DIC.
b. septic shock (especially meningococcemia), incompatible blood
transfusions, rickettsial infections, snakebite, purpura fulminans, giant
hemangioma, and malignancies, especially acute promyelocytic
leukemia
c. clotting consumes both the physiologic:
I.
Anticoagulants (protein C, protein S, antithrombin III)
II.
Procoagulants, resulting in a deficiency of factor VIII, factor V,
prothrombin, fibrinogen, and platelets.
d. The clinical result of this sequence of events is hemorrhage
Clinical Manifestations
a. Bleeding from sites of venipuncture or surgical incision.
b. The skin may show petechiae and ecchymoses.
c. Tissue necrosis may involve infarction of large areas of skin,
subcutaneous tissue, or kidneys.
d. Anemia caused by hemolysis may develop rapidly owing to
microangiopathic hemolytic anemia
Laboratory Findings
a. Factors (II, V, VIII, and fibrinogen) and platelets may be consumed by
the ongoing intravascular clotting process,
b. Prolongation of the prothrombin, partial thromboplastin, and thrombin
times.
c. Platelet counts may be profoundly depressed.
d. The blood smear may contain fragmented, burr, and helmet-shaped
red blood cells (schistocytes).
e. Fibrinogen degradation products (FDPs, d-dimers) appear in the blood
Treatment
a. Treat the trigger that caused the DIC
b. Restore normal homeostasis by correcting the shock, acidosis, and
hypoxia that usually complicate the DIC
c. Platelet infusions (for thrombocytopenia),
d. Cryoprecipitate (for hypofibrinogenemia),
e. Fresh frozen plasma (for replacement of other coagulation factors)
f. Heparin at a dose of 5-10 U/kg/hr without a loading dose may be used
for those with acute promyelocytic leukemia.
g. Heparin is not indicated and has been reported to be ineffective in
septic shock, snake envenomation, heat stroke, massive head injury,

and incompatible blood transfusion reaction, unless there is clear

evidence of vascular thrombosis.
h. The heparin is usually started together with clotting factor and platelet
replacement
Hemolytic-uremic syndrome
Most common cause of acute renal failure in young children; characterized by
triad:
a. microangiopathic hemolytic anemia,
b. thrombocytopenia, and
c. Uremia.
Etiology
a. Toxin-producing escherichia coli precedes 80% or more of HUS
b. Shigella, salmonella, campylobacter, streptococcus pneumoniae,
bartonella) and
c. Viral (coxsackievirus, echovirus, influenza, varicella, hiv, epstein-barr)
infections.
d. Oral contraceptives, mitomycin, cyclosporine
e. SLE, malignant hypertension, preeclampsia, postpartum renal failure,
and radiation nephritis.
f. Occurrence in more than one member of a family suggests some
genetic predisposition
Pathology
a. Glomerular changes include thickening of the capillary walls, narrowing
of the capillary lumens, and widening of the mesangium.
b. Electron microscopy shows these changes to be the result of
subendothelial and mesangial deposition of a granular, amorphous
material of unknown origin.
c. Fibrin thrombi can be found in glomerular capillaries and arterioles and
may lead to cortical necrosis.
Pathogenesis.
a. The primary event in pathogenesis of the syndrome appears to be
endothelial cell injury.
b. The microangiopathic anemia results from mechanical damage to the
red blood cells (rbcs) as they pass through the altered vasculature
c. Thrombocytopenia is caused by intrarenal platelet adhesion or damage
Clinical manifestations
a. Hus is most common in children < 4 yr.
b. Preceded by a gastroenteritis characterized by fever, vomiting,
abdominal pain, and diarrhea that is often bloody
c. Sudden onset of pallor, irritability, weakness, lethargy, and oliguria
usually occurs 5-10 days after the initial gastrointestinal or respiratory
illness
d. Physical examination may reveal edema, petechiae,
hepatosplenomegaly, and marked irritability.
Diagnosis and differential diagnosis
a. The hemoglobin value is commonly in the range of 5-9 g/dl
b. Plasma hemoglobin levels are elevated

c. Coombs test result is negative.

d. The leukocyte count may increase to 30,000/mm3.
e. Thrombocytopenia (20,000-100,000/mm3)
f. Low-grade microscopic hematuria and proteinuria
g. Partial thromboplastin time and prothrombin time are usually normal
Complications include
a. Anemia,
b. Acidosis,
c. Hyperkalemia,
d. Fluid overload,
e. Heart failure,
f. Hypertension, and
g. Uremia
Prognosis and treatment
a. Peritoneal dialysis:
a. Controls fluid and electrolyte abnormalities,
b. Maintains a normal intravascular volume,
c. Contribute to the dissolution of vascular thrombi by removing
fibrinolysis inhibitors and circulating plasminogen activating
inhibitor-1, thereby promoting endogenous fibrinolytic pathways.
b. A silicon dioxide-derived univalent absorbent that binds shiga toxin
within the intestinal lumen, suggested a reduction in the risk of
developing HUS in children when given within 3 days of the onset of a
diarrheal prodrome.
c. More than 90% of patients survive the acute phase of HUS with a
diarrheal prodrome with aggressive management.
d. End-stage renal disease occurs in approximately 9% of these patients
Haemophilia A (factor VIII deficiency) & B (factor XI deficiency)
Introduction:
1. Haemophilia is a group of hereditary genetic disorders that impair the
body's ability to control blood clotting or coagulation
2. Haemophilia A: clotting factor VIII deficiency; is the most common;1 in
5,00010,000 male
3. Haemophilia B: factor IX deficiency; 1 in about 20,00034,000 male
births..
4. Hemophilia C: reduced levels of factor XI; an autosomal deficiency;mild
to moderate bleeding
Causes
Genetics:
1. Haemophilia A:
a. It is a recessive X-linked genetic disorder involving a lack of
functional clotting Factor VIII and represents 80% of haemophilia
cases.
b. Female carriers can inherit the defective gene from either their
mother or father, or it may be a new mutation.
c. Only under rare circumstances do females actually have
haemophilia. Eg. XO Turner.
d. spontaneous mutations are common.
2. Haemophilia B:

a. It is a recessive X-linked genetic disorder involving a lack of

functional clotting Factor IX. It comprises approximately 20% of
haemophilia cases.
3. Haemophilia C:
a. It is an autosomal genetic disorder (i.e. not X-linked) involving a
lack of functional clotting Factor XI. Haemophilia C is not completely
recessive: heterozygous individuals also show increased bleeding.
Clinical:
1. The hemostatic level for factor VIII is >3040%, and for factor IX, it is >25
30%. The lower limit of levels for factors VIII and IX in normal individuals is
approximately 50%.
2. In hemophilia A or hemophilia B, clot formation is delayed and is not
robust. Thus, patients with hemophilia do not bleed more rapidly. There is,
instead, a slowing of the rate of clot formation.
3. When untreated bleeding occurs in a closed space such as a joint,
cessation of bleeding may be the result of tamponade. With open wounds,
in which tamponade cannot occur, profuse bleeding may result in
significant blood loss.
4. Occasionally, neonates with hemophilia may sustain intracranial
hemorrhage.
5. But, surprisingly, only about 30% of affected male infants with hemophilia
bleed with circumcision.
6. Bleeding from minor traumatic lacerations of the mouth may persist for
hours or days
7. Haemorthrosis:
a. The hallmark of hemophilia is the hemarthrosis.
b. Bleeding into joints may be induced by minor trauma; but may be
spontaneous.
c. The earliest joint to suffer is the ankle, because of the lack of
stability of this joint as the toddler assumes an upright posture.
d. In the older child and adolescent, hemarthroses of the knees and
elbows are the most debilitating.
e. Patients with severe hemophilia often develop a "target" joint where
repetitive episodes of bleeding occur.
8. Patients may lose large volumes of blood into the iliopsoas muscle with
inability to extend the hip and symptoms of shock.
9. Life-threatening bleeding in the hemophilic patient is caused by bleeding
into vital structures (central nervous system, upper airway) or by
exsanguination (external, gastrointestinal, or iliopsoas hemorrhage).
10.
Patients with mild hemophilia may experience prolonged bleeding
only after dental work, surgery, or injuries from moderate trauma.
Complications
1. Joint damage from haemarthrosis,
2. Transfusion transmitted infection from blood transfusions
3. Adverse reactions to clotting factor treatment,
4. Intracranial haemorrhage is a serious medical emergency
DIFFERENTIAL DIAGNOSIS.
In young infants with severe bleeding manifestations, the differential
diagnosis includes:
a. Severe thrombocytopenia;

b. Severe platelet function disorders, such as bernard-soulier

syndrome and glanzmann thrombasthenia;
c. Type 3 (severe) von willebrand disease;
d. Vitamin K deficiency.
Laboratory Findings:
a. Activated partial thrompoblastin time: In severe hemophilia, this
APTT is usually two to three times the upper limits of normal.
b. The other screening tests of the hemostatic mechanism, platelet count,
bleeding time, prothrombin time, and thrombin time are normal.
c. vWF activity will be normal
d. Unless the patient has an inhibitor to factor VIII, the mixing of normal
plasma with patient plasma results in correction of the PTT. If correction
does not occur on mixing, an inhibitor may be present.
e. The specific assay for factor VIII and factor IX will confirm the diagnosis
of hemophilia.
Management:
Hemophilia A
a. The prevention of trauma is important
b. Aspirin and other nonsteroidal anti-inflammatory drugs that affect
platelet function should be avoided
c. Immunizatin against hepatitis B virus
d. Periodic screening for hepatitis and abnormalities in liver function.
e. REPLACEMENT THERAPY:
i. When bleeding occurs, levels of factor VIII or IX must be
raised to hemostatic levels (35-40 U/dL) and for lifethreatening or major hemorrhages to 100 U/dL (100%).
ii. Prophylaxis has been recommended for severe haemophilia
to prevent spontaneous bleeding and early joint deformities
iii. Augmentation of Factor VIII release in mild haemophilia: The
patient's endogenously produced factor VIII can be released
by the administration of desmopressin acetate;
Hemophilia B
i. The mainstay of treatment in hemophilia B is exogenous factor IX.
Therefore, 1 U/kg of plasma-derived factor IX concentrate or
recombinant factor IX is expected to increase plasma factor IX
activity by approximately 1%.
Hemophilia C:
a. Treatment includes infusion of fresh frozen plasma (FFP);
b. Platelet transfusion may also be useful for acute hemorrhage in
patients with deficiency of platelet-associated factor XI.
c. Desmopressin has been used in some cases.
d. The prognosis for an average life span in patients with factor XI
deficiency is excellent.
Prophylaxis:
a. Prophylactic treatment is usually provided every 2-3 days to maintain a
measurable plasma level of clotting factor (1-2 U/dL)
b. Because gene therapy may be available within the lifetime of
paediatric patients, keeping joints normal through prophylaxis is
important.
Chronic Complications:

a.
b.
c.
d.

Chronic joint destruction due to bleeding into joints.

The risk of HIV and Hepatitis C or B, due to multiple transfusions
The development of an inhibitor to either factor viii or factor ix.
Factor IX therapy has also resulted in nephrotic syndrome in some
patients.
Prognosis:
1. Prior to the 1960s average life expectancy was only 11 years.
2. Today with appropriate treatment, males with haemophilia typically have
a near normal quality of life with an average lifespan approximately 10
years shorter than an unaffected male
VON WILLEBRANDS DISEASE
I.

II.

III.

IV.

V.

Epidemiology:
a. Von Willebrand disease (VWD) is the most common hereditary bleeding
disorder, and is present in 1-2% of the general population.
b. VWD is inherited autosomally, but most centers report more women
than men being affected
c. Because menorrhagia is a major symptom, it may cause more women
to seek diagnosis.
Classification:
a. The protein is quantitatively reduced but not absent (type 1),
b. Qualitatively abnormal (type 2),
c. Absent (type 3)
VWF:
a. vWF is a large glycoprotein that is synthesized in megakaryocytes and
endothelial cells as pre-pro-vWF. Sequential cleavage releases mature
vWF which undergoes multimerization and is stored in specific cellular
storage granules in endothelial cells and the granule in platelets.
VWF is released from these storage sites into the plasma, where it
circulates. It has two major physiologic roles.
i. As a carrier protein for the procoagulant cofactor FVIII. This has
the consequence that low levels of VWF result in correspondingly
low levels of FVIII
ii. It has an essential role in platelet adhesion, platelet aggregation
and eventual platelet plug formation.
Clinical features:
a. Patients with VWD usually have symptoms of mucocutaneous
hemorrhage, including excessive bruising, epistaxis, menorrhagia, and
postoperative hemorrhage, particularly after mucosal surgery such as
tonsillectomy or wisdom tooth extraction.
b. teenager's menstrual history is abnormal
c. Because VWF is an acute-phase protein, stress will increase its level.
Thus, patients may not bleed with procedures that incur major stress,
such as appendectomy and childbirth, but may bleed excessively at the
time of cosmetic or mucosal surgery.
d. Bruising symptoms may diminish during pregnancy, because the VWF
levels may double or triple during pregnancy.
Treatment of VWD:
a. Desmopressin therapy:

i. The most common form of VWD is type 1. In these patients the

synthetic drug desmopressin (DDAVP) induces the release of
VWF from the endothelial cells.
ii. A small subset of children and adults, especially infants, fail to
release VWF in response to DDAVP. In these circumstances
replacement therapy must be used.
b. Replacement therapy:
i. Replacement therapy uses plasma-derived VWF containing
concentrates that also contain factor VIII.
ii. These will be useful in presurgical management or in
prophylaxis.
iii. When used for acute bleeding, however, these VWF concentrates
may need to be supplemented by an infusion of recombinant
factor VIII for the first infusion.

LYMPHADENOPATHY
Lymphadenoapathy:
a. Lymphadenopathy: abnormal in either size, consistency or number
b. They are not considered enlarged until their diameter exceeds 1 cm for
cervical and axillary nodes and 1.5 cm for inguinal nodes. Adenopathy in
the supraclavicular and epitrochlear regions >.5 cm are usually pathologic
c. "generalized: enlarged in two or more noncontiguous areas
d. regional" if only one area is involved.
Etiology:
1. Lymphadenopathy might be caused by proliferation of cells:
a. Intrinsic to the node, such as lymphocytes, plasma cells, monocytes
or histiocytes or
b. By infiltration of cells extrinsic to the node, such as neutrophils and
malignant cells.
2. Reactive hyperplasia, defined as a polyclonal proliferation of one or more
cell types
3. Lymphadenopathy is also a presenting sign of malignancies such as
leukemia, lymphoma,
Epidemiology
1. Adenopathy in childhood vary from 38-45%, and lymphadenopathy is one
of the most common clinical problems encountered in pediatrics
2. (3.2 percent) required a biopsy, (1.1 percent) had a malignancy.
Etiology of Generalized Lymphadenopathy
I. Nonspecific reactive hyperplasia (polyclonal)
II. Infection
A. Bacterial:
Staphylococcus, streptococcus, anaerobes, tuberculosis, atypical
mycobacteria, Bartonella henselae (cat scratch disease, brucellosis,
Salmonella typhi, diphtheria, C. trachomatis lymphogranuloma
venereum), calymmatobacterium granulomatis, francisella
tularensis
B. Viral:

EpsteinBarr virus, cytomegalovirus, adenovirus, rhinovirus,

coronavirus, respiratory syncytial virus, influenza, coxsackie virus,
rubella, rubeola, varicella, HIV, herpes simplex virus, human herpes
virus 6 (HHV-6)
Protozoal:
Toxoplasmosis, malaria, trypanosomiasis
D. Spirochetal:
Syphilis, rickettsia typhi (murine typhus)
E. Fungal:
Coccidioidomycosis (valley fever), histoplasmosis, cryptococcus,
aspergillosis
F. Postvaccination:
Smallpox, live attenuated measles, DPT, Salk vaccine, typhoid fever
III. Malignant etiologies
The acute leukemias:
Acute lymphoblastic leukemia (ALL)
Acute myeloblastic leukemia (AML).
Lymphomas
More often present with regional lymphadenopathy, but
generalized lymphadenopathy occurs.
IV. Storage diseases:
Niemann-pick disease:
Sphingomyelin and other lipids accumulate in the
spleen, liver, lymph nodes, and CNS.
Gaucher disease:
The accumulation of the glucosylceramide leads to the
engorgement of the spleen, lymph nodes, and the
bone marrow.
Additional findings: hepatosplenomegaly and
developmental delay; diagnoses are established by
leukocyte assay.
IV. Drug reactions:
Phenytoin,
Pyrimethamine,
Phenylbutazone,
Allopurinol,
Isoniazid.
V. Other non neoplastic disorders:
Langerhans cell histiocytosis
Epstein-Barr virus (EBV)VI. Autoimmune etiologies:
Juvenile rheumatoid arthritis,
Sarcoidosis ; SLE
Graft verses host disease
Clinical evaluation
1. Size: > 2.5-3 cm granulomas and cancer
2. Site:

i.
ii.
iii.
iv.
v.

epitrochlear: cancer; syphilis

cervical or axillary adenopathy: cat-scratch disease ,
infectious mononucleosis : cervical adenopathy
sexually transmitted diseases - inguinal adenopathy
right supraclavicular node : cancer in the mediastinum, lungs or
esophagus.
vi. The left supraclavicular (Virchow's) node: testes, ovaries,
kidneys, pancreas, prostate, stomach or gallbladder.
3. Pain and tenderness: pyogenic
4. Consistency:
i. Stony-hard nodes: cancer
ii. Firm, rubbery nodes: lymphoma.
iii. Softer nodes: infections or inflammation
iv. Fluctuant: abscess
v. Shotty: viral illnesses.
5. Matting. Tuberculosis, sarcoidosis or lymphogranuloma venereum or
malignant (e.g., metastatic carcinoma or lymphomas).
Generalized lymphadenopathy:

1. Mononucleosis-type syndromes
1.
Epstein-Barr virus: lymphadenopathy, fatigue, malaise, fever and an increased
atypical lymphocyte count; positive results on a heterophilic antibody test
(Monospot test) confirms the diagnosis
2.
Other causes of the mononucleosis syndrome: identified with IgM and Ig M serolog
1. Toxoplasmosis,
2. Cytomegalovirus infection,
3. Streptococcal pharyngitis,
4. Hepatitis b infection and
5. Acute human immunodeficiency virus (hiv) infection.
2. Ulceroglandular syndrome

1. This syndrome is defined by the presence of a skin lesion with

associated regional lymphadenopathy.
2. The classic cause is tularemia, acquired by contact with an infected
rabbit or tick;
3. More common causes include streptococcal infection (e.g., impetigo),
cat-scratch disease and Lyme disease
3. Oculoglandular syndrome
1.
This syndrome involves the combination of conjunctivitis and associated preauricu
nodes.
2.
Common causes include viral kerato-conjunctivitis and cat-scratch disease resultin
from an ocular lesion.

4. Hiv infection
1.
Enlargement of the lymph nodes that persists for at least three months in at least
extrainguinal sites is defined as persistent generalized lymphadenopathy and is
common in patients in the early stages of HIV infection.
Evaluation
1. Blood count and erythrocyte sedimentation rate
2. EBV: heterophilic antibody test (Monospot test)

3. Skin testing for tuberculosis

4. Bacteriologic culture of regional lesions (e.g., throat)
5. serologic tests for:
Bartonella henselae (IFA), syphilis (VDRL) toxoplasmosis,
cytomegalovirus (CMV), human immunodeficiency virus (HIV),
6. Chest radiograph and CT scan (if necessary); abdominal sonogram
and CT, if indicated
7. EKG and echocardiogram if Kawasaki disease is suspected
8. Lymph node aspiration and culture;
9. Fine needle aspiration cytology;
10.Bone marrow examination if leukemia or lymphoma is suspected
Indications for Biopsy
1. Persistent or unexplained fever, weight loss, night sweats
2. Hard nodes, or fixation of the nodes to surrounding tissues
3. Increase in size over baseline in 2 wk
4. No regression to normal in 812 wk,
5. If new signs and symptoms develop.
6. Initial physical examination and history suggest malignancy
7. size is > 2.5 cm in absence of signs of infection
8. Supraclavicular adenopathy.
Choice of node:
1. Upper cervical and inguinal areas should be avoided; lower cervical and
axillary nodes are more likely to give reliable information
2. The largest node should be biopsied, not the most accessible one.
3. The node should be removed intact with the capsule, not piecemeal
4. The lymph node should be immediately submitted to the pathologist
fresh or in sufficient tissue culture medium to prevent the tissue from
drying out.
TREATMENT:
1. Guided by the probable etiologic factor
2. If bacterial infection is suspected, antibiotic treatment covering at least
streptococci and staphylococci is indicated
3. If pus is present, it may be aspirated
Surgical drainage is required for an abscess