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Paediatrics A Unit
Prof. Dr. P.L. Siddaraju
By Dr. Nithyanand Patil
• Thalassemia was first described by Cooley
in 1925 as “a hereditary hemolytic anemia
with characteristic frog-like or mongoloid
facies, skeletal changes and splenomegaly”.
Whipple & bradford coined the term
‘Thalassemia’- meaning ‘The sea in the
blood’ (Mediterranean)
The list shows their globin
chains
The alpha chains are identical
in each
Every chain has a similar
structure
They vary in some of the amino
acids
The percentages are those seen
GENETICS
in
theglobin
adult.chain (not hemoglobin)
Each
is controlled by a separate gene.
Genes are listed with the number
inherited from each parent and the
chromosome on which they lie.
There are two different gamma
genes (and chains) that differ by
one amino acid - a matter of little
clinical significance.
The gamma, delta and beta genes
lie next to each other on
chromosome 11.
The two alpha genes lie next to
HEMOGOLOBIN
PERCENTAGES
ADULT vs NEWBORN
This list shows the percentage of
each normal hemoglobin in the
adult and newborn.
An "adult" as far as hemoglobins
are concerned is any child over the
age of one year!
The switch in percentages occurs
as a result of an increase in beta
chain production and a decrease
in gamma chain production
beginning at the 6th month of
fetal life.
Delta chain production is
minimal at birth and reaches
normal levels (about 3% of total)
at about one year of life.
HEMOGLOBIN DEECTS
The three main types of
hemoglobin defect are listed
here.
Since all are very common
combinations are al so
common.
INHERITANCE PATTERNS
This diagram shows the inheritance
pattern of one (Hb S) and of two (Hb S
and Hb C) beta chain structural
defects.
These are relatively simple because
there are only two beta chain genes.
The situation is much more
complicated in the case of alpha
chains because two alpha genes are
inherited from each parent, giving a
total of four.
THALASSEMIA
The thalassemias are a widespread
collection of genetic disorders in which
there is an imbalance in globin chain
production -- almost always a decrease
or absence of production of one or
rarely two globin chains.
They are named according to the
chain that is decreased.
alpha thalassemia-very commonaffects Hb A, Hb A2, and Hb F
production.
beta thalassemia-common-affects Hb
A production delta-beta thalassemiafairly common-affects Hb A and Hb A2
production delta thalassemia-rareaffects Hb A2 production.
Clinically unimportant gamma
thalassemia-rare-affects Hb F
production in fetus
Thalassemia definitions
The more severe the
imbalance between for
instance alpha and beta chain
production the worse the
disease.
The terms major and minor
etc are now only used as
clinical (or severity)
descriptions.
Major used to be synonymous
with homozygous.
Minor used to be synonymous
But they can only be applied in these
genetic
senses to the beta
with
heterozygous.
thalassemias since there are only two beta genes whereas with four
alpha genes there can be four abnormalities. depending on whether
one, two, three or four genes are affected.
ALPHA THALASSEMIA
A brief comparison of the
clinical effects and the
proportions of Hb H and Hb
Barts when one, two, three, or
four genes are deleted is
shown in this Table.
When alpha chain production
is reduced, the excess beta
and gamma chains can each
form tetramers (Hb H and
Hb Barts).
The excess alpha chains in
the beta thalassemias do not
form tetramers.
•Patho Physiology of Thalassemia
•
Types of β-Thalassemia:
a. Homozygous
b. Hetrozygos
c. Intermedia
β-Thalassemia, Homozygous Forms (Major and Intermedia)
Pathogenesis
1.
2.
3.
4.
Variable reduction of β-chain synthesis (β˚, β, and
variants.
-Chain excess results in intracellular percipitation of
insoluble -Chains.
Increased but ineffective erythropoiesis with many red
cell precursors prematurely destroyed is related to Chain excess.
Shortened red cell life span and variable splenic
sequestration.
Sequelae
1. Hyperplastic marrow: bone marrow expansion with cortical
thinning.
2. Increased iron absorption and iron overload (especially
with repeated blood transfusion) resulting in the following
pathology:
a. Cirrhosis of the liver
b. Endocrine disturbances, e.g., diabetes mellitus
c. Skin hyperpigmentation
d. Cardiac hemosiderosis
3. Hypersplenism
Clinical Features
1.
2.
3.
4.
5.
Failure to thrive in early childhood: common presentation
Anemia
Jaundice, usually slight; gallstones
Hepatosplenomegaly, which may be massive; hypersplenism
Abnormal facies, prominence of malar eminences, frontal bossing,
depression of bridge of the nose, exposure of upper central teeth.
a. Skull radiographs showing hair-on-end appearance caused by
widening of diploeic spaces
b. Fracture resulting from marrow expansion and abnormal bone
structure
c. Generalized skeletal osteoporosis
6. Growth retardation: primary amenorrhea in females; delayed puberty in
males caused by chronic anemia and endocrine disturbances
7. Leg ulcers
8. If untreated, 80% die in the first year of life
Note hepatosplenomegaly
The children show mongoloid facies characterized by bossing
of the skull, prominent frontal and parietal eminences, with
flattened vault, straight Forehead, hypertrophy of maxilla,
prominent malar eminences, depressed bridge of the nose and
puffy eyes.
Complications
Complications develop as a result of these situations:
Inadequate treatment in the first years of life so that some irreversible
damage occurs
Poor compliance
Excessive blood consumption
Insufficient energetic application of chelation therapy
Even in carefully managed patients, the following complications may
develop:
1. Endocrine disturbances (e.g., retarded growth, delayed puberty, insulin
dependent diabetes, hypogonadism, adrenal insufficiency, hypothyoidism,
hypoparathyroidism).
2. Cirrhosis of the liver and liver failure.
3. Cardiac failure caused by anemia, increased plasma volume, and
myocardial iron overload. Is often associated with arrhythmia, pericarditis.
4. Spinal cord compression is caused by epidural extramedullary
hematopoiesis. Surgical excision of epidural mass and radiotheraphy in a
dose of 2,000-3,000 cGy is recommended.
Laboratory Investigations
The level of Hb is . It is usually between 2 and 6
g/dL. Fetal Hb level is  while HbA2 is normal.
Cells Total erythrocyte counts are  and usually
range between 2 to 3 million/mm³. Hematrocrit is .
MCV and MCH or MCHC are . Reticulocyte count
appears  . in % of reticulocytes is not as high as
the cells are destroyed in the marrow before they are
released as reticulocytes. There is mild leucocytosis
and thrombocytosis due to prolonged stimulation of
the bone marrow.
Peripheral Smear.
Red cells show hypochromia,
anisocytosis and poikilocytosis. Many
microcytes and occasional macrocytes
with a variable number of target and
tear drop cells are seen. There is
marked basophilic stippling and
variable polychromasia. Fragmented
red cells, nuclear remnats like Howell
Jolly bodies, and Heinz bodies may be
seen. A large number of early,
intermediate and late erythroblasts are
the most characteristic findings in the
P/S.
Thalassemia Major
Thalassemia Minor
Bone marrow. The bone marrow is hypercellular with erythroid
hyperplasia with a increased number of stippled erythroblasts and
sideroblasts. Granulopoiesis and thrombopoiesis are relatively
preserved. Hemosiderin deposits in the marrow are increased.
Osmotic fragility. The fragility of the cells on exposure to
hypotonic saline is decreased. The cells being thinner than usual
can absorb more water before bursting. Hemolysis may continue
till they are incubated with 0.2 percent saline and it may not be
complete even in distilled water.(NESTROF TEST +VE).
Serum bilirubin level is moderately  between 1 to 3 mg/dl. This
depends on the rate of hemolytic activity, functional capacity of the
liver to excrete the bilirubin and the mass of hemoglobin available
for hemolysis. Urinary excretion is markedly . There may be
evidence
of
progressive
liver
dysfunction.
Serum iron levels are high as a result of increased iron
absorption, ineffective utilization and release of iron from
continuous hemolysis of red cells. Iron binding capacity is .
Serum ferritin levels are markedly raised which reflect total
iron stores. Level of the fetal Hb and HbA2 may be . Fetal
Hb level get  following transfusion and thus be diagnosis of
thalassemia may become difficult. HbA2 levels are normal or
slightly raised. Free erythrocyte porphyrin level is normal.
51 Chromium labelled red cell life span is
reduced.
Liver Function Test – SGOT/SGPT are altered.
Hemoglobin electrophoresis: Cellulose acetate pH 8.4,Citrate
agar pH 6
ELECTROPHORESIS
Electrophoresis is a means
of separating hemoglobins.
It depends on the migration
of the hemoglobin molecules
dissolved in a buffer on, or
in, a supporting medium
when an electric current is
passed through them.
Radiological changes in thalassemia
Earliest bony changes occur in the small bones of the hands
which show a rectangular appearance. Medullary portion of
the bone is widened and the bony cortex is thinned out with
a coarse trabecular pattern in the medulla.
Diploid spaces in the skull are widened. As these traverse between
the bone trabeculae in the outer table of the skull, the latter looks
atrophied. Interrupted porosity gives hair on end appearance in Xray film of the skull.
History

Race
Family History
Age of Onset

Clinical Examination 
Pallor
Jaundice
Splenomegaly
Skeletal Deformity
Pigmentation

Blood Count and Film

Hb MCV MCH Retics
RBC Inclusions in Blood or
Marrow
Hb H Precipitation

Hemoglobin Electrophrosis 
Presence of Abnormal Hb
to include Analysis at pH 6-7
for Hb H and Hb Barts

Hb A2 and Hb F Estimation

To confirm  Thalassemia

a
b
Intracellular
Distribution Globin-Chain
Of Hb F
Synthesis
c
Structural
Analysis of Hb Variants.
Management
1. Hypertransfusion protocol† to maintain a pretransfusion Hb between 10.5 and
11.0 g/dl at all times using the following:
a. Washed or leukocyte-filtered, packed red cells to avoid antileukocyte
antibodies. The post-transfusion Hb should not rise above 16 gm/dl because
higher levels cause an increase in blood viscosity, increased risk of thrombosis,
and reduced tissue oxygenation.
b. Blood that closely matches patient’s genotype to avoid antibody formation.
c. Blood should be started when diagnosis is made and the Hb levels falls below
7 g/dl and remains there for a week or more
Hypertransfusion results in the following:
a. Growth and development are maximised.
b. Extramedullary hemotrpoiesis is minimized thereby decreasing facial and
skeletal abnormalities.
c. Excessive iron absorption from gut is reduced.
d. The development of splenomegaly and hypersplenism is retarded because it
reduces the number of red cells containing -chain precipitates that reach the
spleen.
2. Chelation therapy
a. Objectives:
(1) To remove excess intracellular iron
(2) To bind free extracellular iron
(3) To reduce iron burden to minimal levels
b. Iron overload results from the following:
(1) Increased gut absorption of iron
(2) Chronic hemolysis
(3) Ongoing transfusion therapy
c. Chelation is attained with the use of Desferrioxamine in the
following way:
(1) Chelation is started more or less at the same time as
starting transfusions.
(2) Continuous subcutaneous infusion in a dose of 40
mg/kg/day over 8-10 hours nightly via portable electronic
pump plus 100 mg of vitamin C orally results in considerable
iron chelation and delays development of iron overload and
cirrhosis.
(3) In selected cases, with severe iron overload, give
desferrioxamine IV in high dose, maximum 100 mg/kg over 8
hours, on the days of transfusion.
(4) The aim is to maintain serum ferritin close to 1,000 ng/ml,
which should be monitored every 6 months.
d. Complications of Desferrioxamine administration:
(1) Local painless swelling at infusion site. Decrease the
concentration of the solution infused by increasing the
amount of water used with a given dose.
(2) Local reactions: pruritus, rash, hyperemia. Add
hydrocortisone 2 mg/ml to Desferrioxamine solution.
(3) “Anaphylactoid” reactions: treat by desensitization.
(4) Toxic effects on the eye: cataracts, reduction of visual
fields and visual activity, an night blindness occurs with
prolonged or high dose theraphy and regress when treatment
is suspended.
(5) Hearing impairment occurs only with prolonged or highdose therapy.
Deferiprone (DFP) is an effective oral iron chelating agent
with minimal toxicity. It is given in a dose of 75-100
mg/kg/day in 2-3 divided doses. The most common sideeffect is arthropathy. Agranulocytosis is rare toxicity.
Neocyte transfusion. Special cell separators are available for
obtaining younger cells with longer life span (neocytes).
Infusion of these cells instead of the whole blood increases
the interval between two transfusions and decreases the
transfusion requirement and hence the iron load.
3. Splenectomy
a. This procedure reduces transfusion requirements in patients
with hypersplenism.
B. Prophylatic pneumococcal and hemophilus influenza B
vaccine 2 weeks before splenectomy and prophylactic
penicillin 250 mg BID life-long post splenectomy are given to
reduce the risk of overwhelming postsplenectomy infection.
Whenever possible splenectomy should be postponed until
after the fifth year of age.
c. Indications for splenectomy:
(1) Persistent increase in blood transfusion requirements by
50% or more over initial needs for more than 6 months.
(2) Yearly packed cell transfusion requirements exceed 250
ml/kg/year
(3) Evidence of severe leukopenia and/or
thrombocytopenia.
4. Leg ulcers
Leg ulcers are very difficult to treat. Patients should take the
following measures:
a. Wear a toweling band round the ankles.
b. Sleep with end of bed raised 10 cm.
c. Keep legs and feet raised for 1 to 2 hours during the day
d. Take zinc sulfate by mouth
e. Oxygenate the ulcers
5. Supportive care
a. Folic acid is not necessary in hypertransfused patients; 1 mg
daily orally is given to untransfused (intermedia patients).
b. Hepatitis B vaccination should be given to all patients.
c. Digitalis and diuretics are given when indicated for
congestive heart failure.
d. Endocrine intervention, i.e., L-thyroxine growth hormone,
estrogen, testosterone, are given when indicated.
e. Cholecystectomy is advised when evidence of gallstones
occurs.
f. Genetic counselling and antenatal diagonis via chrionic
villus sampling or amniocentesis are suggested.
6. Follow-up of patients with thalassemia:
Prior to treatment
Study the case and do complete
red cell typing
Before each transfusion:
Hb, crossmatch and red cell
antibody detection, and serum
transfaminases (in areas with a
high incidence of hepatitis) are
performed. Record the date of
transfusion, net weight and
mean hematocrit of the blood
preparation, and the Hb of the
patient.
After each transfusion:
Measure the post-transfusion
Hb
Every 3 months:
Every 6 months:
Every year:
Measure height and weight
Estimate ferritin
Evaluate growth and
development. Evaluate iron
balance. Complete evaluation
of the case including:
> Cardiac function
> Endocrine function
> Monitoring visual and
auditory activity
> Viral serologies
Variable intervals:
Cardiac and endocrinological
investigations according to the
clinical state of the patient
7. Future directions
a. Oral chelators. Clinical testing of a number of oral chelating
compounds is under way. 1,2-Dimethyl 1-2-hydroxypyridone (L1) in a dose of 75 mg/kg/day orally has comparable
efficacy to subcutaneous Desferrioxamine and may soon be
available for clinical use in the United States. Controversy
exists at present about its potential toxicity.
b.
Pharmacologic upgrading of fetal Hb synthesis
(1) High levels of fetal Hb (HbF) ameliorate the symptoms
of -thalassemia by increasing hemoglobinization of the
thalassemic red cell and decreasing the accumulation of
unmatched -chains, which cause ineffective erythropoiesis.
Gene Manipulation -chains by -chains which
combine with -chains to form HbF
(2) Trials are in progress with several agents that increase
HbF synthesis:
(a) 5-Azacytidine
(b) Hydroxyurea
(c) Cytosine arabinoside
(d) Busulfan
(e) Butyrate
These agents can decrease or eliminat transfusion
dependence, but side effects include neutropenia, increased
susceptibility to infection, and possible tumorgenicity.
c. Bone marrow transplant
(1) Marrow transplantation from an HLA-identical sibling is
a curative mode of theraphy.
(2) The greater the degree of hepatomegaly, hemosiderosis,
and portal fibrosis of the liver before transplant, the
worse the outcome.
(3) A reasonable approach would be to employ allogeneic
BMT at the earliest signs of hepatic enlargement or
portal fibrosis, if a suitably matched donor is available.
(4) Bone marrow transplantation is a controversial mode of
therapy because its risks must be weighed against the
fact that patients who are least symptomatic have the
best transplant results. The following information is
available about transplantation:
(a) Results are better among patients younger than 3
years who have received few transfusions and are
without significant complications.
(b) Graft-versus-host disease (GVH) occurs less frequently in
younger patients.
(c) The refinement of methods of preparation for
transplantation have brought about a drastic reduction in
mortality.
d. Heart Transplant
Heart transplant has been successfully carried out in
thalassemia and should be considered in severe
hemochromatotic myocardiopathy with cardiac failure in the
absence of cirrhosis.
e. Gene Therapy
(1) Insertion of normal globin genes into marrow stem cells
may ultimately cure thalassemic syndromes.
(2) The practical application of this technique is not feasible
in the near future.
Thalassemia Control
Marriage Counselling
Prenatal Diagnosis can be made from fetal blood by
determining the  vs. -chain ratio. A ratio of <0.025 is
suggestive of thalassemia major and needs MTP.
Molecular diagnosis can be made by study of different
loci of  globin gene by RFLP & PCR.
Amniocentesis
CVS