thalassemia

Nur Muhammad Artha

DEFINITION
○ Thalassemia is a group of inherited
disorders of hemoglobin synthesis
characterized by a reduced or absent
one or more of the globin chains of
adult hemoglobin.

○ They characterised by varying degrees

of ineffective hematopoiesis and
increased hemolysis

○ ICD classification: D-56

 Thalassemia
• defective production of globin portion of
hemoglobin molecule.
• Globin chains structurally normal but have
imbalance in production of two different types
• of chains.
May be either homozygous defect or
heterozygous defect.
•
Two major types of thalassemia:
– Alpha (α) - Caused by defect in rate of
synthesis of alpha chains.
– Beta (β) - Caused by defect in rate of
synthesis in beta chains. 3
HEMOGLOBIN A α β

β α
○ Fetal Hemoglobin (2 alpha, 2 gamma)

○ Hemoglobin A2 (2 alpha, 2 delta)

● Small amounts in body
NORMAL HUMAN HAEMOGLOBINS

Haemoglobin Structural
formula
Adult Hb-A α2 β2 97%
Hb-A2 α2 δ2
1.5-3.2%
Fetal Hb-F α2 γ2 0.5-1%
Embryonic Hb-Gower 1 ζ2 ε2
Hb-Gower 2 α2 ε2
 GENETIC TYPES OF THALASSEMIA :
There are two basic groups of thalassemia.

❑ Alpha ( α )Thalassemia
In alpha-thalassemia, the alpha genes are deleted;
loss of one gene (α-/α) or both genes (α-/α-) from each
chromosome 16 may occur, in association with the
production of some or no alpha globin chains
❑ Beta ( β )Thalassemia
In beta-thalassemia defective production usually
results from disabling point mutations causing no (β0) or
reduced (β-) beta chain production.
CHROMOSOMES
○ Thalassemia is inherited as an autosmal recessive
disease.
EPIDEMIOLOGY

○ Recent data indicate that about 7% of the world

population is carrier of hemoglobin disorder.
○ About 100,000 children are born every year world
over with the homozygous state for thalassemia.
There are around 65,000 - 67,000 thalassemia
patients in our country.
○ In India prevalence of this gene varies, 1-17 %
(3.3%).
○ Common in certain Communities like sindhis,
punjabis, khatris, khukrajas, bhanushalies, baniyas,
lohanas, kuchies, mahars, kolies, agries, goudas,
lingayats .
ALPHA THALASSEMIA
○ Alpha Thalassemia: deficient/absent alpha subunits
● Excess beta subunits
● Excess gamma subunits newborns
○ Tetramers formed:
● Hemoglobin H adults
● Hemoglobin Bart’s newborns
○ types:
● Silent Carrier
● Trait (Minor)
● Hemoglobin H Disease
● Hydrops fetalis(Hb Bart’s)
GENETIC BASIS OF ALPHA THALASSEMIA
○ Encoding genes on chromosome 16 (short arm)
○ Each cell has 4 copies of the alpha globin gene
● Each gene responsible for ¼ production of alpha globin
○ 4 possible mutation states:
● Loss of ONE gene ! silent carrier
● Loss of TWO genes ! thalassemia minor (trait)
● Loss of THREE genes ! Hemoglobin H
○ Accumulation of beta chains
○ Association of beta chains in groups of 4 ! Hemoglobin H
● Loss of FOUR genes ! Hemoglobin Barts
○ NO alpha chains produced ∴ only gamma chains present
○ Association of 4 gamma chains ! Hemoglobin Barts
CLASSIFICATION & TERMINOLOGY
ALPHA THALASSEMIA

• Normal αα/αα
• Silent carrier - α/αα
• Minor -α/-α
--/αα
• Hb H disease --/-α
• Barts hydrops fetalis --/--
CLINICAL OUTCOMES OF ALPHA THALASSEMIA
○ Silent carriers
• asymptomatic
• “normal”
○ Alpha Thalassemia trait
• no anemia /mild anemia
• microcytosis
-unusually small red blood cells due to fewer Hb in RBC
○ Hb H disease
• microcytosis & hemolysis (breakdown of RBC)
- results in severe anemia
• bone deformities
• splenomegaly (enlargement of spleen)
• “severe and life threatening”
• Golf ball inclusions on micrscopy
 Silent Carrier State

• Deletion of one alpha gene, leaving

three functional alpha genes.
• Alpha/Beta chain ratio nearly
normal.
• No hematologic abnormalities
present.

13
 Alpha Thalassemia Trait
(Alpha Thalassemia Minor)

• Deletion of one or two α-globin genes.

• Exhibits mild microcytic, hypochromic anemia
(MCV = 70-75 fL)
• May be confused with iron deficiency anemia.

14
CLINICAL OUTCOMES OF ALPHA THALASSEMIA
○ Bart’s Hydrops fetalis
• Hb Bart’s
• fatal hydrops fetalis
- fluid build-up in fetal compartments, leads to
death occurs in utero
 Bart’s Hydrops Fetalis Syndrome
• deletion of all four α-globin genes
• Sign= edema and ascites caused by
accumulation serous fluid in fetal tissues as
result of severe anemia. Also
hepatosplenomegaly and cardiomegaly.
•
Hemoglobin Bart's has high oxygen affinity so
cannot carry oxygen to tissues. Fetus dies in
utero or shortly after birth. At birth, see
severe hypochromic, microcytic anemia.
• Pregnancies dangerous to mother. Increased
risk of toxemia and severe postpartum
hemorrhage. 16
• long-term survivors =those who have
received monthly intrauterine
transfusions until delivery followed by
lifelong monthly transfusions after birth.

17
 BETA THALASSEMIA
○ Beta Thalassemia: deficient/absent beta subunits
● Commonly found in Mediterranean, Middle East, Asia,
and Africa
○ Three types:
● Minor
● Intermedia
● Major (Cooley anemia)
○ asymptomatic at birth as HbF functions
GENETIC BASIS OF BETA THALASSEMIA
○ Encoding genes on chromosome 11 (short arm)
○ Each cell contains 2 copies of beta globin gene
● beta globin protein level = alpha globin protein level
○ Suppression of gene more likely than deletion
● 2 mutations: beta-+-thal / beta-0-thal
○ “Loss” of ONE gene ! thalassemia minor (trait)
○ “Loss” of BOTH gene ! complex picture
● 2 beta-+-thal ! thalassemia intermedia / thalassemia
major
● 2 beta-0-thal ! thalassemia major
○ Excess of alpha globin chains
 CLASSICAL SYNDROMES OF
BETA THALASSEMIA
• Silent carrier state =
heterogenous beta mutations ,
no hematologic abnormalities
• Beta thalassemia minor
• Beta thalassemia major

20
CLASSIFICATION & TERMINOLOGY
BETA THALASSEMIA
• Normal β/β

• Minor β/β0
β/β+

• Intermedia β0/β+
β+/β+

• Major β0/β0
β+/β
CLINICAL OUTCOMES OF BETA THALASSEMIA
○ Beta Thalassemia minor (trait)
• asymptomatic
• microcytosis
• minor anemia
• Elevated HbA2 >3.4%
○ Beta Thalassemia intermedia .
• symptoms similar to Cooley Anemia but less severe
○ Beta Thalassemia major (Cooley Anemia)
• most severe form
• moderate to severe anemia
• intramedullary hemolysis (RBC die before full
development)
• peripheral hemolysis & splenomegaly
• skeletal abnormalities (overcompensation by bone
marrow)
• congestive heart failure,pulmonary hypertension
 Beta Thalassemia Minor
• Only has one copy of the beta thalassemia
• gene Caused by heterogenous mutations
• Usually presents as mild, asymptomatic
hemolytic anemia .
• Hemoglobin level in 10-13 g/dL range with
normal or slightly elevated RBC count.
• Normally require no treatment.

23
 Beta Thalassemia Major 1 of
3

• child born with thalassemia major has two

genes for beta thalassemia.
• Characterized by severe microcytic,
hypochromic anemia.
• Detected early in childhood:
– Infants fail to thrive.
– Have pallor, variable degree of jaundice,
abdominal enlargement, and
hepatosplenomegaly.
•
Hemoglobin level between 4 and 8 gm/dL.

24
 Beta Thalassemia Major 2 of
3
• Severe anemia causes marked bone changes in
skull, long bones, and hand bones due to
expansion of marrow space for increased
• erythropoiesis.
• Physical growth and development delayed.
Peripheral blood shows markedly hypochromic,
microcytic erythrocytes with extreme
• poikilocytosis, such as target cells, teardrop
cells.
•
MCV in range of 50 to 60
fL. Low retic count seen
(2-8%). 25
 management
• regular blood transfusions. The aim
is to maintain the haemoglobin
concentration above 10 g/dl.
• iron chelation with subcutaneous
desferrioxamine, or with an oral iron
chelator drug ( deferasirox) starting
from 2 to 3 years of age = treat iron
overload.
• Alternative treatment for β-
thalassaemia major = bone marrow
transplantation 26
 Beta Thalassemia Major 3 of
3

• Regular transfusions usually begin around

one year of age and continue throughout
life.
• Danger in continuous tranfusion therapy:
– Development of iron overload.
– Development of alloimmunization
(developing antibodies to transfused
RBCs).
– Risk of transfusion-transmitted diseases.

27
 management
• regular blood transfusions. The aim
is to maintain the haemoglobin
concentration above 10 g/dl.
• iron chelation with subcutaneous
desferrioxamine, or with an oral iron
chelator drug ( deferasirox) starting
from 2 to 3 years of age = treat iron
overload.
• Alternative treatment for β-
thalassaemia major = bone marrow
transplantation 28
PATHOPHYSIOLOGY
○ Disturbance of ratio between Alpha & non
alpha globin chain synthesis then absent or
decrease production of one or more globin
chains
○ Formation of abnormal Hb structures
○ Ineffective erythropoiesis
○ Excessive RBCs Destruction
○ Iron Overload
○ Extra-medullary hematopoiesis
PATHOPHYSIOLOGY..CONT..
SIGNS & SYMPTOMS
○ Beta Thalassaemia Minor :
Usually no signs or symptoms
except for a mild persistent anemia not responding
to hematinics.
○ BetaThalassaemia Major : manifests after 6 months
1. Pallor- fatigue, irritability
2. Growth retardation.
3. Recurrent infections

4. Bony abnormalities specially of the facial

bones,hemolytic facies, caput quadtratum
5. Enlarged spleen and liver.
6. Delayed sexual development
7. Features of complications .
THALASSEMIA COMPLICATIONS
○ Complications can be grouped as
(1) transfusion-transmitted infections,
(2) transfusional iron overload,
(3) toxicities of iron chelation therapy, and
(4) bacterial infections
COMPLICTIONS ..CONT..
○ Cardiac complications
○ Liver complications
○ Endocrine complications
○ Bone complications
○ Other complications
● Infections: yersinia,parvovirus B19
● Dental Complications
● Growth retardation
● Leg ulcers
CARDIAC COMPLICATIONS
○ Cardiac dysfunction(both systolic and diastolic
dysfuction)
○ Arrhythmias
○ Ferritin greater than 2500 mg/L or a liver iron
concentration > 15 mg Fe/g dry weightis associated
with high risk of cardiac death in thalassemia
○ ferritin and liver iron may not correlate with cardiac
iron load, cardiac iron can be specifically and
reproducibly measured using cardiac MRI T2*.
Cardiac MRI T2* less than 20 ms correlates with a
progressive and significant decline in LVEF
CARDIAC COMPLICATIONS CONT..
○ Monitoring: 6 monthly cardiac physical examination,
cardiac function yearly starting at age of 10 years, if
history suggestive of arrhythmias ECG, 24-hour
Holter monitoring should be done.

○ Chelation therapy to reduce high iron load lowers

the likelihood of developing cardiac dysfunction
 CARDIAC COMPLICATIONS..CONT
Cardiac MRI T2 Cardiac iron load Cardiac function intervention

values greater not usually not usually compliance and

than 20 ms associated with associated with importance of
significant iron load cardiac dysfunction chelation stressed

values between 10 significant cardiac a risk of eventual more aggressive

and 20 ms iron deposition cardiac chelation program
decompensation should be
implemented

values < 10 ms Very high cardiac significant risk of Aggressive

iron load more immediate chelation therapy
cardiac should be started
decompensation immediately and
without aggressive cardiac function
intervention monitored
CARDIAC COMPLICATIONS..CONT
○ Where cardiac MRI T2* is not available, • chelation
decisions should be based on ferritin, LIC and
cardiac function assessment
○ Patients with ferritin > 2500 mg/ml and LIC >15g
Fe/g dry weight should be chelated more
aggressively.
○ those with ferritin < 2500 mg/ml and LIC 7 – 15 g
Fe/g dry weight should have chelation adjusted
accordingly and compliance encouraged.
○ Cardiologic intervention and management for heart
failure and arrhythmia should follow cardiology
standards apart from aggressive chelation
LIVER COMPLICATIONS
○ includes- transfusion-related viral hepatitis
(Hepatitis B, C), iron overload, drug toxicity, and
biliary disease due to gallstones.
○ Liver enzymes should be monitored routinely.
○ Liver iron concentration should be monitored
routinely and chelation therapy initiated and
adjusted to reduce complications of iron overload.
○ In the presence of elevated liver iron, liver fibrosis,
and cirrhosis may be accelerated by alcohol, liver-
toxic drugs, and untreated viral hepatitis, Limit such
exposure.
ENDOCRINE COMPLICATIONS
○ Iron overload is responsible for dysfunction of many
of endocrine glands like thyroid, parathyroid
pituitary gland, gonads and pancreas.
○ These include-
● short stature (34%),
● delayed puberty, hypogonadotropic hypogonadism (35
– 55%),
● hypothyroidism (10%),
● hypoparathyroidism (4%), and
● diabetes mellitus (5.6 – 20%)
ENDOCRINE COMPLICATIONS -
INTERVENTIONS

○ Short stature-
● The diagnosis of growth hormone deficiency, other
hormonal or nutritional deficiencies or deferoxamine
toxicity should be considered
● Growth hormone stimulation testing should be done
and, if indicated, growth hormone therapy started
○ Hypothyroidism
● TSH levels should be measured annually beginning at
12 years of age since hypothyroidism often develops
after adolescence.
● Hypothyroidism should be treated with thyroid hormone
replacement.
ENDOCRINE COMPLICATIONS -
INTERVENTIONS

○ Impaired Glucose Tolerance and Diabetes

● Improvement of iron load with adequate combination
chelation therapy may decrease insulin resistance and
decrease glucose intolerance
● Impaired glucose tolerance and diabetes should be
managed as per diabetes protocols with emphasis on
glycemic control, diet, exercise, and management of
complications.
 ENDOCRINE COMPLICATIONS -
INTERVENTIONS
○ Delayed Puberty and Hypogonadism
● most common endocrine complication
● all children should be assessed yearly from the age of 10
years
● All patients with delayed puberty or hypogonadism should
receive appropriate investigations including bone age and
hormonal assessments, hormonal replacement therapy, and
subsequent follow-up by an endocrinologist
○ Hypoparathyroidism
● All patients over the age of 12 years should have calcium and
phosphate levels checked at least every 6 months.
● If these are abnormal, parathyroid hormone level should be
measured. Hypoparathyroidism should be managed as per
endocrine standards
BONE COMPLICATIONS
○ Bone disorders are common and multifactorial in
patients with thalassemia .
○ Related to inadequate transfusion, iron-overload,
over-chelation, and other endocrine factors
contribute to the development of osteopenia and
osteoporosis
○ Interventions:
● Adequate blood transfusions
● Adequate chelation therapy should be maintained
● No Over-chelation
● Hormone replacement therapy
● Calcitonin,bisphosphonates
● Diet rich in calcium and vitamin D
HYPERSPLENISM- SPLENECTOMY
○ Indictions of splenectomy
● An increase in the yearly requirement of packed cells
more than 1.5 times the basal requirement, i.e. packed
cell 200 to 220 cc per kg/ year.
● Massive splenic enlargement posing risk of splenic
rupture, or when it is associated with left upper
quadrant pain or erly satiety
● Presence of leukopenia or thrombocytopenia due to
hyperspleenism
○ Splenectomy should be delayed till the patientis 5
years of age as there is risk of overwhleming sepsis
below this age
○ Risk of post-splenectomy serious infections can be
reduced by:
● Immunization against pneumococcal, meningococcal,
and Hib and salmonella typhi infection atleast 3 weeks
before splenectomy
● Chemoprophylaxis with oral penicillin,
○ 125 mg twice daily for children upto 2 years

○ 250 mg twice daily for children 2 years and above

○ Post splenectomy there may be transient or

persistent thrombocytosis. Aspirin 50-100 mg/day
for patients if platelet count >8,00,000/mm3
IMMUNIZATION PRIOR TO SPLENECTOMY
○ Pneumcoccal vaccine. 0.5 ml SC
● If child has received a complete primary course PLUS
a single booster dose
○ Age<2 years: ( give one dose PCV13 Prevenar13 )
○ Age > 2years: ( give one dose PPV 23 Pneumovax 23
revaccinate after 3 years )
● If child has not recieved primary course
○ Age 16 months – 5years : give two doses PCV13 Prevenar13
8 weeks apart
○ If aged 5-18 years - one dose
○ give one dose PPV 23 Pneumovax 23 at least 8 weeks after
the last PCV13 dose , revaccinate after 3 years.
○ Meningococcal vaccine:
● Quadravalent meningococcal (Menactra) 0.5
mL IM upper deltoid.

o Children aged 2 through 6 years :Two doses of

Menactra® at least 8 weeks apart, followed by a single
booster dose 3 years later and then a single booster
dose every 5 years
○ Children aged 7 years and over and adults through
55 years :Two doses of Menactra® at least 8 weeks
apart, followed by a single booster dose every 5 years
○ Haemophilus b conjugate : One dose
regardless of previous vaccination history
RECOMMENDED MONITORING FOR COMPLICATIONS
OF B-THALASSEMIA
RECOMMENDED MONITORING FOR
COMPLICATIONS OF B-THALASSEMIA
CAUSES OF DEATH
○ Congestive heart failure
○ Arrhythmia
○ Sepsis secondary to increased susceptability to
infection post spleenectomy
○ Multiorgan failure due to hemochromatosis
LABORATORY
DIAGNOSIS OF
THALASSEMIA
44
○ Complete Blood Count (CBC) with red cell
indices and Peripheral Blood Film (PBF)
Examination and reticulocyte count.
○ Hb low, total RBC count and Hct decreased
○ Thalassemics have uniform microcytosis with
out increase in RDW
○ PS of Thalassemia Child
Characteristic bizarre picture of red cells, which
are microcytic, hypochromic, with poikilocytosis,
polychromasia, moderate basophilic stippling, and
fragmented erythrocytes, target cells, and large
number of normoblasts
 Thalassemia trait Iron
deficiency
anemia
RDW Normal(11.5-14.5) high
RBC count High relative low
to
hematocrit,Hb
levels major Iron
Thalassemia
deficiency
anemia
serum Iron Serum iron high Low
levels Sr.ferritin high Low
TIBC decreased Increased
Transferrin
saturation:
increased decreased
○ The baseline serum ferritin and liver enzymes
including ALT, AST, bilirubin, lactate dehydrogenase
(LDH) should be measured.
○ Full red cell phenoptype [C, c, D, E, e, K, k, Jka,
Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis]
○ Serologic testing for hepatitis A, B, and C, and HIV
should be performed as baseline measures.
○ All first-degree family members should undergo
HLA-typing, if potential future allogeneic
hematopoietic stem cell transplant is considered an
option.
HB ELECTROPHORESIS
59
 Reticulocyte Count

• Usually elevated. Degree of

elevation depends upon severity
of thalassemia.

60
Brilliant Cresyl Blue Stain

• Incubation with brilliant cresyl blue stain

causes Hemoglobin H to precipitate.
Results in characteristic appearance of
multiple discrete inclusions -golf ball
appearance of RBCs. Inclusions are evenly
distributed throughout cell.

61
 Hemoglobin Electrophoresis

• Important role in diagnosing and differentiating

various forms of thalassemias.
• Can differentiate among Hb A, Hb A2, and Hb F, as
well as detect presence of abnormal hemoglobins
such as hemoglobin Bart's.

62
LAB DIAGNOSIS ..CONT.
○ Osmotic fragility test : decreased
○ Urinary urobilinogen: increased (Ehrlich test)
○ Stool examination: dark stools, increased
stercobilinogen.
○ Radiological changes: seen after 1 year
● X-ray of metacarpals,ribs, vertebra show thinning of cortex
● X-ray of skull shows “hair on end appearance”
● Generalised skeletal osteoporosis
MANAGEMENT OF THALASSEMIA MAJOR

○ Comprehensive management includes

the following:
• Confirmation of the diagnosis
• Correction of anemia– Packed red cell transfusions
• Removal of excess iron– Chelation Therapy
• Management of complications – Endocrine
and Cardiac complications
• Pharmacological methods to increase gamma
chain
synthesis
• Supportive care

• Curative Treatment– Stem Cell Transplantation

• Future treatment– Gene replacement therapy.
○ A team approach includes:
• Pediatric hematologist,
• Pediatrician,
• Blood transfusion specialist
• Endocrinologist,
• Psychologist and
• Social worker, etc
TRANSFUSION THERAPY IN
THALASSEMIA
○ Transfusion therapy in thalassemia has
two goals:
• To prevent anemia
• To suppress endogenous erythropoiesis

○ Regular Blood Transfusions are Presently the

Mainstay of Treatment of Thalassemia Major.
○ Concept of Neocyte transfusion
TRANSFUSION PROTOCOLS
○ Palliative– Pretransfusion - Hb level is around < 7 gm%
and mean Hb maintained is < 8.5 gm/dl.
○ Hyper Transfusion– Pretransfusion Hb level is
around > 10gm% and mean Hb. Maintained is
> 12 gm%.
○ Super Transfusion– Pretransfusion Hb level is
around > 12gm% and mean Hb. Maintained is
>14gm%.
○ Moderate– Transfusion- Pretransfusion- Hb level is
around 9-10.5 gm% and mean Hb. Maintained is >12gm
%.

Current recommendation?
TYPE OF TRANSFUSION
○ Leukoreduced packed red cell transfusion is
desired type of blood for thalassemic children
○ Reduction of leukocytes to 5000000 is considered
adequate.(reduced by 70%)
○ It helps in prevention of transfusion reactions and is
achieved by centrifugation;/saline washing/filtration.
METHODS FOR LEUKODEPLETION
○ Centrifugation– Packed red cell transfusions
○ Saline-cell washing (Triple Saline Washed)
○ Deglycerolized–red cells.
○ Third generation leucocyte filters
○ Irradiated blood cells
BENEFITS OF BLOOD TRANFUSION-
THALASSEMIA

○ Improves tissue oxygenation, and prevents chronic

hypoxia
○ Improves normal growth and development
○ Prevents erythropoiesis thus avoiding expansion of
the bone marrow and extra medullary
erythropoiesis
○ Reduces hemolytic facies
○ Reduces hepatosplenomegaly and cardiomyopathy
○ Reduces gastro-intestinal absorption of iron.
WHEN TO START THE TRANSFUSION
○ Blood transfusion is started as soon as diagnosis
firmly established (Except in children > 18 months of
age).

○ If age is > 18 months, these children are observed to r/o

Thalassemia Intermedia and if Hb drops < 7 gms%,
regular transfusion started.
○ The most ideal way to transfuse thalassemics is using

group and type specific saline washed packed red

cells (HCT - 65 to 75%) that are compatible by direct
antiglobulin test (Coomb’s crossmatched)
RATE AND FREQUENCY OF
TRANSFUSIONS
○ 10-15 ml/kg of saline washed packed red cells every 3
to 4 weeks.
○ Rate not more than 5 ml/kg/hr, however, in patients with
cardiac dysfunction not more than 2-3 ml/kg/hr should
be given.
○ Shorter intervals of 2 to 3 weeks are more physiological.
○ Average time taken is 3-4 hours
○ Approximately 180 ml/kg of red cells are required to be
transfused per year in non-splenectomized,
nonsensitized patients to maintain the hemoglobin
above 10 gms%, whereas splenectomized patients
require 133 ml/kg per year.
○ Even without hypersplenism, the requirement is 30%
higher in non-splenectomized patients
COMPLICATIONS OF TRANSFUSION
○ NHFTR (Non hemolytic febrile transfusion reaction)
○ Allergic reactions
○ Acute hemolytic reactions
○ Delayed hemolytic reactions
○ TRALI-transfusion related acute lung injury
○ TACO- transfusion associated circulatory overload
○ Alloimmunizaton.
○ Transfusion transmitted infections
○ Iron overload

○ Steps to Prevent These Infections Include

▪ Screening of blood products.
▪ All thalassemic children should recieve hepatitis
vaccination if not previously immunised
▪ Leukodepletion can minimize CMV infection
IRON OVERLOAD AND CHELATION THERAPY
○ Iron Overload Occurs in Thalassemic Patients
due to
▪ Treatment with multiple transfusions
▪ Ineffective erythropoiesis
▪ Excessive dietary absorption of iron from gut, to
compensate the large turnover of red cell mass
▪ Lack of physiologic excretory mechanism for the
excess iron
○ The goal of iron chelation is to reduce the iron
store and subsequently maintain at low level
(sr.ferritin less than 1000ng/ml).
INITIATION OF CHELATION THERAPY
○ Serum ferritin >1000ng/dl
○ Patient has received 15-20 transfusions
○ Hepatic iron concentration exceeds 3.2mg/ g dry
weight
CHELATING AGENTS
○ Deferoxamine(DFO)
▪ Route:SC/IV
▪ Dose: 25-50 mg/kg/day
▪ Schedule: over 8 to 10 hrs for 5-6 nights a week with the
help of subcutaneous desferal infusion pump
▪ MOA:chelates loosely bound iron, iron from
ferritin,hemosiderin ,not from transferrin
▪ Excretion :Urine(80%,urine red)/Feces
▪ Plasma clearance t1/2: 20 minutes
▪ Adverse effects Local skin reaction, ototoxicity, infections
,ophthalmic toxicity, skeletal impairment
▪ Monitoring Long bone films in growing children, annual
eye and ear check-up
CONSIDERATION OF AGGRESSIVE CHELATION
THERAPY

○ Severe iron over load

● Persistently very high ferritin value
● Liver iron >15mg/ g dry weight
○ Significant cardiac disease
● Cardiac arrhythmias
● Evidence of falling left ventricular function
● Evidence of very severe heart iron loading(MRI T2* <6
ms)
○ Prior to bone marrow transplantation when rapid
reversal of iron loading may be desirable

○ tab Vitamin C 1hr prior to infusion .

○ Deferipone(Kelfer)
▪ It mobilizes iron from transferrin, ferritin, and
hemosiderin.
▪ Dose: 75 to 100 mg/kg body weight/day in
three to four divided doses
▪ Excretion:Urine
▪ Plasma clearance t1/2:53-166 minutes
▪ Adverse effects: Agranulocytosis, GIT
disturbances,transaminase elevation,
arthralgias
▪ Monitoring:Weekly CBC
DEFERIPONE ..CONT
○ Drug should be discontinued whenever
● Total count drops to < 3000/mm 3
● Absolute neutophil count drops to < 1000/mm 3

○ Zinc deficiency may develop, zinc supplementation

may be necessary

○ It should be first line drug for patients not receiving

DFO because of high cost, toxicity or poor
compliance of the later.
○ Deferasirox (exjade)
▪ A novel chelating agent belongs to tridentate tiazole,with
high affinity to iron as Fe+++ and chelates at a ratio of
2:1 (Deferasirox: Iron).
▪ Dose :20-30 mg/kg/day
▪ Schedule: daily ,OD
▪ Excretion:Feces
▪ Plasma clearance t1/2:1-16 hours
▪ It should be given approximately same time each day on
an empty stomach 30 minutes prior to food. Tablet
should be dispersed in water/orange /apple juice.
▪ It is available as 250/500 mg tablet for oral suspension
dispersible tablets
▪ Monitoring:Monthly RFT, LFT and urine analysis
▪ Side effects: GI disturbances , rash, renal dysfunction
SHUTTLE HYPOTHESIS
○ Co-administration of ICL 670 (Deferasirox) with Inj
DFO has synergic effect and helps in reducing dose
of both the drugs thus improving the compliance
and cost of the treatment as is done with oral
chelation therapy with deriprone and inj. desferal.

○Shuttle effect
also seen with this combination, as ICL 670-
Deferasirox acts as intracellular chelator and DFO as
extracellular.
MANIPULATION OF HBF SWITCHING
○ Hydroxyurea
○ Histone Deacetylase Inhibitors
● Butyric Acid Analogs
○ 5-azacytidine,( risk of cancer –not used now)
○ Erythropoietin has been tried to induce HbF
production with varying success
STEM CELL TRANSPLANTATION
○ This is only the curative therapy available today.
○ Sources of stem cells:Bone Marrow, Peripheral
Blood, Cord Blood,Fetal Liver.
○ Though expensive, it is cost effective as compared
to yearly cost of regular blood transfusion and
chelation therapy.
○ cost 8-10 lakhs.
○ Umblical cord stem cells have good results(lower
GVHD, longer engraftment)
GENE THERAPY
Lenti Viral vector derived from Human
Immunodeficiency Virus, where a large fragment of
human beta gene and its locus control region, have
been introduced, though experimental, more
effectiv therapies will become available near future
to cure the disease.
PREVENTION OF THALASSEMIA-CARRIER
SCREENING

○ Thalassemia minor or carrier state can be easily

detected in a person by doing simple blood test HbA2 by
hemoglobin electrophoresis or variant machine or
column chromatography
○ Prevention includes population education, mass
screening, genetic counseling and antenatal diagnosis
and therapeutic abortion of affected pregnancy

○ Carrier detection:The only confirmatory test is HbA2

estimation.
○ To conduct an effective mass screening program, the
targeted population should belong to the premarital and
newly married groups, i.e. before they have begun their
families.
ANTENATAL DIAGNOSIS
○ When both partners, who are thalassemia minors, plan to
have their baby, they are told to report to their hematologist as
soon as possible after pregnancy is confirmed.
○ Chorionic villous sampling (CVS) done between 9th and 11th
week of pregnancy.
○ amniocentesis or cordocentesis-16 to 18 weeks of pregnancy.
○ Test result:
●‘Affected’ which means the fetus has thalassemia
major, or
●‘Unaffected’ meaning that the fetus is either
thalassemia minor or normal.
●Affected fetuses are advised to be terminated and
unaffected fetuses to be continued
REFERENCES

○ IAP TEXT BOOK OF PEDIATRICS 5th Ed

○ Advances in pediatrics pedicon 2012
○ IAP Pediatric Hematology
○ Nelson Text Book Pediatrics
○ Standards for the Clinical Care of Children and
Adults with Thalassaemia in the UK
○ Guidelines for the Clinical Care of Patients with
Thalassemia in Canada
Thank you