The document discusses modern trends in the management of thalassemia. It summarizes that thalassemia is a genetic blood disorder resulting from reduced or absent production of hemoglobin chains. For patients with thalassemia major, regular blood transfusions are the main treatment to prevent anemia and suppress ineffective red blood cell production. The transfusions aim to maintain hemoglobin levels between 10-12 gm/dl. Managing iron overload from frequent transfusions also requires chelation therapy.
• Thalassemia
• Hemoglobinopathies
• Incidence of thalassemia in Thailand
• Mode of inheritance
• How to name thalassemia ?
• Common types of thalassemia
• Alpha Thalassemia
• Symbolism Alpha Thalassemia
• Classification & Terminology Alpha Thalassemia
• Types of a-thalassemia
• Compound heterozygotes
• Comparison of α Thalassemias
• Beta thalassemias (β thalassemias)
• Types of β Thalassemia
• β Thalassemia Symptoms Include
• Diagnosis of Beta Thalassemia
• Prevention
• What Is The Treatment For Thalassemia
• Thalassemia
• Hemoglobinopathies
• Incidence of thalassemia in Thailand
• Mode of inheritance
• How to name thalassemia ?
• Common types of thalassemia
• Alpha Thalassemia
• Symbolism Alpha Thalassemia
• Classification & Terminology Alpha Thalassemia
• Types of a-thalassemia
• Compound heterozygotes
• Comparison of α Thalassemias
• Beta thalassemias (β thalassemias)
• Types of β Thalassemia
• β Thalassemia Symptoms Include
• Diagnosis of Beta Thalassemia
• Prevention
• What Is The Treatment For Thalassemia
Get here,
1. WHAT IS THALASSEMIA?
2. Molecular Basis of Thalassemia.
3. Types of Thalassemia.
4. - Thalassemia.
5.Types of - Thalassemia.
6. 휷- Thalassemia.
7. Types of 휷- Thalassemia.
8. Thalassemia Syndrome.
9.Treatment
Get here,
1. WHAT IS THALASSEMIA?
2. Molecular Basis of Thalassemia.
3. Types of Thalassemia.
4. - Thalassemia.
5.Types of - Thalassemia.
6. 휷- Thalassemia.
7. Types of 휷- Thalassemia.
8. Thalassemia Syndrome.
9.Treatment
case presentation on diagnosis of beta thalassemia majorDrShinyKajal
case history of 9 month old infant
Paediatric Clinical Approach to this case
examination
workup at blood centre
HPLC screening
laboratory findings
screening of father mother
prominent facial features
PBF and bone marrow findings
usg abdomen
xray skull
prbc transfusion therapy in thalassemia major
classification of thalassemia
national burden in india
pathogenesis- anemia skull bone iron overload
world thalassemia day
This presentation is uploaded to create awareness regarding thalassamia among common people and it also help the tutors of paramedics and nursing to teach their students about it.
Inherited abnormalities of hemoglobin synthesis characterised by structurally abnormal hemoglobin variants.
The disorders of Hb divided into 2 main groups :-
Structural globin chain variants such as Sickle cell anaemia
Disorders of synthesis of globin chains such as Thalassemia
Prenatal evaluation and postnatal early outcomes of fetal
Thalassemia
1. MODERN TRAINDS IN MANAGEMENT OF THALASSEMIA
Dr.M.R.Lokeshwar
Consultant Pediatric Hematologist,
Imperial Mahal, 3rd floor, Dadar TT, Mumbai - 400014.
The thalassemias are the most common single gene disorder in the world and represent a major
health burden worldwide.
It is a heterogeneous disorder recessively inherited resulting from various mutations of the genes,
which code for globin chain of Hb, leading to reduced or absent synthesis of globin chains.
When b chain synthesis is affected it is called as b -thalassemia.
It was first described by Cooley and Lee in 1925 and the first case of b-Thalassemia in India was
reported by Dr.Mukherjee from Calcutta in 1938.
Epidemiology :
Over 180 million people in the world and around 20 million in India carry the gene for b -
Thalassemia.
One-Lac children are born world over with the homozygous state for Thalassemia,
(8,000-10,000 children of whom are born inIndia).
The frequency of Thalassemia trait is 3-18% in north India to 1-3% or less in the south. A
higher frequency noted in certaincommunities viz. Sindhis, Kutchis, Lohanas,
Bhanushalis, Punjabis, Mahars, Agris, Goud Saraswats, Gowdas etc.
Pathophysiology :
It is characterized by an imbalance in the production of a and B globin polypeptide chains of
hemoglobin.
In a -Thalassemia, a chain synthesis is decreased. In b -thalassemia, b chain synthesis is
decreased. Excessive a chains precipitate in red cell membrane and damage it. It leads to
premature red cell destruction both in the bone marrow and peripheral circulation
particularly in reticuloendothelial system of spleen (ineffective erythropoiesis and
hemolysis).
Synthesis of gamma chain persists after fetal life. Increased fetal hemoglobin (HbF) with
its high affinity for oxygen leads to tissue hypoxia, which in turn stimulates
erythropoietin secretion leading to both medullary and extramedullary erythropoiesis
(expansion of bone marrow space) causing a characteristic hemolytic facies with
fronotoparietal and occipital bossing, malar prominence and malocclusions of teeth.
Complications include distortion of ribs and vertebrae and pathological fracture of the
long bones, splenomegaly and its complications (hypersplenism), hepatomegaly,
gallstones and chronic leg ulcers.
2. Clinical manifestations of
b-thalassemia :
The spectrum of clinical manifestations of Beta-Thalassemia varies widely. One end of the
spectrum is the serious homozygous form (Thalassemia Major) that presents in early infancy (6-
18 months) with progressive pallor, splenohepatomegaly and bony changes and if left untreated,
is invariably fatal during the first few years of life; and the other end of the spectrum is a
heterozyous form (thalassemia minor) in which the patient can lead a practically normal life
except for a mild persistent anemia and have a normal life span. In between these two extremes
are forms with varying degrees of clinical manifestations of anemia, splenohepatomegely and
bony changes who maintain their life fairly comfortably and are not dependent on blood
transfusion for their survival and are called thalassemia intermedia and are also homozygous.
Diagnosis :
CBC is frequently sufficient to postulate a diagnosis of thalassemia. Peripheral blood
smears are diagnostic, with microcytic, hypochromic, poikilocytic, and polychromatic red
cells. There is also moderate basophilic stippling with fragmented erythrocytes, target
cells and large number of normoblasts and reticulocytes ranges from 2-4%.
Osmotic fragility reveals reduced fragility.
Bone marrow examination though not required for diagnosis, shows normoblastic
erythroid hyperplasia.
Hb electrophoresis is diagnostic. Fetal hemoglobin is increased in the patient and HbA2
is over 3.4% in both parents.
Radiological findings include widening of medulla due to bone marrow hyperplasia,
thinning of cortex and trabeculation in the long bones-metacarpals and metatarsals. Skull
X-ray shows hair on end appearance.
Periodic tests for organ dysfunctions is necessary which includes SGOT, SGPT, GGT,
Sr.Bilirubin, Sr. Calcium, Sr. Creatinine, etc.
Management of thalassemic child consists of :
Confirmation of diagnosis
Correction of the anemia with repeated RBCs transfusions.
Removal of iron with iron chelating agents.
Treatment of complications.
Correction of hemopoiesis by bone marrow transplantation.
Prevention of the disease by antenatal diagnosis and genetic counselling.
Pharmacological methods to increase gamma-chain synthesis.
Gene replacement therapy.
Management of thalassemia major should be preferably done at a comprehensive thalassemia
care center with outdoor transfusion facilities. A team approach includes a pediatric
hematologist, a blood transfusion specialist, a psychologist and a social worker etc. This not only
3. helps the patient and the family to face various medical and psychosocial problems, but also
helps in early detection and management of complications.
TRANSFUSION THERAPY :
Transfusion therapy in Thalassemia has two goals
To prevent anemia,
To suppress endogenous erythropoiesis to avoid ineffective erythropoiesis.
Blood transfusion is mandatory for all children with Thalassemia major and for those
children with Thalassemia intermedia who cannot maintain Hb above 7 gm% or for those
who show evidence of growth retardation, severe bony changes or hypersplenism.
Regular blood transfusions are presently the mainstay of treatment of Thalassemia.
Pathophysiology :
It is characterized by an imbalance in the production of a and B globin polypeptide chains of
hemoglobin.
In a -Thalassemia, a chain synthesis is decreased. In b -thalassemia, b chain synthesis is
decreased. Excessive a chains precipitate in red cell membrane and damage it. It leads to
premature red cell destruction both in the bone marrow and peripheral circulation
particularly in reticuloendothelial system of spleen (ineffective erythropoiesis and
hemolysis).
Synthesis of gamma chain persists after fetal life. Increased fetal hemoglobin (HbF) with
its high affinity for oxygen leads to tissue hypoxia, which in turn stimulates
erythropoietin secretion leading to both medullary and extramedullary erythropoiesis
(expansion of bone marrow space) causing a characteristic hemolytic facies with
fronotoparietal and occipital bossing, malar prominence and malocclusions of teeth.
Complications include distortion of ribs and vertebrae and pathological fracture of the
long bones, splenomegaly and its complications (hypersplenism), hepatomegaly,
gallstones and chronic leg ulcers.
When to transfuse :
Transfusion is started at the time of diagnosis, that is when the child becomes clinically
symptomatic.
Thalassemia intermedia presents a complex therapeutic problem as these children may
lead near normal life without beingtransfusion dependent. Occasionally it may not be
clear whether one is dealing with Thalassemia intermedia or major.
Majority of Thalassemia intermedia can be detected by
o Age of onset of symptoms is usually more than two year.
o Increased indirect hyperbilirubinemia of 2 mg/dl or more.
o High reticulocyte count more than 10% at the time of diagnosis.
o Hb is usually maintained above 7-10 gm% without blood transfusion.
4. If there is a doubt about the diagnosis, it is wiser to follow up these children regularly and
transfusion therapy should be started only if Hb drops to less than 6-7 gm% and then
regular transfusions are continued to maintain Hb level above 10-12 gm%.
What to transfuse :
Transfuse them with triple saline washed packed cells to avoid transfusion reactions as
saline washing minimises reactions dueto leucocytes and plasma proteins.
If cold centrifuge is required and is not available, simple packed cells may be given.
Frozen cells: Freezing the RBCs to -80 degree Celsius, with an addition of glyerol to
protect RBCs from damage of freezing andthawing, preserves 2,3-DPG and ATP in the
red cells. Thus frozen cells can be stored as long as seven years at -20 degreeCelsius.
However, cost and high technology is involved, which do not permit its use even in
developed countries.
Leucocyte filters are also effective in eliminating neutrophils. Various filters available are
Immugard 500, Sepsea, Travanol,Erypure B, Pal leucocytes filters, which cost around
Rs.150-500, and are not reusable. They are superfluous for those patientswho have not
developed febrile reactions.
How much to transfuse :
Transfusion regimen may be (1) low transfusion regimen where Hb is maintained around
6-10 gm%, (2)hypertransfusion: Hblevel 10-12 gm% and supertransfusion where Hb is
maintained at 12-14 gm%.
The popular transfusion regimen of today is a hypertransfusion regime which aims at
maintaining mean hemoglobin levels at12.5 gm/dl and pre-transfusion level not less than
10 gm%.
Such a regimen permits normal growth and physical activity, suppresses erythropoiesis,
thus preventing skeletal changes andgastrointestinal iron absorption and also inhibits
extra-medullary hemopoiesis, thereby preventing splenomegaly andhypersplenism.
With this regime, requirement of blood is high only at the start of therapy, and does not
produce more iron overload than the lowtransfusion regime.
Pre-transfusion Hb level should be high enough to inhibit bone marrow activity i.e.
around 9.5-10 gm%.
Post-transfusion Hb should not go above 16 gm/dl, since it can lead to hyperviscosity and
its complications.
When this therapy is started late in life when already hypersplenism has set in,
splenectomy becomes mandatory.
TRANSFUSION THERAPY :
Amount and Frequency of transfusion :
5. It is desirable that patients receive not more than 10 cc packed cells/kg/day, which raises
Hb level by about 3.5 gm/dl. In most of the patients, transfusion of about 10cc of packed
RBC/kg every third week is adequate to maintain Pre-transfusion baseline Hb level at
desired 10-11 gm/dl.
Rate of transfusion should be 5-7 ml/kg body weight/hour to avoid sudden increase in
blood volume.
In patients with cardiac insufficiency transfusions may have to be given every second
week and sometimes every week. The duration of transfusion should be prolonged by
decreasing the rate to 1-3 ml/kg/hr and not more than 5 ml/kg/hour.
How often to transfuse :
Transfusions should preferably be given on an out-patient basis, at intervals of 2-4 weeks.
Blood to be transfused should be crossmatched using Coomb's sera to minimize
reactions. Blood should be taken from avoluntary donor and should be screened for
hepatitis B antigen, HCV, Syphilis, malaria and HIV.
The patients should be assessed annually for mean hemoglobin levels maintained overall blood
requirement, physical growth and development, evidence of hypersplenism, antibody
development and iron overload.
On an average the annual blood requirement is 180-200 ml of blood/kg. However, if the
requirement exceeds this level, hypersplenism or development of anti-red cell antibodies
have to be considered.
Complications of transfusions :
Febrile Reactions :
o It is seen in 3-20% of patients and may be due to leucocyte or platelet antibodies,
antibodies against RBC antigens, allergicreactions to other plasma or blood
proteins, or due to pyrogens present in transfused blood. Chills followed by fever
may occurwithin an hour of transfusion or may be delayed for 24 hours.
Headache, nausea, and vomiting may be associated.
o Febrile reactions usually respond to antipyretic and antihistaminic agents.
Leucocyte filters are also effective in eliminatingneutrophils, which are
responsible for pyrogenic reactions.
Hemolytic Transfusion Reactions : It occurs in 5-15% of cases.
o These are due to major or minor blood group mismatch and are characterized by
fever, chills, tachycardia, nausea, vomiting,pallor, restlessness, anxiety, flushing
of face, precordial oppression and pain, increased pulse rate and respiratory
rate,generalized tingling sensation, pain in back and thigh, shock with cold and
clammy skin, cyanosis and collapse. Delirium andconvulsions may develop. Most
feared complications are acute renal failure, hemorrhagic diathesis due to DIC and
anaphylacticshock, all of which may be of life threatening proportions.
6. o Patients may develop indirect hyperbilirubinemia, hemoglobinemia,
hemoglobinuria, reticulocytosis and positive Coomb's testand can occasionally go
into acute renal failure and shock.
o On onset of any early symptoms, transfusion should be stopped immediately.
Anything unusual that alarms the mother should be respected. Older children
(with Thalassemia) sometimes can even sense that something has gone wrong. As
the motheralways remembers the blood group of the child it is a sound policy to
show her the label on the bottle before starting thetransfusion. For the first fifteen
minutes, transfusion should be given slowly so as to detect any reactions at the
earliestmoment.
o If facilities are available all patients should be typed for the common RBC
antigens i.e. Rh, Cc, Dd, Ee, Kell, Kidd, and Duffy(before starting regular
transfusion). Monitoring of the antibodies must be continued life long.
Other reactions uncommonly seen and thought to be of uncertain etiology are sudden
development of hypertension, convulsions,cerebral hemorrhage and edema after multiple
transfusions.
Transfusion transmitted diseases like malaria, syphilis, hepatitis B, Hepatitis C,
Cytomegalovirus, and HIV infection can occur. All thalassemics who are negative for the
hepatitis B surface antigen and antibody, should receive hepatitis b vaccine -4 doses at
day 0, 1 month, 2nd month and 12th month intramuscularly. It also can be given
intradermally in the dose of 0.1 cc, thus reducing the cost. This has been found to be
effective by some workers. However efficacy is not well proven.
IRON OVERLOAD AND CHELATION
THERAPY :
Two factors contribute to iron overload in a thalassemic child:
Enhanced gastrointestinal absorption of iron.
Transfusional siderosis.
Normal body iron content is 3-5 gm, whereas in a thalassemic child it could be around
0.75 gm/kg.
It results from increased GI absorption of iron and blood received during transfusion
therapy.
In normal individual 1 mg of iron/day is absorbed from the gut, while in a thalassemic
child it may be as high as 10mg /day.
7. Each cubic centimeter of packed cells contains 1-1.6 mg of iron. With an average annual
transfusion requirement of 180 cc/kg of packed cells, the body accumulates 200 mg/kg of
iron every year.
Transfusional iron overload leads to deposition of iron in the heart leading to
cardiomyopathy and irregularity of heartbeats, in the pancreas, in the islet of langerhans
leading to diabetes, in the liver and spleen leading to hepatosplenomegaly, hepatic
fibrosis and cirrhosis of liver, in the pituitary glands leading to growth retardation,
delayed puberty character, in the thyroid and parathyroid gland leading to those
subclinical or clinical organ dysfunction, and in the skin leading to bronze or black
discoloration of skin.
Increased susceptibility to bacterial infection especially yersenia is seen with iron
overload, because relatively high serum iron levels may favor bacterial growth, or
because of blockage of the mononuclear phagocyte system by the excessive red cell
destruction.
Iron accumulation in the myocardium can lead to death, either by involving the
conducting tissues or by causing intractable cardiac failure due to cardiomyopathy.
Serum ferritin concentration reflects the iron overload and is usually above 1000 ug/L. S.
Ferritin above 7500 ug/L are found to be lethal.
Despite extensive research for ideal chelating agent, desferrioxamine is currently the only
chelating agent of real value for the management of thalassemia, being able to promote
the excretion of iron.
DESFERRIOXAMINE (DFO) :
Desferrioxamine is a hydroxylamine compound produced by streptomyces pyloses.
A single gram of DFO is able to bind 85 mg of iron.
Desferal (Desferrioxamine) should be started before the age of 3-5 years.
Given on daily basis for a minimum of 5-6 times per week, it is given subcutaneously
over 6-8 hours using an infusion pump. The daily dose of Desferal is about 30-70 mg/kg
and should be tailored according to the need of the patient.
In general, the goal is to keep the serum ferritin level below 1000 ng/ml.
TOXICITY OF DESFERAL :
Toxicity is minimal, no tachyphylaxis has been observed.
When given parenterally there may be liberation of histamine leading to bradycardia,
hypo/hypertension, rigors, headache, photophobia,feeling cold and hot etc.
When given subcutaneously- local pain, induration, irritability and redness may occur.
Visual abnormality may occur and includes decreased acuity of vision, peripheral field
vision defects, defective dark adaptation, thinningof retinal vessels, retinal stippling and
abnormal visual evoked responses and cataract, in 4-10% of patients.
8. High incidence of high frequency sensori-neural hearing loss has been reported in 4-38%
of patient. As the auditory and visual toxicityare reversible, yearly slit lamp examination
and audiometry are mandatory.
Delayed linear growth has also been reported in children under three years of age treated
with Desferal and may be accompanied bymild skeletal abnormalities such as short trunk,
sternal protrusion and genu valgum.
ROLE OF VITAMIN 'C' :
Ascorbic acid deficiency increases insoluble iron (hemosiderin). Vitamin C helps in
conversion of hemosiderin into ferritin from whichiron can be chelated.
High doses of Vitamin C can lead to increased free radical reaction and lipid peroxidaton
resulting in tissue damage and rapid cardiacdecompensation and even death. Addition of
vitamin C 100 mg daily prior to DFO therapy increases iron excretion. 60% of DFO
chelatediron is excreted in urine, and 40% in stool.
NEWER CHELATING AGENTS :
Over the last 20 years, more than 500 oral chelating compounds have been tried all over
the world in search of an ideal chelating agentwhich can be effective, cheap, safe and can
be given orally.
Among the various drugs under trial, few have completed animals studies, a few are
being tried in human volunteers.
The only drug which has entered human trial is Dimethylhydroxy Pyridone (1,2 Diemethy1-3-
Hydroxy Pyrid-4-one (L1), developed in Hider's laboratory-London (40), also called as
Deferriprone and is available in India with the brand name of Kelfer.
Deferriprone (L1) :
It mobilizes iron from transferrin, ferritin, and hemosiderin. It is undergoing extensive
trials in USA, UK, Canada, India and various othercentres.
Doses administered are 50-100 mg/kg body weight.
Results show that it is 70-100% as effective as desferrioxamine.
There has been no evidence of ear or eye toxicity. Urinary excretion of Ca, Cu, Mn, Mg
was not affected. Kidney and liver parameters did not show any alteration.
A few children had GI symptoms like nausea, vomiting, pain in abdomen and diarrhea.
20-30% children had arthropathy, which was reversible after reducing the dose or on
stopping L1. Physical findings included synovialthickening, synovial effusion,
chondromalacia, mild flexion deformity of the knee, painful external rotation of the hip
and vaguegeneralized backache.
ANA, dsDNA, antihistone antibodies were positive in a few cases.
Drug-included lupus has been reported in few cases.
Absolute neutropenia and thrombocytopenia also have been reported in occasional cases.
Physical examination particularly of the joints and complete blood count including
platelet count must be done regularly when child is onDeferriprone (L1) therapy.
9. SPLENECTOMY :
With the advent of hyper and super-transfusion therapy, splenomegaly and hypersplenism
have become a rarity and hence splenectomyis usually not needed in these patients.
If the child has already developed splenomegaly and signs of hypersplenism and is above
5 years of age, splenectomy is indicated.
The indications for splenectomy are :
o An increase in the yearly requirement of packed cells more than double the basal
requirement i.e. packed cell 200 cc/kg/year or more.
o Decrease in WBC and platelet count, which is a late manifestation of
hypersplenism.
All children needing splenectomy should receive pneumococcal vaccine (pneumovax
MSD), H-influenza vaccine, and meningococcal vaccine 4 weeks prior to surgery. In
endemic areas, prophylactic antimalarial treatment may be given to prevent malaria.
Prophylactic penicillin therapy must be continued life-long.
Episodes of infection should be treated promptly and newer antibiotics may be
empirically started to prevent septicemia and other complications (if necessary these
children should be hospitalized). Blood culture and sensitivity of antibiotics must be
performed to guide treatment.
BONE MARROW TRANSPLANTATION :
A ray of hope for permanent cure and better future for children with genetic disorders has
brightened with the rapid advancement in the techniques and the success of bone marrow
transplantation.
The credit of first bone marrow transplantation in thalassemia major goes to E.Donald
Thomas who performed this procedure in an 18 month old thalassemic child in 1982
using HLA matched elder sister as donor. This child was cured of thalassemia. The first
BMT in thalassemia in India was successfully done by Dr.M.Chandi at Christian Medical
Collage, Vellore.
The principles of bone marrow transplantation in thalassemia are:
o To destroy and prevent regeneration of defective stem cells,
o sufficient immune suppression for good engraftment of normal marrow,
o to infuse stem cells with normal gene for b globin.
o To prevent GVHD with high doses therapy of Busulphan, Cyclophosphamide,
total body irradiation and other modalities.
All over the world over 1000 transplantations have been done with a 70-80% cure
rate.
The three most important adverse prognostic factors for survival and
event-free survival are the presence of hepatomegaly (liver more than 2
cms. below costal margin), portal fibrosis and iron overload. (Lucarelli et
al).
10. Bone marrow transplantation is most successful in patients who are young,
properly transfused, well-chelated and in goodclinical shape without
hepatomegaly.
The cost of BMT in India is around Rs.4-5 lacs and is being done at
Christian Medical Collage, Vellore and Tata Memorial Hospital,Parel,
Mumbai, and AIIMS in Delhi.
NEOCYTE TRANSFUSION :
Propper et al in 1980, introduced the concept of transfusing thalassemic children with
young red cells (Neocytes).
In conventionally used unit of blood, red cells have a survival of 60 days. The mean age
of a neocytes being 120 days, theysurvive in the recipient for 90 days, thus reducing the
amount of blood required and prolonging the interval between twotransfusions.
IBM-2991 can be utilized for both washing the red cells and dividing them into
populations of different ages by differentialcentrifugation technique.
There is a reduction in the total units of blood transfused and iron overload.
However this is not cost effective. The requirement of blood donors is increased and it
requires costly equipment, technologyand highly developed transfusion services. It is also
time consuming.
PHARMACOLOGICAL METHODS TO
INCREASE GAMMA CHAIN
PRODUCTION AND GENE MANIPULATION :
Main pathology of b thalassemia is reduced production of b-chain leading to excess of unpaired a
-globin chain which precipitate leading to ineffective erythropoiesis or hemolysis of RBCs
resulting in anemia.
It has been noted that hypomethylation of gene increases its expression and when
methylated, the gene is not expressed. A number of drugs like 5'Azacytidine and
hydroxyurea have been shown to increase the production of gamma chains both in
animals and human beings by causing hypomethylation of gene by decreasing the activity
of the enzyme DNA methyl transferase.
This increase in gamma chain synthesis prevents the Alpha chain precipitation by
forming HbF (a 2 g 2) and thereby increasing the life span of red cells.
5-Azacytidine is recommended in the dose of 2 mg/kg/day intravenous infusion in ringer
lactate or saline solution at the rate of 6 mg/hour for 7 days.
This leads to an increase in Hb from 8 to 10.8 gm% in 2-3 weeks and an increase in fetal
Hb from 1.06% to 20% on the 40th day.
Side effects like nausea, vomiting, suppression of bone marrow and potential
carcinogenesis have put limitations on its use in practice and unless a more effective
compound with less toxicity becomes available such therapy is not recommended for
thalassemia major.
11. Augmenting the production of g chain reduces imbalance of globin chain and increases synthesis
of HbF and thus lessening the severity of the disease. Various drugs that stimulate HbF
production are 5-azacytidine, hydroxyurea, Butyrate compounds and erythropoietin.
Butyrates :
These are found naturally increased in diabetic mothers. Their babies at birth have 100 % HbF.
In vitro trials found the efficacy of these drugs in increasing the HbF production. This drug is
given I.V. infusion slowly over 6-8 hours in dose of 200-400 mg/kg/day and has shown to
increase HbF to 8-12% and cause a rise in Hb by 2-3 gm%. The problem with this drug is the
tedious I.V. route. Oral analogue, Na Butyrate is useful in some patients to sustain the response
after IV therapy. The side effects are few and include nausea, vomiting, electrolyte disturbances
and occasional seizures. The actual efficacy of this drug is found to be lacking in many patients
with sickle cell anemia and thalassemia intermedia. Further trials are awaited before it becomes
available commercially. L-carnitine, an analogue of butyrate, has been tried in thalassemic
patients but response obtained has been poor in most of the trials.
Genetic Engineering :
Insertion of normal gene in the stem cells of recipient remains a known challenging goal of
future therapy. There are two main approaches to gene therapy : 1) Somatic approach in which
non-germ line cells are involved. 2) Transgenic approach in which transfused gene can be
expressed in subsequent generations. This therapy is still in experimental stage and likely to be
therapy of future management of thalassemia.
Antenatal diagnosis and genetic counseling :
As thalassemia is inherited in an autosomal recessive manner there are 25% chances of
producing thalassemia major child in each pregnancy.
Population screening, identification of carriers, genetic counseling, antenatal diagnosis in women
at risk and selective termination of affected fetus can prevent the birth of thalassemia major
child.
br> Prenatal diagnosis can be done by estimation of relative rate of globin biosynthesis by
fetoscopy and fetal blood sampling around 16-18 weeks of intrauterine life or by analysis of
foetal DNA by ultrasound guided chorionic villous biopsy at around 8-9 weeks of gestation or
foetal amniocytes by amniocentesis.
Conclusion :
With the better understanding of molecular biology and pathophysiology of thalassemia,
advances in the transfusion therapy, organized quality care and effective chelation therapy,
thalassemics can become fully active members of the society with proper physical, mental and
sexual growth (without any disfiguration). They are able to profit from their opportunities and
enjoy positions that they are entitled to in the society. With the free availability of oral chelators
in near future, and establishment of more and more outdoor transfusion centres and thalassemia
societies, the management of thalassemia major will become easier and economically feasible.
With the advent of BMT, cure is possible. Gene therapy still remains a hope for the future. In
developed countries where all these facilities are already available, more and more thalassemic
12. children are leading a normal healthy life and even achieving parenthood. Prenatal screening and
diagnosis as well as modern management of thalassemia are technologically complex and
expensive, and thus their benefits remain limited only to the industrialized developed world & in
certain centres in India. Unfortunately, developing countries like ours still have a long way to go.
REFERENCES :
1. Piomelli S, Loew T. Management of thalassemia major (Cooley's anemia) Hematol
Oncol Clin North Am 1991, 5: 557-69.
2. Piomelli S. Cooley's anemia management : 25 years of progress. In :Bucker CD, Gale
RP, Lucarelli G. Advances and controversies in thalassemia therapy - bone marrow
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3. Lokeshwar MR, Mangalani M, Rao S, et al. Current trends in thalassemia therapy.
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Also See Frequently Asked Questions On "Thalessemia"
Also See Expertise Views On "Thalessemia"
Last created on 06-11-2000
Last updated on 01-07-2006