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- Dr. Eyad Arafat
- Hematologist
- Al-Bashir Hosp
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- The Thalassemia is an inherited disorder of hemoglobin synthesis and
structure, and the management of the patients of Thalassemia depend=
s on
the type of Thalassemia and severity.
- With the dramatic developments that have occurred in the past two
decades in the clinical management of Thalassemia major, particular=
ly
impressive improvement has been observed in the survival rate among
patients in Thalassemia major.&nbs=
p;
However the disease-free and complications-free survival
reflecting better quality of life has yet to be achieved.
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- Management of β-Thalassemia major.
- Management of β -Thalassemia intermedia.
- Management of β -Thalassemia&n=
bsp;
minor and α-Thalassemia
minor.
- Management of the acutely ill Thalassemia patient.
- Management of Thalassemia complications.
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4
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- Primary management of patients with Thalassemia major and other
transfusion – dependent Thalassemia syndromes can be considered
under four major headings :
- 1. Transfusion Therapy.
- 2. Splenectomy.
- 3. Iron chelation therapy..
- 4. Bone marrow transplantation.
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5
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- The transfusion scheme should keep the Hb-level up to 12 g/dl , which permits normal
physical activity and normal growth and prevent chronic hypoxemia and
reduces compensatory marrow hyperplasia. This in turn prevents :
- 1. Secondary bone changes.
- 2.Hypervolemia, secondary bone to marrow hyperplasia, which can p=
lace
a strain on the heart.
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- 3.The development of splenomegaly and hypersplenism (because the num=
ber
of abnormal red cells reaching the spleen is reduced).
- 4. Excessive gastro-intestinal iron absorption, which can contribute=
to
Thalassemia iron overload (Iron absorption is directly proportional =
to
the degree of marrow hyperplasia and inversely proportional to the
patients Hb-level.
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7
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- Regular blood transfus=
ion
should be started when a diagnoses of a typical hemozygous Thalassem=
ia
is made and the Hb-level falls below 7 g/dl and remains therefore a =
week
or more(in the absence of other factors such as infection_.Transfusi=
on
should be considered even when the Hb is over 7g/dl if there is impa=
ired
growth , severe bone change, or the spleen is rapidly enlarged.
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- The aim of blood transfusion is to give red blood cells with the min=
imum
possible white blood cell or plasma, which can cause antibody format=
ion
of allergy reactions.
- =
;
The type of blood preparation that can be given are=
:
- 1. filtered blood is
recommended for all Thalassemia patient’s, in order to minimize
the risks associated with formation of antibodies to white blood cel=
ls.
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- 2.Washed red cells to prevent reactions in patient’s in
antibodies to white cells or plasma proteins.
- 3.packed red cell to some protection against immunization, and r=
educes
the volume transfused and the risk of circulatory overload
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- 4. Frozen blood is best for rare patient’s with difficult
cross-matching problems ro
sensitivity to plasma proteins, because of the extensive washing
involved.
- 5. ?Neocyte” Transfusion. The transfusion interval can be
somewhat increased and blood consumption somewhat reduced by transfu=
sion
young red cells, which survive longer.
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- The transfusion interval varies from two weeks to six weeks, so the =
pre
and post transfusion Hb levels required to maintain the recommended =
mean
hemoglobin at 12g can vary. There is no evidence of any major clinic=
al
differences in the well being
of patients, without cardio logical problems transfused at fr=
om 2
weekly of or if weekly intervals, in choosing a transfusion on scheme
factor, such as:
- 1. the distance from the patient’s marrow to the center.
- 2. We should be remember that frequent visits to hospital can be
socially and psychologically disturbing.
- 3. The average rate of Hb fall is approximately 1 gr. Per week (unle=
ss
the patient is hyperplasic).
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- Pretransfusion Hb levels necessary to maintain an approximate mean=
Hb
of 12g/dl in relation to transfusion intervals.
- The post-transfusion Hb should not rise where 15.5 g/dl :
- 1.Higher levels increase blood viscasity, reduce tissue oxygenation =
and
increase the risk of Thalassemia, especially if other risk factors a=
re
present ( infectijn, metabolic acidosis, diabetes, high platelet cou=
nt
following splenoctomy).
- 2.Higher levels alsom lead to an increased, which cannot then be
adequately controlled with chelation therapy.
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- The requirements for blood transfusion are to achieve the desired Hb
level, and not to overload the circulation.
- The rate at which blood can be transfused depends on the patient/s Hb
level and cardiovascular status :
- 1. When there is no cardiac problems: it is generally considered
acceptable to administ=
rator
10-15 ml and blood (or packed cells) per kg body weight in about two
hours, if the transfusion done more slowly, over 3-4 hours, larger
volumes as 20 ml/kg can be transfused.
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- 2. When cardiac failure is present or when the Hb level is less than=
5
g/dl : for these patient’s, transfusion of small amounts of bl=
ood
at 1 or 2 weekly intervals is recommended, and diuretic is required,=
not
more than 5 ml/kg should be transfused at one time, and the rate of
transfusion should now exceed 2 ml/kg per hour.
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- The human body has very little ability to excrete Iron, and iron balance is
maintained by limiting gastro-intestinal iron absorption, additional
iron being absorbed only when it is required iron may accumulate when
the intestinal route is by-passed, or the regulation of
gastro-intestinal iron absorption is altered. In Thalassemia both these e=
vents
occur and can lead to very sever iron overload.
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- 1.Blood transfusion by-passes the intestinal barrier. One ml of pu=
re
red cells contains 1.16 mg of iron, so an average 450 ml of donar bl=
ood
contains about 230mg of iron ,so patient receiving 30 units of blood=
/
year receives over 6g of elemental iron/year (The normal body iron s=
tore
is about 1g) The iron stores increase to many times normal.
- 2, Gastro-intestinal iron absorption is increased in Thalassemia,
unless the patient Hb is kept in normal range. Normal iron absorptio=
n is
about.1-1,5 mg/day, but in untransfused or low-transfused patient wi=
th
Thalassemia major it is about 3-4 mg/day and can reach 10mg/day if o=
ral
iron preparation are given.
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- Chronic iron overload caused tissue damage, it can load to cardiac,
liver and endocrine problem so and can ultimately leed to death, so
evaluation, prevention and treatment of iron overload are very
important.
- Iron chelating agents are drugs that bind iron and remove it from the
body. They used to eliminate excess iron.
- The only medical iron chelating agent widely available at present are
desferrioxamine (deferoxamine) and calcium DTPA
(diethylenetriamine-penta-acetate).
- Several oral iron chelating agents are under development and clinical
trials appear very promising.
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- The most widely used measure is serum ferritin estimation, in the
absence of chronic liver disease, the ferritim level usual
correlates well with =
the
iron load. Aferritin =
level
at less than 20 mg/dl indicates iron deficiency, value above 100 mg=
for
women and 250 mg for men indicate iron overload.
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- In unchelated patient’s the iron load can be calculated reliably fro=
m the
total number of units of blood transfused, this calculation is not
useful in chelated patient/’s.
- Other methods, liver biopsy and quantitative measurement of liver i=
ron
(mg of fe/g dry wt) is highly reliable but should be reserved for c=
ases
with special indications. CAT scanning, magnetic nuclear resonance
scanning, and measuring iron in the skin are reliable but expensive,
and are not available in many places.
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- Invitro, 1g of desferrioxamine binds at most 85 mg of iron, invivo =
its
capacity is determined by the following factors :
- The amount of iron in stores.
- The route of administration of desferoxiamine-less iron is excreted
when the chelator is given intramuscularly than when it is infused
slowly I.v or s.c.
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- 3. The patient’s vitamin-c status . Vitamin c depletion is co=
mmon
in iron overload which reduce iron excretion in response to
desferoxiamine.
- 4. The duration (years) of administration-because total body iron l=
oad
falls with effective chelator therapy.
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- Chelation therapy should be started as soon as transfusion treatment=
has
deposited enough iron to protect against desferoxiamine toxicity.
- Chelation therapy is recommended to be started after the first 10-15
blood transfusions, or when serum ferritin level has reached 1000 ng=
/ml.
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- Subcutaneous infusion of 10% desferoxiamine solution using a syringe
pump is the recommended method.
- The drug should be infused slowly over 8-10 h.
- Continuous intravenous infusion. It must be done in patient’s =
when
intensive chelation is needed, implanted intravenous delivery system
(portacath, hickman line) can be used for intensive infusion at home=
.
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- Continuous I.V. infusion is indicated for patient’s :
- A. when have cardiac problems secondary to iron overload.
- B. Who have early cardiomyopathy detectable only by sensitive meth=
ods.
- C. Who are incapable of using subcutaneous chelator for any reason=
.
- Continuous I.v. infusion can remove very large quantities of iron and
also protect against iron toxicity.
- It can be very affective in improving cardiac function, and is somet=
imes
life-saving.
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- There is n fixed dose suitable for all patient's.
- The average daily dose is usually between 20-60 mg/kg/day :
- Patient’s with a serum ferritin at less than 2000 require ab=
out
25 mg/kg/day.
- Patient’s with serum ferritin at 2000 to soon require about =
35
mg/kg/day.
- Patient’s with a higher serum ferritin require up to 55
mg/kg/day.
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- Good transfusion programs retard the developments of splenomegaly, b=
ut
progressive splenic sequestration of transfused cells is observed by age 7 years in many optimally
transfused children.
- In Thalassemia the evolution of hypersplenism starts with increased destruction of red blood ce=
lls.
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- An annual blood requirement of 1.5 times (or over 1.5 times) that in
splenectomized patient’s on the same transfusion schame is the
accepted indicator for splenectomy.
- Spleen size is another useful indicator – more the an 6 cm bel=
ow
the costal margin.
- The presence of leucopenia or thrombocytopenix is an absolute indica=
tion
for splenectomy..
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- 1. Infections-specially with yerssinia and pneumococal pneumonia =
211;
patient’s should be immunized against pneumococal infection 4-6
weeks prior to splenectomy when possible prophylactic antibiotics sh=
ould
be continued for at least 2 years : L.A.penicillin 1,200,000 I.m or oral penicillin 250 mg a=
t bed
time.
- 2. Thrombocytosis.
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- Definition –people with 2 Thalassemia genes who remain well
without transfusion ha=
ve
Thalassemia intermedia, they becomes transfusion-dependant later than
2-3 years of age, and can tolerate Hb > 7g/dl.
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- Patient’s with intermedia who are able to maintain Hb 7,5 g/dl
usually do not require chronic transfusion therapy when are persiste=
nt
clinical problems-abnormal faces, pathological fracture, growth
retardation or masses of ectopic marrow, patients require regular
transfusion , the transfusion scheme should be the same as in
Thalassaemeia major.
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- Pts’ who manage to lead normal life, and do not have other pro=
blem
should not be started =
on
transfusion treatment, the Hb can drop temporarily in such pt’=
s ,
who may need occasional transfusions for specific reasons
(infection)
- Most pregnant women with Thalassaemeia intermediates should be trans=
form
throughout pregnancy
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- Untransformed pt’s with Thalassaemeia inter- media may develop
iron overload as a result af increased gastro- intestinal iron abrup=
tion
they should be advised to avoid:-
- eating meet particularly rich in iron (liver, spleen)
- Iron supplemented cereals.
- to drink a cup of tea with every meal.
- Chelation therapy should certainly be started wihen the serum ferrit=
in
has risen above 2000 ng/ml . It is usually sufficient to give
Desferoxamine s.c are 1 or 2 days a week only
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Splenectomy
Indications :<=
/div>
- clinical signs of hyper- splenism (splenomegaly with drop in Hb leve=
l,
following off in growth)
- Splenic enlargement of 6 cm or more is nearly always accompanied by =
some
Hypersplenism
- Hypersplenism with
leucopenia and or thrombocytopenia
- High blood transfusion requirement
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- Patient with ∞- and β- Thalassaemeia minor are not in need
for blood transfusion or chelation therapy , they may need iron
treatment if they develop iron deficiency anemia.
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- Complication in Thalassaemeia, specially in Thalassaemeia major
pt’s develop as a results of:
- 1- Non – availability of appropriate treatment with blood and
desferaxiamine
- 2- Inadequate treatment in early life, so that some irreversible dam=
age
has occurred
- 3- Insufficiently aggressive prescription of chelation therapy in the
past.
- 4-Poor compliance with Desferal treatment
- 5-Excessive blood consumption ( often due to an inappropriately high transfusion scheme, or=
to
Hypersplenism
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- Endocrine complications:
- A) retorted growth, in the past , this commonly accrued in the early
years of life because of chronic anemia. Now it is usually seen only
around the time of puberty
- - Growth retardation especially in pat’s younger than 12 years=
may
also be due to excessively high doses at desferaxiamine
- -Growth hormone deficiency is a relatively common cause of growth
retardation in Thalassaemeia.
- Growth hormone should be given only if growth hormone deficiency has
been defensively established
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- B) Disturbed Pubertal Development many Thalassaemeia pt’s suff=
er
form delayed and set of failure of puberty, same girls develop secon=
dary
amenorrhea and some boys secondary impotence and infertility
- Replacement therapy with low doses of testosterone or estrogen stimu=
late
development of secondary sexual characteristics, allow growth and av=
oid
atrophy of the gonads. High doses may close the epiphyses and jeopar=
dize
fertility
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- C) Hypothyroidism : Develop primary hypothyroidism with or without
clinical sings, asymptomatic pt’s require observation ,
symptomatic pt’s require replacement therapy
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- D) hypoparathyroidism: is common in very heavily iron loaded
pt’s it prsents as hypo- calcemia , the pt. complains of tingl=
ing
or eching untreated pt’s may develop conclusion
- e) Diabetes mellitus: is common among Thalassaemeia pt’s of
pubertal age or older , specially in those with chronic liver diseas=
e,
they are insulin-dependent and the diabetes is difficult to control.=
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- Cardiac iron overload can cause arrhythmias and cardiac failure, the
immediate treatment of these abnormalities is the same as in non-
Thalassaemeia pt’s , the presence of cardiac compilations is an
indication for continuous i.v. chelation, therapy and anti –
failure drugs.
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- Many Thalassaemeia pt’s develop liver disease , including
cirrhosis as result of
- 1- liver overloads
- 2- chronic hepatitis, as complication of blood transfusion (HCV, HBV=
)
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- Hypertension, convulsions and cerebral hemorrhage following transfus=
ion
in pt who have previously been maintain at very low Hb- level
- Neurological complications may do to extra- medullar hematopoiesis in
the brain in pt. with inadequate blood transfusion
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