etiology

Beta-globin gene mutations

Mutations in globin genes cause thalassemias. Beta thalassemia affects 1 or both of the beta-globin genes. (Alpha
thalassemia affects the alpha-globin gene[s].) These mutations, by causing impaired synthesis of the beta-globin
protein component of Hb, result in anemia. [1, 2]
Beta thalassemia is inherited as an autosomal recessive disorder. The defect can be a complete absence of the betaglobin protein (ie, beta-zero thalassemia) or a severely reduced synthesis of the beta-globin protein (ie, beta-plus
thalassemia). (See the image below.)
Peripheral smear in beta-zero thalassemia minor sh
Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
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Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.The
genetic defect usually is a missense or nonsense mutation in the beta-globin gene, although occasional defects due to
gene deletions of the beta-globin gene and surrounding regions also have been reported.
In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is
defective, resulting in an approximately 50% decrease in the synthesis of the beta-globin protein.
In beta thalassemia major (ie, homozygous beta thalassemia), the production of the beta-globin chains is severely
impaired because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >>
beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. (See the image below.)
Peripheral smear from a patient with beta-zero tha
Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and
anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
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Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and
anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. The excess
unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in
intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective
erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary
hematopoiesis.

 Although beta thalassemia is caused by a genetic mutation in the beta-globin gene (which is located on
chromosome 11), many additional factors influence the clinical manifestations of the disease. That is, the
same mutations may have different clinical manifestations in different patients. The factors below are known
to influence the clinical phenotype.
Intracellular fetal Hb concentrations
The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells
determines, in part, the severity of the disease. Patients with high fetal Hb have milder disease.
Coinheritance of alpha thalassemia
Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe
alpha-beta chain imbalance.
Coexistence of sickle cell trait
The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with
most of the symptoms and complications of sickle cell disease. Unlike sickle cell trait, in which most Hb-onHb electrophoresis is Hb A (AS), S is the dominant Hb (SA) and usually constitutes about 60% or more of
the circulating Hb, depending on the transfusion status of the patient and the nature of the coexisting betathalassemia mutation (ie, beta-zero vs beta-plus).

patofisiology

eta-thalassemia syndromes reflect deficient -globin synthesis usually owing to a mutation in

the eta-globin locus. The relative excess of -globin results in the formation of insoluble
aggregates leading to ineffective erythropoiesis and shortened red cell survival. A relatively
high capacity for fetal hemoglobin synthesis is a major genetic modifier of disease severity,
Iron overload secondary to red cell transfusions causes an increase in liver iron and leading to
endocrine and cardiac dysfunction. [15, 16]
The thalassemias are inherited disorders of hemoglobin
(Hb) synthesis. Their clinical severity widely varies, ranging from asymptomatic forms to
severe or even fatal entities.. Beta -thalassemia is due to impaired production of beta globin
chains, which leads to a relative excess of alpha globin chains. These excess alpha globin
chains are unstable, incapable of forming soluble tetramers on their own, and precipitate
within the cell, leading to a variety of clinical manifestations. The degree of alpha globin chain
excess determines the severity of subsequent clinical manifestations, which are profound in
patients homozygous for impaired beta globin synthesis and much less pronounced in
heterozygotes who generally have minimal or mild anemia and no symptoms. [15, 16]
Alpha thalassemia, in comparison, is due to impaired production of alpha globin chains,
which leads to a relative excess of beta globin chains. The toxicity of the excess beta globin
chains in alpha thalassemia on the red cell membrane skeleton appears to be less than that of
the excess partially oxidized alpha globin chains in beta thalassemia. Unbalanced alpha
globin chain synthesis leads to hemolysis of red cells in the peripheral circulation and, more
importantly, to the extensive destruction of erythroid precursors within the bone marrow and
in extra medullary sites, such as the liver and spleen (ineffective erythropoiesis. [16, 17]

Nursing care
Children with thalassemia traits do not require medical or follow-up care after the initial
diagnosis is made. [22] People with -thalassemia trait should be warned that their condition
can be misdiagnosed as the more common iron deficiency anemia. They should avoid routine
use of iron supplements. [23] Children with Severe thalassemia, require medical treatment.
Blood transfusion was the first effective measure thus prolonged life. [22] Multiple blood
transfusions can result in iron overload. Iron overload can be treated by chelation therapy,
that resulted in improved life expectancy in those with thalassemia major. [24]
Bone marrow transplantation (BMT) may offer the possibility of a cure in young people who
have an Human Leukocytes antigen matched donor. [25] The success rates of BMT ranged
between 8090% range, while mortality rate is about 3%. [25] There are no randomized
controlled trials which have tested the safety and efficacy of non-identical donor bone
marrow transplantation in persons with - thallassemia who are dependent on blood
transfusion. [26] If the person does not have an HLA-matched compatible donor, another
method called bone marrow transplantation (BMT) from haploidentical mother to child
(mismatched donor) may be used. In a study of 31 people, the thalassemia-free survival
rate 70%, rejection 23%, and mortality 7%. The best results are with very young people. [27]

Diagnose test
Blood tests
In cases of beta thalassemia, the red blood cells appear small (microcytic) and pale (hypochromic), compared to
those seen on normal blood smears. The red blood cells may also be nucleated, an indication that they are
immature forms (also known as erythroblasts).
In thalassemia major, the hemoglobin (Hb) level is usually less than 7 g/dl; the mean corpuscolar volume
(MCV) less than 70 fl and the mean corpuscolar Hb (MCH) is over 20 pg.
In thalassemia intermedia, the hemoglobin level is between 7 and 10 g/dl; the MCV between 50 and 80 fl and
MCH between 16 and 24 pg.
Thalassemia minor is characterized by a reduced MCV and MCH and an increased haemoglobin A2 level.
Molecular genetic analysis
DNA analysis can be performed to check for mutations in the genes that code for the beta globin chains found
in hemoglobin. The test is not usually carried out routinely but may be performed in cases where a physician
suspects the condition based on signs and symptoms such as anemia, breathlessness and the results of blood
tests. DNA analysis can help diagnose the condition as well as determining carrier status in other members of
the family.

management
Guidelines for management for each severity group of thalassemias are as following
Severe beta-thalassemia diseases with a baseline hemoglobin lower than 7.0 grams per deciliter or
hema- tocrit less than 20%, can receive the following forms of treatment:
- Allogeneic hematopoietic stem cell transplantation. This can potentially cure the disease but an appropriate HLA-matched donor is required. There are also some possible complications during and after
trans- plant process, but most cases can be reversible or resolved.
- High or Hypertransfusion regularly together with adequate iron chelation therapy. This approach
is affordable and suitable for compliant patients and parents. The patient will have normal growth and
height, no facial deformity, and possibly a normal sized liver and spleen. This strategy of management is
mandatory for the safety and successful outcome of patients following stem cell transplantation.
- Low transfusion, occasional and supportive as needed. Iron chelation and/or splenectomy may be
indicated. This approach is suitable for poor compliant patients and parents.
Moderately severe thalassemia diseases with base- line hemoglobin about 7-9 grams per deciliter or
hema- tocrit about 20-27%, can receive the following forms of treatment:
- High transfusion together with adequate iron chelation therapy in some selected cases.
- Low transfusion occasionally when acute hemolysis crisis occurs. Splenectomy is indicated in some
cases.

Mild thalassemia diseases in which the baseline hemoglobin is over 9 grams per deciliter or hematocrit more than 27% may
receive transfusions only in the event of acute hemolysis crisis. Basic treatment consists of daily oral folic acid intake.
Asymptomatic or thalassemia trait or carrier, do not require regular follow up or medication. Only genetic counseling is
offered when indicated.
Blood transfusion therapy
Regular blood transfusion program must be provided for those suffering anemia problem from severe beta-thal- assemia
diseases, using good-quality, safe, contamination
-free, pathogens screened blood components complying with standard guidelines of universal precaution by the National
Blood Centre, Thai Red Cross Society and International Blood Banks. Occasional blood transfusion regimen must also be
provided for those with acute crisis of hemolytic anemia due to underlying thalassemia
intermedia. Nursing staffs must be high experiences in taking good care for patients receiving blood transfusion.
Iron chelation therapy.
Each packed-red-cell blood unit contains a certain amount of iron. When a blood transfusion is given to a patient repeatedly,
the iron compound will gradually deposit in his/her body tissue. Everyone has a a limit of excreting excessive iron. In patients
who receive numerous blood transfusions, an accumulated toxic iron overload will develop. This leads to vital organ
damage, affecting the liver, heart, pancreas, and many endocrine glands. To combat with this problem, the patient must be
treated with ironchelating medications.
Chelation therapy should begin after 12 to 15 blood transfusions or within 1 8 months of frequent trans- fusions. This
correlates with a serum ferritin level over 1,000 nanograms per milliliter. Liver iron con- centration (LIC) which is
measured by liver biopsy is the best measure of total iron loading. However this invasive liver procedure may not be
routinely performed because of patients discomfort. In cases where it is performed, LIC should be more than
3,000 micrograms per gram dry weight before begin- ning chelation. The methods may be subcutaneous or intravenous
infusion of desferioxamine, oral intake of deferiprone, or intake of modern drugs such as desferasirox, etc. Responsible
hematologist will assess and determine which ones are suitable to be used in patient on case by case basis.
Supportive treatment and care.
On progression of disease in patients who did not get appropriate and sufficient treatment, several compli- cations can occur.
Patients must be aware of potential problems, such as increased size of spleen, congestive heart failure, increased tendency of
clot formation inside blood vessels, increased susceptibility to infection from certain microorganisms, growth failure,
endocrine dys- function, delayed physical and sexual maturity, etc., so they may be treated early. For those who have had
trou- ble from adverse manifestations, a holistic approach and treatment must be provided in order to relieve or even solve the
problems.

 Curative treatment
Bone Marrow Transplantation (or Hematopoietic
Stem Cell Transplantation).
This modern procedure has been the only accepted meth- od worldwide to cure beta-thalassemia diseases by means of allograft
transplantation. In this procedure, the patient requires a hematopoietic stem cell donation from an HLA- matched healthy donor,
possibly from a sibling or unrelated suitable volunteers. The patients blood, as well as that of the potential donor, will be tested for
typing and matching. In the case of lacking an HLA-identical sibling, the patient will be registered to search for an appropriate
unrelated donor through standard volunteer donor registries and public cord blood banks. Sources of donors stem cells may be
achieved from their bone marrow, peripheral blood, or umbilical cord blood.
Due to the sophisticated scheme of patient care, high risk of complications and high expense of treatment, indications for eligible
candidates for undergoing stem cell transplanta- tion are as follows:
1.Transfusion-dependent or severe hemolytic anemic beta-thalassemia diseases.
2. Available HLA-matched, non-affected, stem cell donors. The chance of a same-parent sibling having an HLA- match with a patient
is about 1 out of 4, or 25%. The chance of a volunteer unrelated donor having an HLA- match is about 1:10,000 to 1:100,000.
3. Financial status. The cost of allogeneic hematopoietic stem cell transplantation for thalassemia children varies from 700,000 to
1,500,000 Thai Baht, depending on individual body weight and sources of donor stem cells.
Estimated disease-free survival rates of patients after transplantion varies from about 75% to 92%, depending on the experience of
each institute team. From the patients per- spective, the better treatment outcomes are associated with younger patients, lower
number of blood transfusion units, preferred use of leuko-depleted (leukocyte-filtered) packed red cells, absence of enlarged of liver
and spleen, and regular adequate iron chelation to avoid liver fibrosis and myocar- dium damage. In terms of donors, better
outcome are related with higher degree of completely compatible HLA alleles between donors and patients (recipients), and
adequacy of stem cell dose to the patients body weight. HLA-matched sibling stem cell transplantations achieve more success- ful
disease-free long-term survival and less post-transplant complications than HLA-mismatched, unrelated donor transplants.
Allogeneic bone marrow transplantation is the com- plex scheme of therapy and integration of medical sci- ences and technology.
Bangkok Hospital Medical Center offers this well-organized comprehensive program as a specialized, aerosol-filtration equipped,
isolation units setting for particular group of patients who have full- filled indication for undergoing transplantations. The institute
has experienced a considerable number of successful bone marrow and cord blood stem cell trans- plants for thalassemia children
and young adults. The details regarding this curative therapy will be informed, discussed, and explained by relevant bone marrow
trans- plant physicians on patient case by case basis.

komplikasi
Complications associated with beta thalassemia, aside
from the aforementioned anemia, are as follows (see
Prognosis,
Presentation,
Workup,
Treatment,
and
Medication):
Extramedullary hematopoiesis
Asplenia secondary to splenectomy
Medical complications from long-term transfusional
therapy - Iron overload and transfusion-associated
infections (eg, hepatitis)
Increased risk for infections resulting from asplenia (eg,
encapsulated organisms such as pneumococcus) or from
iron overload (eg, Yersinia species)
Cholelithiasis (eg, bilirubin stones)

 Some of the complications associated with beta thalassemia (especially thalassemia

major) include:
Enlargement of the spleen increases the risk of injury and rupture of the organ which can
be life threatening. An enlarged spleen also presses against other vital organs, in which
case it may need to be removed in a procedure called a splenectomy. Since the spleen
plays an important part in fighting infection, a splenectomy can result in an increased
risk of infection.
Liver complications include hepatitis, enlarged liver or scarring of the liver (cirrhosis).
Affected bone marrow and bone deformities increase the risk of joint pain, osteoporosis
and susceptibility to fracture.
Other complications include pulmonary hypertension (high blood pressurewithin the
blood vessels of the lungs), thromboembolic complications and sepsis after splenectomy.
Blood transfusion is also associated with complications. Regular transfusions can
increase the risk of iron overload which can lead to complications such as:

Hormonal disturbances - Iron overload can disrupt the endocrine system and balance of hormones,
which can result in hypogonadism (low functioning of the genital and reproductive organs),
infertility, underactive thyroid and diabetes. The secretion of growth hormone may also be
impaired and retard growth.
Liver damage and fibrosis
Heart damage and disease