Practical and its trait. Beta-thalassemia is the mutation on

Practical
2

 

Question
1

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Table
1 above shows the quantitative amount HbA2 in the EDTA blood sample given with
respective to each patient.

 

HbA2 is an important diagnostic parameter in
beta-thalassemia, however not the only parameter. The differences in HBA2
concentration on people vary, determining a patient with beta-thalassemia and
its trait. Beta-thalassemia is the mutation on the beta-globin chain and its
synthesis is controlled by gene on chromosome 11. The normal range of HbA2 is between
2.2-3.5% and above 3.5% indicates beta-thalassemia. This also rules out that
patient A is normal as he/she falls in between the range but patient B might be
suffering from beta-thalassemia as the patient’s HbA2 range exceeds the normal
range. The elevated concentration of HbA2 only indicates that there is a
presence of heamoglobinopathy for patient B but it does not necessarily mean
that the patient is suffering from beta-thalassemia. Confirmatory tests such as
HbA1 and HbF panels are needed to conclude and support this diagnosis of
patient B. HbA1is an alpha-globin chain which is an identical protein to HbA2,
located on chromosome 16. In normal adult blood, HbA1 levels are high but HbA2
and HbF levels are relatively low. However, in thalassemia minor patients, the
HbA1 levels are normal but HbA2 and HbF levels are slightly elevated. In
thalassemia major patients HbA1 is almost absent but HbA2 and HbF are elevated.
This elevation of HbA2 and HbF acts as a coping mechanism to compensate for
erythrocytes production. HbF is haemoglobin foetus and is normal adults the
values are less than 0.6% of total adult haemoglobin. However, in
beta-thalassemia patients, the screening of beta-thalassemia is crucial for
family counselling as it not only allows parents to identify if they are
carriers (heterozygous) as often carriers are symptomatic but it also provides
genetic information about a patient’s unborn child when she goes for antenatal
check-ups.

 

 

 

 

 

Table
1 above shows the reference range for thalassemia respectively.

 

 

Question
2

Therapies for beta-thalassemia differ based on its types
and severity of symptoms. There are three types of beta-thalassemia –
thalassemia minor, thalassemia intermedia and thalassemia major (Cooley’s anaemia).
Out of which, thalassemia major is the most severe. Regular blood transfusion
is necessary for thalassemia major patient because erythrocytes survive for
about 120 days and to maintain patient’s haemoglobin level at 9-10g/dL.
Therefore to maintain a healthy supply of erythrocyte, recurrent transfusion is
needed every 4 months. There is risk of transmitting infections like viral
hepatitis in recurrent transfusion. These patients are also crossed match their
Rh and ABO group typing by the blood bank prior to first transfusion to prevent
alloimmunization. This strategy not only treats anaemia but also supresses the
endogenous erythropoiesis which would in turn supresses’ extramedullary
haematopoiesis.

Due to recurrent blood transfusion, these patients are
prone to iron overload as haemoglobin is rich in iron. Therefore, iron
chelation therapy is required to prevent damage to the heart, liver and other
parts. Excess iron is removed from the body through Deferoxamine and Deferasirox
as medicines used in this therapy.

Splenectomy (surgically removing spleen) eliminates the
accelerated destruction through extra-corpuscular haemolysis mechanism of the
normal donors erythrocyte in the recipient’s circulation. This therefore decreases
the frequency of blood transfusion and blood consumption, ultimately reducing
iron overload. Splenomegaly (enlargement of spleen) is found in thalassemia
patients due to the misshapen shape of erythrocyte.

Allogenic hematopoietic stem cell transplantation is also
another possible therapy for thalassemia major patients. This therapy
transplants a matching donor’s stem cells. Therefore, as with any
transplantation procedure, this too has the complications of graft vs host
disease, rejection of donor’s stem cells, haemorrhagic cystitis and
transplantation mortality are to be considered prior to this approach. 

Lastly, gene therapy is also known to be appropriate for
thalassemia major patients. Autologous hematopoietic stem cells (AHSC) are
harvested from the patient, which then gets genetically modified with a vector
called lentiviral – that expresses a normal globin gene. After appropriate
conditioning therapy that destroys the current HSC that is in circulation, the
genetically modified AHSC would be infused into the patient. Genome editing
technique that specifically target single-mutation, replacing with normal
sequence is one of the newer techniques with regards to gene therapy.

 

References

 

 

 

Practical 3

Question 1

The hand
drawn graph is attached with this report. As the lab result obtained was
abnormal, a standard curve was not achievable. However, points were plotted
that indicates obtained results.

Question 2

The two
MCF (mean corpuscular fragility) values for hereditary spherocytosis at 50%
lysis will be 0.5% NaCl and for
normal blood will be 0.4% NaCl.

Question 3

Hereditary spherocytosis is a type of
congenital haemolytic anaemia, which is mainly caused by autosomal dominant
gene. This is due to the defects in the proteins involved for vertical
interaction between the membrane skeleton and lipid bilayer of the
erythrocytes. When this interaction is compromised, the membrane surface area
is lost. The loss of cohesion between bilayer and skeleton takes place, causing
instability of the lipid bilayer that releases free-lipid vesicles. In normal
patients, the bone marrow produces biconcave shaped erythrocytes, whereas
patients with this disease produce a spherical erythrocyte, which therefore die
prematurely as they are unable to pass through splenic microcirculation.  A defect in the membrane vertical linkage
includes protein Ankyrin, band 3, beta and alpha spectrin and paladin (protein
4.2).

 

Combinations of genes for a specific trait
that are located on the chromosome, each received from a parent (mother and
father) are responsible for genetic disorders. Only a single copy of an
abnormal gene is required for a dominant genetic disorder to take place. This
abnormal gene can either be inherited from a parent or a genetic mutation for
the affected patient. Passing down of this abnormal gene to offspring during
each pregnancy is 50%. Parent could be heterozygous or homozygous as the allele
required for trait to be produced is dominant. An example of  Heterozygous and homozygous parent and their chances of affected
offspring could be seen below. 

 

 

 

 

Figure 2 above shows the Punnett square for an example of
heterozygous affected parent and homozygous normal parent

 

References

 

 

Practical 4

 

Question 1a

Table above show patients ABO
and Rh group respectively

 

1b)

Table above shows the
recommended blood type of each group for respective patients for a successful
blood transfusion (without hemolytic transfusion reaction).

If Patient 1
needed a blood transfusion, the best possible blood groups to give in the ABO
system would be either A or O for a successful blood transfusion. B group will cause
transfusion reaction. This is because patient 1 has A antigen present on
his/her erythrocyte. It also means that the naturally occurring antibody
against B blood group (anti-B) is present in the A blood group and these
antibodies are commonly IgG, although sometimes IgM. If B blood group is
transfused, it results in agglutinated blood (clumping of RBCs), which leads to
the destruction of donor’s RBC due to the immune response from recipient. Likewise
for patient 2, who has a B blood type, can only receive blood from B or O blood
group. Failure to compliance will lead to similar effects explained for patient
1. Similar to patient 1, patient 2 also has naturally occurring antibody in the
plasma (anti-A) for B blood group. When transfused the wrong type, complications
of blood transfusion arises. Hemolytic transfusion reaction (HTR) is an example
of such complication. It could either be immediate or delayed. Immediate could
be extremely life threatening, associated with massive intravascular hemolysis
(complement-activated) which are commonly ABO specific and extravascular
hemolysis are usually Rh associated, so unable to activate complement, therefore
generally less fetal. For the Rh group type, patient 1 could receive from both
negative and positive blood types but patient 2 can only receive from negative
blood group. This is because, for a positive blood type, it has a Rh (+) factor
protein (represented by D) present on the erythrocyte. While a negative blood
type, it has no Rh (-)(represented by d) factor protein present on the
erythrocyte. Therefore, when patient 1 (A+) gets blood transfused on (A-/O-) no
reaction can take place because, there are no naturally occurring anti-d in Rh+
group. However, Patient B has Rh (-) blood group, having naturally occurring
anti-D antibodies. Therefore a Rh+ blood transfused to a Rh- patient will cause
a reaction.

Rapid
appearance of anemia and mild jaundice are sometimes common in HTR. Some
clinical significance of major hemolytic transfusion reaction is hemolytic
shock phase (HSP), oliguric phase and diuretic phase. HSP may take effect after
just a few milliliter of transfused blood from donor or within 1-2hrs of
transfusion. Clinical symptoms of this includes urticaria, pain in the lumbar
region, flushing, precordial pain, headache, shortness of breath, rigours,
pyrexia and fall in blood pressure. Intermediate leukocytosis (15-20×10^9) is
common. Some patients with oliguric phase face hemolytic reaction as renal
tubular necrosis with acute renal failure. Lastly, in the diuretic phase, fluid
and electrolyte imbalances may take place, while patient is in recovering from
acute renal failure.

 

 

Question 2a)

Patient 1: Antibody
present is Anti-Kell and Lu^a

Patient 2: Antibody
present is Anti-D and C^w

 

2b)  

 

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