The Haemoglobin Molecule and Thalassaemia Flashcards
1
Q
What is Hb like extracellular, what can it do
A
Toxic and can activate free radicals
2
Q
what % of haemoglobin is made as an erythroblast vs reticulocyte
A
65% made in erythroblast stage
35% made in reticulocyte stage
3
Q
Structure of Hb A?
A
- 4 globin chains 2 alpha, 2 beta
- Haem (synthesised in mitochondria)
- Globin (synthesised in ribosomes)
4
Q
Where is haem synthesised within the cell
A
synthesised in mitochondria)
5
Q
Where is globin synthesised in the cell
A
synthesised in ribosomes)
6
Q
Iron is transported to the cell via….
A
transferrin
7
Q
transferrin transports ….
A
Iron is transported to the cell
8
Q
Examples of things that contain haem…?
A
myoglobin, cytochromes, peroxidases, catalases and tryptophan
9
Q
What is the variation in haem?
A
The same in all Hb
10
Q
What form of iron is in haem
A
Ferrous (Fe2+)
11
Q
Haem is a combination of … (X ring with Y)
A
protoporphyrin ring with central iron atom (ferroprotoporphyrin)
12
Q
What enzyme synthesises haem
A
delta-ALAS
13
Q
What is delta-ALAS
A
enzyme that synthesises haem
14
Q
What is the regulator of haem synthesis and how
A
Haem, negatively feedbacks to impact the production of delta-ALAS enzyme
15
Q
How many globin chains are there
A
8
16
Q
How many clusters of globin chains are there
A
2
17
Q
What are the 2 globin chain clusters
A
alpha and beta
18
Q
Which globin chains are important in embryonic development
A
Zeta and epsilon
19
Q
Which globin chains are in the alpha cluster
A
Alpha and zeta
20
Q
Which globin chains are in the beta cluster
A
beta, gamma, delta and epsilon
21
Q
Where is the beta cluster found
A
short arm of chromosome 11
22
Q
Where is the alpha cluster found
A
short arm of chromosome 16
23
Q
short arm of chromosome 16 contains which globin gene cluster
A
alpha
24
Q
short arm of chromosome 11 contains which globin gene cluster
A
beta
25
In embryogenesis the production of red cells is mainly in the ...
yolk sac
26
During foetal life the production of red cells is mainly in the ...
liver and spleen
27
the switch from liver and spleen to bone marrow for red cell production occurs ..
- Shortly after birth
28
The switch to alpha globin production occurs
6-8weeks prenatal age
29
- The switch from gamma to beta globin occurs ....
3-6 months after birth
30
Why is alpha thalassemia lethal in utero
Because the switch to alpha globin production occurs at 6-8 weeks prenatal age
31
How many amino acids in alpha globin
141 AAs
32
How many amino acids in all globin apart from alpha
146 AAs
33
Secondary structure of globin?
- 75% of all and globin chains have a helical arrangement
34
Tertiary structure of globin?
- Approximate sphere
- Hydrophilic surface (charged polar side-chains), hydrophobic core
- Haem pocket
35
Primary structure of globin?
- -globin = 141 AAs
| - Non--globins all equal 146 AAs
36
2, 3 DPG prefers haemoglobin in its X state and so aids the transfer of oxygen Y haem molecule.
```
X = deoxygenated
Y = away from the
```
37
What does the position of the oxygen dissociation curve depend upon (4)
1. Conc. of 2,3-DPG
2. pH ([H+] ion conc.)
3. CO2 in red blood cells
4. Structure of Hb
38
What does a left shift of the oxygen dissociation curve mean
increased affinity (easier to bind, more difficult to let go of oxygen)
39
What does a right shift of the oxygen dissociation curve mean
decreased affinity (more difficult to bind, easier to let go of oxygen)
40
factors causing right shift of oxygen dissociation curve (4)
1. High 2,3-DPG
2. High H+
3. High CO2
4. HbS
41
factors causing left shift of oxygen dissociation curve
1. Low 2,3-DPG
| 2. Hb
42
2 types of HAEMOGLOBINOPATHIES and what is the problem in them
1. Structural variants of haemoglobin (sickle cell disease etc.)
2. Defects in globin chain synthesis (thalassaemia)
43
Genetic disorders characterised by defects of globin chain synthesis are...
thalassemias
44
Most common inherited gene disorder worldwide is...
thalassemia
45
Distribution of thalassaemia Ties quite tightly with the distribution of ...
malaria
46
3 ways of classifying thalassemia?
- Classified in terms of globin type effected (alpha, beta, delta etc.)
- Classified in terms of clinical severity:
- Nowadays we try and classify according to transfusion dependant/independent
47
Difference between thalassemia major and minor
Minor “trait” Carriers of thalassaemia
Intermedia (when the alleles are β+β0)
Major (note: cannot produce any HbA)
48
what causes beta thalassemia
- Deletion or mutation in the beta globin gene(s) resulting in Reduced or absent production of beta globin chains
49
what type of inheritance is beta thalassemia
Mendelian autosomal recessive inheritance
50
What are Microcytic hypochromic red cell indices
reduced MCV, reduced MCHC
51
What is the MCV of beta thalassemia
reduced
52
What is the MCH of thalassemia
reduced
53
RBC count relative to Hb in thalassemia
increased
54
What abnormal types of cells are in a blood film for betathalassemia (2)
Target cells Howell Jolly bodies
55
anisocytosis in thalassemia?
No
56
poikilocytosis in thalassemia?
Yes
57
Hb electropherisis shows in beta thalassemia ... (types of Hb and their change)
Raised HbA2 and raised HbF
58
Hb electropherisis shows in alpha thalassemia ... (types of Hb and their change)
Normal HbA2 and HbF, raised or lowered HbH
59
What condition does THALASSAEMIA MAJOR cause
- Severe anaemia
60
What treatment is required for life if you have THALASSAEMIA MAJOR
regular blood transfusion
| - Iron chelation therapy
61
When is clinical presentation of beta thalassemia major and why then
- Clinical presentation usually after 4-6 months of life Switch from gamma to beta globin production
62
Size of RBC if BThalM
microcytosis
63
Clinical presentation of bthal
- Severe anaemia usually presenting after 4 months
| - Hepatosplenomegaly
64
What is seen on blood films of thalmajor
shows gross hypochromia, poikilocytosis and many NRBCs
65
Clinical features of bthal (7)
- Chronic fatigue
- Failure to thrive
- Jaundice
- Delay in growth and puberty
- Skeletal deformity
- Splenomegaly
- Iron overload
66
B-THALASSAEMIA biggest CAUSE OF DEATH?
cardiac disease
67
Definitely needed treatments for B-thalassemia major?
- Regular blood transfusions- always
| - Iron chelation therapy- always
68
Supportive therapies for beta-thal major
- Possible splenectomy
- Supportive medical care
- Hormone therapy
- Hydroxyurea to boost HbF
- Bone marrow transplant Only curative measure
- Silencing of BC11a gene which is what is responsible for the switch from gamma to β globin chains.
69
What should you consider if transfusion requirement is super high
consider splenomegaly Reduces transfusion requirements
70
what is needed in splenectomised patients (think infect)
- Prophylaxis in splenectomised patients Need immunisation and antibiotics
71
what is DEFERASIROX (EXJADE):
iron chelation therapy
72
E.g. of iron chelation therapy
DEFERASIROX (EXJADE):
DESFERRIOXAMINE (DESFERAL):
DEFERIPRONE (FERRIPOX)
73
side effects of iron chelation therapy?
GI symptoms
Hepatitic impairment
Renal impairment
74
Advantages of desferrioxamine
3 decades of use
Survival benefit
Heart failure prevented and reversed
75
Advantages of deferiprone
Oral admin
| Cardiac protection
76
Advantages of deferasirox
Oral admin
once a day
specific
77
Disdvantages of desferrioxamine
Parenteral admin
| Dose dependent ocular, auditory, skeletal toxicity
78
Disdvantages of deferiprone
3x a day
Unpredictable
Toxicity (agranulocytosis)
79
Disdvantages of deferasirox
short clinical experience
| cardiac protection uncertain
80
4 ways of monitoring iron overload
SERUM FERRITIN:
LIVER BIOPSY:
T2* CARDIAC AND HEPATIC MRI:
FERRISCAN (R2 MRI
81
problems associated with thala treatment in developing countries (5)
- Lack of awareness
- Lack of experience of healthcare providers
- Availability of blood
- Cost and compliance with iron chelation therapy
- Availability of and very high cost of bone marrow transplant
