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Haematology Y2 > The Haemoglobin Molecule and Thalassaemia > Flashcards

The Haemoglobin Molecule and Thalassaemia Flashcards

1
Q

What is Hb like extracellular, what can it do

A

Toxic and can activate free radicals

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2
Q

what % of haemoglobin is made as an erythroblast vs reticulocyte

A

65% made in erythroblast stage

35% made in reticulocyte stage

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3
Q

Structure of Hb A?

A
  • 4 globin chains 2 alpha, 2 beta
  • Haem (synthesised in mitochondria)
  • Globin (synthesised in ribosomes)
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4
Q

Where is haem synthesised within the cell

A

synthesised in mitochondria)

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5
Q

Where is globin synthesised in the cell

A

synthesised in ribosomes)

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6
Q

Iron is transported to the cell via….

A

transferrin

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7
Q

transferrin transports ….

A

Iron is transported to the cell

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8
Q

Examples of things that contain haem…?

A

myoglobin, cytochromes, peroxidases, catalases and tryptophan

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9
Q

What is the variation in haem?

A

The same in all Hb

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10
Q

What form of iron is in haem

A

Ferrous (Fe2+)

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11
Q

Haem is a combination of … (X ring with Y)

A

protoporphyrin ring with central iron atom (ferroprotoporphyrin)

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12
Q

What enzyme synthesises haem

A

delta-ALAS

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13
Q

What is delta-ALAS

A

enzyme that synthesises haem

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14
Q

What is the regulator of haem synthesis and how

A

Haem, negatively feedbacks to impact the production of delta-ALAS enzyme

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15
Q

How many globin chains are there

A

8

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16
Q

How many clusters of globin chains are there

A

2

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17
Q

What are the 2 globin chain clusters

A

alpha and beta

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18
Q

Which globin chains are important in embryonic development

A

Zeta and epsilon

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19
Q

Which globin chains are in the alpha cluster

A

Alpha and zeta

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20
Q

Which globin chains are in the beta cluster

A

beta, gamma, delta and epsilon

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21
Q

Where is the beta cluster found

A

short arm of chromosome 11

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22
Q

Where is the alpha cluster found

A

short arm of chromosome 16

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23
Q

short arm of chromosome 16 contains which globin gene cluster

A

alpha

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24
Q

short arm of chromosome 11 contains which globin gene cluster

A

beta

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25
Q

In embryogenesis the production of red cells is mainly in the …

A

yolk sac

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26
Q

During foetal life the production of red cells is mainly in the …

A

liver and spleen

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27
Q

the switch from liver and spleen to bone marrow for red cell production occurs ..

A
  • Shortly after birth
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28
Q

The switch to alpha globin production occurs

A

6-8weeks prenatal age

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29
Q
  • The switch from gamma to beta globin occurs ….
A

3-6 months after birth

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30
Q

Why is alpha thalassemia lethal in utero

A

Because the switch to alpha globin production occurs at 6-8 weeks prenatal age

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31
Q

How many amino acids in alpha globin

A

141 AAs

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32
Q

How many amino acids in all globin apart from alpha

A

146 AAs

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33
Q

Secondary structure of globin?

A
  • 75% of all  and  globin chains have a helical arrangement
34
Q

Tertiary structure of globin?

A
  • Approximate sphere
  • Hydrophilic surface (charged polar side-chains), hydrophobic core
  • Haem pocket
35
Q

Primary structure of globin?

A
  • -globin = 141 AAs

- Non--globins all equal 146 AAs

36
Q

2, 3 DPG prefers haemoglobin in its X state and so aids the transfer of oxygen Y haem molecule.

A 
X = deoxygenated
Y = away from the
37
Q

What does the position of the oxygen dissociation curve depend upon (4)

A
  1. Conc. of 2,3-DPG
  2. pH ([H+] ion conc.)
  3. CO2 in red blood cells
  4. Structure of Hb
38
Q

What does a left shift of the oxygen dissociation curve mean

A

increased affinity (easier to bind, more difficult to let go of oxygen)

39
Q

What does a right shift of the oxygen dissociation curve mean

A

decreased affinity (more difficult to bind, easier to let go of oxygen)

40
Q

factors causing right shift of oxygen dissociation curve (4)

A
  1. High 2,3-DPG
  2. High H+
  3. High CO2
  4. HbS
41
Q

factors causing left shift of oxygen dissociation curve

A
  1. Low 2,3-DPG

2. Hb

42
Q

2 types of HAEMOGLOBINOPATHIES and what is the problem in them

A
  1. Structural variants of haemoglobin (sickle cell disease etc.)
  2. Defects in globin chain synthesis (thalassaemia)
43
Q

Genetic disorders characterised by defects of globin chain synthesis are…

A

thalassemias

44
Q

Most common inherited gene disorder worldwide is…

A

thalassemia

45
Q

Distribution of thalassaemia Ties quite tightly with the distribution of …

A

malaria

46
Q

3 ways of classifying thalassemia?

A
  • 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
Q

Difference between thalassemia major and minor

A

Minor “trait” Carriers of thalassaemia
Intermedia (when the alleles are β+β0)
Major (note: cannot produce any HbA)

48
Q

what causes beta thalassemia

A
  • Deletion or mutation in the beta globin gene(s) resulting in Reduced or absent production of beta globin chains
49
Q

what type of inheritance is beta thalassemia

A

Mendelian autosomal recessive inheritance

50
Q

What are Microcytic hypochromic red cell indices

A

reduced MCV, reduced MCHC

51
Q

What is the MCV of beta thalassemia

A

reduced

52
Q

What is the MCH of thalassemia

A

reduced

53
Q

RBC count relative to Hb in thalassemia

A

increased

54
Q

What abnormal types of cells are in a blood film for betathalassemia (2)

A

Target cells Howell Jolly bodies

55
Q

anisocytosis in thalassemia?

A

No

56
Q

poikilocytosis in thalassemia?

A

Yes

57
Q

Hb electropherisis shows in beta thalassemia … (types of Hb and their change)

A

Raised HbA2 and raised HbF

58
Q

Hb electropherisis shows in alpha thalassemia … (types of Hb and their change)

A

Normal HbA2 and HbF, raised or lowered HbH

59
Q

What condition does THALASSAEMIA MAJOR cause

A
  • Severe anaemia
60
Q

What treatment is required for life if you have THALASSAEMIA MAJOR

A

regular blood transfusion

- Iron chelation therapy

61
Q

When is clinical presentation of beta thalassemia major and why then

A
  • Clinical presentation usually after 4-6 months of life Switch from gamma to beta globin production
62
Q

Size of RBC if BThalM

A

microcytosis

63
Q

Clinical presentation of bthal

A
  • Severe anaemia usually presenting after 4 months

- Hepatosplenomegaly

64
Q

What is seen on blood films of thalmajor

A

shows gross hypochromia, poikilocytosis and many NRBCs

65
Q

Clinical features of bthal (7)

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice
  • Delay in growth and puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload
66
Q

B-THALASSAEMIA biggest CAUSE OF DEATH?

A

cardiac disease

67
Q

Definitely needed treatments for B-thalassemia major?

A
  • Regular blood transfusions- always

- Iron chelation therapy- always

68
Q

Supportive therapies for beta-thal major

A
  • 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
Q

What should you consider if transfusion requirement is super high

A

consider splenomegaly Reduces transfusion requirements

70
Q

what is needed in splenectomised patients (think infect)

A
  • Prophylaxis in splenectomised patients Need immunisation and antibiotics
71
Q

what is DEFERASIROX (EXJADE):

A

iron chelation therapy

72
Q

E.g. of iron chelation therapy

A

DEFERASIROX (EXJADE):
DESFERRIOXAMINE (DESFERAL):
DEFERIPRONE (FERRIPOX)

73
Q

side effects of iron chelation therapy?

A

GI symptoms
Hepatitic impairment
Renal impairment

74
Q

Advantages of desferrioxamine

A

3 decades of use
Survival benefit
Heart failure prevented and reversed

75
Q

Advantages of deferiprone

A

Oral admin

Cardiac protection

76
Q

Advantages of deferasirox

A

Oral admin
once a day
specific

77
Q

Disdvantages of desferrioxamine

A

Parenteral admin

Dose dependent ocular, auditory, skeletal toxicity

78
Q

Disdvantages of deferiprone

A

3x a day
Unpredictable
Toxicity (agranulocytosis)

79
Q

Disdvantages of deferasirox

A

short clinical experience

cardiac protection uncertain

80
Q

4 ways of monitoring iron overload

A

SERUM FERRITIN:
LIVER BIOPSY:
T2* CARDIAC AND HEPATIC MRI:
FERRISCAN (R2 MRI

81
Q

problems associated with thala treatment in developing countries (5)

A
  • 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

Haematology Y2 (11 decks)

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