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I need to learen > The Haemoglobin Molecule and Thalassaemia > Flashcards

The Haemoglobin Molecule and Thalassaemia Flashcards

1
Q

What is the role of red blood cells, what is it’s normal concentration and what does it contain

A

Carrys oxygen from lungs to tissue and CO2 from tissue to lungs
3.5-5 x 10^12/L
Contains haemoglobin
No nucleus

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2
Q

Where is haemoglobin found, what is its normal concentration and how much is produced/destroyed every day

A

Found only in RBCs
normal conc. = 120-165g/L
Approx 90mg/kg produced and destroyed in the body every day

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3
Q

Describe the structure of haemoglobin

A

4 polypeptide subunits of 2 alpha chains and 2 beta chains with a prosthetic haem group

4 haem+4 globin chains = 1 Hb molecule

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4
Q

Which organelles are involved in haemoglobin synthesis

A

haem - mitochondria

globin - ribosomes

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5
Q

Describe the structure of haem

A

Same in all types of Hb
Combination of protoporphyrin ring with central iron atom, usually in the ferrous form (Fe2+)
Able to reversibly bind to oxygen

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6
Q

Describe the synthesis of haem

A

Mainly in the mitochondria which contains the ALAS enzyme
more haem made = -ive feedback on enzyme activity
Iron is brought to the mitochondria (via transferrin) for haem synthesis

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7
Q

When are the genes coding for the globin in foetal haemoglobin switched off?

A

It is decreased towards birth and in the first year after birth.
After 1 year of life, the normal adult pattern of haemoglobin synthesis would have been established.

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8
Q

Describe the global gene clusters

A

Eight functional globin chains, arranged in two clusters:

beta cluster (b, g, d and e globin genes) on the short arm of chromosome 11

alpha cluster (a x2 and z globin genes) on the short arm of chromosome 16

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9
Q

Describe the changes in location of RBC production in the foetus

A

Main site of RBC production at first is the yolk sac, then liver, then spleen
After birth, main production is the bone marrow

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10
Q

Describe the alteration of gene expression and globin production in the foetus

A
  1. zeta and epsilon globin chains immediately
  2. switch to alpha and gamma (3-6 months of life)
  3. Then alpha and beta
    Little delta globin synthesis
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11
Q

How many alpha genes are there in total

A

There are 2 alpha globin genes from each parent so there are 4 alpha globin genes in total.

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12
Q

What makes up Hb A and what is the normal percentage

A

alpha2,beta2

96-98%

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13
Q

What makes up Hb A2 and what is the normal percentage

A

alpha2,delta2

1.5-3.2%

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14
Q

What makes up Hb F and what is the normal percentage

A

alpha2,g2

0.5-0.8%

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15
Q

Describe the secondary structure of globin

A

75% alpha and beta chains in helical arrangement
Structure varies with the no. of O2 molecules bound
With no or few O2 bound, Hb is in the ‘tight’ configuration and is stabilised by 2,3-BPG.

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16
Q

Describe the tertiary structure of globin

A

approx sphere
Hydrophilic surface (charged polar side chains) and a hydrophobic core
Haem pocket

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17
Q

Describe the oxygen-haemoglobin dissociation curve

A

Sigmoid shape

Binding of one molecule facilitate the second molecule binding (cooperativity)

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18
Q

What is P50 on the oxygen dissociation curve

A

Partial pressure of O2 at which Hb is half saturated with O2

26.6mmHg

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19
Q

What is the advantage of the cooperative binding of haemoglobin

A

Deoxyhaemoglobin (tight form) has a very low affinity for O2, so it will only pick it up when the pO2 is very high, like in the lungs, and it won’t take O2 away from metabolically active tissues that need it.

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20
Q

What does position of the Hb-oxygen dissociation curve depend on

A

Concentration of 2,3-DPG
H+ ion concentration (pH)
CO2 in red blood cells
Structure of Hb

21
Q

What causes right shift on the oxygen-dissociation curve

A

High 2,3-DPG
High H+
High CO2
HbS

22
Q

What causes left shift on the oxygen-dissociation curve

A

Low 2,3-DPG
Low H+
Low CO2
HbF

23
Q

What are haemoglobinopathies

A

Structural variants of haemoglobin
or
Defects in globin chain synthesis (thalassaemia)

24
Q

Define thalassaemia

A

Disorders in which there is a reduced production of one of the two types of globin chains in haemoglobin leading to an imbalanced globin chain synthesis

25
Q

What are the two clinical variations of thalassemia

A

Thalassemia trait = common variant with little clinical significance

Transfusion dependent – Thalassemia Major = fatal without transfusion

26
Q

What is the most common type of mutation in alpha and beta thalassaemia

A

alpha - deletion

Beta - point mutation

27
Q

Describe beta thalassaemia major

A

Severe defect in both β chains (beta0)

28
Q

What are the clinical features of beta thalassaemia major in the first year of life and why may it be a problem in the first 2-3 months

A

Profound anemia
Failure to thrive
Malaise (general discomfort feeling)
Splenomegaly

Problem as there is a switch from HbF to HbA

29
Q

Why does beta thalassaemia major cause splenomegaly

A

α chains form tetramers (α4), which precipitate in bone marrow causing ineffective erythropoiesis
If they do enter the circulation, the spleen removes them -> splenomegaly

30
Q

Describe the inheritance of beta thalassaemia

A

Autosomal recessive
B0 = thal. major (both genes)
B+ = only one gene damaged
Carriers are aymsymptomatic but to have microcytic hypo chromic indicies

31
Q

What investigations should be done for thalassaemia

A

FBC
Rilm
Hb EPS/HPLC
Globin chains synthesis/ DNA studies

32
Q

What will show on the film for a beta thalassaemia major

A 
Extreme hypochromia 
Microcytosis 
Poikilocytosis 
Tear drop cells + elliptical
Howell jolly bodies
33
Q

Which are the 2 major inclusion bodies seen in beta thalassaemia

A 
Alpha globin precipitates
Pappenheimer bodies (Perls stain - inky blue granules)
34
Q

What are the clinical features of beta thalassaemia major

A 
Splenomegaly
Skeletal deformity (increased BM)
Chronic fatigue
Failure to thrive
Jaundice
Iron overload
35
Q

What is the life expectancy of un-treated beta thalassaemia patients

A

Death at 7 years without transfusion

36
Q

What is the life expectancy of treated (transfusion) beta thalassaemia patients and why

A

25
Iron overload -> liver cirrhosis, heart failure, diabetes, endocrine failure
potential viral transmission

37
Q

What is the treatment for thalassaemia major

A 
Regular blood transfusions
Iron chelation therapy
(Splenectomy
Supportive medical care
Hormone therapy
Hydroxyurea to boost HbF
Bone marrow transplant)
38
Q

What are the types of iron chelation therapies

A

Deferasirox (Exjade)
Desferrioxamine (deferral)
Deferiprone (ferriprox)

39
Q

What is the purpose of iron chelation therapy

A

Remove iron to prevent overload

40
Q

Why is desferrioxamine not used as much as other iron chelation therapies

A

SC injected (not orally active)
Expensive
Compliance issues
Increased risk of Klebsiella and Yersinia infection

41
Q

Describe Deferasirox (Exjade) (admin, dose)

A

Oral

Dose 20-40mg/kg

42
Q

What are the unwanted effects of defarasirox

A

rash
GI symptoms
hepatitis
renal impairment

43
Q

Describe deferiprone (admin and dose)

A

Oral

Dose 5-100 mg/kg/day

44
Q

What is used to monitor iron overload

A

Serum ferritin
Liver iron
Hepatic and cardiac MRI

45
Q

Describe HbE beta thalassaemia

A

Very common combo in south east Asia

Variable in expression - may be as severe as beta thalassaemia major

46
Q

Describe beta thalassaemia trait

A

Little drop in Hb
May cause mild anaemia
high RBC, low MCV and MCH. In β-thalassaemia trait, haemoglobin electrophoresis will show a greater proportion of HbA2 (d chains not β).

47
Q

Describe alpha thalassamia

A

Varying prognoses depending on how many chains are affected
2 or 3 - mild anaemia
1 - HnH formation + severe anaemia
0 - haemoglobin Barts - fatal in utero

48
Q

What is the chance of HbBarts with 2 parents with only 2 alpha chains

A

25%

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