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Y2 MCD - Haem (additional) > Haem 4: The haemoglobin molecule + thalassaemia > Flashcards

Haem 4: The haemoglobin molecule + thalassaemia Flashcards

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1
Q

What are the key points about RBCs?

A
  • Carry oxygen from lungs to tissues
  • Transfer CO2 from tissues to lungs
  • 3.5-5 x1012/L
  • Contain Hb –> approx. 640 million molecules per cell
  • No nucleus/mitochondria
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2
Q

What are the key points about haemoglobin?

A
  • Found exclusively in RBCs
  • MV 64-64.5kDa
  • 120-165g/L –> normal conc in adults
  • 90mg/kg produced + destroyed in body each day
  • Each Hb contains 3.4mg Fe
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3
Q

When does Hb synthesis occur?

A

During RBC development:

  • 65% erythroblast stage
  • 35% reticulocyte stage
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4
Q

What is the basic structure of haemoglobin?

A
  • Haem

- Globin

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5
Q

Where is haem synthesised?

A
  • Mitochondria
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6
Q

Where is globin synthesised?

A
  • Ribosomes
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7
Q

What proteins is haem contained in?

A
  • Haemoglobin
  • Myoglobin
  • Cytochromes
  • Peroxidases
  • Catalases
  • Tryptophan
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8
Q

How does haem structure vary between these proteins?

A

IT DOESN’T!

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9
Q

What is the structure of haem?

A

ferroprotoporphyrin  protoporphyrin ring + central iron atom (usually Fe2+)

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10
Q

What enzyme do the mitochondria contain that is involved in haem synthesis?

A

ALAS

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11
Q

How are different haemoglobin molecules formed?

A

haem + different globin types

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12
Q

How many functional globin chains are there?

A

eight

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13
Q

How are these globin chains arranged? Where are these clusters found?

A

two clusters:

  • Beta cluster = short arm of chromosome 11
  • Alpha cluster = short arm of chromosome 16
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14
Q

Which globin genes make up the beta cluster?

A

beta, gamma, delta and epsilon globin genes

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15
Q

Which globin genes make up the alpha cluster?

A

alpha and zeta globin genes

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16
Q

What are the normal forms of adult haemoglobin?

A
  • HbA
  • HbA2
  • HbF
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17
Q

What are the structures of these haemoglobins?

A
  • HbA = a2b2
  • HbA2 = a2d2
  • HbF = a2g2
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18
Q

What are the normal percentages of these haemoglobins?

A
  • HbA = 96-8%
  • HbA2 = 1.5-3.2%
  • HbF = 0.5-0.8%
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19
Q

What is primary structure of globin?

A
  • a = 141 AA

- non-a = 146 AA

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20
Q

What is the secondary structure of globin?

A
  • 75% alpha and beta chains = helical arrangement
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21
Q

What is the tertiary structure of globin?

A
  • Approximate sphere
  • Hydrophilic surface = charged polar side chains, hydrophobic core
  • Haem pocket
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22
Q

oxygen dissociation curve

What does the sigmoid shape of the oxygen-haemoglobin dissociation curve show?

A

the binding of one molecule facilitates the second molecule binding = cooperativity

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23
Q

What is P50?

A

the partial pressure of O2 at which Hb is half saturated with O2 = 26.6mmHg

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24
Q

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

A
  • concentration of 2,3 DPG
  • H+ ion concentration (pH)
  • Co2 in RBCs
  • Hb structure
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25
What does a right shift of the Hb-oxygen dissociation curve indicate?
easy oxygen delivery
26
What causes a right shift in the curve?
- HIGH 2,3-DPG - High H+ - High CO2 - HbS
27
What does a left shift indicate?
Hb gives up oxygen less readily
28
What causes a left shift in the curve?
- Low 2,3-DPG | - HbF
29
What are haemoglobinopathies?
- Genetic defects that result in abnormal structure of one of the globin chains of the haemoglobin molecule
30
What is thalassaemia?
- A genetic defect that results in production of an abnormally low quantity of a given haemoglobin chain/chains
31
What is the classification of thalassaemia based on?
- Globin type affected | - Clinical severity = minor ‘trait’, intermedia, major
32
Where are the alpha-like genes found?
chromosome 16
33
Where are the beta-like genes found?
chromosome 11
34
What is beta thalassaemia?
deletion/mutation in beta globin gene(s) => reduced or absent production of beta globin chains
35
Where is beta thalassaemia most prevalent?
mainly Mediterranean countries
36
What sort of inheritance does beta thalassaemia exhibit?
autosomal recessive
37
What symptoms do carriers exhibit?
asymptomatic => except for microcytic hypochromic indices
38
How can the variation in severity be explained?
mutations vary in severity => explained by degree of suppression of globin chain synthesis => some mutation result in no globin production (b0) whereas others have decreased levels of production (b+) 2x b0 = beta thalassaemia MAJOR 2x b+ = beta thalassaemia INTERMEDIA (milder form)
39
What do the lab tests for beta thalassemia show?
- FBC  microcytic hypochromic indices + increased RBCs relative to Hb - Film => target cells, poikilocytosis but no anisocytosis - Bb EPS / HPLC => raised HbA2 + raised HbF - Globin chain synthesis/DNA studies => Xmnl polymorphism
40
What is the main feature of thalassaemia?
microcytic hypochromic blood picture in the absence of iron deficiency
41
What does the Hb EPS/HPLC test show in alpha thalassaemia?
- Normal HbA2 - Normal HbF - +/- HbH
42
What is the only reliable way of diagnosing alpha thalassaemias?
DNA analysis
43
What does the blood film of a beta thalassaemia trait show?
- Microcytosis - Hypochromia - Occasional cells showing basophilic stippling
44
What are the features of thalassaemia major?
- Carry 2 abnormal copies of beta globin gene - Severe anaemia => incompatible with life without regular blood transfusions - Clinical presentation usually after 4-6 months of life
45
What does the peripheral blood film show in someone with beta thalassaemia major?
- extreme hypochromia, microcytosis + poikilocytosis - Howell Jolly bodies* - Nucleated RBCs* * N.B. these are the result of splenectophy(?) + hyperplastic bone marrow
46
Why do beta thalassaemia major patients become iron overloaded?
as they require regular transfusion support  2-3 units per month
47
How is the iron overload treated?
iron chelators
48
What may be seen on the blood films of beta thalassaemia major patients on long term transfusion regimens?
Pappenheimer bodies (iron deposits) => seen as coarse blue granules in the RBCs
49
What are the two forms of inclusion bodies that may be seen in beta thalassaemia?
- Alpha globin precipitates | - Pappenheimer bodies
50
How do beta thalassaemia major patients present?
- Severe anaemia => usually presenting after 4 months - Hepatosplenomegaly - Blood film shows gross hypochromia, poikilocytosis + many NRBCs - Bone marrow – erythroid hyperplasia - Extra-medullary haematopoiesis
51
What are the clinical features of beta thalassaemia?
- Chronic fatigue - Failure to thrive - Jaundice - Delay in growth + puberty - Skeletal deformity - Splenomegaly - Iron overload
52
What are some other possible complications of beta thalassaemia?
- Cholelithiasis + biliary sepsis - Cardiac failure - Endocrinopathies - Liver failure
53
What is the treatment for thalassaemia major?
- Regular blood transfusions - Iron chelation therapy - Splenectomy - Supportive medical care - Hormone therapy - Hydroxyurea to boost HbF - Bone marrow transplant
54
What are the key points about transfusions in thalassaemia major?
- Phenotyped red cells - Aim for pre-transfusion Hb 95-100g/L - Regular transfusion 2-4 weekly - Splenectomy (if high requirement)
55
What are the key points about iron chelation therapy in thalassaemia major?
- Start after 10-12 transfusions / when serum ferritin > 1000mcg/l - Audiology + ophthalmology screening prior to starting
56
What drugs can be used in iron chelation therapy?
- Deferasirox (Exjade) - Desferrioxamine (Desferal) - Deferiprone (Ferriprox) - Combination therapy
57
What are the key points about Deferasirox (Exjade)?
- Oral - Dose 20-40mg/kg - SE: GI symptoms, hepatitis, renal impairment
58
What are the key points about Desferrioxamine (Desferal)?
- SC infusion 8-1 hours 5-7 days per week (or IV in cardiac iron overload) - Dose 20-50mg/kg/day - SE: vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone sensorineural loss, increased risk of Klebsiella + Yersinia - Compliance - Vitamin C
59
What are the key points about Deferiprone (Ferriprox)?
- Oral - Dose 5-100mg/kg/day - Effective in reducing myocardial iron - SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy
60
What are the pros and cons of Desferrioxamine?
``` pros: - three decades experience - survival benefit - heart failure prevented + reversed cons: - parenteral administration - limits compliance - toxicity  ocular, auditory, skeletal ```
61
What are the pros and cons of Deferiprone?
``` pros: - oral administration - cardiac protection cons: - 3x/day / 7days/week - short plasma t ½ - unpredictable control of body iron - toxicity  agranulocytosis (0.5%), arthropathy, zinc deficiency ```
62
What are the pros and cons of Deferasirox?
``` pros: - oral administration - once daily - control of body iron - specific cons: - short clinical experience - cardiac protection uncertain - toxicity limited but lack of long term data ```
63
How is iron overload monitored?
- Serum ferritin - Liver biopsy - T2 cardiac + hepatic MRI - Ferriscan – R2 MRI
64
What are the features of sickle beta thalassaemia?
- Sickled cells - Target cells - Microcytosis - Hypochromia - HbS is the dominant Hb as little/no HbA is being produced => precipitates as it does in homozygote sickle cell patients
65
What are the features of HbE beta thalassaemia?
- Globin chain of HbE is unstable => can be classed as mild form of beta thalassaemia at molecular level - Classed as beta thalassaemia intermedia => can be as severe as beta thalassaemia major - Prevalent in SE Asia
66
What are the features of alpha thalassaemia?
- Deletion/mutation in alpha globin gene(s) - Reduced/absent production of alpha globin chains - Affects both foetus + adult - Excess beta + gamma chains form tetramers of HbH + Hb Barts respectively - Severity depends on number of alpha globin genes affected
67
What are the features of a thalassaemia carrier?
- Carry single abnormal copy of beta globin gene - Usually asymptomatic => mild anaemia - (aka thalassaemia minor/trait)
68
What are the key problems associated with treatment of thalassaemia is developing countries?
- Lack of awareness of the problems - Lack of experience of health care - Blood availability - Cost/compliance with iron chelation therapy - Availability of + high cost of bone marrow transplant

Y2 MCD - Haem (additional) (1 decks)

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