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

Haem 4: The haemoglobin molecule + thalassaemia Flashcards

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
Q

What does a right shift of the Hb-oxygen dissociation curve indicate?

A

easy oxygen delivery

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26
Q

What causes a right shift in the curve?

A
  • HIGH 2,3-DPG
  • High H+
  • High CO2
  • HbS
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27
Q

What does a left shift indicate?

A

Hb gives up oxygen less readily

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28
Q

What causes a left shift in the curve?

A
  • Low 2,3-DPG

- HbF

29
Q

What are haemoglobinopathies?

A
  • Genetic defects that result in abnormal structure of one of the globin chains of the haemoglobin molecule
30
Q

What is thalassaemia?

A
  • A genetic defect that results in production of an abnormally low quantity of a given haemoglobin chain/chains
31
Q

What is the classification of thalassaemia based on?

A
  • Globin type affected

- Clinical severity = minor ‘trait’, intermedia, major

32
Q

Where are the alpha-like genes found?

A

chromosome 16

33
Q

Where are the beta-like genes found?

A

chromosome 11

34
Q

What is beta thalassaemia?

A

deletion/mutation in beta globin gene(s) => reduced or absent production of beta globin chains

35
Q

Where is beta thalassaemia most prevalent?

A

mainly Mediterranean countries

36
Q

What sort of inheritance does beta thalassaemia exhibit?

A

autosomal recessive

37
Q

What symptoms do carriers exhibit?

A

asymptomatic => except for microcytic hypochromic indices

38
Q

How can the variation in severity be explained?

A

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
Q

What do the lab tests for beta thalassemia show?

A
  • 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
Q

What is the main feature of thalassaemia?

A

microcytic hypochromic blood picture in the absence of iron deficiency

41
Q

What does the Hb EPS/HPLC test show in alpha thalassaemia?

A
  • Normal HbA2
  • Normal HbF
  • +/- HbH
42
Q

What is the only reliable way of diagnosing alpha thalassaemias?

A

DNA analysis

43
Q

What does the blood film of a beta thalassaemia trait show?

A
  • Microcytosis
  • Hypochromia
  • Occasional cells showing basophilic stippling
44
Q

What are the features of thalassaemia major?

A
  • 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
Q

What does the peripheral blood film show in someone with beta thalassaemia major?

A
  • extreme hypochromia, microcytosis + poikilocytosis
  • Howell Jolly bodies*
  • Nucleated RBCs*
  • N.B. these are the result of splenectophy(?) + hyperplastic bone marrow
46
Q

Why do beta thalassaemia major patients become iron overloaded?

A

as they require regular transfusion support  2-3 units per month

47
Q

How is the iron overload treated?

A

iron chelators

48
Q

What may be seen on the blood films of beta thalassaemia major patients on long term transfusion regimens?

A

Pappenheimer bodies (iron deposits) => seen as coarse blue granules in the RBCs

49
Q

What are the two forms of inclusion bodies that may be seen in beta thalassaemia?

A
  • Alpha globin precipitates

- Pappenheimer bodies

50
Q

How do beta thalassaemia major patients present?

A
  • Severe anaemia => usually presenting after 4 months
  • Hepatosplenomegaly
  • Blood film shows gross hypochromia, poikilocytosis + many NRBCs
  • Bone marrow – erythroid hyperplasia
  • Extra-medullary haematopoiesis
51
Q

What are the clinical features of beta thalassaemia?

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice
  • Delay in growth + puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload
52
Q

What are some other possible complications of beta thalassaemia?

A
  • Cholelithiasis + biliary sepsis
  • Cardiac failure
  • Endocrinopathies
  • Liver failure
53
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
54
Q

What are the key points about transfusions in thalassaemia major?

A
  • Phenotyped red cells
  • Aim for pre-transfusion Hb 95-100g/L
  • Regular transfusion 2-4 weekly
  • Splenectomy (if high requirement)
55
Q

What are the key points about iron chelation therapy in thalassaemia major?

A
  • Start after 10-12 transfusions / when serum ferritin > 1000mcg/l
  • Audiology + ophthalmology screening prior to starting
56
Q

What drugs can be used in iron chelation therapy?

A
  • Deferasirox (Exjade)
  • Desferrioxamine (Desferal)
  • Deferiprone (Ferriprox)
  • Combination therapy
57
Q

What are the key points about Deferasirox (Exjade)?

A
  • Oral
  • Dose 20-40mg/kg
  • SE: GI symptoms, hepatitis, renal impairment
58
Q

What are the key points about Desferrioxamine (Desferal)?

A
  • 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
Q

What are the key points about Deferiprone (Ferriprox)?

A
  • Oral
  • Dose 5-100mg/kg/day
  • Effective in reducing myocardial iron
  • SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy
60
Q

What are the pros and cons of Desferrioxamine?

A 
pros:
-	three decades experience
-	survival benefit
-	heart failure prevented + reversed
cons:
-	parenteral administration
-	limits compliance
-	toxicity  ocular, auditory, skeletal
61
Q

What are the pros and cons of Deferiprone?

A 
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
Q

What are the pros and cons of Deferasirox?

A 
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
Q

How is iron overload monitored?

A
  • Serum ferritin
  • Liver biopsy
  • T2 cardiac + hepatic MRI
  • Ferriscan – R2 MRI
64
Q

What are the features of sickle beta thalassaemia?

A
  • 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
Q

What are the features of HbE beta thalassaemia?

A
  • 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
Q

What are the features of alpha thalassaemia?

A
  • 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
Q

What are the features of a thalassaemia carrier?

A
  • Carry single abnormal copy of beta globin gene
  • Usually asymptomatic => mild anaemia
  • (aka thalassaemia minor/trait)
68
Q

What are the key problems associated with treatment of thalassaemia is developing countries?

A
  • 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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