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Y2 MCD > 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 (each cell= 640mil molecule)
No nucleus or mitochondria

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2
Q

Describe haemoglobin

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

When does haemoglobin synthesis occur

A

During development of RBC and begins in pro-erythroblast
65% erythroblast stage
35% reticulocyte

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4
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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5
Q

Describe the synthesis of haemoglobin

A

haem - mitochondria

global - ribosomes

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6
Q

Describe the structure of haem

A

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

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7
Q

Where else may haem been found

A 
myoglobin
cytochromes
peroxides
catalase
tryptophan
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8
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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9
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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10
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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11
Q

Describe the gene expression and switching of globin

A

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

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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)
P 50 (partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg

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18
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

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19
Q

What causes right shift on the oxygen-dissociation curve

A

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

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20
Q

What causes left shift on the oxygen-dissociation curve

A

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

21
Q

What are haemoglobinopathies

A

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

22
Q

Describe beta thalassaemia and where it is prevalent

A

Deletion or mutation in beta globin gene(s)
Reduced or absent production of b globin chains

Mainly Mediterranean countries (Greece, Cyprus, Southern Italy).

23
Q

Explain how beta thalassaemia is inherited

A

Autosomal recessive

Carriers are aymsymptomatic but to have microcytic hypo chromic indicies

24
Q

What investigations should be done for thalassaemia

A

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

25
Q

What causes thalassaemia major, what does it result in and when does it clinically present

A

2 abnormal copies of the beta globin gene
Severe anaemia, incompatible with life without regular blood transfusions
Clinical presentation usually after 4-6 months of life

26
Q

What will show on the film for a beta thalassaemia major

A

Extreme hypochromia
Microcytosis
Poikilocytosis
Howell jolly bodies and nucleated RBCs (from splenectophy and hyper plastic bone marrow)

27
Q

Which are the 2 major inclusion bodies seen in beta thalassaemia

A 
Alpha globin precipitates
Pappenheimer bodies (Perls stain - inky blue granules)
28
Q

Describe the clinical presentation of thalassaemia major

A

(after 4. months)
Hepatosplenomegaly
Facial changes, frontal bossing and thickening of maxillary bones (Bone marrow - erythroid hyperplasia)
Extra-medullary haematopoiesis (spleomegally)

29
Q

What are the clinical features of beta thalassaemia

A 
Chronic fatigue
Failure to thrive
Jaundice
Delay in growth and puberty
Skeletal deformity
Splenomegaly
Iron overload
30
Q

What are some complications of beta thalassamia

A

Cholelithiasis and biliary sepsis (gall stone formation)
Cardiac failure
Endocrinopathies
Liver failure

31
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)
32
Q

Describe the transfusions needed for thalassaemia major treatment

A

Phenotyped red cells
Aim for pre-transfusion Hb 95-100g/L
Regular transfusion 2-4 weekly
If high requirement, consider splenectomy

33
Q

Describe the management of infection for thalassaemia major treatment

A

Yersinia
Other gram negative sepsis (infections thrive in iron overload)

Prophylaxis in splenectomised patients - immunisation and antibiotics

34
Q

Describe iron chelation therapy

A

Start after 10-12 transfusions or when serum ferritin >1000 mcg/l
Audiology and ophthalmology screening prior to starting due to toxicity of iron removing drugs

35
Q

What are the types of iron chelation therapies

A

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

36
Q

Describe Deferasirox (Exjade)

A

Oral
Dose 20-40mg/kg

unwanted effects:
rash, GI symptoms, hepatitis, renal impairment

37
Q

Describe desferrioxamine

A

Sc infusion 8-12 hours 5-7 days per week (or IV in cardiac iron overload)
Dose 20-50 mg/kg/day
Compliance
Vitamin C

38
Q

What are the unwanted effects of desferrioxamine

A 
Vertebral dysplasia
pseudo-rickets
genu valgum
retinopathy
high tone sensorineural loss
increased risk of Klebsiella and Yersinia infection
39
Q

Describe deferiprone and its unwanted effects

A

Oral
Dose 5-100 mg/kg/day
Effective in reducing myocardial iron

Unwanted effects:
GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy

40
Q

What are the advantages and disadvantages of desferrioaxamine

A

2 decades experience
Survival benefit
Heart failure prevented and recersed

Parenteral administration (limits compliance)
Toxicity (dose-dependent) - ocular, auditory, skeletal
41
Q

What are the advantages and disadvantages of deferiprone

A

Oral administration
Cardiac protection

Frequency of administration is high due to short plasma half life
Unpredictable control of body iron
toxicity - agranulocytosis, arthropathy, zinc deficiency

42
Q

What are the advantages and disadvantages of deferasirox

A

Oral admin
Once daily
Control of body iron specific

Short clinical experience
Cardiac protection uncertain
toxicity limited but little data

43
Q

How is serum ferritin used to monitor iron overload

A

> 2500 associated with significantly increased complications
Acute phase protein
Check every 3 months if transfused, otherwise annually

44
Q

How may a MRI be used for iron overload monitoring

A

Cardiac and hepatic MRIs
<20ms = increased risk of impaired LF function
Check annually or 3-6 monthly if cardiac dysfunction

45
Q

How may a ferriscan be used to monitor iron overload

A 
R2 MRI 
Non-invasive quantitation of LIC
Not affected by inflammation or cirrhosis
<3mg/g normal
>15mg/g associated with cardic disease
Check annually or 6monthly if result >20
46
Q

What would be seen in a blood film for sickle beta thalassamia

A 
Sickled cells
Target cells
Microcytosis
Hypochromia 
(As little or no HbA is being produced, HbS will be the dominant haemoglobin and will precipitate as it does in homozygote sickle cell patients)
47
Q

Describe HbE beta thalassaemia

A

Very common combo in south east Asia

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

48
Q

Describe alpha thalassaemia

A

deletion or mutation in alpha globin genes
Reduced or absent production of a globin chains
Affects both foetus and adult
Excess beta and gamma chains form tetramers of HbH and Hb Barts respectively
Severity depends on number of alpha globin genes affected

49
Q

What is special about alpha globin genes

A

There are TWO alpha globin genes from each parent so there are FOUR alpha globin genes in total.

Y2 MCD (23 decks)

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