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YR2: MCD Haematology > The Haemoglobin Molecule and Thalassemia > Flashcards

The Haemoglobin Molecule and Thalassemia Flashcards

1
Q

State the 3 different haemoglobins that are present in the human body.

A

HbA: alpha + beta = 95%
HbA2: alpha + delta = 1-3.5%
HbF: alpha + gamma = trace

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2
Q

Describe how affinity of haemoglobin changes with oxygen binding and how this helps its role of oxygen transport.

A

The more O2 binds, the greater the affinity of the Hb for O2.
Beneficial because if deoxyHb has low affinity for O2 (as no O2 is already bound), it will only pick up O2 if O2 sat. is very high (i.e. lungs) so won’t take up O2 in metabolically active tissues where O2 sat. is low + where tissues need O2.
Similarly, oxyHb has a high affinity for O2 so will only give up O2 in environments where the O2 sat. is very low (i.e. respiring tissues that need O2)

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3
Q

State 2 factors that can shift the oxygen dissociation curve to the left and what this means

A

Gives up O2 less readily
Low 2,3-DPG
Increased pH

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4
Q

State 3 factors that can shift the oxygen dissociation curve to the right and what this means

A

Gives up O2 more readily
High 2,3-DPG
High [H+]
High CO2

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5
Q

What effect do HbS and HbF have on the oxygen dissociation curve?

A

HbS has a lower affinity for O2 than HbA so it shifts the ODC right
HbF has a higher affinity for O2 than HbA so it shifts the ODC left

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6
Q

Which globin chains are present in early embryonic life but are switched off after about 3 months gestation?

A

Zeta

Epsilon

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7
Q

Which globins are present in foetal haemoglobin?

A

Alpha

Gamma

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8
Q

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

A

Decreased towards birth + in 1st year after birth.

After 1 year of life, normal adult pattern of Hb synthesis is established.

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9
Q

On which chromosomes are the 2 globin gene clusters and which genes are present in each cluster?

A 
Chromosome 16: ALPHA cluster 
2 alpha genes  
Zeta gene  
Chromosome 11: BETA cluster 
Beta gene  
Gamma gene 
Delta gene  
Epsilon gene
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10
Q

What is thalassemia?

A

Genetic disorders characterised by a defect in globin chain synthesis (alpha or beta)

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11
Q

What are the 2 clinical variations of thalassemia?

A 
Trait (minor)= carrier state, usually asymptomatic
(Intermedia= spectrum of phenotypes) 
Transfusion dependent (Major)= fatal without transfusion
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12
Q

What is the outcome of alpha thalassemia major?

A

Fatal in utero because alpha globin is needed to make HbF (alpha + gamma)

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13
Q

What is the outcome of beta thalassemia major?

A

Diagnosed + treated in early infancy with regular transfusions

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14
Q

What is the name given to the loss of function of 3 alpha globin genes?

A

Haemoglobin H

Need life-long transfusions

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15
Q

What is the name given to the loss of function of 4 alpha globin genes?

A

Haemoglobin barts

Fatal in utero because alpha globin is needed to make HbF

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16
Q

What is beta thalassemia major? Describe how the disease progresses.

A

Severe defect in both beta globin chains
The foetus will have no problem in utero because they have normal functioning HbF (doesn’t need beta globin)
At 2-3 month after birth, there is transition from HbF to HbA
Here, baby becomes profoundly anaemic.
Need life-long transfusions from this point.

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17
Q

State the classic features of an FBC of a patient with thalassemia

A

Microcytic hypochromic blood picture in absence of iron deficiency
Increased RBCs relative to Hb

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18
Q

What can be used to distinguish between alpha thalassemia trait and beta thalassemia trait?

A

Haemoglobin electrophoresis can be used to measure relative proportions of HbA2
Beta = raised HbA2 (> 3.5%) + raised HbF
Alpha = normal HbA2 + normal HbF

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19
Q

Why does the distribution of thalassaemia correlate with M. falciparum distribution?

A

Thalassaemias offer protection against malaria

Make it harder for parasite to enter RBC

20
Q

What is beta + thalassemia?

A

Reduction in beta globin output but there is still some residual beta globin gene expression

21
Q

What is beta 0 thalassemia?

A

NO output of beta globin

22
Q

What are the clinical presentations of beta thalassemia major that are present in the first year of life?

A

Profound anaemia
Hepatosplenomegaly (due to extra medullary haematopoiesis)
Blood film shows gross hypochromia, poikilocytosis + NRBC’s
Erythroid hyperplasia (BM trying to increase output)

23
Q

List 7 clinical features of beta thalassemia.

A 
Chronic fatigue
Failure to thrive
Jaundice
Delay in growth
Skeletal deformity
Splenomegaly
Iron overload
24
Q

List 4 complications that arise in beta thalassemia major due to iron overload

A

Liver failure
Cardiac failure
Endocrinopathies
Cholelithiasis + biliary sepsis

25
Q

Name 3 drugs that can be used as iron chelators. List any negative aspects of these drugs.

A

Desferrioxamine (DFO)
Must be given via subcutaneous infusion + Expensive
Deferiprone: Urinary excretion
Deferasirox: Faecal excretion

26
Q

What are the 4 methods of monitoring iron overload?

A

Serum ferritin
Liver biopsy
T2 cardiac + hepatic MRI
Ferriscan- R2 MRI

27
Q

What are 4 good aspects of stem cell transplantation?

A

No transfusions
No chelation
Growth is normal
Curative treatment

28
Q

What are 4 bad aspects of stem cell transplantation?

A

Transplant associated mortality is high over the age of 17 (30%)
Relatively few transplants done in adults
Infertility due to stem cell transplant
If the patient is iron overloaded at the time of transplantation there is a massively increased risk

29
Q

When is haemoglobin synthesised?

A

65% erythroblast stage

35% reticulocyte stage

30
Q

Where are the 2 components of Hb synthesised?

A 
Haem= Mitochondria
Globin= Ribosomes
31
Q

Which enzyme is involved in the manufacture of Haem? How?

A

Delta-ALA

When excess haem is produced, it exerts a negative feedback on this enzyme + synthesis of haem is reduced

32
Q

What is haem composed of?

A

Protoporphyrin ring with central iron atom

33
Q

What technique can be used to separate different Haemaglobins based on their charge and molecular mass?

A

High performance liquid chromatography (HPLC)

34
Q

Describe the primary, secondary and tertiary structure of globin

A

Primary: alpha= 141 AA’s, non-alpha= 146 AA’s
Secondary: 75% A + B chains helical arrangement
Tertiary: ~Sphere, hydrophilic surface, haem pocket

35
Q

Describe the shape of the oxygen-haemoglobin dissociation curve. What is p50?

A

Sigmoid shape

P50= pO2 at which half Hb is saturated with O2 ~26.6mmHg

36
Q

What are the 2 types of haemoglobinopathy?

A

Structural variants of Hb being produced e.g. HbS

Defects in globin chain synthesis (Thalassaemia)

37
Q

What causes B thalassaemia?

A

Point mutation in B globin gene

Results in reduced or absent production of B globin chains

38
Q

Describe 3 features on a blood film seen in thalassaemia

A

Hypochromia
Target cells
Poikilocytosis

39
Q

What is the only reliable way of diagnosing alpha thalassaemias?

A

DNA analysis

40
Q

List 7 treatment options for thalassaemia major

A 
Regular blood transfusions
Iron chelation therapy
Splenectomy
Supportive medical care
Hormone therapy
Hydroxyurea to boost HbF
BM transplant
41
Q

What is required in splenectomised patients? Why?

A

Prophylaxis (immunisation + antibiotics)

More susceptible to infection, particularly from encapsulated bacteria

42
Q

List 4 side effects of deferasirox

A

Rash
GI symptoms
Hepatitis
Renal impairment

43
Q

List 4 side effects of Desferrioxamine

A

Vertebral dysplasia
Pseudo-rickets
Retinopathy
High tone sensorineural loss

44
Q

List 4 side effects of Deferiprone

A

GI disturbance
Hepatic impairment
Neutropenia
Agranulocytosis

45
Q

What is the best way of prescribing iron chelators?

A

Combination therapy- reducing dose of individual drugs, thus reducing side effects

YR2: MCD Haematology (11 decks)

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