The Haemoglobin Molecule and Thalassemia Flashcards

1
Q

What are the different types of globin proteins?

A

Alpha, Beta, Gamma, Delta (and embryonic- epsilon and zeta)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

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

A

The more oxygen binds, the greater the affinity of the haemoglobin for oxygen.
This is good because if deoxyhaemoglobin has a low affinity for oxygen(as no oxygen is already bound), it will only pick up oxygen if the oxygen saturation is very high (i.e. in the lungs) so it will not take up oxygen in the metabolically active tissues where the oxygen saturation is low and where the tissues need oxygen.
Similarly, oxyhaemoglobin has a high affinity for oxygen so it will only give up oxygen in environments where the oxygen saturation is very low (i.e. respiring tissues that need oxygen)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What effect does 2,3-DPG have on oxygen delivery?

A

It facilitates oxygen delivery by making the haemoglobin molecule less flexible and pushing out the oxygen.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

State 3 factors that can shift the oxygen dissociation curve to the right.

A

Increase in 2,3-DPG
Increase in [H+]
CO2 (hypercapnia)
Increase temperature

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

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

A

Zeta and epsilon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Which globins are present in foetal haemoglobin?

A

Alpha

Gamma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Which globin chains are present in HbA2?

A

Alpha

Delta

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

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

A
Chromosome 16 – ALPHA cluster 
 TWO alpha genes  
 Zeta gene  
Chromosome 11 – BETA cluster 
 Beta gene  
 Gamma gene 
 Delta gene  
 Epsilon gene
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is thalassemia?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is thalassemia classified in terms of clinical severity?

A

Minor: Thalassemia trait = common variant with little clinical significance

Intermediate: Thalassemia intermedia

Major: Transfusion dependent – Thalassemia Major = fatal without transfusion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the outcome of alpha thalassemia major?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Clinical features of thalassemia major?

A

a. Severe anaemia presenting at 4 months leading to Chronic fatigue
b. Failure to thrive
c. Jaundice
d. Hyperactive bone marrow
e. Delay in growth and puberty
f. Extramedullary haematopoiesis
g. Skeletal deformity (bone marrow expansion due to extramed haematopoiesis causing the distinctive facial features)
h. Hepatosplenomegaly
i. Iron overload (patients with thalassaemia absorb more iron in GI tract)

17
Q

Which 2 types of abnormal haemoglobin can result due to Alpha thalassaemia

A

Haemoglobin H and Hb barts

Lack of Alpha chain forms tetramers of Beta chains instead of 2 alpha and beta= HbH

Same but tetramer of gamma chain= Hb barts

18
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 (which doesn’t need beta globin)
At around 2-3 month after birth, you get a transition from HbF to HbA
At this time the baby will become profoundly anaemic.
They will need life-long transfusions from this point onwards.

19
Q

State some features of thalassemia trait.

A

This the carrier state of thalassemia.
They may be mildly anaemic but they can also be normal.
Usually have a LOW MCH and LOW MCV

20
Q

Summarise the laboratory diagnosis of Thalassemia

A
Start simple:
-	FBC 
-	Film 
Complex tests:
-	Hb electrophoresis/ HPLC 
-	DNA studies eg PCR to look at genes for globin chains
21
Q

What types of mutation cause alpha thalassemia and beta thalassemia?

A

both can be caused by deletion or point mutation in the respective alpha/beta globin gene

22
Q

Which ethnic groups have a high prevalence of thalassemia?

A
Chinese 
South-east Asian 
Greek 
Turkish 
Cypriot
23
Q

Laboratory diagnosis: What features would you see when looking at FBC of thalassemia?

A
  • Poikilocytosis (no anisocytosis)
  • Target cells
  • Hypochromasia
  • Nucleated RBC
24
Q

What are the consequences of regular blood transfusions used to treat beta thalassemia major?

A

Iron overload: Chronic transfusion has been associated with iron accumulation. There’s not enough transferrin to bind to all the iron, the unbound iron can catalyse production of reactive oxygen species which can damage the liver (cirrhosis), heart (cardiac failure), endocrine organs (hypopituitarism, hypothyroidism, diabetes) etc.
Also increases chance of infection.

25
Q

Name three iron chelator drugs that can be used to treat iron overload.

A

Desferrioxamine (DFO/desferal)
Deferiprone
Deferasirox

26
Q

What are the key indicators when monitoring the iron overload in the management of thalassemia patients

A
  1. Serum ferritin (but not that accurate as it is also an ACP that rises in inflammation etc)
  2. Cardiac and hepatic MRI to measure iron levels in heart and liver

Liver biopsy used to be done but not anymore

27
Q

Laboratory diagnosis: What features would you see when looking at Blood film of thalassemia?

A

target cells
poikilocytosis (different shape)
NO anisocytosis(different size)
Microcytic and hypochromic (relate this to the FBC card earlier)

28
Q

Laboratory diagnosis:

What is the most definitive test for thalassemia

A

DNA studies - PCR, sanger sequencing etc

Most alpha thalassemias are diagnosed this way because they are quite hard to diagnose (HPLC gives normal HbA2 and HbF)

29
Q

Complications of thalassemia

A
Cholelithiasis (gallstones)
Biliary sepsis
Cardiac failure
endocrinopathies
liver failure
30
Q

Treatments for thalassemia major (minor usually asymtomatic)

A

Main treatments:

  • Regular blood transfusions
  • Iron chelation therapy (remove XS iron)

Other treatments:

  • Splenectomy (patients may have splenomegaly due to extramedullary hematopoiesis)
  • Supportive medical care for cardiac, liver problems
  • Hormone therapy, iron overload can cause hypogonadism
  • Hydroxyurea to boost HbF production
  • Bone marrow transplant
31
Q

Why are thalassemia patients prone to infection? What can be done to reduce the chances?

A

They tend to have iron overload and there are pathogens that thrive on iron especially gram - bacteria like YERSINIA

Also, thalassemia patients could have splenectomy due to splenomegaly via extramedullar haematopoiesis which is an important immune organ.

to prevent this, immunisation in splenectomised patients is good. (prophylaxis)

32
Q

Main concern for management of thalassemia patients

A

infection and monitor iron overload

33
Q

What are:
Sickle b thalassemia
HbE b thalassemia

A

Sickle b thal:
inherits one sickle allele from one parent and b thal allele from the other parent
NB sickle allele is also a mutation on the beta globin gene. So this disease is basically inheriting two different faulty beta globin alleles from the 2 parents

HbE b thal:

  • Single point Mutation in beta chain, forming HbE which is an abnormal haemoglobin
  • Reduced synthesis of functional beta chain leads to beta thalassemia