Lecture 3/4 - Sickle cell

Question 1

Sickle cell statistics:

Answer 1

UK: 10-15.000 affected in all ages
World: 300,000 affected individuals born each year
High-incidence areas: 2-3% of all births

UK life expectancy: 40-60 years
Developing nations: 50-90% childhood mortality

Question 2

Biochemical basis of sickle cell

Answer 2

E->V replacement on the sixth position of the beta globin change.

Typically, once deoxygenated, the chains within the erythrocyte repel due to the E charge, but the neutral charge allows for hydrophobic interactions to make the chains bind and distort, forming incorrect RBC shapes

Question 3

Why sickle cell isn’t present during pregnancy

Answer 3

Hbb is replaced by Hbf: no beta chains present to interact

Question 4

Are cells always sickled?

Answer 4

No, only when deoxygenated. When oxygenated, the haemoglobin returns to normal

Question 5

How does chronic red blood cell damage occur?

Answer 5

Repeated polymerisation and depolymerisation of haemoglobin eventually results in not only membrane and membrane pump damage but also results in the polymerisation not reversing and the haemoglobin becoming denatured, potentially causing a permanent sickle shape while also dehydrating the cell (pump issue)

Question 6

Do all red cells form a sickle shape when oxygen concentration is low?

Answer 6

No, the sickling process takes time to occur, so most cells can return to the lungs before major sickling occurs, meaning that affected individuals do not have sickling at all times

Question 7

Under what circumstances is the sickling rate increased?

Answer 7

During hypoxia, fever, and when the individual is dehydrated

Question 8

Under what circumstances is the sickling rate decreased?

Answer 8

Oxygenation, hydration, control of infection

Question 9

Why do people have different severities of sickle cell?

Answer 9

Co-factors present - i.e, HPFH: foetal Hbf present, reducing sickle damage

Question 10

Why are sickle cell sufferers often anaemic?

Answer 10

RBC survival is greatly diminished (120 days -> possibly 8) and cells cannot be produced at a rate to prevent anaemia (sickle haemoglobin levels are around 70/80g/l while typical haemoglobin levels are around 130-140g/l)

Question 11

Possible effects of sickle cell

Answer 11

Blocked blood vessels - bone pain/damage, chest crisis, sepsis, stroke

Question 12

The advantage of sickle cell genes

Answer 12

If an individual is heterozygous for the sickle cell gene, the malaria parasite’s life cycle is not efficiently completed as the parasite is prevented from altering the RBC’s cytoskeleton and becoming sticky

Question 13

Why is life expectancy lowered for sickle cell sufferers?

Answer 13

People adapt to chronic anaemia by increasing cardiac output, this is why sickle cell isn’t obvious within the young - over time chronic problems arise

Question 14

Dactylitis

Answer 14

Blockage of blood vessels supplying the bones in the hands/feet, causing bones to die and infections to arise - inflammation occurs and the hand has severe swelling and pain

Question 15

Skeletal deformities

Answer 15

One skeletal deformity that sickle cell can cause is when blockage of the vessels supplying bones occurs, damaging the growth plate, causing deformed finger lengths, for example

Question 16

Spleen damage

Answer 16

Repeated sickling - fibrosis and calcification, higher risks if sudden and severe infections

Question 17

Sickle cell treatment (milder cases)

Answer 17

Pain relief - comfort, better breathing and self-care
Hydration - adequate fluids will preserve blood flow and cause red cell hydration
Treat cause - reverse causes
Assess - how much care is needed
Return to life - slay!

Question 18

Sickle cell treatment (more severe cases)

Answer 18

Mild measures with:

Transfusion - increase haemoglobin conc
Exchange transfusion - for life-threatening cases - replace sickle blood with normal blood
Experimental clinical trials

Question 19

Sickle cell treatments (long-term)

Answer 19

Education, vaccination, antibiotics, folic acid (cheap, promotes blood production)

Cell physicology modification:
Rasing HbF - hydroxycarbamide (£250/yr) - increases intracellular HbF

Bone marrow transplant, sickle blood replacement

Question 20

Experimental therapy

Answer 20

Gene therapy - replace sickle haemoglobin/increase HbF

Anti-sickling molecules - prevent sickle haemoglobin formation

Anti-adhesion molecules - reduce RBC adhesion

Modifying vascular tone - relaxing capillaries, improving blood flow

Question 21

Diagnostic test balance

Answer 21

Speed, accuracy, expertise, throughput (amount to process), and cost must all be considered.

Question 22

Types of diagnostic tests

Answer 22

Cell biological approach - look for cells
Physiological approach - detect polymerisation
Biochemical analysis - detect abnormal charge
Gene analysis - detect mutation

Question 23

Blood smear test: advantages and disadvantages

Answer 23

Cheap and fairly rapid

Expertise required, relatively low sensitivity (can be rare), not good for multiple condition diagnosis

Question 24

Haemoglobin solubility test: what is it, what the results mean, and the advantages and disadvantages

Answer 24

Detergent to lyse cells, reducing agent added.

• If a person suffers from sickle cell, a cloudy solution is formed
• If not, a transparent solution is formed

Cheap, quick, sensitive, easy - amazing in an emergency (pre-op)
Broad - does not distinguish between heterozygotes and homozygotes

Question 25

Flatbed electrophoresis: what is it, what the results mean, and the advantages and disadvantages

Answer 25

Uses electrical charge to diagnose

Monitoring movement

Pretty slow

Question 26

High-pressure column chromatography: what is it, what the results mean, and the advantages and disadvantages

Answer 26

Uses high pressure with electrical charge to diagnose

Monitoring movement as haemoglobin emerges from a charged column

Accurate, intermediate cost, great for complex cases, and can be scaled up for large sample numbers

Not quick enough for emergent need and expertise required

Question 27

Genetic testing: what is it, what the results mean, and the advantages and disadvantages

Answer 27

Testing genes for HbSS gene

have a guess.

Tests are accurate and can be used when complex cases make diagnosis difficult

Cost, time, and expertise