Lecture 3/4 - Sickle cell Flashcards
Sickle cell statistics:
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
Biochemical basis of sickle cell
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
Why sickle cell isn’t present during pregnancy
Hbb is replaced by Hbf: no beta chains present to interact
Are cells always sickled?
No, only when deoxygenated. When oxygenated, the haemoglobin returns to normal
How does chronic red blood cell damage occur?
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)
Do all red cells form a sickle shape when oxygen concentration is low?
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
Under what circumstances is the sickling rate increased?
During hypoxia, fever, and when the individual is dehydrated
Under what circumstances is the sickling rate decreased?
Oxygenation, hydration, control of infection
Why do people have different severities of sickle cell?
Co-factors present - i.e, HPFH: foetal Hbf present, reducing sickle damage
Why are sickle cell sufferers often anaemic?
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)
Possible effects of sickle cell
Blocked blood vessels - bone pain/damage, chest crisis, sepsis, stroke
The advantage of sickle cell genes
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
Why is life expectancy lowered for sickle cell sufferers?
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
Dactylitis
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
Skeletal deformities
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
Spleen damage
Repeated sickling - fibrosis and calcification, higher risks if sudden and severe infections
Sickle cell treatment (milder cases)
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!
Sickle cell treatment (more severe cases)
Mild measures with:
Transfusion - increase haemoglobin conc
Exchange transfusion - for life-threatening cases - replace sickle blood with normal blood
Experimental clinical trials
Sickle cell treatments (long-term)
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
Experimental therapy
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
Diagnostic test balance
Speed, accuracy, expertise, throughput (amount to process), and cost must all be considered.
Types of diagnostic tests
Cell biological approach - look for cells
Physiological approach - detect polymerisation
Biochemical analysis - detect abnormal charge
Gene analysis - detect mutation
Blood smear test: advantages and disadvantages
Cheap and fairly rapid
Expertise required, relatively low sensitivity (can be rare), not good for multiple condition diagnosis
Haemoglobin solubility test: what is it, what the results mean, and the advantages and disadvantages
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
Flatbed electrophoresis: what is it, what the results mean, and the advantages and disadvantages
Uses electrical charge to diagnose
Monitoring movement
Pretty slow
High-pressure column chromatography: what is it, what the results mean, and the advantages and disadvantages
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
Genetic testing: what is it, what the results mean, and the advantages and disadvantages
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
