CSI 2 - Sickle Cell Disease Flashcards
What is normal Hb comprised of?
2 alpha, 2 beta chains - tetrameter
Properties of HbA
chains arranged tetrahedrally, allosteric protein allows cooperative binding
Difference between HbS and HbA
HbS is created by an autosomal recessive mutation in the beta globin chains (HBB) –> it’s misshapen
What is it called when a person is heterozygous for the sickle cell gene
Sickle cell trait
What is the mutation described as?
Non-conservative missense mutation
Which amino acid is substituted and at what location?
Glutamate (negatively charged) for Valine (neutral and therefore hydrophobic)
What consequences does that have for the sickle cell Hb?
Same oxygen affinity but when deoxygenated it crystallises out and due to the valine interlocking protrusion, the HbS polymerises
What increases sickling and why?
acidosis –> lower oxygen affinity, so more HbS is deoxygenated
low flow blood vessels –> smaller diameter
Why is it so dangerous?
Can lead to occlusion of the blood vessels –> infarction
What is the definition of electrophoresis?
Technique used to separate molecules based on their charge and mass
Why do sickle cell patients have a higher than normal reticulocyte count?
Because bone marrow has to produce more RBCs to compensate for the defective sickling
What is the difference between a reticulocyte and an erythrocyte?
Polychromatic with a network of reticular rna which is absent in mature cells
What is splenomegaly and why does it arise in sickle cell patients?
enlargement of the spleen due to micro-infarctions as a result of accumulated sickled erythrocytes => needs to compensate for loss of function and it enlarges.
Most common symptoms of sickle cell anaemia
- vision loss
- bone crises
- strokes
Explain why vision loss occurs
- sickle cells accumulate within microvessels of the reitna
- pressure increases
- vessels are damaged
- ischaemia causes chemokine release
- angiogenesis occurs and collaterals form
- they are easily damaged and can grow across areas of vision
Explain the types of strokes and why they occur
Most common - ischaemic stroke
- cerebral artery blocked resulting in oxygen deficiency
- silent strokes occur due to damage to smaller blood vessels and are asymptomatic
Haemmorrhagic stroke:
- occurs due to angiogenesis
- collaterals easily broken
Blockage of major cerebral arteries:
- major symptomatic stroke
- selectins released which promote clotting of blood
- susceptibility of sickling increased
Explain bone crises?
- reduced flow to the bone marrow - microvascular occlusion
- prolonged ischaemia leads to infarction
- ischaemia exacerbates sickling
What is the sickle solubility test?
- Blood is taken
- Sodium dithionide is added which lyses the cells
- Hb is released
- HbA dissolves easily in plasma to give a clear solution whilst HbS clumps together (turbid solution with increased optical density) (deoxygenation buffer allows a precipitate to form) –> Test doesn’t distinguish between sickle cell trait and disease
List the different treatments for SCA
- Blood transfusions
- Pain killers and opioids (only for last resort)
- Keeping warm and hydrated, avoiding high altitudes and low oxygen levels
- Hydroxycarbamide
- Bone marrow transplants
- Gene therapy (viral vectors insert functional gene into haemopoietic stem cell)
- Antibiotics (penicillin) and routine vaccinations for children (additional flu and hep B vaccines)
What measures must be taken during a blood transfusion and why?
Iron chelation therapy reduces exccess iron levels which can build up to toxic levels
What are the side effects of hydroxycarbamide?
Suppresses reticulocyte and neutrophil production => increased risk of infection
What is the downside to bone marrow transplant?
Only available to young patients, matched donor needs to be found
What is the downside to gene therapy?
Expensive
What is a target cell?
Has Hb in area of central pallor where it shouldn’t be
What is HbA2 comprised of?
two alpha and two delta chains
What is HbF comprised of?
two alpha chains and two gamma chains
Why do sickle cell patients have elevated HbF?
It has a greater affinity for oxygen, so ability to capture oxygen increases and it acts as a compensatory mechanism.
Describe the bands on the Hb electrophoresis
HbA2 is closest to negative side
HbS is in the middle
HbF is next
HbA is the closest to the positive electrode
Why are there higher levels of haemopoiesis and what does this result in?
There is a high erythrocyte degradation because sickle cells are more susceptible to lysis => compensatory mechanism of releasing reticulocytes
What are Howell-Jolly bodies and why are they there?
RBCs with nuclear remnants due to impaired function of spleen (where the nuclei are usually removed)
What are some other symptoms of sickle cell anaemia
Jaundice (due to excess unconjugated bilirubin due to haemolysis)
Splenomegaly
What are the acute crises?
Dactylitis (pain in hand joints)
Splenic sequestration
Acute chest syndrome, sepsis (bacterial infections, spleen is damaged)
What are chronic?
Gall stones due to bilirubin release priapism kidney damage avascular necrosis of hips and shoulders leg ulcers retinopathy iron overload due to transfusions
Explain what screening is offered to a newborn baby
Screened using a haemoglobin isoelectric focusing (Hb IEF), by taking a heel-prick test
Explain what happens in electrophoresis of HbS?
AFSC control; intense band in HbS region showing greater concentration; lower normocytic Hb band
HbF band is relatively prevalent due to compensatory mechanism
HbS is further away from anode because valine is uncharged
What painkillers can be given for bone crises?
Ibuprofen and aspirin
What effects does Hydroxycarbamide have?
Reduces vaso-occlusion since neutrophils promote vascular adhesion and they are produced less
Stimulates production of foetal Hb
What other things are also prescribed?
anti-adhesion therapy, folic acid supplements, antibiotics
Patient triggers of vaso-occlusive crises
cold weather
strenuous exercise - increased deoxygenation of Hb => promotes cell sickling
dehydration
