Case 2: Sickle cell Anaemia Flashcards
(37 cards)
What chains make up normal Hb?
2 α chains and 2 β chains
What kind of mutation causes sickle cell anaemia?
A point (substitution) mutation
What amino acid is swapped out?
Glutamate, a hydrophillic, negatively charged amino acid, on a β chain.
What amino acid replaces glutamate?
Valine 6, a hydrophobic, non-polar amino acid
What causes the HbS polymer?
The mutant hydrophobic valine (valine 6) along with alanine and leucine, reside on the exterior of the haemoglobin molecules. They can make hydrophobic interactions with each other, forming a hydrophobic socket (they clump together) rather than making hydrogen bonds with water, which gives rise to the insoluble polymer HbS.
What type of genetic disorder is Sickle cell anaemia?
Autosomal recessive (both copies need to be lost in order for the person to have the disorder).
Why don’t the other hydrophobic amino acids stick together?
They don’t form the knob + socket structure due to steric hindrance (a ridge prevents them for interacting).
What causes the RBCs to gain a sickle shape?
The rigid HbS polymer fibres distort the shape of RBCs.
Why do carriers (heterozygotes) also have sickled RBCs in their blood films?
If a person has one copy of the sickle cell allele, half of their red blood cells will be misshapen (the HbS allele is codominant for the phenotype).
Why do sickle cells function normally when oxygenated?
When oxygen binds to Hb, it causes a conformational change which changes the position of amino acids (there is no longer a hydrophobic pocket). This is positive co-operativity.
What tends to cause sickling?
- Acidosis (e.g. build up of lactic acid)
- Low flow of blood
What can be seen in the blood film of a sufferer of sickle cell anaemia?
- High concentration of reticulocytes (large, immature RBCs)
- Target cells (abnormal RBCs that have Hb in their centre of pallor)
- Sickled cells
- Normal RBCs (oxygenated sickled cells)
- Howell jolly bodies
What can be seen in the blood film of a carrier of the sickle cell trait?
- Normal RBCs
- Reticulocytes
- Howell jolly bodies (RBCs with nuclear fragments)
Why are reticulocytes and target cells found in sickle cell blood films?
- The number of immature RBCs is very high because the bone marrow has to produce more RBCs to compensate for the defective sickled cells.
- The spleen also becomes overworked so it cannot remove the defective cells.
Why are Howell-jolly bodies found in the blood film?
The spleen becomes overworked and is unable to remove all defective cells.
What are the symptoms of SCD?
- Vision loss
- Stroke
- Bone crises
- Splenomegaly
Why can SCD cause vision loss?
- Sickle cells can aggregate and occlude the small blood vessels which can cause damage to retina tissues (ischaemia).
- Ischaemia can also result in the release of chemokines which stimulate the growth of new blood vessels (angiogenesis forming collaterals) in an effort to maintain oxygen supply. These collaterals can grow across the eye/ burst as they are very fragile.
What is the cause of bone crises?
There is reduced blood flow to the bone marrow due to sickling within blood vessels (microvascular occlusion) which means cells become deprived of oxygen. Therefore, osteonecrosis/ infarction may occur.
What is splenomegaly?
An enlarged spleen due to microfarctions caused by sickle cell occlusions.
What are the different types of stroke?
- Silent stroke
- Ischaemic stroke
- Haemorrhagic stroke
What is the cause of ischaemic strokes?
Cerebral arteries feeding the brain with blood can become blocked due to the sickling leading to deprivation of brain tissue.
What is a silent stroke?
Asymptomatic strokes caused by the occlusion (caused by the sickling) of one of the smaller arteries.
What can cause haemorragic strokes?
When the fragile collaterals produced by angiogenesis rupture, it can bleed into the surrounding brain, damaging brain cells.
What is the difference between acute and chronic pain? Use SCD as an example.
Acute pain is pain that goes away quickly like pain from crises/ bone infections. Chronic pain is ongoing and can worsen over time. This may be caused by the loss of organ function or joint replacements.
