Sickle Cell Disease Flashcards
The distribution of which deadly disease matches the distribution of sickle cell disease?
Plasmodium falciparum (malaria)
What mutation is responsible for sickle haemoglobin?
Mutation of codon 6 of the beta globin gene
The mutation changed glutamic acid to valine
In sickle haemoglobin there are TWO normal alpha chains and TWO variant beta chains
Describe the difference in character between the amino acids thatchange in this mutation.
Glutamic acid = polar + soluble (negatively charged)
Valine = non-polar + insoluble
Under which conditions do the cells sickle and why do they sickle?
The effects of valine substitution are only seen in the deoxyhaemoglobin S conformation, which becomes insoluble
HbS polymerises to form fibres called tactoids
The deoxyhaemoglobin S can form intertetrameric contacts and form long fibres within the cell
This polymerization causes the distortion of the cells
What are the 3 stages in the sickling of red blood cells?
Distortion
Polymerisation initially reversible with formation of oxyhaemoglobinS
Dehydration (irreversible from now on)
Increased adherence to the vascular endothelium
Use three words to describe sickled red blood cells.
Rigid
Dehydrated
Adherent
Originally, it was not understood why sickling causes such profound clinical problems because it appeared that the normal transit time of red blood cells is sufficient for the red cells tobecome reoxygenated and for the polymers to be broken downbefore much sickling takes place. What key feature of sickle cells explains their ability to cause such problems?
The sickle cells are more adherent to the vascular endothelium so they stick to the vessel walls and increase their transit time
This allows more time for the polymerisation to occur
What is the difference between sickle cell disease and sickle cell anaemia?
Sickle cell disease = generic term that encompasses all disease syndromes due to sickling
Sickle cell anaemia = homozygous (SS)
What effect does sickling have on the lifespan of red blood cells?
As the cells are distorted, the body more avidly removes them
They have a lifespan of around 20 days
What are the consequences of increased haemolysis?
Anaemia
Gallstones
Aplastic Crisis
Other than the increased break down of red blood cells, what else is partly responsible for anaemia in sickle cell patients?
There is reduced erythropoietic drive as HbS has a low affinity for oxygen so it delivers the oxygen more effectively to tissues
So hypoxia doesn’t stimulate EPO release from the kidneys as much
Why does increased haemolysis cause gallstones?
Increased haemolysis means increased release of bilirubin and other red cell breakdown products
These get excreted through the biliary tract and carry a risk of causing gallstones
How can sickle cell disease lead to aplastic anaemia crisis?
Aplastic crisis is caused by Parvovirus B19 infection (a common respiratory virus)
The virus infects developing red cells in the bone marrow and blocks their production
This doesn’t have much effect on normal people with a 120-day red cell lifespan
But because the lifespan of red cells in sickle cell disease is so low, a parvovirus infection could cause a steep drop in haemoglobin (anaemia)
What genetic modifier can increase the risk of getting gallstones in patients with hereditary haemolytic anaemia (like sickle cell disease)?
Coinheritance of Gilbert’s Syndrome
Blockage of the microvascular circulation is a major problem in sickle cell disease. State three tissues that are commonly infarcted and the consequences of infarction in these tissues.
Spleen – leads to hyposplenism (which causes increased risk of life-threatening infection by capsulated bacteria (mainly pneumococcal))
Bones and joints – dactylitis, avascular necrosis, osteomyelitis
Skin – ulceration