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 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
What is this syndrome caused by?
Reduced activity of UGT (UGT 1A1)
Caused by an extra TA dinucleotide in the promoter on each chromosome (there are normally 6 TA repeats)
It increases the risk of gallstones 3-5 fold
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
How can sickle cell disease affect the lungs?
Acute chest syndrome (vaso-occlusive crisis of the pulmonary vasculature)
Chronic damage – pulmonary hypertension
How can sickle cell disease affect the urinary tract?
Haematuria (due to papillary necrosis)
Hyposthenuria (inability to control urine concentration – can lead to dehydration)
Renal failure
Priapism (painful erections)
How can sickle cell disease affect the brain?
Stroke
Cognitive impairment
How can sickle cell disease affect the eyes?
Proliferative retinopathy
Pulmonary hypertension correlates with the severity of the haemolysis. What is the likely mechanism explains this effect?
The free plasma Hb resulting from the haemolysis will scavenge nitric oxide and, hence, deplete the nitric oxide
This takes away the vasodilation effects of nitric oxide, causing vasoconstriction of certain vascular beds (including pulmonary circulation)
What are the early presentations of sickle cell disease?
Dactylitis
Splenic sequestration (accumulation of red cells in the spleen leading to a drop in blood count)
Infection (pneumococcal (capsulated))
What are painful crises and what could they be triggered by?
Painful crises in sickle cell disease are episodes of extreme pain caused by blood vessels becoming occluded. They can be triggered by: Dehydration Exertion Hypoxia Infection Psychological stress
State some general measures taken for patients with sickle celldisease.
Folic acid supplementation Vaccines Penicillin Monitor spleen size Blood transfusions for acute anaemia events, acute chest syndrome and stoke
Describe how you would manage a painful sickle cell crisis.
Pain management (opioids) Hydration Keep warm Oxygen if hypoxic Exclude infection (blood and urine cultures; CXR)
What complications are transfusions used to prevent?
Stroke
Acute chest syndrome
In which group of patients is haematopoietic stem cell transplantation effective and just how effective is it?
Young patients (< 16 yrs with severe disease) Curative in 85-90% But relatively few children will find perfectly matched donors
Name a drug that is used to induce HbF in sickle cell patients and explain the principle behind this treatment.
Hydroxyurea/Hydroxycarbamide
It is a ribonucleotide reductase inhibitor (cytotoxic)
It induces the production of red cell in the bone marrow that mainly contain HbF
So, over time, there will be an increase in the number of red cells that are unable to sickle
It significantly reduces the frequency of crises
Butyrate also has a similar effect
State some laboratory features of sickle cell disease.
Hb LOW (typically 6-8 g/dL) Reticulocytes HIGH (except in aplastic crisis) Blood film: Sickle cells Boat cells Target cells Howell-Jolly bodies
State two methods of diagnosing sickle cell disease.
Solubility Test:
Blood sample is mixed with a reducing agent
Oxyhaemoglobin is converted to deoxyhaemoglobin
Solubility decreases
In the presence of deoxyhaemoglobin S – the solution becomes TURBID
This does NOT distinguish between HbS and HbAS
Electrophoresis – takes advantage of the difference in charge between HbS, HbAS and HbA
Describe the features of a patient with sickle cell trait.
Genotype: HbAS Normal life expectancy Normal blood count Usually asymptomatic Rarely painless haematuria (due to papillary necrosis) Under conditions of hypoxia they may have some complications due to sickling of red cells (e.g. anaesthesia, high altitude, extreme exertion)
