Sickle Cell Disease Flashcards

1
Q

The distribution of which deadly disease matches the distribution of sickle cell disease?

A

Plasmodium falciparum (malaria)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What mutation is responsible for sickle haemoglobin?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Describe the difference in character between the amino acids thatchange in this mutation.

A

Glutamic acid = polar + soluble (negatively charged)

Valine = non-polar + insoluble

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Under which conditions do the cells sickle and why do they sickle?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the 3 stages in the sickling of red blood cells?

A

Distortion
 Polymerisation initially reversible with formation of oxyhaemoglobinS
Dehydration (irreversible from now on)
Increased adherence to the vascular endothelium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Use three words to describe sickled red blood cells.

A

Rigid
Dehydrated
Adherent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

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?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the difference between sickle cell disease and sickle cell anaemia?

A

Sickle cell disease = generic term that encompasses all disease syndromes due to sickling
Sickle cell anaemia = homozygous (SS)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What effect does sickling have on the lifespan of red blood cells?

A

As the cells are distorted, the body more avidly removes them
They have a lifespan of around 20 days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the consequences of increased haemolysis?

A

Anaemia
Gallstones
Aplastic Crisis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Other than the increased break down of red blood cells, what else is partly responsible for anaemia in sickle cell patients?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why does increased haemolysis cause gallstones?

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How can sickle cell disease lead to aplastic anaemia crisis?

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What genetic modifier can increase the risk of getting gallstones in patients with hereditary haemolytic anaemia (like sickle cell disease)?

A

Coinheritance of Gilbert’s Syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

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.

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How can sickle cell disease affect the lungs?

A

Acute chest syndrome (vaso-occlusive crisis of the pulmonary vasculature)
Chronic damage – pulmonary hypertension

17
Q

How can sickle cell disease affect the brain?

A

Stroke

18
Q

Pulmonary hypertension correlates with the severity of the haemolysis. What is the likely mechanism explains this effect?

A

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)

19
Q

What are the early presentations of sickle cell disease?

A

Dactylitis
Splenic sequestration (accumulation of red cells in the spleen leading to a drop in blood count)
Infection (pneumococcal (capsulated))

20
Q

What are painful crises and what could they be triggered by?

A
They can be triggered by: 
 Dehydration  
 Exertion 
 Hypoxia
 Infection  
 Psychological stress
21
Q

State some general measures taken for patients with sickle celldisease.

A
Folic acid supplementation 
Vaccines  
Penicillin 
Monitor spleen size  
Blood transfusions for acute anaemia events, acute chest syndrome and stoke
22
Q

Describe how you would manage a painful sickle cell crisis.

A
Pain management (opioids)  
Hydration  
Keep warm 
Oxygen if hypoxic  
Exclude infection (blood and urine cultures; CXR)
23
Q

What complications are transfusions used to prevent?

A

Stroke

Acute chest syndrome

24
Q

In which group of patients is haematopoietic stem cell transplantation effective and just how effective is it?

A
Young patients (< 16 yrs with severe disease) 
Curative in 85-90%
But relatively few children will find perfectly matched donors
25
Q

Name a drug that is used to induce HbF in sickle cell patients and explain the principle behind this treatment.

A

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

26
Q

State some laboratory features of sickle cell disease.

A
Hb LOW (typically 6-8 g/dL) 
Reticulocytes HIGH (except in aplastic crisis) 
Blood film: 
 Sickle cells 
 Boat cells 
 Target cells 
 Howell-Jolly bodies
27
Q

State two methods of diagnosing sickle cell disease.

A

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

28
Q

Describe the features of a patient with sickle cell trait.

A
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)