5 - Sickle Cell Disease

Question 1

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

Answer 1

Plasmodium falciparum (malaria)

Question 2

What mutation is responsible for sickle haemoglobin?

Answer 2

Mutation of codon 6 of the beta globin gene

The mutation changed glutamic acid to valine

Question 3

Describe the chains in sickle haemoglobin

Answer 3

there are TWO normal alpha chains and TWO variant beta chains

Question 4

Describe the difference in character between the amino acids that change in this mutation.

Answer 4

Glutamic acid = polar + soluble (negatively charged)

Valine = non-polar + insoluble

Question 5

When are the impacts of the valine substitution seen?

Answer 5

only seen in the deoxyhaemoglobin S conformation, which becomes insoluble

Question 6

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

Answer 6

HbS polymerises to form fibres called tactoids
The deoxyhaemoglobin S can form intertetrameric contacts and form long fibres within the cell
This polymerisation causes the distortion of the cells

Question 7

What are the 3 stages in the sickling of red blood cells? (mention reversibility)

Answer 7

• Distortion - polymerisation initially is reversible with formation of oxyhaemoglobin S
• Dehydration (irreversible from now on)
• Increased adherence to the vascular endothelium

Question 8

What three words are best to describe sickled red blood cells?

Answer 8

Rigid
Dehydrated
Adherent

Question 9

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 to become reoxygenated and for the polymers to be broken down before much sickling takes place. What key feature of sickle cells explains their ability to cause such problems?

Answer 9

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

Question 10

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

Answer 10

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

Question 11

Wha heterozygous states can be present in sickle cell disorders?

Answer 11

SC

Sβ

Question 12

What effect does sickling have on the lifespan of red blood cells? What impact can this then go on to have?

Answer 12

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

Question 13

What are the consequences of increased haemolysis?

Answer 13

Anaemia
Gallstones
Aplastic Crisis

Question 14

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

Answer 14

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

Question 15

Why does increased haemolysis cause gallstones?

Answer 15

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

Question 16

How can sickle cell disease lead to aplastic crisis?

Answer 16

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)

Question 17

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

Answer 17

Coinheritance of Gilbert’s Syndrome

Question 18

What causes Gilbert’s syndrome?

Answer 18

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

Question 19

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.

Answer 19

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

Question 20

How can sickle cell disease affect the lungs?

Answer 20

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

Question 21

How can sickle cell disease affect the urinary tract?

Answer 21

Haematuria (due to papillary necrosis)
Hyposthenuria (inability to control urine concentration – can lead to dehydration)
Renal failure
Priapism (painful erections)

Question 22

How can sickle cell disease affect the brain?

Answer 22

Stroke

Cognitive impairment

Question 23

How can sickle cell disease affect the eyes?

Answer 23

Proliferative retinopathy

Question 24

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

Answer 24

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)

Question 25

What are the early presentations of sickle cell disease?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

State some general measures taken for patients with sickle cell disease.

Answer 27

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

Question 28

Describe how you would manage a painful sickle cell crisis.

Answer 28

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

Question 29

What complications are transfusions used to prevent?

Answer 29

Stroke

Acute chest syndrome

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

State some laboratory features of sickle cell disease.

Answer 32

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

Question 33

State two methods of diagnosing sickle cell disease.

Answer 33

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

Question 34

Describe the features of a patient with sickle cell trait.

Answer 34

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)

Question 35

extra notes

Answer 35

• Sickling can also be caused by co-inheritence of HbS and either Haemoglobin C or Beta thalassemia trait
• Haemoglobin C is another beta globin variant

Question 36

extra notes

Answer 36

Chest Crisis = hypoxia resulting from death of lung tissue

Question 37

extra notes

Answer 37

Reticulocyte count is:
o RAISED in splenic sequestration crisis
o Lowered in aplastic crisis

Question 38

extra notes

Answer 38

Median life expectance for sickle cell anaemia = 42-48 years
o Death is most commonly associated with chest syndrome

Question 39

extra notes

Answer 39

Blood film in SCA may show signs of hyposplenism – Howell-Jolly bodies

Question 40

extra notes

Answer 40

There are some non-sickling haemoglobins that run with HbS, which is why sickle solubility testing is also required for diagnosis