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
In sickle haemoglobin there are TWO normal alpha chains and TWO variant beta chains

Question 3

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

Answer 3

Glutamic acid = polar + soluble (negatively charged)

Valine = non-polar + insoluble

Question 4

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

Answer 4

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

Question 5

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

Answer 5

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

Question 6

Use three words to describe sickled red blood cells.

Answer 6

Rigid
Dehydrated
Adherent

Question 7

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 7

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 8

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

Answer 8

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

Question 9

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

Answer 9

As the cells are distorted, the body more avidly removes them
They have a lifespan of around 20 days (usually 120 days)

Question 10

What are the consequences of a shortened red cell lifespan due to increased haemolysis?

Answer 10

Anaemia - due to reduced erythropoietin drive as HbS is a low affinity Hb
Gallstones - co-inheritance w Gilbert syndrome further increases risk
Aplastic Crisis (temporary cessation of RBC production)- Parvovirus B19

Question 11

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

Answer 11

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 12

Why does increased haemolysis cause gallstones?

Answer 12

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 13

How can sickle cell disease lead to aplastic crisis?

Answer 13

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 14

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

Answer 14

Coinheritance of Gilbert’s Syndrome

Question 15

What is Gilbert’s syndrome caused by?

Answer 15

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 16

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 16

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 17

How can sickle cell disease affect the lungs?

Answer 17

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

Question 18

How can sickle cell disease affect the urinary tract?

Answer 18

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

Question 19

How can sickle cell disease affect the brain?

Answer 19

Stroke

Cognitive impairment

Question 20

How can sickle cell disease affect the eyes?

Answer 20

Proliferative retinopathy

Question 21

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

Answer 21

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 22

What are the early presentations of sickle cell disease?

Answer 22

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

Question 23

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

Answer 23

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 24

State some general measures taken for patients with sickle celldisease.

Answer 24

Folic acid supplementation (anaemia)
Vaccines (splenic dysfunction)
Penicillin (splenic dysfunction)
Monitor spleen size (splenic dysfunction)- acute splenic sequestration can lead to enlarged, malfunctioning spleen
Blood transfusions for acute anaemia events, acute chest syndrome and stoke

Question 25

Describe how you would manage a painful sickle cell crisis.

Answer 25

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

Question 26

What complications are transfusions used to prevent?

Answer 26

Stroke

Acute chest syndrome

Question 27

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

Answer 27

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

Question 28

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

Answer 28

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 29

State some laboratory features of sickle cell disease.

Answer 29

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 30

State two methods of diagnosing sickle cell disease.

Answer 30

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 31

Describe the features of a patient with sickle cell trait.

Answer 31

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)