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

Missense mutation at codon 6 of the B globin gene
Glutamic acid replaced by Valine
Sickle haemoglobin: 2 normal alpha chains + 2 variant beta chains

Question 3

Describe the difference in character between the amino acids that change in the mutation causing sickle haemoglobin

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

Effects of valine substitution are only seen in the deoxyHb S conformation, which becomes insoluble
HbS polymerises to form fibres (tactoids)
The deoxyhaemoglobin S can form intertetrameric contacts + form long fibres within the cell
This polymerization causes 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 oxyHbS
Dehydration (irreversible from now on)
Increased adherence to the vascular endothelium

Question 6

Use 3 words to describe sickled red blood cells.

Answer 6

Rigid (less able to traverse vascular endothelium)
Dehydrated (further concentrates HbS in RBC’s, favouring polymerisation)
Adherent (get stuck in circulation, cause ischaemia)

Question 7

Originally, it appeared that the normal transit time of RBC’s was 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

Sickle cells are more adherent to vascular endothelium so they stick to the vessel walls + increase their transit time
This allows more time for polymerisation to occur

Question 8

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

Answer 8

SCD = generic term that encompasses all disease syndromes due to sickling  
SCA = 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
Their lifespan is ~20 days

Question 10

What are the consequences of increased haemolysis?

Answer 10

Anaemia
Gallstones
Aplastic Crisis (Parvovirus B19- arrests maturation of developing RBCs)

Question 11

Other than the increased break down of RBC’s, what else is partly responsible for anaemia in sickle cell patients?

Answer 11

A reduced erythropoietic drive: as HbS has a low affinity for O2 so it delivers O2 more effectively to tissues
Thus, hypoxia doesn’t stimulate EPO release from the kidneys as much

Question 12

Why does increased haemolysis cause gallstones?

Answer 12

Increases BR + other red cell breakdown products

These get excreted through the biliary tract + can cause gallstones

Question 13

How can sickle cell disease lead to aplastic crisis?

Answer 13

Aplastic crisis is caused by Parvovirus B19
infects developing red cells in BM + arrests maturation
With such reduced lifespan of RBC’s in SCD, results in dramatic fall in Hb (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 1A1
Caused by an extra TA dinucleotide in the promoter on each chromosome (there are normally 6 TA repeats)
Increases risk of gallstones 3-5 fold

Question 16

Blockage of the microvascular circulation is a major problem in sickle cell disease. State 3 tissues that are commonly infarcted and the consequences of infarction in these tissues.

Answer 16

Spleen: hyposplenism (increases susceptibility to infection by encapsulated bacteria e.g. pneumococcal sepsis)
Bones + 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

Free plasma Hb resulting from the haemolysis will scavenge NO, hence, depleting NO
This removes vasodilation effects of NO, causing vasoconstriction of certain vascular beds (including pulmonary circulation)

Question 22

What are the early presentations of sickle cell disease?

Answer 22

Dactylitis (inflammation of digits)
Splenic sequestration (accumulation of red cells in the spleen leading to a drop in blood count)
Infection (S. pneumoniae)

Question 23

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

Answer 23

Episodes of extreme pain caused by blood vessels becoming occluded. 
Can be triggered by: 
Dehydration  
Exertion 
Hypoxia
Infection  
Psychological stress

Question 24

State 6 general measures taken for patients with sickle cell disease.

Answer 24

Folic acid supplementation 
Vaccination
Penicillin prophylaxis
Monitor spleen size  
Blood transfusions for acute anaemia events, acute chest syndrome + stroke
Pregnancy care

Question 25

List 5 ways in which you manage a painful sickle cell crisis.

Answer 25

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

Question 26

What complications are exchange 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)
Increases production of HbF
Over time, increases number of red cells that are unable to sickle
Reduces WBC production by BM
Improves hydration of RBC’s
Generates NO which improves blood flow
Significantly reduces the frequency of crises

Question 29

State some laboratory features of sickle cell disease.

Answer 29

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

Question 30

State 2 methods of diagnosing sickle cell disease.

Answer 30

Solubility Test:
Blood sample is mixed with a reducing agent, OxyHb is converted to deoxyHb
Solubility decreases
In the presence of deoxyHb S: solution becomes TURBID
Does NOT differentiate HbS + HbAS
Electrophoresis/ HPLC: takes advantage of the difference in charge between HbS, HbAS + 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)

Question 32

When does onset of symptoms of sickle cell disorders usually arise?

Answer 32

Coincides with switch from HbF to HbA synthesis

~3-6 months

Question 33

List 5 sickle emergencies

Answer 33

Infection leading to septic shock
Neurological signs/ symptoms (ischaemic/ haemorhagic stroke)
Anaemia
Hypoxia 
Priapism

Question 34

What characterises acute chest syndrome? When does it usually develop?

Answer 34

New pulmonary infiltrate on CXR with:
fever, cough, chest pain, tachypnoea.
Develops in context of vaso-occlusive crisis, surgery + pregnancy

Question 35

List 4 limitations of HSCT

Answer 35

Donor availability
Length of treatment (months)
Transplant related mortality
Long term effects e.g. infertility

Question 36

What are the 3 main indications for HSCT for SCD?

Answer 36

CNS disease
Recurrent severe vaso-occlusive crisis
Recurrent acute chest syndrome