5: Sickle Cell

Question 1

What is the sickle cell gene? Why does the sickle cell form?

Answer 1

Missense mutation at codon 6 for beta globin chain
Glutamic acid replaced by Valine
Valine = Non-polar + INSOLUBLE
Deoxyhaemoglobin S is therefore insoluble
HbS polymerises to form fibres

Question 2

What are the stages of sickling?

Answer 2

1. Distortion
2. Dehydration
3. Increased adherence to vascular endothelium

Question 3

Where is sickle gene most prevalent in the world? Why?

Answer 3

West Africa, Mediterranean, India, south-east asia

Because carriers of sickle gene are protected against malaria

Question 4

Prevalence of SCD in Europe/UK/US?

Answer 4

Europe - 60,000
UK - 12000-15000
US - 100,000

Question 5

How many births per year are affected?

Answer 5

300,000

Question 6

Describe the pathogenesis of sickle cell anaemia (SS)

Answer 6

1. Shortened red cell lifespan (5-7 days)
   This leads to:
   - Anaemia
   - Gall stones
   - Aplastic crisis (caused by virus B19)
   Anaemia also partly due to reduced erythropoietic drive, since HbS readily dissociates oxygen to tissues
2. Vaso-occlusion
   - Tissue damage/infarction
   - Pain
   - Dysfunction

Question 7

What are the consequences of infarction in different tissues?

Answer 7

Spleen -> Hyposplenism
Bones/joints -> chronic damage, dactylitis
Skin -> chronic/recurrent leg ulcers

Question 8

How is SCA associated with pulmonary hypertension?

Answer 8

Free plasma haemoglobin (as a result of haemolysis) scavenges NO and reduces its bioavailability causing vasoconstriction.

Question 9

Complications of SCA?

Answer 9

Lungs:

• Acute chest syndrome (highest cause of death in SCD)
• Pulmonary hypertension

Urinary tract

• Haematuria
• Imparied conc. of urine
• RENAL FAILURE

Brain

• Stroke
• Cognitive impairment

Eyes
- Proliferative retinopathy

Question 10

Early presentation of SCA?

Answer 10

Because beta globin is affected in SCD it is not seen in the fetus before birth.
Symptoms are rare before 3-6 months of age

Early manifestations:

• Dactylitis
• Splenic sequestration
• Infection (S. pneumoniae)

Question 11

What are SCA emergency complications?

Answer 11

Septic shock (BP<90/60)
Neurological signs/symptoms
SpO2 <92%
Signs of acute severe anaemia (Hb <50g/dL)
Priapism (erection) >4hrs

Question 12

Prevalence of stroke in SCA

Answer 12

8% of SS

Question 13

Prevalence of gallstones

Answer 13

By 25 years -> 50% in SS

Question 14

Haematological features of SCA

Answer 14

Low Hb (60-80g/L)
High reticulocytes (except in aplastic crisis)
Film:
- Sickled cells
- Target cells
- Howell-Jolly bodies

Question 15

Diagnosis and definitive diagnosis of SCA

Answer 15

Diagnosis of carrier or SS: Add reducing agent to blood
oxyHb converted to deoxyHb
deoxyHbS should polymerise and become insoluble
Solution becomes turbid
Cannot not differetiate between SS or carrier of sickle cell

Definitive diagnosis: electrophoresis/HPLC

Question 16

Management of SCA

Answer 16

Folic acid
Penicilin
Vaccination
Monitor spleen size
Blood transfusion for acute anaemic events, chest syndrome and stroke
Pregnancy care
Haematopoietic stem cell transplantation (
Induction of fetal Hb (HbF)

Question 17

Management of painful crisis in SCA

Answer 17

Pain relief (opioid like diamorphine)
Hydration
Oxygen if hypoxic
Treat infection

Question 18

How can a painful crisis be triggered?

Answer 18

Infection
Exertion
Dehydration
Hypoxia
Psychological stress

Question 19

What are current disease-modifying therapies for SCA?

Answer 19

Transfusion
Hydroxycarbamide (Hydroxyurea)
Haematopoietic stem cell transplantation

Question 20

How does hydroxyurea work?

Answer 20

Increases production of HbF which inhibits polymerisation of HbS
Also generates NO improving blood flow

Question 21

When might you indicate HSCT? (haematopoietic stem cell transplantation)

Answer 21

CNS disease

If hydroxyurea fails

Question 22

Limitations of HSCT?

Answer 22

Donor availability
Transplant related mortality
Long term effects such as infertility and organ toxicity

Question 23

Difference between Sickle cell disease and sickle cell anaemia?

Answer 23

SCD = includes SCA and all other conditions involving sickling

SCA = Homozygous SS disease

Question 24

What is sickle cell trait?

Answer 24

Sickle cell carrier (HbAS)
Normal blood count and life expectancy
Usually asymptomatic
Rare painless haematuria

Question 25

What are some current developments in treatment of sickl cell?

Answer 25

Gene therapy
Gene editing
P-selectin inhibitor (molecule needed for adherence)