Haematology: Sickle Cell Disease

Question 1

What are haemoglobinopathies?

Answer 1

Red blood cell disorders that cause haemolytic anaemia because of reduced or absent production of HbA (alpha and beta thalassaemias) or because of the production of an abnormal Hb e.g in sickle cell disease

Question 2

Beta thalassaemia and sickle cell disease are caused by mutations in…

Answer 2

Beta globin gene

Question 3

Clinical manifestations of haemoglobinopathies affecting the beta chain are delayed until when?

Answer 3

After 6 months - when most of the HbF present at birth has been replaced by HbA

Question 4

Is sickle cell disease the most common inherited disorder in the UK?

Answer 4

Yes

1 in 2000 live births

Question 5

Describe the inheritance

Answer 5

Autosomal recessive

Question 6

What causes it?

Answer 6

Inheritance of HbS - this forms as a result of a point mutation in codon 6 of the beta globin gene
This causes a change in the amino acid encoded for glutamine to valine

Question 7

What are the main forms of sickle cell disease?

Answer 7

Sickle cell anaemia (HbSS) - patients are homozygous for HbS (virtually all Hb is HbS, they have small amount of HbF and no HbA because they have the sickle cell mutation in both beta globin genes)
HbSC disease (HbSC) - affected children inherit HbS from one parent and HbC from the other (HbC is formed as a result of a different point mutation in beta globin), so they also have no HbA
Sickle beta thalassaemia- HbS from one parent and beta thalassaemia trait from the other, so no normal HbA
Carriers (sickle trait) - inheritance of HbS from one parent and normal beta globin from other

Question 8

What percentage of carrier’s Hb is HbS?

Answer 8

40%

Question 9

Are carriers (sickle cell trait) symptomatic?

Answer 9

No, but they can transmit HbS to offspring

Question 10

How can sickle cell trait be identified?

Answer 10

Only as a result of blood tests

Question 11

In all forms of sickle cell disease, HbS polymerises within RBCs forming…

Answer 11

Rigid, tubular, spiral bodies which deform the red cells into sickle shape

Question 12

What happens to sickled red cells?

Answer 12

Reduced lifespan

Trapped in microcirculation causing blood vessel occlusion

Question 13

Would does blood vessel occlusion due to the sickled cells cause?

Answer 13

Ischaemia in an organ or bone

Question 14

What exacerbates the ischaemia due to vessel occlusion?

Answer 14

Low oxygen tension
Dehydration
Cold

Question 15

What is the most severe form of the disease?

Answer 15

HbSS

Question 16

What is one of the most important factors that modifies severity of sickle cell disease?

Answer 16

The amount of HbF - most patients with sickle cell disease have 1% HbF levels, but genetic variation means that some patients naturally produce more HbF - marked reduction in disease severity

Question 17

How does sickle cell disease clinically manifest?

Answer 17

All have moderate anaemia 60-100g/L
Clinically detectable jaundice from chronic haemolysis
Increased susceptibility to infection from encapsulated organisms
Painful crises - due to vessel occlusion, affect many organs
Acute anaemia - sudden drop in Hb
Priapism
Splenomegaly
Long term problems

Question 18

What type of infections are patients most at risk from?

Answer 18

Encapsulated organisms
Pneumococci, haemophilius influenzae
Also increased risk of osteomyelitis caused by salmonella

Question 19

Why is there a susceptibility to infection?

Answer 19

Due to hyposplenism due to chronic sickling and microinfarction in the spleen in infancy

Question 20

When is the risk of overwhelming sepsis greatest?

Answer 20

In early childhood

Question 21

How do painful crises commonly present?

Answer 21

Common mode in late infancy: hand-foot syndrome: dactylitis with swelling and pain in fingers and/or feet from vaso-occlusion
Bones of limbs and spine = most common site

Question 22

What is the most serious type of painful crisis?

Answer 22

Acute chest syndrome - can lead to severe hypoxia and need for mechanical ventilation and transfusion

Question 23

Avascular necrosis of what can occur?

Answer 23

Femoral head

Question 24

What can an acute vaso-occlusive crisis be precipitated by?

Answer 24

Cold, dehydration, exercise, stress, hypoxia, infection

Question 25

What can cause acute anaemia?

Answer 25

Haemolytic crisis - may be associated with infection
Aplastic crisis - e.g due to parvovirus (complete but temporary cessation of RBC production)
Sequestration crisis - sudden splenic/hepatic enlargement, abdo pain and circulatory collapse from accumulation of sickle cells in spleen

Question 26

What is priapism?

Answer 26

Prolonged erection of penis

Question 27

Why does priapism need prompt treatment?

Answer 27

With exchange transfusion

As may lead to fibrosis of corpora cavernosa and subsequent erectile impotence

Question 28

What long term problems can occur?

Answer 28

Short stature and delayed puberty
Stroke and cognitive problems e.g poor concentration
Adenotonsillar hypertrophy - causing sleep apnoea syndrome leading to nocturnal hypoxia, which can lead to vaso-occlusive crisis
Cardiac enlargement due to chronic anaemia
HF from anaemia
Renal dysfunction
Pigment gallstones - increased bile pigment production
Leg ulcers (uncommon in children)
Psychosocial problems

Question 29

In terms of management, what prophylactic approaches should be taken?

Answer 29

Full immunisation including a giant pneumococcal, haemophilius influenzae type B, and meningococcal infection
Daily oral penicillin throughout childhood to ensure coverage of all pneumococcal groups
Once daily oral folic acid
Try to avoid cold exposure, dehydration, excessive exercise, hypoxia - provoke crisis

Question 30

How should an acute crisis be treated?

Answer 30

Oral/IV analgesia
Oxygen 
IV fluids 
Antibiotics if infection suspected
Exchange transfusion if acute chest syndrome or priapism

Question 31

Children who have recurrent admissions for vaso-occlusive crises or acute chest syndrome may benefit from…

Answer 31

Hydroxycarbamide- increases HbF production

Monitor for WBC suppression

Question 32

The most severely affected children who have had a stroke or who do not respond to hydroxycarbamide may be offered…

Answer 32

Bone marrow transplant- the only cure, but usually only possible if sibling who is HLA identical

Question 33

What is the mortality rate in childhood?

Answer 33

Around 3%, usually from bacterial infection

Question 34

Why is the neonatal Guthrie test screening important?

Answer 34

Allows penicillin prophylaxis to be started in early infancy instead of awaiting clinical presentation

Question 35

Can prenatal diagnosis be carried out?

Answer 35

Yes by chorionic villus sampling at end of first trimester

Question 36

Those with HbSC typically have fewer crises than HbSS, but they may develop what in adulthood?

Answer 36

Proliferative retinopathy

Prone to osteonecrosis of hips and shoulders

Question 37

Who is sickle cell disease most common in?

Answer 37

Patients whose parents are black and originate from tropical Africa or the Caribbean
Also found in Middle East
Lower prevalence in rest of world expect Northern Europeans

Question 38

What symptoms are associated with acute chest syndrome?

Answer 38

Chest pain
Fever
Breathing problems - cough, SOB, wheeze

Question 39

What causes acute chest syndrome?

Answer 39

Infection or blockage to blood flow