Haematology: Sickle Cell Disease Flashcards
What are haemoglobinopathies?
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
Beta thalassaemia and sickle cell disease are caused by mutations in…
Beta globin gene
Clinical manifestations of haemoglobinopathies affecting the beta chain are delayed until when?
After 6 months - when most of the HbF present at birth has been replaced by HbA
Is sickle cell disease the most common inherited disorder in the UK?
Yes
1 in 2000 live births
Describe the inheritance
Autosomal recessive
What causes it?
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
What are the main forms of sickle cell disease?
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
What percentage of carrier’s Hb is HbS?
40%
Are carriers (sickle cell trait) symptomatic?
No, but they can transmit HbS to offspring
How can sickle cell trait be identified?
Only as a result of blood tests
In all forms of sickle cell disease, HbS polymerises within RBCs forming…
Rigid, tubular, spiral bodies which deform the red cells into sickle shape
What happens to sickled red cells?
Reduced lifespan
Trapped in microcirculation causing blood vessel occlusion
Would does blood vessel occlusion due to the sickled cells cause?
Ischaemia in an organ or bone
What exacerbates the ischaemia due to vessel occlusion?
Low oxygen tension
Dehydration
Cold
What is the most severe form of the disease?
HbSS
What is one of the most important factors that modifies severity of sickle cell disease?
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
How does sickle cell disease clinically manifest?
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
What type of infections are patients most at risk from?
Encapsulated organisms
Pneumococci, haemophilius influenzae
Also increased risk of osteomyelitis caused by salmonella
Why is there a susceptibility to infection?
Due to hyposplenism due to chronic sickling and microinfarction in the spleen in infancy
When is the risk of overwhelming sepsis greatest?
In early childhood
How do painful crises commonly present?
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
What is the most serious type of painful crisis?
Acute chest syndrome - can lead to severe hypoxia and need for mechanical ventilation and transfusion
Avascular necrosis of what can occur?
Femoral head
What can an acute vaso-occlusive crisis be precipitated by?
Cold, dehydration, exercise, stress, hypoxia, infection
What can cause acute anaemia?
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
What is priapism?
Prolonged erection of penis
Why does priapism need prompt treatment?
With exchange transfusion
As may lead to fibrosis of corpora cavernosa and subsequent erectile impotence
What long term problems can occur?
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
In terms of management, what prophylactic approaches should be taken?
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
How should an acute crisis be treated?
Oral/IV analgesia Oxygen IV fluids Antibiotics if infection suspected Exchange transfusion if acute chest syndrome or priapism
Children who have recurrent admissions for vaso-occlusive crises or acute chest syndrome may benefit from…
Hydroxycarbamide- increases HbF production
Monitor for WBC suppression
The most severely affected children who have had a stroke or who do not respond to hydroxycarbamide may be offered…
Bone marrow transplant- the only cure, but usually only possible if sibling who is HLA identical
What is the mortality rate in childhood?
Around 3%, usually from bacterial infection
Why is the neonatal Guthrie test screening important?
Allows penicillin prophylaxis to be started in early infancy instead of awaiting clinical presentation
Can prenatal diagnosis be carried out?
Yes by chorionic villus sampling at end of first trimester
Those with HbSC typically have fewer crises than HbSS, but they may develop what in adulthood?
Proliferative retinopathy
Prone to osteonecrosis of hips and shoulders
Who is sickle cell disease most common in?
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
What symptoms are associated with acute chest syndrome?
Chest pain
Fever
Breathing problems - cough, SOB, wheeze
What causes acute chest syndrome?
Infection or blockage to blood flow
