Sickle Cell Disease Flashcards
Describe the population genetics of sickle cells disease
- Up to 10% of Caribbeans and 25% Africans (sub-Saharan) carry sickle gene
- Around 200,000 affected births annually worldwide – majority of these in Africa
- Global migration has played a part in the spread of sickle cell disease to developed countries
Describe the epidemiology of sickle cell disease in the UK
- Prevalence of 12,000 – 15,000 people (70% of these people reside in Greater London)
- There are 350 new births per annum (it is the most common monogenic disorder)
What is HbS - what is the mutation and which AA is formed?
- Point (missense) mutation at codon 6 of the gene for β globin
- Glutamic acid (POLAR, SOLUBLE) is replaced by valine (which is NON-POLAR and INSOLUBLE)
What is the difference in the sickle cell Hb compared to normal?
In sickle haemoglobin we have two normal alpha chains and two variant beta chains
What is the effect of deoxyhaemoglobin S being insoluble?
- HbS polymerises to form fibres called “tactoids”
- The deoxy Hb molecule can now form intertetramer contacts and long polymers of HbS form within the red cells
- In the presence of HbS (homozygous state), the shape of RBCs distort, leading to irreversibly sickled cells
What effect does the valine substitution have?
Deoxy Hb S is insoluble, oxyhaemoglobin S isn’t affected
What are the stages of cellular change in sickle cell disease?
- Distortion: Polymerisation initially reversible with formation of oxyHbS
- Dehydration
- Increased adherence to vascular endothelium (the cell membrane expresses a different profile of adhesion molecules)
What is sickle cell disease?
A generic term for all the sickling disorders
Sickle cell disease includes sickle cell anaemia (SS) and compound heterozygous states e.g. SC, Sb thalassaemia
What is the inheritance pattern of sickle cell?
Autosomal recessive
However presents with different severities in different people
How does the life span of a sickle cell differ to a normal red cell and what is the effect?
Shortened red cell lifespan Can lead to: - anaemia - gallstones - aplastic crisis
What effect may be seen in vasculature due to sickle cell and what can this result in?
Vaso-occlusion due to Hb polymerisation and increased adherence Can lead to: - Tissue damage - Necrosis - Infarction - Pain - Dysfunction
What are the consequences of tissue infarction?
- Damage to spleen: Hyposplenism (infection prone)
- Bones/Joints: dactylitis, avascular necrosis, osteomyelitis
- Skin: ulceration
Why does pulmonary hypertension occur in SC patients?
- Correlates with the severity of haemolysis
- The likely mechanism is that the free plasma haemoglobin resulting from intravascular haemolysis scavenges NO -> vasoconstriction
- Associated with increased mortality
Why does sickle cell lead to anaemia?
Partly due to a reduced erythropoietic drive, as haemoglobin S is a low affinity haemoglobin.
What is dactylitis?
Dactylitis is a pain crisis affecting the hands and feet. Hands and feet are acutely swollen, very painful and tender. Caused by vaso-occlusion
In childhood, if this involved the epiphyseal bone (growing bone), it may lead to stunting of individual digits.
What is the clinical presentation of sickle cell disease?
- In children, the most classical problems are painful dactylitis
- Infection susceptibility due to hyposplenism (particularly with streptococcus pneumoniae)
- Splenic sequestration and aplastic crisis can be distinguished by the presence/absence of reticulocytes
- Splenic sequestration can lead to hypovolaemic shock and eventual death from severe anaemia
Both require urgent transfusions
When does sickle cell usually present and why?
- Clinical problems usually start at 4-6 months as the HbF disappears and HbS predominates
- Early manifestations onset coincides with switch from foetal to adult Hb synthesis
