5. Sickle cell disease Flashcards
What does the distribution of SCD match?
Endemic Plasmodium falciparum malaria
What is the prevalence of SCD in the UK?
12,000-15,000
How many people are born with SCD in the UK?
350 births per annum (most common monogenic disorder)
What is HbS?
- Point (missense) mutation at codon 6 of the gene for β globin
- Glutamic acid (polar, soluble) is replaced by valine (non-polar, insoluble)
- Therefore - two normal alpha chains and two variant beta chain
- HbS polymerises to form fibres called ‘tactoids’
- Intertetrameric contacts stabilise structure
- The effects are seen on the deoxy Hb conformation
- Long polymers of HbS form within the red cells
Which disorders does the term ‘sickle cell disease’ include?
- Sickle cell anaemia (SS)
* Compound heterozygous states e.g. SC, Sb thalassaemia
How does SCD affect red cells and the microvasculature?
- Shorter red cell lifespan - haemolysis: anaemia, gall stones, aplastic crisis
- Blockage to microvascular circulation - due to Hb polymerisation and increased adherence: tissue damage and necrosis, pain, dysfunction
How does SCD interfere with vasoregulation?
- Haemolysis that occurs releases free Hb into the plasma
- This cell-free Hb limits the bioavailability of NO binding to it
- NO is a potent vasodilator so this process is interfered with
- Results in pulmonary hypertension (20-30% of adults with SCD)
What are the consequences of tissue infarctions in different parts of the body, caused by SCD?
- Spleen - hyposplenism
- Bones/joints - dactylitis, avascular necrosis, osteomyelitis
- Skin - ulceration
What is dactylitis?
- Pain crisis affecting the hands and feet
- Swollen, painful and tendor
- Involved in the epiphyseal bone in childhood - may lead to stunting of individual digits
- Result of a vasoocclusive crisis with bone infarcts
What effect can SCD have on the lungs, urinary tract, brain and eyes?
- Lungs - acute chest syndrome, pulmonary hypertension
- Urinary tract - haematuria (papillary necrosis), impaired conc. of urine (hyposthenuria), renal failure, priapism
- Brain - stroke, cognitive impairment
- Eyes - proliferative retinopathy
When and how does SCD present?
• Clinical problems usually start 4-6 months as the HbF disappears and HbS predominates
- coincides with switch from foetal to adult Hb synthesis
• Most classical problems are dactylitis in children
• Infection susceptibility due to hyposplenism
• Splenic sequestration and aplastic crisis can be distinguished by the presence of reticulocytes
- can lead to hypovolaemic shock and death
What is acute chest syndrome?
- Vaso-occlusive crisis of the pulmonary vasculature
- Pulmonary infiltrates are characteristic
- Fever, cough, chest pain and tachypnoea
- Incidence: SS > SC > Sβ-thal
- Responds well to blood transfusion
What are the important sickle emergencies?
- Septic shock (BP <90/60) and neurological signs/symptoms (cerebral haemorrhage)
- SpO2 <92% on air (due to hypoxia => acute chest syndrome)
- Signs/symptoms of anaemia with Hb <5 or fall >3g/dl from baseline
- Priapism > 4 hours
Explain the role of SCD in strokes in children
- SCD is the most common cause of stroke in children
- Commonly seen in ages 2-9 years
- Involves major cerebral vessels
- Stenosis can be picked up by transcranial Doppler imaging
What can a painful crisis in SCD be triggered by?
- Infection
- Exertion
- Dehydration
- Hypoxia
- Psychological stress
What is the median survival of SCD patients?
- 48 years in females
* 42 years in males
What general measures can be taken to manage SCD?
- Folic acid
- Penicillin (prophylaxis)
- Vaccination
- Monitor spleen size
- Blood transfusion for acute events
- Pregnancy care
What measures can be taken to manage painful crises of SCD?
- Pain relief (opioids - diamorphine)
- Hydration
- Keep warm
- Oxygen if hypoxic
- Exclude infection
When is exchange transfusion carried out?
- Stroke
* Acute chest syndrome
When is a haematopoietic stem cell transplant carried out?
- <16 yr with severe disease
- Survival: 90-95%
- Cure: 85-90%
Why is the induction of HbF useful?
- HbF inhibits polymerisation of HbS
* Achieved with hydroxyurea, butyrate
What are the laboratory features of SCD?
- Low Hb (6-8g/dl)
- High reticulocytes, except in aplastic crisis
- Sickle cells, boat cells, target cells, Howell-Jolly bodies
What is the solubility test?
- Non-definitive
- oxyHb converted to deoxy Hb in the presence of a reducing agent
- Solution becomes turbid - reflects insolubility of HbS
- Does not differentiate AS from SS - electrophoresis needed
What can provide a definitive diagnosis of SCD?
- Electrophoresis or high performance liquid chromatography
* Separates proteins according to charge
If a lady with HbAS has a partner with HbSS, should she be offered genetic counselling?
No
