Sickle Cell Disease Flashcards
Distribution of sickle cell disease matches that of ….. ….. ….. …..
Distribution of sickle cell disease matches that of endemic plasmodium falciparum malaria
Describe what type of genetic disease sickle cell is and the inheritance pattern (three words)
Monogenic autosomal recessive
How does HbS come about, describe what it is and why its bad, and what is the structure of sickle haemoglobin?
- Missense mutation at codon 6 of the gene for ß-globin
- Therefore the normal glutamic acid - polar and soluble, is substituted with valine which is non-polar and insoluble
- This influences the solubility of the deoxyHb molecule and the potential bonds that the globin chain can form
- You form tactoid intertetrameric contacts which stabilise the structure but also contribute to the insolubility
- In sickle haemoglobin, we have 2 normal α chains and 2 variant ß chains
Deoxyhaemoglobin HbS is insoluble…
1) Why?
2) What kind of changes to the sickle RBC conformation does this result in and how?
1)
- Because there is a missense mutation at codon 6 of the gene for ß-globin
- This missense mutation results in substitution of the normal glutamic acid A.A which is polar and soluble with valine which is non-polar and insoluble
2)
- Intratetrameric contacts (between deoxyhaemoglobin HbS tetramers) form
- So HbS polymerisation occurs to form fibres called ‘tactoids’
- Eventually the RBCs sickle
What are the 3 stages in the sickling of RBCs?
- Distortion - polymerisation initially reversible with formation of oxyHbS, subsequently irreversible
- Dehydration
- Increased adherence to vascular endothelium
How do sickle cells have increased adherence to vascular endothelium?
- The CSM of the RBCs express a different adhesion profile
- This makes them more adherent so they adhere to the vascular endothelium
Sickle cell disease is an umbrella term, what conditions does it include?
- Sickle cell anaemia
- Compound heterozygous states e.g. SC, Sickle-ß thalassaemia
1) What is the basic principle causing shortened RBC lifespan?
2) In what conditions will you see shortened RBC lifespan or are sequelae of the haemolysis?
1) Haemolysis
2)
- Haemolytic anaemia
- Gall stones
- Aplastic crisis (caused by parvovirus B19)
Why does sickle cell disease lead to problems with the circulation, what kind of problems, and what conditions will this lead to?
- HbS polymerisation and increased vascular adherence leads to vaso-occlusion in the microcirculation
- Infarction - tissue damage and necrosis
- Pain
- Dysfunction
1) What type of HTN is associated with sickle cell and what does it correlate to?
2) Mechanistically, how does sickle cell lead to HTN?
1)
- Pulmonary HTN
- Pulmonary HTN is associated with the severity of haemolysis
2)
- Haemolysis that occurs in sickle cell disease results in release of free Hb into the plasma
- This cell free Hb limits the bioavailability of NO by binding to it
- NO is a potent vasodilator so by reducing its bioavailability, there’s effectively vasoconstriction which leads to HTN
What are the consequences of infarction from sickle cell disease in the following sites?
1) Spleen
2) Bones / joints
3) Skin
1)
- Hyposplenism (infection)
2)
- Dactylitis
- Avascular necrosis
- Osteomyelitis
3)
- Ulceration
Why does dactylitis occur and what are the signs and symptoms in dactylitis?
- As a result of infarction in sickle cell disease
- A pain crisis affecting the hands and feet
- Hands and feet are acutely swollen, painful and tender
- If this affects the epiphyseal bones, it may lead to stunting of individual digits
Apart from the primary signs and symptoms of sickle cell disease, what other associated diseases may occur in
1) The lungs
2) The urinary tract
3) The spleen
4) The brain
5) The eyes
1)
- Acute chest syndrome
- Pulmonary HTN - leading to chronic lung damage
2)
- Haematuria due to papillary necrosis
- Hyposthenuria (impaired conc of urine)
- Renal failure
- Priapism
3)
- Hyposplenism
- Splenic sequestration (pooling of RBCs within the spleen) - this in turn can lead to hypovalaemia and death
4)
- Stroke
- Cognitive impairment due to cerebral infarction
5)
- Proliferative retinopathy
Why do the symptoms of sickle cell disease not occur immediately in the neonate, and at what point do clinical symptoms occur?
- Because HbF (foetal haemoglobin) predominates and HbF = 2 alpha and 2 gamma chains so there’s no beta chains that can be affected
- At 4-6 months, when the gamma-beta switch aka switch from HbF to adult Hb occurs…..
- HbS (= 2 alpha chains and 2 mutated beta chains) begins to predominate so clinical symptoms begin to appear
1) What 2 spleen problems can arise as a result of sickle cell disease and where applicable , why do these arise. Also what complications can arise as a result of these splenic problems?
2) How to treat both of these splenic problems?
1)
- Hyposplenism due to infarction - this makes infection (often by strep. pneumoniae) more likely
- Splenic sequestration (blood pools in the spleen) - this can lead to hypovolaemia and eventual death
2)
- Blood transfusion
1) What is the pathophysiology of acute chest syndrome?
2) What are the clinical signs of acute chest syndome?
3) Describe what you can see on this X-ray of the lungs which are indicative of acute chest syndrome?
4) How to treat ACS?
1)
- Vaso-occlusion within the pulmonary vasculature as a result of SCD directly also….
- SCD → bone ischaemia and necrosis → release of bone marrow and fat emboli into the venous circulation
- Inflammation and hypoxia associated with the free fatty acids from the fat emboli propagates the vaso-occlusion also
- Can result due to pregnancy and surgery also
2)
- SOB
- Fever
- Cough
- Chest pain
- Tachypnoea
- Possible pain in limbs
3)
- Pulmonary bilateral basal infiltrates
4)
- Exchange blood transfusion
How can we image to determine stroke in patients with SCD and what would you see?
- Use transcranial Doppler imaging
- You’ll see stenosis of the major cerebral arteries including the intracranial internal carotids and the middle cerebral artery in particular
