Sickle Cell disease Flashcards
What genetic mutation results in sickle cell disease? Why does sickle cell anaemia arise from this?
Missense mutation at codon 6 of the gene for b globin chain. Glutamic acid replaced by valine. Valine = non polar and insoluble compared to glutamine. DeoxyHbS is insoluble HbS polymerises to form tactics. Intertetrameric contacts stabilise structure.
What are the stages of sickling in red cells?
•Distortion
- Polymerisation initially reversible with formation of oxyHbS
- Subsequently irreversible
- Dehydration
- Increased adherence to vascular endothelium.
rigid, adherent, dehydrated.
What disorders are encompassed within the term ‘sickle cell disease’?
Sickle cell anaemia (SS) and compound
heterozygous states e.g. SC, Sbeta thalassaemia.
Autosomal recessive disorders but clinically very heterozygous.
Explain the pathogenesis of sickle cell disease.
•Shortened red cell lifespan - haemolysis - leading to
–Anaemia (partly due to low erythropoieticdrive as haemoglobin S is a low affinity haemoglobin)
–Gall Stones
–Aplastic Crisis (Parvovirus B19)
•Blockage to microvascularcirculation (vaso-occlusion)
–Tissue damage and necrosis (Infarction)
–Pain
–Dysfunction
What are the consequences of tissue infarction in the spleen, bones and skin?
•Spleen
- hyposplenism
•Bones/Joints
- dactylitis
- avascular necrosis
- osteomyelitis
•Skin
- chronic/recurrent leg ulcers
Explain the pathogenesis of vaso-occlusion in SCD.
Due to deformed shape and increased adherence ability they block microvasculature which attracts neutrophils.
How is vasodilation inihibited in response to vaso-occlusion in SCD?
Cell-free haemoglobinlimits nitric oxide bioavailability
How is SCD and haemolysis related to pulmonary hypertension?
Free plasma Hb from intravascular haemolysis scavenges NO and inhibits its effect of vasodilation.
Associated with increased mortality.
Give some complications of SCD.
Lungs -
Acutechestsyndrome
Chronicdamage
Pulmonaryhypertension
Urinary tract -
Haematuria(papillary necrosis)
Impairedconcentration of urine (hyposthenuria)
Renal failure
Priapism
Brain -
Stroke
Cognitiveimpairment
Eyes -
Proliferativeretinopathy
When does SCD present clinically?
Switch from fetal to adult Hb synthesis. Symptoms rare before 3-6 months.
What are the early manifestations of SCD?
Dactylitis
Splenic sequestration
Infection-S. pneumoniae
What emergencies can arise from SCD?
- Septic shock (BP <90/60)
- Neurologicalsigns or symptoms
- SpO2<92% on air
- Symptoms/signs of anaemiawith Hb<5 or fall >3g/dl from baseline
Priapism>4 hours
What are the clinical features of acute chest syndrome?
Fever
Cough
Chest pain
Tachypnoea
In what forms of SCD is acute chest syndrome most common?
SS>SC>Sb+Thal
How does acute chest syndrome occur?
In context of vaso-occlusive crisis, e.g. surgery, pregnancy.
What bone complications can arise from SCD?
Avascular Necrosis of the Femoral Head
Osteomyelitis due to Salmonella Infection
How common is stroke in SCD?
8% of SS individuals.
Most common in 2-9 year olds.
Involves major cerebral vessels.
How does SCD relate to gallstone occurance? What effect does Gilbert syndrome have on this risk?
50% patients after 25 years.
Coinheritance increases risk.
What are the laboratoy features of SCD?
- Hb low (typically 6-8 g/dl)
- Reticulocytes high (except in aplastic crisis)
- Film
Sickled cells
Boat cells
Target cells
Howell Jolly bodies
How can SCD be diagnosed with a solubility test?
In presence of a reducing agent oxyHb converted to deoxy Hb
Solubility decreases
Solution becomes turbid
Does not differentiate AS from SS
How can a definitive diagnosis of SCD be made?
Electrophoresis or high performance liquid Chromatography (HPLC) separates proteins according to charge
What general measures are taken to manage SCD?
–Folic acid
–Penicillin
–Vaccination
–Monitor spleen size
–Blood transfusion for acute anaemic events, chest syndrome and stroke
–Pregnancy care
How are painful SCD crises managed?
–Pain relief (opioids)
–Hydration
–Keep warm
–Oxygen if hypoxic
–Exclude infection:
- Blood and urine cultures
- CXR
What can trigger a painful crisis?
Infection
Exertion
Dehydration
Hypoxia
Psychological stress
