5: Sickle Cell Flashcards
What is the sickle cell gene? Why does the sickle cell form?
Missense mutation at codon 6 for beta globin chain
Glutamic acid replaced by Valine
Valine = Non-polar + INSOLUBLE
Deoxyhaemoglobin S is therefore insoluble
HbS polymerises to form fibres
What are the stages of sickling?
- Distortion
- Dehydration
- Increased adherence to vascular endothelium
Where is sickle gene most prevalent in the world? Why?
West Africa, Mediterranean, India, south-east asia
Because carriers of sickle gene are protected against malaria
Prevalence of SCD in Europe/UK/US?
Europe - 60,000
UK - 12000-15000
US - 100,000
How many births per year are affected?
300,000
Describe the pathogenesis of sickle cell anaemia (SS)
- Shortened red cell lifespan (5-7 days)
This leads to:
- Anaemia
- Gall stones
- Aplastic crisis (caused by virus B19)
Anaemia also partly due to reduced erythropoietic drive, since HbS readily dissociates oxygen to tissues - Vaso-occlusion
- Tissue damage/infarction
- Pain
- Dysfunction
What are the consequences of infarction in different tissues?
Spleen -> Hyposplenism
Bones/joints -> chronic damage, dactylitis
Skin -> chronic/recurrent leg ulcers
How is SCA associated with pulmonary hypertension?
Free plasma haemoglobin (as a result of haemolysis) scavenges NO and reduces its bioavailability causing vasoconstriction.
Complications of SCA?
Lungs:
- Acute chest syndrome (highest cause of death in SCD)
- Pulmonary hypertension
Urinary tract
- Haematuria
- Imparied conc. of urine
- RENAL FAILURE
Brain
- Stroke
- Cognitive impairment
Eyes
- Proliferative retinopathy
Early presentation of SCA?
Because beta globin is affected in SCD it is not seen in the fetus before birth.
Symptoms are rare before 3-6 months of age
Early manifestations:
- Dactylitis
- Splenic sequestration
- Infection (S. pneumoniae)
What are SCA emergency complications?
Septic shock (BP<90/60) Neurological signs/symptoms SpO2 <92% Signs of acute severe anaemia (Hb <50g/dL) Priapism (erection) >4hrs
Prevalence of stroke in SCA
8% of SS
Prevalence of gallstones
By 25 years -> 50% in SS
Haematological features of SCA
Low Hb (60-80g/L) High reticulocytes (except in aplastic crisis) Film: - Sickled cells - Target cells - Howell-Jolly bodies
Diagnosis and definitive diagnosis of SCA
Diagnosis of carrier or SS: Add reducing agent to blood
oxyHb converted to deoxyHb
deoxyHbS should polymerise and become insoluble
Solution becomes turbid
Cannot not differetiate between SS or carrier of sickle cell
Definitive diagnosis: electrophoresis/HPLC
Management of SCA
Folic acid Penicilin Vaccination Monitor spleen size Blood transfusion for acute anaemic events, chest syndrome and stroke Pregnancy care Haematopoietic stem cell transplantation ( Induction of fetal Hb (HbF)
Management of painful crisis in SCA
Pain relief (opioid like diamorphine)
Hydration
Oxygen if hypoxic
Treat infection
How can a painful crisis be triggered?
Infection Exertion Dehydration Hypoxia Psychological stress
What are current disease-modifying therapies for SCA?
Transfusion
Hydroxycarbamide (Hydroxyurea)
Haematopoietic stem cell transplantation
How does hydroxyurea work?
Increases production of HbF which inhibits polymerisation of HbS
Also generates NO improving blood flow
When might you indicate HSCT? (haematopoietic stem cell transplantation)
CNS disease
If hydroxyurea fails
Limitations of HSCT?
Donor availability
Transplant related mortality
Long term effects such as infertility and organ toxicity
Difference between Sickle cell disease and sickle cell anaemia?
SCD = includes SCA and all other conditions involving sickling
SCA = Homozygous SS disease
What is sickle cell trait?
Sickle cell carrier (HbAS)
Normal blood count and life expectancy
Usually asymptomatic
Rare painless haematuria
What are some current developments in treatment of sickl cell?
Gene therapy
Gene editing
P-selectin inhibitor (molecule needed for adherence)
