Week 4 Flashcards
how does the sickling of RBCs appear
polymerisation of sickle Hb occurs
distorts the shape of RBC corpuscles
under deoxygenated conditions = sickling
how is motility shown between HbA and HbS
how are different Hb molecules are distinguished by..
electrophoresis
what is HbA
the normal dominant gene
what is HbS
the sickle gene - recessive
HbAS
sickle carrier - heterozygous
what makes up the normal adult Hb
two alpha globin chains
two beta globin chains
each with a haem group containing iron
what does foetal Hb contain
two globin
two gamma globin
each with a haem group
what is the mutation on HbS
a missense mutation on the 6th amino acid on the beta globin chain
where GAG becomes GTG
glutamic acid to valine
how is the HbS mutation detected
PCR
physiological effects of HbS mutation
repeated polymerisation of HbS
damages the RBC membrane
reduces RBC lifespan
from 120 to 10-20 days
what is vaso-occlusion
where sickled cells block blood flow
so tissues do not receive enough blood
occurs in narrow blood vessels
what are haemoglobinopathies
group of blood disorders caused by altered haemoglobins
categories of hamoglobinopathies
Hb variants and thalassemias
alpha thalassemia
deletion of alpha globin gene
beta thalassemia
mutation causes beta globin production
sickle alpha or beta thalassemia
shows mild SCD symptoms
what is the HbC variant
a missense mutation that replaces the sixth amino acid with lysin
homozygous HbC causes haemolysis, spenomegaly and jaundice
but milder than HbS
what is HbAS
asymptomatic carriers
what is HbSC
compound heterozygotes
milder than SCD
prone to vascular retinopathy and avascular necrosis of the femoral head
heterozygous advantage
one HbS allele protects against malaria symptoms
leading to more SCD in countries with common malaria
what causes vaso occlusion in SCD
adhesion between sickle cells and endothelium
what is the effect of inflammation
activates nociceptors and causes pain
when do symptoms begin for SCD
around 6 months after loss of foetal haemoglobin
what causes less oxygen supply to tissues in SCD pts
RBC are unable to change shape
they obstruct small arteries
and reduce oxygen supply to tissues
how do sickled cells cause a short RBC life span
membranes of RBCs are damaged
cells are taken up by the reticuloendothelial system
shorter cell survival = rapid RBC turnover
leads to anaemia
aim of antenatal screening
to identify parents with SCT
how does antenatal screening work
it is offered to all pregnant women in high prevalence areas and based on family origin
a blood sample is analysed by capillary electrophoresis
or high performance liquid chromatography (HLPC)
results of antenatal screening: if the mother has SCT
risk of using anaesthetic during birth
biological father is screened
results of antenatal screening: if both parents have SCT
offer prenatal diagnosis
a genetic analysis of the foetal sample
collected by amniocentesis or chorionic villus sampling
how to prevent vaso-occlusion
avoid dehydration, low oxygen, high acid and vigorous exercise
other symptom prevention
avoid temperature changes
avoid infection by streptococcus pneumoniae (vaccine)
monitoring the outpatient clinic
treatments for SCD
prophylactic penicillin
hydroxyurea
NSAIDS
folic acid
blood transfusion
hydrocarbamide
crizanlizumab
haeatopoietic stem cell transplant
what does prophylactic penicillin do
prevent the risk of overwhelming sepsis
from splenic infarction (obstruction of blood supply)
what does hydroxyurea do
increases HbF levels when taken once a day
prevents intracellular sickling
reduces vaso-occlusion and hemolysis
what does crizanlizumab do
prevents RBC adhesion to endothelial cells
what are the gene therapy strategies
to improve abnormal beta globin
to restore gamma globin
what mechanism does gene addition take for gene therapy of SCD
by lentiviral vector
beta globin with anti sickling properties is inserted
gamma globin restores HbF production
gene editing for SCD
beta globin correction or modification
gamma globin upregulation
how does gamma globin upregulation work
disrupts BCL11A
which typically shuts off gamma globin after foetal development
restoring gamma production - prevents sickling
what technique is used to alter the BCL11A gene
CRISPR-Cas9
BCL11A function is disrupted in RBC precursors
what is the target of gene therapies for SCD
haematopoietic stem cells
- a cell that can differentiate into RBCs
for continued healthy RBC supply
why not do gene therapy on RBC
no nucleus!
