Week 4 Flashcards

1
Q

how does the sickling of RBCs appear

A

polymerisation of sickle Hb occurs

distorts the shape of RBC corpuscles

under deoxygenated conditions = sickling

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2
Q

how is motility shown between HbA and HbS

how are different Hb molecules are distinguished by..

A

electrophoresis

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3
Q

what is HbA

A

the normal dominant gene

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4
Q

what is HbS

A

the sickle gene - recessive

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5
Q

HbAS

A

sickle carrier - heterozygous

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6
Q

what makes up the normal adult Hb

A

two alpha globin chains
two beta globin chains
each with a haem group containing iron

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7
Q

what does foetal Hb contain

A

two globin
two gamma globin
each with a haem group

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8
Q

what is the mutation on HbS

A

a missense mutation on the 6th amino acid on the beta globin chain

where GAG becomes GTG

glutamic acid to valine

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9
Q

how is the HbS mutation detected

A

PCR

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10
Q

physiological effects of HbS mutation

A

repeated polymerisation of HbS

damages the RBC membrane

reduces RBC lifespan

from 120 to 10-20 days

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11
Q

what is vaso-occlusion

A

where sickled cells block blood flow
so tissues do not receive enough blood

occurs in narrow blood vessels

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12
Q

what are haemoglobinopathies

A

group of blood disorders caused by altered haemoglobins

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13
Q

categories of hamoglobinopathies

A

Hb variants and thalassemias

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14
Q

alpha thalassemia

A

deletion of alpha globin gene

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15
Q

beta thalassemia

A

mutation causes beta globin production

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16
Q

sickle alpha or beta thalassemia

A

shows mild SCD symptoms

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17
Q

what is the HbC variant

A

a missense mutation that replaces the sixth amino acid with lysin

homozygous HbC causes haemolysis, spenomegaly and jaundice

but milder than HbS

18
Q

what is HbAS

A

asymptomatic carriers

19
Q

what is HbSC

A

compound heterozygotes

milder than SCD

prone to vascular retinopathy and avascular necrosis of the femoral head

20
Q

heterozygous advantage

A

one HbS allele protects against malaria symptoms

leading to more SCD in countries with common malaria

21
Q

what causes vaso occlusion in SCD

A

adhesion between sickle cells and endothelium

22
Q

what is the effect of inflammation

A

activates nociceptors and causes pain

23
Q

when do symptoms begin for SCD

A

around 6 months after loss of foetal haemoglobin

24
Q

what causes less oxygen supply to tissues in SCD pts

A

RBC are unable to change shape

they obstruct small arteries

and reduce oxygen supply to tissues

25
Q

how do sickled cells cause a short RBC life span

A

membranes of RBCs are damaged

cells are taken up by the reticuloendothelial system

shorter cell survival = rapid RBC turnover

leads to anaemia

26
Q

aim of antenatal screening

A

to identify parents with SCT

27
Q

how does antenatal screening work

A

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)

28
Q

results of antenatal screening: if the mother has SCT

A

risk of using anaesthetic during birth

biological father is screened

29
Q

results of antenatal screening: if both parents have SCT

A

offer prenatal diagnosis

a genetic analysis of the foetal sample

collected by amniocentesis or chorionic villus sampling

30
Q

how to prevent vaso-occlusion

A

avoid dehydration, low oxygen, high acid and vigorous exercise

31
Q

other symptom prevention

A

avoid temperature changes
avoid infection by streptococcus pneumoniae (vaccine)
monitoring the outpatient clinic

32
Q

treatments for SCD

A

prophylactic penicillin
hydroxyurea
NSAIDS
folic acid
blood transfusion
hydrocarbamide
crizanlizumab
haeatopoietic stem cell transplant

33
Q

what does prophylactic penicillin do

A

prevent the risk of overwhelming sepsis
from splenic infarction (obstruction of blood supply)

34
Q

what does hydroxyurea do

A

increases HbF levels when taken once a day

prevents intracellular sickling

reduces vaso-occlusion and hemolysis

35
Q

what does crizanlizumab do

A

prevents RBC adhesion to endothelial cells

36
Q

what are the gene therapy strategies

A

to improve abnormal beta globin

to restore gamma globin

37
Q

what mechanism does gene addition take for gene therapy of SCD

A

by lentiviral vector

beta globin with anti sickling properties is inserted

gamma globin restores HbF production

38
Q

gene editing for SCD

A

beta globin correction or modification

gamma globin upregulation

39
Q

how does gamma globin upregulation work

A

disrupts BCL11A
which typically shuts off gamma globin after foetal development
restoring gamma production - prevents sickling

40
Q

what technique is used to alter the BCL11A gene

A

CRISPR-Cas9
BCL11A function is disrupted in RBC precursors

41
Q

what is the target of gene therapies for SCD

A

haematopoietic stem cells
- a cell that can differentiate into RBCs
for continued healthy RBC supply

42
Q

why not do gene therapy on RBC

A

no nucleus!