Week 4

Question 1

how does the sickling of RBCs appear

Answer 1

polymerisation of sickle Hb occurs

distorts the shape of RBC corpuscles

under deoxygenated conditions = sickling

Question 2

how is motility shown between HbA and HbS

how are different Hb molecules are distinguished by..

Answer 2

electrophoresis

Question 3

what is HbA

Answer 3

the normal dominant gene

Question 4

what is HbS

Answer 4

the sickle gene - recessive

Question 5

HbAS

Answer 5

sickle carrier - heterozygous

Question 6

what makes up the normal adult Hb

Answer 6

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

Question 7

what does foetal Hb contain

Answer 7

two globin
two gamma globin
each with a haem group

Question 8

what is the mutation on HbS

Answer 8

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

where GAG becomes GTG

glutamic acid to valine

Question 9

how is the HbS mutation detected

Answer 9

PCR

Question 10

physiological effects of HbS mutation

Answer 10

repeated polymerisation of HbS

damages the RBC membrane

reduces RBC lifespan

from 120 to 10-20 days

Question 11

what is vaso-occlusion

Answer 11

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

occurs in narrow blood vessels

Question 12

what are haemoglobinopathies

Answer 12

group of blood disorders caused by altered haemoglobins

Question 13

categories of hamoglobinopathies

Answer 13

Hb variants and thalassemias

Question 14

alpha thalassemia

Answer 14

deletion of alpha globin gene

Question 15

beta thalassemia

Answer 15

mutation causes beta globin production

Question 16

sickle alpha or beta thalassemia

Answer 16

shows mild SCD symptoms

Question 17

what is the HbC variant

Answer 17

a missense mutation that replaces the sixth amino acid with lysin

homozygous HbC causes haemolysis, spenomegaly and jaundice

but milder than HbS

Question 18

what is HbAS

Answer 18

asymptomatic carriers

Question 19

what is HbSC

Answer 19

compound heterozygotes

milder than SCD

prone to vascular retinopathy and avascular necrosis of the femoral head

Question 20

heterozygous advantage

Answer 20

one HbS allele protects against malaria symptoms

leading to more SCD in countries with common malaria

Question 21

what causes vaso occlusion in SCD

Answer 21

adhesion between sickle cells and endothelium

Question 22

what is the effect of inflammation

Answer 22

activates nociceptors and causes pain

Question 23

when do symptoms begin for SCD

Answer 23

around 6 months after loss of foetal haemoglobin

Question 24

what causes less oxygen supply to tissues in SCD pts

Answer 24

RBC are unable to change shape

they obstruct small arteries

and reduce oxygen supply to tissues

Question 25

how do sickled cells cause a short RBC life span

Answer 25

membranes of RBCs are damaged cells are taken up by the reticuloendothelial system shorter cell survival = rapid RBC turnover leads to anaemia

Question 26

aim of antenatal screening

Answer 26

to identify parents with SCT

Question 27

how does antenatal screening work

Answer 27

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)

Question 28

results of antenatal screening: if the mother has SCT

Answer 28

risk of using anaesthetic during birth biological father is screened

Question 29

results of antenatal screening: if both parents have SCT

Answer 29

offer prenatal diagnosis a genetic analysis of the foetal sample collected by amniocentesis or chorionic villus sampling

Question 30

how to prevent vaso-occlusion

Answer 30

avoid dehydration, low oxygen, high acid and vigorous exercise

Question 31

other symptom prevention

Answer 31

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

Question 32

treatments for SCD

Answer 32

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

Question 33

what does prophylactic penicillin do

Answer 33

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

Question 34

what does hydroxyurea do

Answer 34

increases HbF levels when taken once a day prevents intracellular sickling reduces vaso-occlusion and hemolysis

Question 35

what does crizanlizumab do

Answer 35

prevents RBC adhesion to endothelial cells

Question 36

what are the gene therapy strategies

Answer 36

to improve abnormal beta globin to restore gamma globin

Question 37

what mechanism does gene addition take for gene therapy of SCD

Answer 37

by lentiviral vector beta globin with anti sickling properties is inserted gamma globin restores HbF production

Question 38

gene editing for SCD

Answer 38

beta globin correction or modification gamma globin upregulation

Question 39

how does gamma globin upregulation work

Answer 39

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

Question 40

what technique is used to alter the BCL11A gene

Answer 40

CRISPR-Cas9 BCL11A function is disrupted in RBC precursors

Question 41

what is the target of gene therapies for SCD

Answer 41

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

Question 42

why not do gene therapy on RBC

Answer 42

no nucleus!