Sickle Cell

Question 1

Sickle cell disease prevalence?

Answer 1

A molecular disease where one molecular change determines whole pathology ; found very often in London

Question 2

Haemoglobin is…

Answer 2

SOLUBLE in cytoplasm of RBC ; outside hydrophilic and inside hydrophobic

Question 3

Sickle cell Haemoglobin

Answer 3

Single point mutation

Question 4

Electron micrograph of a sickle cell?

Answer 4

Often are haemolysed because of polymerised haemoglobin forming these insoluble rod like structures

Question 5

How many chains in each Hb unit?

Answer 5

4 subunits - two alpha and two beta

Question 6

Point amino acid substitution?

Answer 6

Glutamate to Valine at position 6

Question 7

What does glutamate to valine sub lead to?

Answer 7

Valine is hydrophobic so this substitution now binds with the 3 amino acids in the central pocket of hydrophobicity which causes the two haemoglobin molecules to clump together

Question 8

What three amino acids are in the pocket of hydrophobicity?

Answer 8

ALA 70
LEU 88
PHE 85
These are all on one beta chain and then the valine on the other beta chain (valine forms that knob)

Question 9

How does the binding acc work?

Answer 9

A lot of regions of hydrophobicity and van der waal’s forces (high SA) that helps the two molecules bind

Question 10

Deoxyhaemoglobin?

Answer 10

Molecule undergoes a slight conformational shift so that binding is so much more effective ; sickling far more prevalent

Question 11

Protection from malaria is associated with…?

Answer 11

SICKLE CELL TRAIT (not the acc disease) - here the cells do not actually deform because of healthy haemoglobin too

Question 12

Action of Malaria

Answer 12

Invades RBCs and makes them hypoxic - now the ones that are invaded only start sickling ; SPLEEN then clears any abnormal blood cells and malaria does not get a chance to take hold

Question 13

Higher your HbF

Answer 13

More it mitigates against sickle cell anaemia (prevents polymerisation)

Question 14

Hydroxyurea

Answer 14

Tries to increase HbF in blood as a treatment

Question 15

In HbS

Answer 15

Hb is low since a lot of the cells are haemolysed
Haemolysis also causes the bone marrow to start churning out reticulocytes WHICH ARE MUCH BIGGER HENCE WHY MCV GOES UP

Question 16

Older RBCs are in a positive patient?

Answer 16

More likely the cells are to sickle

Question 17

Boat cells?

Answer 17

Look a bit deformed and ovalish not really sickles ; malformed

Question 18

Sickle cell is associated with

Answer 18

Polychromasia ; reticulocytes stain blue because of RNA and RBCs stain red

Question 19

Howell-Jolly bodies

Answer 19

Expelled nucleus (just DNA) - job of the bone marrow ; before RBC is put into circulation

Question 20

When deoxygenated

Answer 20

Haemoglobin orientated in such a way that valine binds to hydrophobic pocket effectively

Question 21

Visual loss

Answer 21

Sickle cells block vessels to the retina and these are particularly narrow so less oxygen/nutrients/glucose - could lead to haemorrhage/blood loss

Question 22

Jaundice

Answer 22

Sickled cells more likely to lyse on their own but also one of the jobs of the spleen is to clear abnormal cells too - bilirubin is built up when haemolysis occurs and liver cannot metabolis bilirubin fast enough so builds up

Question 23

Where is jaundice always seen?

Answer 23

In the eye

Question 24

RBCs

Answer 24

Undergo haemolysis and deposits their contents into bloodstream - they can damage endothelium and induce inflammation - damage to endothelium means more things stick to it ; in this case its more sickle cells clumping so more blood flow restriction

Question 25

Vaso-occlussion

Answer 25

More restricted blood flow = more hypoxia = more sickling

Question 26

Younger you are with vaso-occlusion?

Answer 26

More collateral blood vessels form to get a healthy suply of blood - these tend to be fragile - this rupture could lead to haemorrhage

Question 27

Vasculopathy

Answer 27

Occurs when a thrombus forms in the arterial lumen

Question 28

Bone pain

Answer 28

Vaso-occlusion within bone tissue ; mediators are released that initiate pain

Question 29

Strenuous + prolonged Exercise

Answer 29

Acute tissue hypoxia - more sicklingM

Question 30

Moderate exercise

Answer 30

Vessels tend to be more potent and open

Question 31

Cold weather

Answer 31

Vasoconstriction (move away from peripheral areas) - sickle cells are likely to clog up blood flow

Question 32

Infection

Answer 32

Metabolic demand for tissues goes up as it is fighting infection - leads to acute tissue hypoxia = more sickling

Question 33

Dehydration

Answer 33

INCREASES VISCOSITY - RBCs are more compacted - more likely to clog up

Question 34

What is linked to dehydration

Answer 34

Exercise + infection

Question 35

Managing her crises

Answer 35

Hot water bottle Pain relief - ibuprofen Hydration Only hot countries Prophylactic antibiotics - to prevent the worst of the infection Jogging

Question 36

Treatment options

Answer 36

Blood transfusion - Blood thinners - prophylaxis Morphine - pain relief (within 30 mins) - no CANNULAR via soft cut through subcutaneous tissue (then can get IV access) Fluids - makes blood less viscous Oxygen - if hypoxic Antibiotics for any infection

Question 37

Prophylaxis

Answer 37

Treatment given to prevent disease

Question 38

ICE

Answer 38

Ideas - having a crisis Concerns - pain Expectations - get relief (or wanting better instructions etc than last time)

Question 39

Ideas

Answer 39

Complex set of beliefs that makes them come to you - with a cough ; ah i should go to a doctor, no I MIGHT HAVE A CHEST INFECTION

Question 40

Gene editing can help in two ways - first way?

Answer 40

Using a guide RNA - Cas9 enzyme targets and repairs faulty B-globin gene ; base is corrected from T to A to produced normal RBCs

Question 41

Second way?

Answer 41

Cas9 promotes production of foetal haemoglobin by breaking a gene that encodes a repressor like BCL11A