Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

CSI > CSI 2: Sickle Cell Disease > Flashcards

CSI 2: Sickle Cell Disease Flashcards

1
Q

Haemoglobin’s key structural features

A
  • 4 globin chains [2 alpha, 2 beta]
  • 4 haem groups [each a porphyrin ring bound to Fe2+, that can carry 1 oxygen molecule]
  • Quaternary structure mainly alpha helices
  • Hydrophobic core, hydrophilic surface
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How many globin chains are there and what codes for each?

A

Eight
Alpha globin cluster - alpha1, alpha2, zeta
Beta globin cluster - epsilon, G gamma, G alpha, delta, beta

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Types of Hb found in healthy adults

A

HbA - 2 alpha, 2 beta
HbA2 - 2 alpha, 2 delta
HbF [very small amount] - 2 alpha, 2 gamma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

P_50

A

Value at which 50% of the haem groups are bound to oxygen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Describe why Hb’s affinity for oxygen helps it transport oxygen around the body appropriately

A
  • In the lungs, partial pressure is 100 torr and Hb is quickly saturated, picking up oxygen due to its high affinity for oxygen
  • Approaching the tissues, where partial pressure is 26 torr, Hb can release around 66% of the oxygen bound to it
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is positive cooperativity?

A

Once one oxygen molecule binds to a haem group within a Hb molecule, there is a conformational change, which makes it easier for another oxygen molecule to bind to the next haem group.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How is 2,3-BPG formed?

A

Via the Rapoport-Luebering Shuttle from some of the 1,3-BPG produced in glycolysis, using bisphosphoglycerate mutase [isomerisation]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is 2,3-BPG’s effect on the oxygen dissociation curve?

A
  • Allosteric effector that binds to a site in deoxyHb distant from haem groups stabilising the structure
  • Decreases the affinity of Hb for oxygen, allowing more oxygen to be released at tissues
  • Partially responsible for the oxygen dissociation curve (pure Hb looks like myoglobin)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the Bohr effect? Why is it helpful?

A

Rapidly respiring cells → decreasing pH, increasing CO2
H+ and CO2 - both allosteric effectors, decreasing affinity of Hb for oxygen, allowing for oxygen release at tissues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Foetal Hb and oxygen dissociation

A
  • Gamma chain differs from beta chain by one single AA substitution
  • Decreased affinity for 2,3-BPG
  • Increased affinity for oxygen
  • Allows for obtaining oxygen from maternal HbA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How is HbS different from HbA?

A

HbS → non-conservative missense mutation
Glutamate at position 6 on the betaglobin chain is replaced by valine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What kind of mutation causes the formation of HbS?

A

Autosomal recessive
- 2 copies of the mutation are required to manifest symptoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How does sickling occur when Hb is deoxygenated?

A
  • Conformational change means hydrophobic valine residue protrudes from surface
  • Groove formed by phenylalanine-85, leucine-88 and alanine-70 on another Hb forms hydrophobic interactions with the valine-6
  • HbS polymerises into long rods (7Hbs make a nucleus i.e. initiation point for fibre formation)
  • Rigid fibres distort shape of RBC
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What does the hydrophobic pocket refer to?

A

Hydrophobic interactions between the groove formed by phenylalanine-85, leucine-88 and alanine-70 on one Hb and valine-6 on another

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the key indicators of SCD on blood films?

A
  1. Sickle cell
  2. Reticulocytes (compensation)
  3. Target cells (hyposplenism)
  4. Polychromasia

Also Howell-Jolly bodies (hyposplenism)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the key indicators of SCD on blood cell count?

A
  1. Low Hb count
  2. High reticulocyte count
  3. High mean cell volume
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are three ways you could diagnose SCA?

A
  1. Blood films & cell count
  2. Electrophoresis
  3. Sickle cell solubility [not very solid evidence]
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Compare the band patterns of SS, AS and AA having done electrophoresis

A

AA - Band closer to anode (glutamate -ve)
AS - Bands at HbA and HbS
SS - Band further away from anode (valine neutral), stronger band for HbF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

How does a sickle solubility test work?

A
  1. Reducing agent sodium dithionite added
  2. Oxygen released from haemoglobin and sickling occurs if positive
  3. Increase in optical density

*Can’t differentiate between HbSS or HbAS → electrophoresis, high performance liquid chromatagraphy

20
Q

How does sickling lead to jaundice and gallstones?

A
  • Repeated sickling weakens the red blood cell membrane causing intravascular haemolysis (SC shortened 20 day lifespan)
  • Build up of unconjugated bilirubin (breakdown product of haem group of RBC) in blood
  • Yellow colour → jaundice
  • Hardening and solidifying of bile salts → gallstones
21
Q

What are the main complications of SCD?

A
  • Vision loss
  • Jaundice
  • Stroke
  • Bone crises
  • Acute crises (dactylytis, splenic sequestration, acute chest syndrome)
  • Chronic conditions (kidney damage, retinopathy, gallstones)
  • Splenomegaly
22
Q

What is vaso-occlusion?

A

Blockage of microcirculation including capillaries, leading to ischaemia and tissue necrosis

23
Q

How does vaso-occlusion occur?

A
  1. Rigid sickle cells get stuck by binding to p-selectin on the endothelial lining
  2. Sickle cells aggregate together, causing a blockage
24
Q

How does SCA cause vision loss?

A
  1. Vasocclusion of microvessels in the retina, increasing pressure, damaging endothelial lining
  2. Sickle cell ischaemia
    3a. Retinal cell detachment → cell death
    3b. Release of cytokines → stimulates growth of new collateral blood vessels through angiogenesis
    4b. Collaterals grow over areas of vision
    5b. Collateral blood vessel rupture → haemorrhagic stroke
25
Q

What are the two types of stroke?

A

Ischaemic - due to inadequate blood supply to an organ
Haemorrhagic - due to leakage of blood into tissues

26
Q

How does SCA cause bone crises?

A
  1. Reduced blood flow to bone marrow due to microvascular occlusion
  2. Oxygen deprivation
  3. Prolonged ischaemia → infarction → avascular necrosis/osteonecrosis
  4. Ischaemia exacerbated sickling further
  5. Severe joint pain
27
Q

What is an infarction?

A

Tissue death due to inadequate blood supply

28
Q

What is dactylytis?

A

Pain in hand joints due to blood vessels being occluded by sickled cells

29
Q

How is splenic sequestration caused by SCA?

A

Blood vessels leading out of spleen are occluded by sickle cells, causing a pooling of blood in spleen → sudden drop of Hb in bloodstream

30
Q

How is hyposplenism caused and what are its implications?

A

Repeated vaso-occlusion in the abundant vasculature of the spleen impair its function
1. Increases vulnerability to encapsulated bacterial infections → sepsis
2. Splenomegaly - extra splenic tissue growth to compensate for hyposplenism

31
Q

What is acute chest syndrome caused by?

A

Pulmonary vaso occlusion → fever, cough, chest pain, rapid breathing

32
Q

What are the four main triggers of vaso-occlusive crises?

A
  1. Infection
  2. Exercise
  3. Cold temperature
  4. Dehydration
33
Q

How does infection trigger a vaso-occusive crises?

A

Increased basal metabolic rate → more deoxyHb → more sickling

34
Q

How does exercise trigger a vaso-occusive crises?

A

Increased demand for oxygen → more deoxyHb → more sickling

35
Q

How does cold temperature trigger a vaso-occusive crises?

A

Peripheral vasoconstriction → narrowed blood vessels → increased susceptibility to blockage

36
Q

How does dehydration trigger a vaso-occusive crises?

A

Increased blood viscosity → increased chance of aggregation and blockage

37
Q

How can SCD be generally managed?

A
  • Over the counter painkillers (also called analgesia)
  • Limit exercise and prioritise resting
  • High fluid intake
  • Heat packs to stimulate vasodilation, increasing oxygen reaching local tissues
38
Q

Treatments for SCD

A
  • Blood transfusions to treat anaemia
  • Painkillers to treat crises (standard ibuprofen, opioids for severe pain)
  • Bone marrow transplants for severe cases in younger patients with a matched donor
  • Gene therapy
  • Prophylactic antibiotics
  • VTE prophylaxis (preventing thrombosis)
  • IV fluids (maintaining hydration with saline)
  • Cognitive Behaviour Therapy (to take care of mental health issues arising from living with a chronic illness)
39
Q

Interventions to reduce the frequency of future sickle cell crises

A

Hydroxycarbamide
Monoclonal antibody crizanlizumab

40
Q

How does hydroxycarbamide work?

A
  1. Increases synthesis of HbF to compensate
  2. Reduces neutrophil and reticulocyte production (neutrophils promote vaso-occlusion)
41
Q

How does crizanlizumab work?

A

It binds to p-selectin expressed on endothelial surfaces and block sickle cell adhesion to vessels

42
Q

What is a potential downside to blood transfusions? How can this be mitigated?

A

Could cause hemosiderosis (iron overload in organs); iron chelation therapy can help remove excess iron

43
Q

What is a potential downside to hydroxycarbamide?

A

Increased risk of infection because neutrophils numbers are reduced

44
Q

How can CRISPR gene editing be used to tackle SCD?

A

1a. Cas9 enzyme can target the faulty betaglobin gene in sickle cells, using a guide RNA
1b. Incorrect T base is replaced by A, repairing gene

2a. Cas9 breaks gene that encodes repressor of fetal Hb production - BCL11A
2b. DNA damage and error prone repair to BCL11A gene → stop coding for repressor
2c. Gene expressed → fetal Hb produced

45
Q

Applying ICE

A

Ideas → the patient’s perception of what they have, their reasoning

Concerns → what is the patient worried about?

Expectations → what do they think the doctor can do for them? what do they want?

CSI (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions