Haemoglobinopathies

Question 1

What amino acid change occurs due to a single base mutation in sickle cell??

Answer 1

Glutamate–> valine

Question 2

What nucleotide change happens in sickle cell?

Answer 2

Adenine–> thymine

Question 3

Why would cold precipitate a sickle cell crisis?

Answer 3

In cold- vasoconstriction

Therefore capillaries narrow and RBC more likely to get stuck

Question 4

Why would being ill precipitate a sickle cell crisis?

Answer 4

Increased number of WBC in blood
Blood becomes more viscous
TF increases chance of occlusion

Question 5

How would dehydration precipitate a sickle cell crisis?

Answer 5

Less water in blood
Increase in blood viscosity
Increased chance of occlusion

Question 6

What is the word describing when sickled RBC get stuck in blood vessels?

Answer 6

Occlusion

Question 7

What is a sickle cell crisis?

Answer 7

Lack of perfusion to an area (lack of O2 delivered to an area)
Causes ischaemia and pain

Question 8

Define ischaemia

Answer 8

Inadequate blood supply to an organ/area

Question 9

In sickle cell, where does the mutation occur? What is it?

Answer 9

B sub unit of Hb
A–>T
Glutamate–> Valine

Question 10

Why won’t infants show symptoms of sickle cell immediately?

Answer 10

Because they have fetal haemoglobin- 2alpha & 2gamma. As SC affects B sub unit (which they don’t have), they won’t show symptoms until enough HbF has been replaced by HbS for suckling to occur.

Question 11

What are the opposing characteristics of glutamate and valine?

Answer 11

Glutamate is hydrophilic, Valine is hydrophobic

Question 12

Which chromosome is affected in sickle cell?

Answer 12

Chromosome 11

Question 13

Why won’t infants show symptoms of sickle cell immediately?

Answer 13

Because they have fetal haemoglobin- 2alpha & 2gamma. As SC affects B sub unit (which they don’t have), they won’t show symptoms until enough HbF has been replaced by HbS for suckling to occur.

Question 14

What causes sickling of RBC?

Answer 14

Glu->Val. In T/deoxy state, change to T state exposes sticky hydrophobic pockets on β sub unit, Hb molecules polymerise, causing sickling of RBC.

Question 15

What are the consequences of sickling RBC? In brief.

Answer 15

*Transition from R->T state less likely *Less O2 binds to Hb *More O2 released to tissues

Question 16

In sickle cell, how do RBC become irreversibly sickles/damaged?

Answer 16

In oxygenated state, they’re normal/bi concave, in T/deoxy state they’re sickled. When they become oxygenated again they return to biconcave, continuous change reduces elasticity and so they stay sickled.

Question 17

Lifespan of normal and sickled RBC?

Answer 17

Normal= 120 days, Sickled= 20 days

Question 18

Why do sickled RBC have a much shorter lifespan?

Answer 18

As O2 can’t bind as well, O2 forms superoxide which destroys fatty acids in RBC membrane (more likely to lyse) and causes production of Heinz Bodies. Spleen removes RBC with Heinz bodies and macrophages phagocytose RBC with altered membrane.

Question 19

Why do they get anaemia in sickle cell?

Answer 19

Superoxide alters membrane structure causing haemolysis. Bone marrow can’t replace RBC as fast as they are being destroyed.
Also, polymerised Hb can’t bind as much O2

Question 20

How may sickle cell lead to jaundice?

Answer 20

Haemolytic anaemia. Lots of haem being broken down lots of bilirubin, build up of bilirubin causes jaundice. Pre-hepatic jaundice

Question 21

What is a sickle cell crisis?

Answer 21

Due to their reduced flexibility, sickled RBC can’t bend through small capillaries and so get stuck. (Occlusion) causing lack of perfusion to tissues, and lack of O2 (ischaemia)–>causing cell death (infarction) and pain.

Question 22

Which organs are most often affected in a sickle cell crisis? Causing what..?

Answer 22

Bone, chest (pleuritic pain, breathlessness), brain (fits)

Question 23

List a few ways you would manage sickle cell

Answer 23

Avoiding factors that would precipitate a crisis eg keeping warm, hydrated (IV fluids), oxygen (to try and promote R state and binding of O2), antibiotics (to reduce infection), pain killers

Question 24

How has sickle cell trait been favoured in inheritance?

Answer 24

Those who are carriers of SC, TF have 50:50 sickled:normal RBC, are protected against malaria. TF they often live longer than those without trait and so can reproduce and pass on their trait to offspring.

Question 25

What will the haemoglobin of carriers of SC be like?

Answer 25

50:50 normal Hb:HbS

Question 26

Factors that can precipitate a sickle cell crisis

Answer 26

Cold, lack of O2, more CO2, low pH, dehydration, illness, increased 2,3-BPG.

Question 27

What is the genetic inheritance of Thalassaemias?

Answer 27

Autosomal recessive

Question 28

What is a Thalassaemia?

Answer 28

Imbalance between the number of alpha and beta chains in Hb

Question 29

What I the difference between a B and A Thalassaemia?

Answer 29

A are when there is a lack of/absense of Alpha globin chains but B is a lack/absense of Beta globin chains

Question 30

What mutation usually causes a B thalassemia?

Answer 30

Point mutation (SNP)

Question 31

What mutation usually causes A Thalassaemia?

Answer 31

Deletion

Question 32

What is a silent carrier of A Thalassaemia?

Answer 32

Someone who has only one gene for alpha globin chains missing

Question 33

How many copies of the gene for A globin chains do we have if normal?

Answer 33

4

Question 34

How many copies of the B globin chain gene do we have if normal?

Answer 34

2

Question 35

Describe what happens with B Thalassaemia.

Answer 35

Lack/absense of B globin chains, A chain synthesis remains normal TF there is an excess of A chains. A chains precipitate as unstable tetramers leading to their destruction (causing anaemia)

Question 36

What is B Thalassaemia major?

Answer 36

When both the genes for B globin chains are absent

Question 37

Why doesn’t B Thalassaemia appear immediately?

Answer 37

Fetal haemoglobin has no B chains, therefore won’t become apparent until enough HbF has been replaced.

Question 38

How would you treat/manage a Thalassaemia?

Answer 38

Blood transfusions

Eventually stem cell transplant

Question 39

What is hydrops fatalis?

Answer 39

Complete lack of alpha globin chains due to complete absense of all 4 genes. Only B and Gamma chains present. Hb B form polymer wth high affinity for O2
Usually fatal as Hb B can’t release O2 easily

Question 40

Why is hydrops fatalis usually fatal?

Answer 40

Hb B polymers that form have a very high affinity for O2 and so can’t easily release O2 to tissues.

Question 41

Why are there varying levels of severity with A thalassemia?

Answer 41

We have normally 4 genes for Alpha globin chains

Question 42

How would acidosis lead to sickle cell crisis?

Answer 42

Binding of H+ ions promotes T state, change to T state exposes sticky hydrophobic pockets on Valine on β sub unit, Hb polymerise leading to sickling of RBC.