Topic 8: Blood Clotting

Question 1

why does clotting need to be tightly regulated

Answer 1

so happens at the correct time

Question 2

what pathways make up clotting

Answer 2

intrinsic and extrinsic

Question 3

what is the blood clotting cascade

Answer 3

intrinsic and extrinsic -> factor X activation -> thrombin activation -> formation of fibrin clot

Question 4

what is the intrinsic pathway

Answer 4

damaged endothelial lining of blood cells promotes binding of factor XII

Question 5

what is the extrinsic pathway

Answer 5

trauma releases tissue factor (factor III)

Question 6

what is the common end point

Answer 6

factor X activation

Question 7

why is blood clotting a cascade

Answer 7

a series of reactions each catalysed by an enzyme
each steps lead to an amplification of the original signal
very small amounts of initial signal - large formation
so v specific

Question 8

what is the molecular structure of prothrombin

Answer 8

polypeptide chain
towards C terminus a protease ( act on fibrinogen, precursor for fibrin so becomes active)
two kringle domains to help keep prothrombin in inactive form
Gla domains target it to appropriate site of damage

Question 9

what and how is fibrinogen converted

Answer 9

by thrombin into fibrin

Question 10

what is fibrinogen

Answer 10

precursor molecule

Question 11

what is the structure of fibrinogen

Answer 11

composed of 3 polypeptide chains
2 globular heads seperated by rod like triple helical alpha helices
fibrinopeptides - prevent fibrinogen molecules coming together so not form a clot

Question 12

why is fibrinogen inactive

Answer 12

due to fibropeptides which prevent fibrinogen forming a clot

Question 13

how is fibrinogen converted into fibrin

Answer 13

by thrombin
cuts of fibrinopeptides to produce fibrin
the fibrin monomers formed can form non-covalent interactions to form a soft clot
cross linking of soft clot by covalent bonds between Lys and Gln residued - catalysed by transglutaminase (factor XIII)

Question 14

what are other molecules present in the pathway

Answer 14

cofactors: factors V and VIII which stimulate activity of other enzymes

Question 15

how is the pathway sustained

Answer 15

thrombin - positive feedback on factors V, VIII, XI and XIII

Question 16

what are the roles of Gla residues

Answer 16

if damage to lining of endothelial - expose negatively charged phospholipid regions so calcium binds to these
post translational modification of factors II, VII, IX, X in liver - adds COOH groups so more negatively charged (requires vit K) so attracted due to interaction with calcium ions. so goes to site of damage

Question 17

how to stop the clotting process

Answer 17

1. localisation of pro(thrombin), dilution of clotting factors by blood flow and removal by liver
2. digestion by proteases, eg: protein C - negative feedback
3. binding of specific inbibitors, eg: antithrombin III

Question 18

how do you break the clot

Answer 18

fibrinolysis - after sufficient healing

plasminogen (inactive precursor) -> plasmin which breaks down fibrin to fibrin fragments

Question 19

what are molecules that can form plasmin

Answer 19

steptokinase

Question 20

how is clotting regulated

Answer 20

1. inactive zymogens present at low levels
2. proteolytic activation
3. amplification of initial signal by cascade mechanism
4. clustering of clotting factors at site of damage
5. feedback activation by thrombin
6. termination of thrombin
7. clot breakdown controlled by proteolytic activation