L23- Blood clotting cascade

Question 1

haemostasis

Answer 1

Stopping the flow of blood- is the human body’s response to blood vessel injury and bleeding.

Question 3

Hemostasis includes three steps that occur in a rapid sequence:

Answer 3

(1) Vasoconstriction, a brief and intense contraction of blood vessels;
(2) Formation of a platelet plug; and
(3) Blood clotting or coagulation, which reinforces the platelet plug with fibrin mesh that acts as a glue to hold the clot

Question 4

the clotting cascade has three parts

Answer 4

intrinsic

extrinsic

common pathway

Question 5

intrinsic pathway is stimulated when

Answer 5

endothelial lining is damaged- promote binding of factor XII

• more important for amplification of cascade

Question 6

extrinsic pathway is stimulated when

Answer 6

due to trauma- release of tissue factor III

-faster to produce fator X

Question 7

both the intrinsic and extrinsic pathways lead to the

Answer 7

common pathway

Question 8

outline the intrinsic cascade

Answer 8

Slower- more stages

1. Damaged endothelial lining of blood cells promotes binding of factor XII (Hageman factor)
2. Factor XII binds to sub endothelial surface
3. Kallikrein cleaves (activates) XII à XIIa
4. XIIa cleaves XIà XIa
5. XIa cleaves IX à IXa
6. IXa binds VIII and cleaves X à Xa
7. Xa enters the common pathway

Question 9

outline the extrinsic cascade

Answer 9

1. Trauma activates factor VII à VIIA
2. Tissue Factor binds VIIa and activates Xà Xa
3. Xa enters the common pathway

Question 10

outline common pathway

Answer 10

1. Factor X cleaves prothrombin to thrombin
2. Thrombin cleave fibrinogen to fibrin
3. Cross-linking of fibin causes mesh clot

Question 11

the clotting cascade allows

Answer 11

formation of a clot from activation of a very small amount of intita factor –> quick and precise

Question 12

prothrombin

Answer 12

Prothrombin is a plasma protein produced by the liver. Clotting is caused by a series of clotting factors which activate each other, including the conversion of prothrombin to thrombin.

Question 13

the protease (thrombin) part of prothrombin is contained in the

Answer 13

C-terminal domain of the protein (SERINE PROTEASE)

Question 14

two kringle domains in prothrombin help keep

Answer 14

prothrombin in the inactive form

Question 15

gla domains target it to

Answer 15

the appropriate site for it action

• addition of COOh groups to glutamate resides (In GLA) form carboxy glutamate
• allows itneraction with sites of damage and brings together clotting factor

Question 17

what cleaves prothrombin to form thrombin

Answer 17

Xa- stimulated by Va

Question 18

thrombin function

Answer 18

to cleave fibrinogen to fibrin

Question 19

fibrin

Answer 19

an insoluble protein formed from fibrinogen during the clotting of blood. It forms a fibrous mesh that impedes the flow of blood.

Question 20

structure of fibrinogen

Answer 20

• 340kDa protein
• 2 sets of tripeptides, a, b, g, joined at N-termini by disulphide bonds
• N-terminal regions of alpha and B chains are highly negatively charged and prevent aggregation of fibrinogen

Question 21

formation of fibrin clot

Answer 21

1) Thrombin cleaves fibrinopeptides A and B from the central globular domains of fibrinogen
2) Globular domains at the C-terminal ends of the B and Y chains interact with exposed sequences at the N termini of the cleaved b and a chains to form a fibrin mesh/ clot
3) The newly formed clot is stabilised by the formation of amide bonds between the side chains of lysine and glutamine residues in different monomers.
4) This cross-linking reaction is catalysed by transglutaminase, which is activated by protransglutaminase by thrombin

Question 22

classic haemophilia is a defect in

Answer 22

factor VIII

Question 23

factor VIII

Answer 23

VIII (antihaemophilic factor) is not a protease, but markedly stimulates the activity of factor IXa, a serine protease

Question 24

activity of VIII is markely increased by

Answer 24

limited proteolysis by thrombin and factor Xa

Question 25

clotting cascade is an example of

Answer 25

positive feedback

Question 26

treatment for classic haemophilia

Answer 26

recombinant factor VIII

Question 27

stopping the clotting process

Answer 27

1) dilution of prothrombin by blood flow and removal by liver
2) digestion by proteases
3) specific inhibiters

Question 28

digestion of clotting proteases

Answer 28

factors va and VIIIa are degraded by protein C

Question 29

protein C is activated by

Answer 29

thrombin binding to the endothelial receptor thrombomodulin

Question 30

defects in protein C can cause

Answer 30

thrombotic disease

Question 31

specific inhibitors that stop the clotting cascade

Answer 31

antithrombin II (AT3)

• enhanced by heparin binding

Question 32

fibrinolysis

Answer 32

breakdown of clots

Question 33

which enzymes cause fibrinolysis

Answer 33

T-PA

and

streptokinase

–> activate plasminiogen to become plasmin

–> plasmin dissolves the fibrin clot to become fibrin fragments