Lecture 28: Clotting Cascade (Staudinger)

Question 1

What is the extrinsic pathway of platelet activation?

What is the intrinsic pathway of platelet activation?

Answer 1

Activated by external trauma, quicker, involves factor VII

Activated by internal trauma, slower, involves factors XII, XI, IX, VIII

Question 2

What is the common pathway of platelet activation?

Answer 2

E and I pathways converge to finish clotting, involves factors I, II, V and X

Question 3

Overview of the clotting cascade

Answer 3

Endothelial damage > blood exposed to subendothelial substances (collagen, vWF, TF) > platelet adheres to the vascular wall > platelets on the wall express
GIIa/Iia which binds fibrinogen on the platelets and causes them to aggregate on the vascular wall

Question 4

Tissue Factor effects:

Answer 4

On the surface of subendothelial cells, not normally on cells
Binds factor 7 in the blood > activates via proteolysis which produces factor VIIa > factor VIIa converts Factors 9 and 10 to 9a and 10a > these two will cleave PTF II to PTF IIa

Question 5

Thrombin effects:

Answer 5

1. Cleaves fibrinogen to fibrin > non covalent bonding of fibrin monomers
2. Helps activate prothrombin on platelets by converting 5 and 8 to 5a and 8a > these two will enhance the effects of 10a and 9a, respectively

Question 6

How does thrombin also enhance the effect of factor 10?

Answer 6

8a/9a complex provides another pathway for further activation of factor 10

Question 7

What eventually stabilizes the clotting aggregates?

Answer 7

Factor 13a

Question 8

What does heparin do?

Answer 8

Enhances the ability of antithrombin III (ATIII) to inactivate thrombin, factor 9a and 10a. ATIII binds heparin, making it a better substrate for proteases thrombin, factor 9a and 10a > binding of ATIII to the proteases blocks protease activity (suicide inhibition)

Question 9

What is the difference between primary hemostasis and secondary hemostasis?

Answer 9

Primary: platelet aggregation/plug at injury site (weaker plug)
Secondary: fibrin enhances the plug (stronger plug)

Question 10

What is the mechanism of action of anticoagulants?

Answer 10

Inhibits vitamin K action to block clotting

Question 11

What are the two types of oral anticoagulants?

Answer 11

Hydroxycoumarins (Warfarin group) and Indanediones

Question 12

How is Vitamin K activated?

Answer 12

Vitamin K is turned into quinone by Vit. K 2,3 epoxide reductase using NADH
Quinone turned into quinol (active form) by Vit. K Quinon reductase

Question 13

Why is vitamin K important in clotting?

Answer 13

Clotting depends on Vit. K dependent reactions as it is required to synthesize factors 2,7,9,10, Protein S and C

Question 14

What process activates the clotting factors?

Answer 14

Gamma - glutamyl carboxylation

Question 15

Which form of warfarin is more potent in producing an anticoagulant response?

Answer 15

S-warfarin > R warfarin.

Only free warfarin is active pharmacologically

Question 16

How does Protein C and S regulation coagulation?

What happens when you have deficiency in Protein C and S?

Answer 16

• they inactivate Factors 5a and 8a

- increased risk of DVTs

Question 17

What causes Hemophilia A?

Answer 17

Defective Factor 8a > cannot clot properly

Question 18

What does an INR tell you?

Answer 18

Measures the deviation from standard normal clotting time (too high = blood clots way slower than normal and vice versa)

Question 19

What is the difference between PT (prothrombin time) and PTT (partial prothrombin time)?

Answer 19

PT measures extrinsic coagulation pathway (factors 1,2,5,7,9,10)
PTT measures intrinsic coagulation pathway (factors 12, 11, 9, 8, 10, 5, 2, 1, PK and HK

Question 20

What are the normal values for PT and PTT?

Answer 20

PT: 12-13 s
PTT: 25-35 s

Question 21

If you have prolonged PT and normal PTT, what does this signify?

Answer 21

Liver disease, decreased Vit. K, factor 8, DIC or patient is on anticoagulation therapy (warfarin)