Clotting Cascade

Question 1

When a pt is first given Warfarin, why is the full effect not seen for about 48 hours?

Answer 1

Because the previously activated factors in the blood must decline and re-synthesis must begin before warfarin will interfere

Question 2

What is the half life of factor II?

Answer 2

60 hours

Question 3

What is the half life of factor IX?

Answer 3

24 hours

Question 4

What is the half life for factor X?

Answer 4

40-60 hours

Question 5

What are the two pathways for secondary hemostasis?

Answer 5

Intrinsic and extrinsic

Question 6

What is the extrinsic pathway?

Answer 6

Activated by external trauma
Blood escapes vascular system
Quicker than the intrinsic pathway
Involves factor VII

Question 7

What is the intrinsic pathway?

Answer 7

Activated by trauma inside the vascular system
Activated by platelets, exposed endothelium, chemicals or collagen
Slower than the extrinsic pathway
Involves factor XII, XI, IX and VIII

Question 8

What is the common pathway?

Answer 8

Pathways meet and finish the pathway of clot production

Involves factors I, II, V and X

Question 9

What is primary hemostasis?

Answer 9

Platelets in the blood aggregate at the injury site and form a platelet plug to block the hole

Question 10

What is secondary hemostasis?

Answer 10

Platelet plug is further reinforced by a fibrin mesh produced through proteolytic coagulation cascade

Question 11

What is the key difference between primary and secondary hemostasis?

Answer 11

Primary hemostasis makes a weak platelet plug at the injury site while secondary hemostasis makes it strong by generating a fibrin mesh on it

Question 12

What are the major actions of thrombin?

Answer 12

Prothrombin —> thrombin 
Activation of platelets 
Factor XIII -> XIIIa cross linked fibrin 
Fibrinogen —> fibrin 
Factor V -> Va 
Factor VIII —> VIIIa

Question 13

What are the two types of anticoagulants?

Answer 13

Hydroxycoumarins (ex. Warfarin)

Indanediones

Question 14

What is the mechanism of action for anticoagulants?

Answer 14

Vitamin K inhibition

Question 15

What is the first step for the activation of vitamin K?

Answer 15

Vitamin K 2,3 epoxide reductase uses reduced NADH as a cofactor to convert vitamin K 2,3 epoxide —> quinone form

Question 16

What is the second step for the activation of vitamin K?

Answer 16

Quinone reductase reduces the quinone form of vitamin K —> the active vitamin K quinol form

Question 17

What is the role of gamma-glutamyl carboxylation in the vitamin K cycle?

Answer 17

Converts active vitamin K quinol back into the inactive vitamin K 2,3 epoxide
Also converts inactive factors II, VII, IX, X, proteins S and C into their active forms

Question 18

What does warfarin target?

Answer 18

Vitamin K dependent epoxide reductase

Decreases its activity which increases the time it takes for a clot to form

Question 19

What is vitamin K epoxide reductase?

Answer 19

An enzyme that reduces vitamin K after it has been oxidized in the carboxylation of glutamic acid residues in blood coagulation enzymes II, VII, IX and X as well as proteins S and C

Question 20

What is the mechanism of action for warfarin?

Answer 20

Blockade of gamma-carboxylation of several glutamate residues in prothrombin (II) and factors VII, IX and X as well as endogenous anticoagulant proteins C and S

Question 21

What enzymes are involved in the metabolism of warfarin?

Answer 21

CYP2C9 makes S-warfarin

CYP1A2, 3A4, 2C19 make R warfarin

Question 22

Peak plasma concentrations of warfarin occur when?

Answer 22

3 hours after drug administration

Question 23

Describe S warfarin

Answer 23

More highly bound to albumin than R warfarin
Less protein bound than R warfarin
5x more potent as a blood anticoagulant than R warfarin

Question 24

Drugs that alter the level of free warfarin (e.g. by competing or binding to albumin or inhibiting warfarin metabolism) may influence what?

Answer 24

The anticoagulant effect

Question 25

What are the roles of proteins C and S?

Answer 25

Play an important role in regulating anticoagulation
Maintain the permeability of blood vessel walls
Proteolytically inactivate factor Va and factor VIIIa

Question 26

What does a genetic protein C deficiency cause?

Answer 26

A significantly increased risk of venous thrombosis

Question 27

What is hemophilia A?

Answer 27

Called factor VIII deficiency or classic hemophilia A
Genetic disorder caused by missing or defective factor VIII
Usually passed down from parents to children but 1/3 of cases are caused by a spontaneous mutation

Question 28

What is hemophilia B?

Answer 28

Also called factor IX deficiency or Christmas disease

Question 29

What does prothrombin time (PT) measure?

Answer 29

The extrinsic pathway

PET

Question 30

What does the partial thromboplastin time (PTT) measure?

Answer 30

The intrinsic pathway

PITT

Question 31

Which factors are in the final common pathway?

Answer 31

I, II, V and X

1 x 2 x 5 = 10

Question 32

Why does end stage liver disease tend to cause increased PT before increased PTT?

Answer 32

Because of deficient production of factor VII, which has a short circulating half life

Question 33

Which factor has the shortest circulating half life?

Answer 33

Factor VII

Question 34

Which factors are vitamin K dependent?

Answer 34

Factor II, VII, IX, X, protein C and S

Question 35

What conditions may be present in someone with prolonged PT and normal PTT?

Answer 35

Liver disease
Decreased vitamin K, decreased or defective factor VII, chronic low grade disseminated intravascular coagulation (DIC), anticoagulation drug (warfarin) therapy

Question 36

A clotting tendency may be caused by what?

Answer 36

Genetic deficiency of blood factors protein C, S and VLeiden