50 - Drugs Affecting Coagulation

Question 1

Clot vs thrombus

Answer 1

Thrombus forms in vivo, clot in vitro

Question 2

Factors released by activated platelets, upon binding to damaged endothelium

Answer 2

5-HT, ADP. Powerful vasoconstrictors.

Question 3

Mechanism of platelet activation and adhesion
1)
2)
3)
4)
5)

Answer 3

1) ADP released from platelets causes others to activate, change shape
2) Platelets release granule contents (ADP, 5-HT)
3) Mediators synthesised (EG: thromboxane)
4) Platelets aggregate, adhere via fibrinogen bridging between GPIIb, GPIIIa receptors
5) Soft plug formed

Question 4

Some stimuli for platelet activation
1)
2)
3)
4)

Answer 4

1) Collagen
2) Thrombin
3) Thromboxane
4) ADP

Question 5

Mechanism of fibrin deposition
1)
2)

Answer 5

1) Thrombin cleaves fibrinogen to fibrin

2) Thrombin is produced through activation of prothrombin

Question 6

Two pathways that can result in activation of prothrombin

Answer 6

1) Intrinsic - Exposed collagen or foreign material, negative charges
2) Extrinsic - Damaged tissues release thromboplastin

Question 7

Important aspects of the coagulation cascade
1)
2)
3)
4)

Answer 7

1) A small signal (EG: factor XII) leads to a large amount of product (fibrin)
2) Each step leads to the formation of more product (amplification)
3) The factors are proteases
4) The extrinsic pathway is faster than the intrinsic (intrinsic has more steps)

Question 8

Function of thromboplastin

Answer 8

Initiates the extrinsic pathway.

Converts factor VII to VIIa.

Question 9

Point of convergence between intrinsic and extrinsic pathways

Answer 9

Conversion of factor X to Xa

Question 10

Common pathway of intrinsic and extrinsic pathways
1)
2)
3)

Answer 10

1) X–>Xa
2) Xa/Va complex convert prothrombin to thrombin
3) Thrombin converts fibrinogen to fibrin, which forms a stable clot

Question 11

What converts X to Xa from extrinsic pathway?

Answer 11

VIIa

Question 12

What converts X to Xa from intrinsic pathway?

Answer 12

IXa, with Ca2+ and VIII as cofactors

Question 13

Example of a clotting cascade inhibitor

Answer 13

Antithrombin III.

Question 14

Fibrinolysis by plasmin mechanism
1)
2)
3)
4)
5)
6)

Answer 14

1) Thrombomodulin binds to thrombin.
2) Thrombomodulin/thrombin complex activates protein C
3) Activated protein C inactivates factors VIIIa, Va
4) Activated protein C inactivates inhibitor of tissue plasminogen
5) Plasminogen becomes plasmin.
6) Plasmin fibrolyses

Question 15

Examples of where blood stasis can lead to a thrombus

Answer 15

DVT, atrial fibrillation

Question 16

Targets for anti-coagulant drugs
1)
2)
3)

Answer 16

1) Coagulation (fibrin formation)
2) Platelets
3) Fibrinolysis

Question 17

Example of a procoagulant drug

Answer 17

Vitamin K

Question 18

Examples of injectable anticoagulant drugs

Answer 18

Heparin, low molecular weight heparins

Question 19

Short-term anticoagulants

Answer 19

Heparin, low molecular weight heparins

Question 20

Long-term anticoagulants

Answer 20

Warfarin

Question 21

Antithrombin III effect

Answer 21

Inhibits Xa and thrombin

Question 22

Heparin function

Answer 22

Enhances activity of antithrombin III by binding, exposing active site.
This increases antithrombin III inhibition of Xa and thromibn

Question 23

Low molecular weight heparins action

Answer 23

Enhances antithrombin III activity, has same effect on factor Xa as heparin, less effect on thrombin

Question 24

Differences between heparin and LMW heparins
1)
2)
3)

Answer 24

1) Heparin is much larger molecule (60-100 kD vs 2-9kD)
2) LMW heparins have a much longer elimination half life
3) Both are not orally available

Question 25

How is anti-coagulant activity of heparin monitored?

Answer 25

Activated partial thromboplastin time.

Measure of intrinsic pathway

Question 26

Pathway of coagulation that heparin mostly interferes with

Answer 26

Intrinsic pathway

Question 27

Adverse effects of heparin
1)
2)
3)

Answer 27

1) Haemorrhage
2) Thrombocytopaenia (platelet deficiency)
3) Osteoporosis (mechanism unknown)

Question 28

Role of vitamin K

Answer 28

Factors II, VII, IX and X require gamma carboxylation of glutamate on them for function.

Vitamin K is a cofactor in this process.

Question 29

What is warfarin derived from?

Answer 29

Coumarin

Question 30

How does warfarin work?

Answer 30

Inhibits reduction of vitamin K, which is required for gamma carboxylation of II, VII, IX and X.

Inhibits vitamin K reductase

Question 31

Aspects of warfarin function
1)
2)
3)

Answer 31

1) Only active in vivo
2) Delayed onset of function
3) Doesn’t affect already activated factors II, VII, IX and X

Question 32

Adverse effects of warfarin

Answer 32

Haemorrhage

Question 33

Why is warfarin a ‘moody’ drug?
1)
2)
3)

Answer 33

Anticoagulant activity is very labile:

1) Dietary levels of vitamin K change potency a lot.
2) Hepatic disease can impair synthesis of clotting factors
3) Hypermetabolic states can increase metabolism of clotting factors

Question 34

How is warfarin poisoning reversed?

Answer 34

Vitamin K administered (oral or IV).

Fresh frozen plasma

Question 35

Pharmacokinetics of warfarin

Answer 35

1) Orally available
2) Rapidly absorbed
3) Strongly bound to plasma proteins (over 99%)

Question 36

Drug interactions that increase activity of warfarin
1)
2)
3)

Answer 36

1) Aspirin (decreased platelet aggregation)
2) NSAIDs compete for plasma protein binding
3) Drugs can compete for cytochrome p450 metabolism pathway, reducing warfarin clearance (EG: acute alcohol consumption)

Question 37

What can decrease warfarin activity?
1)
2)
3)

Answer 37

1) Pregnancy
2) Induction of liver enzymes (EG: with barbiturates, chronic alcohol consumption)
3) Vitamin K supplements

Question 38

How is warfarin activity monitored?

Answer 38

Prothrombin time.

Measure of the extrinsic pathway.

Question 39

Coagulation test of the intrinsic pathway

Answer 39

Activated partial thromboplastin time.

Question 40

Coagulation test of the extrinsic pathway

Answer 40

Prothrombin time

Question 41

New anticoagulant drugs
1)
2)
3)

Answer 41

1) Indirect factor Xa inhibitors
2) Direct factor X inhibitors
3) Direct thrombin inhibitors

Question 42

Drugs affecting platelet aggregation and adhesion
1)
2)
3)

Answer 42

1) ADP receptor antagonists
2) Thromboxane synthesis inhibitors (EG: aspirin)
3) Glycoprotein GPIIb,GPIIIa inhibitors (prevents fibrin binding, stops platelet aggregation)

Question 43

When are platelet inhibitors used?

Answer 43

As adjunctive therapy with aspirin

In patients intolerant of aspirin

Question 44

Example of GPIIb/IIIa inhibitor

Answer 44

Abciximab.

For IV use in acute risk coronary syndromes

Question 45

Effect of ADP receptor antagonists

Answer 45

Prevent platelet activation

Question 46

Fibrinolytic drugs
1)
2)

Answer 46

1) Streptokinase

2) Alteplase

Question 47

Proportion of aspirin dose inactivated in first-pass metabolism

Answer 47

90%

Question 48

Streptokinase
1)
2)
3)
4)

Answer 48

1) Fibrinolytic
2) IV administration
3) Activates plasminogen
4) Streptococcus-derived, so can only be used once (antigenic)

Question 49

Alteplase
1)
2)
3)
4)
5

Answer 49

1) Human recombinant tissue plasminogen activator
2) Non-antigenic
3) IV-administered (short half-life)
4) More active on fibrin-bound plasminogen, so clot-selective.
5) Extremely expensive