PHARM - Drugs That Modulate Haemostasis and Thrombosis - Week 6

Question 1

Define haemostasis.

Answer 1

Arrest of blood loss from damaged vessels

Question 2

Define coagulation.

Answer 2

Formation of a fibrin clot in a blood vessel

Question 3

Define thrombosis.

Answer 3

Pathological formation of a haemostatic plug in a blood vessel in the absence of blood loss

Question 4

Name the two kinds of thrombi and where they occur.

Answer 4

Arterial thrombus (white)
Venous thrombus (red)

Question 5

What are the three components of a white arterial thrombus?

Answer 5

Platelets and white blood cells in a fibrous mesh

Question 6

What are aterial thrombi associated with?

Answer 6

Vessel wall damage (atherosclerosis)

Question 7

What are venous thrombi associated with?

Answer 7

Blood stasis

Question 8

What are the three components of a venous thrombus?

Answer 8

Fibrin, platelets, and red blood cells

Question 9

What can happen to a venous thrombus?

Answer 9

Can break off and lead to an embolus lodged in the lungs (pulmonary embolism) or the brain (stroke)

Question 10

Define a thromboembolus.

Answer 10

A blockage in a blood vessel caused by a dislodged thrombus.

Question 11

Does damage to a blood vessel lead to vasodilation or vasoconstriction?

Answer 11

Vasoconstriction.

Question 12

Is 5-HT a vasodilator or vasoconstrictor?

Answer 12

Powerful vasoconstrictor

Question 13

Describe in three steps, the mechanism of vasoconstriction following blood vessel damage.

Answer 13

Collagen exposed on a damaged vessel wall.
Platelets stick to the collagen and activate
ADP and 5-HT released from platelets

Question 14

Describe in 5 steps, the mechanism of platelet activation and adhesion.

Answer 14

ADP from activated platelets cause others to activate and morph
Granule contents (ADP/5-HT) are secreted
Mediators are synthesised (thromboxane)
Platelets aggregate and adhere via fibrinogen
Soft plug formed

Question 15

Platelets aggregate and adhere via fibrinogen and bridge between which two receptors?

Answer 15

GPIIb an GPIIIa

Question 16

Briefly describe in steps, how a platelet activates.

Answer 16

PLA2 cleaves phospholipids to release free arachidonic acid
COX enzymes convert arachidonic acid to TXA2
TXA2 mediates increased Ca2+, which induces adhesion and aggregation

Question 17

Name 4 stimuli for platelet activation.

Answer 17

Collagen
Thrombin
Thromboxane
ADP

Question 18

Describe the mechanism of fibrin deposition.

Answer 18

Thrombin cleaves fibrinogen into fibrin, which is an insoluble monomer

Question 19

Is fibrin or fibrinogen soluble?

Answer 19

Fibrinogen

Question 20

Is thrombin found in the plasma? Explain.

Answer 20

No, it is produced by activating prothrombin

Question 21

How many cascade reactions are there in haemostasis? List them and note which is faster.

Answer 21

Two
Extrinsic and intrinsic
Extrinsic is faster

Question 22

What factor is released in the extrinsic pathway?

Answer 22

Thromboplastin

Question 23

What is the action of thromboplastin?

Answer 23

Converts factor VII to VIIa

Question 24

What is the factor for the intrinsic pathway?

Answer 24

Exposed collagen (and negative charges, glass etc)

Question 25

What factor controls cascade inhibition?

Answer 25

Enzyme inhibitors like antithrombin III

Question 26

What is the action of plasmin?

Answer 26

Fibrinolysis

Question 27

Describe the three components of Virchow's triad.

Answer 27

Vessel damage Blood stasis Hypercoagulability

Question 28

Name 2 common situations of blood stasis that leads to thrombus formation.

Answer 28

Atrial fibrillation | Deep vein thrombosis

Question 29

Name a common cause of blood vessel damage that leads to thrombus formation.

Answer 29

Atherosclerosis

Question 30

What is a thrombus in coronary vessels called?

Answer 30

Myocardial infarction

Question 31

What is a thrombus in carotid arteries called?

Answer 31

Stroke

Question 32

Give an example of a procoagulant drug.

Answer 32

Vitamin K

Question 33

Give an example of an injectable anticoagulant and what kind of therapy that drug might be used for.

Answer 33

Heparin - used acutely for short term action

Question 34

Give an example of an oral anticoagulant and what kind of therapy that drug might be used for.

Answer 34

Warfarin - used for prolonged therapy

Question 35

What is the action of factor Xa?

Answer 35

Converts prothrombin into thrombin, which converts fibrinogen into fibrin

Question 36

What is the mechanism of action for heparin?

Answer 36

Enhances the activity of antithrombin III

Question 37

What is the action of antithrombin III?

Answer 37

A natural inhibitor of factor Xa and thrombin

Question 38

Consider light molecular weight heparins. How does their action differ to regular heparin (2)? Compare the anticoagulation effects.

Answer 38

Has the same effect of factor Xa, but less effect on thrombin Anticoagulant effects are similar

Question 39

How is heparin administered and what charge does it have?

Answer 39

Injected and largely negative

Question 40

What is the half-life of low molecular weight heparin and what is a benefit of this?

Answer 40

Longer elimination half life | Used for patient self-administration

Question 41

Are injectable coagulants available orally?

Answer 41

no

Question 42

How can you monitor anticoagulant effects of heparin?

Answer 42

Measuring activated partial thromboplastin time.

Question 43

Define the activated partial thromboplastin time.

Answer 43

Time for clot formation in citrated plasma after the addition of Ca2+, contact activator and phospholipid

Question 44

What is activated partial thromboplastin time a measure of?

Answer 44

Intrinsic pathway

Question 45

Name three adverse effects of heparin and a mechanism why.

Answer 45

Haemorrhage (self explanatory) Thrombocytopaenia (platelet deficiency) Osteoporosis (mechanism unknown)

Question 46

What four clotting factors is vitamin K essential for the formation of? What is required of these factors after synthesis? How does vitamin K play a role here?

Answer 46

Factors II, VII, IX, and X Gamma carboxylation Reduced vitamin K is a cofactor in the carboxylation of glutamate

Question 47

How do oral anticoagulants work (mechanism of action)?

Answer 47

Inhibits the reduction of vitamin K, inhibiting the gamma carboxylation of glutamate in factors II, VII, IX, and X

Question 48

Does warfarin have a rapid or delayed onset of action?

Answer 48

Delayed

Question 49

Can warfarin inhibit factors that are already active?

Answer 49

Noh

Question 50

What does warfarin bind to once absorbed orally?

Answer 50

Plasma proteins

Question 51

Is warfarin rapidly or slowly absorbed orally?

Answer 51

Rapidly

Question 52

Name 4 adverse effects of warfarin and why if applicable.

Answer 52

``` Haemorrhage Vitamin K deficiency Hepatic disease (impaired synthesis of clotting factors) Hypermetabolic states (increased metabolism of clotting factors) ```

Question 53

Name three possible drug interactions that can occur with warfarin and the mechanism involved.

Answer 53

``` Impaired platelet aggregation -aspirin Competition for plasma protein binding -NSAIDs Competition for cytochrome p540 pathway -cimetidine ```

Question 54

What four things can reduce warfarin activity?

Answer 54

Pregnancy Drug interactions -induction of liver enzymes/chronic alcohol use Vitamin K supplements

Question 55

Define prothrombin time and what it measures.

Answer 55

Time for clot formation of plasma after addition of Ca2+ and tissue factors Measures extrinsic pathway

Question 56

Define international normalised ratio.

Answer 56

Ratio of patient thrombin time to normal thrombin time

Question 57

Define NDACs.

Answer 57

Non-vitamin K dependent anticoagulant agents

Question 58

Do NDACs have a high or low molecular weight?

Answer 58

Low

Question 59

Are NDACs orally available or injected?

Answer 59

Orally available.

Question 60

Do NDACs have a more or less predictable dose-response? What does this result in?

Answer 60

More predictable | Results in reduced laboratory monitoring required

Question 61

In what three ways can NDACs have an anticoagulant effect?

Answer 61

Indirect factor Xa inhibitor Direct factor Xa inhibitor Direct thrombin inhibitor

Question 62

Name three drugs that affect platelet activation and adhesion.

Answer 62

ADP receptor antagonists Thromboxane synthesis inhibitors Glycoprotein IIb/IIIa receptor antagonists

Question 63

What are the guidelines for the use of platelet inhibitors (2)?

Answer 63

As an adjunctive therapy with aspirin | In patients intolerant to aspirin

Question 64

What is thromboxane a potent activator of?

Answer 64

Platelets

Question 65

Where are thromboxanes synthesised, from what, and by what?

Answer 65

In platelets from arachidonic acid by cyclo-oxygenase

Question 66

In what three ways does aspirin mediate anticoagulation and how?

Answer 66

Reduces thromboxane synthesis Decreases platelet aggregation Decreases vasoconstriction Is an irreversible cyclo-oxygenase inhibitor

Question 67

Describe low dose aspirin therapy (3). What does it preserve and how?

Answer 67

Platelets are exposed to aspirin as they circulate in the portal vein. Aspirin causes irreversible inhibition of COX in exposed platelets. This decreases platelet aggregation. Endothelial production of prostaglandin I2 is preserved. -beneficial vasodilation is preserved.

Question 68

How do fibrinolytic drugs work?

Answer 68

Activates plasminogen

Question 69

Describe why some fibrinolytic drugs are single use.

Answer 69

Are antigenic so single use like streptokinase

Question 70

What kind of drug is alteplase and is it single use?

Answer 70

It is a fibrinolytic drug that is not single use because it is not antigenic.

Question 71

What is alteplase more active on?

Answer 71

On fibrin-bound plasminogen so it is clot selective.