Anticoagulants, antithrombotics and thrombolytics

Question 1

What are the 2 major components of the hemostatic process?

Answer 1

Platelets (cellular)

Humoral (soluble) factors

Question 2

What is the last step of the clotting cascade?

Answer 2

Fibrinogen to fibrin

Question 3

Why is EDTA able to act as an anticoagulant?

Answer 3

Because calcium is a critical component of the clotting cascade and EDTA chelates it

Question 4

What degrades fibrin? What is its precursor? What is the product of fibrin degradation?

Answer 4

Plasmin
Plasminogen
Fibrin degradation products

Question 5

What are the three ways by which clotting pathway integrity can be assessed?

Answer 5

Prothrombin time (PT)
Activated partial thromboplastin time (PTT)
Thrombin time (TT)

Question 6

What factors are synthesized in the liver? (5)

Answer 6

2, 5, 7, 9, 10

Question 7

What factors require vit K for gamma carboxylation? (5)

Answer 7

2, prothrombin, 7, 9, 10

Question 8

What is unfractionated heparin? What is low molecular weight heparin?

Answer 8

Heparin in natural form - MW from 60K -100K daltons

Heparin with MW lower than 7K

Question 9

How are low molecular weight heparins obtained? What is the source of heparin? (2)

Answer 9

Products of the degradation of heparin

Porcine and bovine sources

Question 10

What are the 3 main factors within the clotting cascade that are inhibited by heparin?

Answer 10

Thrombin
Xa
IXa

Question 11

What are 2 ways to test for heparin activity?

Answer 11

Prolongation of thrombin time

PTT

Question 12

What are 2 ways heparin can be administered? Which is faster?

Answer 12

IV and SubQ

IV faster - immediate

Question 13

Which has a longer half life, unfractionated or low molecular weight heparin?

Answer 13

Low molecular weight heparin

Question 14

What are 2 major side effects of heparin therapy?

Answer 14

Bleeding

Thrombocytopenia

Question 15

What are 2 possible effects of long term heparin use?

Answer 15

Osteoporosis

Hyperkalemia

Question 16

What is an antagonist to heparin?

Answer 16

Protamine sulfate

Question 17

What are the three examples of low molecular weight heparins provided?

Answer 17

Enoxaparin
Dalteparin
Fondaparinux

Question 18

What are the 4 examples of direct thrombin inhibitors provided?

Answer 18

Lepirudin
Bivalrudin
Argatroban
Dabigatran etexilate

Question 19

What is the prototype oral anticoagulant discussed?

Answer 19

Warfarin

Question 20

What is the mechanism of action of warfarin?

Answer 20

Blocks vit K gamma carboxylation of factors 2, 7, 9 and 10

Blocks vit K gamma carboxylation of proteins C and S

Question 21

What is a standard way to monitor warfarin activity?

Answer 21

INR - International normalized ratio

Question 22

Where is warfarin metabolized (2)? Failure of which organ system impacts whether warfarin should be used at all?

Answer 22

Kidney and liver

Liver failure

Question 23

What can decrease warfarin absorption from the GI tract? What is the effects of barbiturates, phenytoin and alcohol on warfarin? What is the effect of vit K on Warfarin?

Answer 23

• Cholestyramine
• Induce CYPs, increased metabolic clearance of warfarin
• vit K antagonizes warfarin

Question 24

What is the major toxicity for warfarin? What class of drugs can worsen this toxicity?

Answer 24

Bleeding

NSAIDs

Question 25

How can frozen plasma be used to treat warfarin overdose? How is this different from treating heparin overdose?

Answer 25

infusion of fresh plasma and vit K can counteract warfarin overdose. Not possible for heparin

Question 26

Why can't warfarin be used in pregnant women? What is a potential effect of high initial dosages of warfarin?

Answer 26

It is a teratogen | Can cause coumadin-induced skin necrosis

Question 27

What are 2 examples of antihemolytic products that are available as concentrates?

Answer 27

Factor VIII and Factor IX

Question 28

How is streptokinase activated? Why must a large loading dose be used during treatment? Why is streptokinase use limited to a short period of time?

Answer 28

Forms 1:1 complest with plasminogen Large dose needed to overcome neutralizing antibodies Because antibodies will form to streptokinase

Question 29

Unlike other thrombolytics, why is Streptokinase likely to cause anaphylaxis and fever?

Answer 29

Most people will already have antibodies (or will develop) to the strep product

Question 30

What is the source of urokinase? How is the half life compared to streptokinase? Where is it metabolized?

Answer 30

Human cells Only 15 mins (half of streptokinase) Metabolized in liver

Question 31

What is the source of tissue plasminogen activator (tPA)? What is its half life? What is the ramification?

Answer 31

Recombinant DNA technology Only 3 mins Must be admin. as continuous infusion

Question 32

How do "CPR within 10 days" and "previous cerebrovascular accident" relate to thrombolytics?

Answer 32

These are contraindications for the use of thrombolytics

Question 33

What do aspirin, ticlodipine and clopidogrel have in common?

Answer 33

They are all inhibitors of platelet aggregation

Question 34

What is the mechanism by which ticlopidine and clopidogrel block platelet aggregation?

Answer 34

Bind purinergic receptor and prevent ADP binding. ADP binding necessary for platelet shape change and aggregation

Question 35

What is a severe toxicity noted with ticlopidine? With clopidogrel?

Answer 35

ticlopidine - neutropenia in 1% of patients | Clopidogrel - thrombotic thrombocytopenia purpura

Question 36

What is abciximab? What is its mechanism?

Answer 36

Human-mouse monoclonal Ab | - Binds platelet GPIIb/IIIa, blocks fibrinogen binding to platelets and platelet aggregation

Question 37

What is tirofiban? What is its mechanism? What is an advantage over abciximab?

Answer 37

Small molecule inhibitor of GPIIb/IIIa - Binds GPIIb/IIIa, blocks fibrinogen binding to platelets and platelet aggregation - Short duration of action, easier to reverse

Question 38

What factor converts fibrinogen to fibrin?

Answer 38

Factor 2a

Question 39

What factor activates factor 2? What are 3 necessary cofactors?

Answer 39

Factor 10a | - Factor 5a, Calcium, Platelets

Question 40

What factor activates factor 9? What are 3 necessary cofactors?

Answer 40

Factor 9a | - Factor 8a, Calcium, Platelets

Question 41

How is factor 9 activated?

Answer 41

Contact system, previously activated factor 9a

Question 42

In addition of factor 9, what else can activate factor 10? What are 2 required cofactors?

Answer 42

Factor 7a | tissue factor, calcium

Question 43

What other factor (beyond 9a) can activate factor 9? What are necessary cofactors (2)?

Answer 43

Factor 7a | Tissue factor and Calcium

Question 44

What molecule must heparin be bound to for it to inhibit thrombin, 10a and 9a?

Answer 44

ATIII

Question 45

What are the 3 direct thrombin inhibitors that must be administered IV? What is 1 direct thrombin inhibitor that can be administered orally?

Answer 45

``` IV lepirudin (renal clearance) bivalirudin argatroban (hepatic clearance) Oral dabigatran etexilate ```