Anticoagulant and antiplatelet drugs

Question 1

What are some examples of indications for anticoagulant drugs?

Answer 1

• Venous thrombosis
• Atrial fibrillation

Question 2

What pathway do anticoagulant drugs target?

Answer 2

Fibrin clot formation pathway

Question 3

How does heparin work and how is it administered?

Answer 3

• Potentiates the effects of anti-thrombin - negative feedback to thrombin and factors VIIa, V, Xa, VIII, XIa and TF
• Immediate effect
• Parenteral (IV or SC) 2 forms - unfractionated and low molecular weight (LMWH)

Question 4

How are patients on heparin monitored?

Answer 4

• Activated partial thromboplastin time (APTT) for unfractionated heparin
• Anti-Xa assay for LMWH but usually no monitoring of LMWH is required as more predictable repsonse

Question 5

What are the potential complications of heparin treatment?

Answer 5

• Bleeding - heparin induced thrombocytopenia (HITT) - monitor FBC in patients on heparin
• Osteoporosis with long term use

Question 6

How are the effects of heparin reversed?

Answer 6

• Stop the heparin!
• Occassionally in severe bleeding - protamine sulphate, reverses antithrombin effect
• Complete reversal for unfractionated
• Partial reversal for LMWH

Question 7

Name some examples of coumarin anti-coagulants and describe their mechanism of action

Answer 7

• Drugs - warfarin, phenindione, acenocoumarin, phenprocoumon
• Mechanism of action - inhibition of vitamin K

Question 8

What are vitamin K dependent coagulation factors and where are they synthesised?

Answer 8

• Factors II (prothrombin), VII, IX and X - protein C and protein S
• Synthesised in liver
• They require vitamin K for final carboxylation step essential for their function

Question 9

What is the mechanism of action of warfarin?

Answer 9

Acts as an anticoagulant by blocking the ability of vitamin K to carboxylate the vitamin K dependent clotting factors (II, VII, IX + X), thereby reducing their coagulant activity

Question 10

How is warfarin therapy given?

Answer 10

• Narrow therapeutic window so need to monitor therapy
• Maintenance - dose should be taken at same time every day

Question 11

What is INR?

Answer 11

• A mathematical correction for differences in the sensitivity of thromboplastin reagents
• Allows for comparison of results between labs and standardizes reporting of the prothrombin time

Question 12

What is the major adverse effect associated with warfarin and what factors may influence this?

Answer 12

Haemorrhage!

Intensity of anti-coagulation, concomitant clinical disorders, concomitant use of other medications, *beware of drug interactions*

Question 13

What are some of the bleeding complications associated with warfarin?

Answer 13

• Mild - skin bruising, epistaxis, haematuria
• Severe - GI, intracerebral, significant drop in Hb

Question 14

How are the effects of warfarin reversed?

Answer 14

Omit warfarin dose -> administer oral vitamin K -> administer clotting factors (FFP) -> clinical and laboratory assessment of response

Question 15

How effective are the administration of vitamin K and clotting factors in managing a warfarin induced bleed?

Answer 15

• Vitamin K - 6 hours
• Clotting factors - immediate

Question 16

Name an example of a direct thrombin inhibitor

Answer 16

Dabigatran - targets thrombin

Question 17

Name examples of activated factor X inhibitors

Answer 17

Rivaroxaban + apixaban

Question 18

What is the benefit of these new anticoagulants?

Answer 18

• Oral and no monitoring required
• Less drug interactions
• Currently no specific antidote for reversal

Question 19

What are these new anticoagulants e.g. apixaban and dabigatran used for?

Answer 19

• Used instead of LMWH as prophylaxis in elective hip and knee replacment surgery
• Used for selected patients for stroke prevention in atrial fibrillation
• Used for treatment of DVT/PE

Question 20

What is atherosclerosis?

Answer 20

• Not the same as arterial thrombosis
• Damage to endothelium
• Recruitment of foamy macrophages rich in cholesterol
• Forms plaques rich in cholesterol

Question 21

Describe stable atherosclerotic plaques and give examples of what conditions they are seen in

Answer 21

• Hyalinsed and calcified
• Stable plaques are seen in angina and intermittent claudication

Question 22

Describe unstable atherosclerotic plaques and give examples of what conditions they are seen in

Answer 22

• Plaques rupture, platelets are recruited and cause acute thrombosis
• Sudden onset of symptoms
• Unstable angina or myocardial infarction (coronary arteries)
• Stroke (cerebral arteries)

Question 23

Describe the relationship between platelets and arterial thrombosis

Answer 23

• Plaque ruptures (more liklely in arteries due to high pressure)
• Platelet adheres to it - exposed endothelium and release of VWF
• Platelets become activated - release granules that active coagulation and recruit other platelets to developing platelet plug
• Platelet aggregation via membrane glycoproteins

Question 24

What are some risk factors for arterial thombosis?

Answer 24

Factors that cause damage to the endothelium, increase in foamy macrophages and platelet activation

• Hypertension - damage to endothelium, platelet activation
• Smoking - endothelium, platelets
• High cholesterol - accumulated in plaque
• Diabetes mellitus - endothelium, platelets, cholesterol

Question 25

What is the adhesion stage of formation of the platelet plug?

Answer 25

Platelets bind to subendothelial collagen via glycoprotein 1b and VWF

Question 26

What is the aggregation stage of platelet plug formation?

Answer 26

Platelets attach to each other via glycoprotein IIb, IIIa and fibrinogen

Question 27

What is the activation stage of platelet plug formation?

Answer 27

• Platelets alter their shape to expose more phospholipid on the surface - provides a greater surface area for coagulation activation and fibrin production to stabilise the clot
• Process is augmented by release of granules that further stimulate platelet activation e.g. thrombin, thromboxane A2 and ADP in order to recruit more platelets to the process
• This occurs via receptors to ADP etc. on the platelet surface

Question 28

What is the mechanism of action of aspirin?

Answer 28

Inhibits cyclo-oxygenase which is necessary to produce thromboxane A2 (a platelet agonist released from granules on activation)

Question 29

What are some of the side effects associated with aspirin?

Answer 29

1. Bleeding
2. Blocks prostaglandin prodution –> GI ulceration and bronchospasm

Question 30

Name some examples of ADP receptor antagonists

Answer 30

Clopidogrel, prasugrel

Question 31

What is the mechanism of action of dipyridamole?

Answer 31

Phosphodiesterase inhibitor - reduced production of cAMP which is a second messenger in platelet activation

Question 32

Name an example of a glycoprotein IIb/IIIa inhibitor

Answer 32

Abciximab - inhibits aggregation of platelets

Question 33

How long do anti-platelets need to be stopped prior to surgery?

Answer 33

• Anti-platelets tend to affect platelet function for their 7-10 day life span
• Stop anti-platelet agents 7 days prior to elective operations
• If serious bleeding - can reverse with platelet transfusion

Question 34

Platelets are central in venous thrombosis and are recrutied to ruptured plaques. Antiplatlet drugs are thus useful in preventing venous thrombosis. T/F?

Answer 34

False - platelets are central in arterial thrombosis and are recruited to ruptured plaques. Platelets are NOT largely involved in venous thrombosis and clots are rich in fibrin. Antiplatelet drugs are useful in preventing arterial thrombosis whilst anticoagulant drugs are useful in prevention of venous thrombosis.