L9 - Antiplatelet and Anticoagulant

Question 1

What is haemostasis?

Answer 1

process which causes bleeding to stop

- first stage of wound healing

Question 2

What does haemostasis involve?

Answer 2

platelet activation and adhesion - forms clot

blood coagulation - fibrin formation which reinforces clot

Question 3

What are the components of the coagulation cascade? What types of drugs have effect in each part?

Answer 3

fast process
- platelet plug formation 
- antiplatelets
slow process
- fibrin clot formation 
- anticoagulants

Question 4

What are the 3 stages in clot formation?

Answer 4

1 - platelet adhesion
2 - platelet shape change
3 - fibrin stabilises platelets

Question 5

What is happens in the 1st step of clot formation?

Answer 5

• decreased prostacyclin (PGI2) production from damaged endothelial cells (vessel damage)
• platelets arrive at site + aggregate
• aggregated platelets produce thrombin

Question 6

What happens in the 2nd step of clot formation?

Answer 6

• thrombin released from platelets in 1st step:
• activates further platelets = reinforce platelet plug
• binds to receptors causing increased intracellular Ca2+ in platelets = shape change + activate
• activated platelets release platelet chemotactic agents (ADP + TXA2)
  = aggregation and reinforcement of clot

Question 7

What happens in the 3rd step of clot formation?

Answer 7

• thrombin (released from platelets in 1st step) conversion of fibrinogen to fibrin
• fibrin fibres bind together to form fibrous clot = stabilises clot

Question 8

What are the platelet chemotactic agents and where are they released from?

Answer 8

• ADP and TXA2

- released from activated platelets

Question 9

What effects does TXA2 (thromboxane A2) have?

Answer 9

• platelet chemotactic agent

- causes vasoconstriction at the site of injury

Question 10

Why is clot formation important?

Answer 10

it is involved in the pathology of cardiovascular disease

- causes thickening and narrowing of blood vessels + reduced blood flow to organs e.g. heart, brain

Question 11

What are the uses of anticoagulants and antiplatelets?

Answer 11

they are used in preventative treatment of angina or TIA or as post-MI treatment

Question 12

What are the three main causes of intravascular thrombi?

Answer 12

• hyper-coagulation (genetic)
• endothelial damage (hypertension)
• stasis (atrial fibrillation)

Question 13

What are the drugs that can prevent thrombosis and what part of the clotting cascade do they act?

Answer 13

• antiplatelets: reduce platelet aggregation
• anticoagulants: reduce blood coagulation (fibrin formation)
• fibrinolytic drugs: increase fibrin breakdown

Question 14

How do antiplatelets exert their effect?

Answer 14

inhibit platelet aggregation by:
- preventing the formation of chemotactic agents
- inhibiting the receptors the chemotactic agents act on
= reduces risk of thrombus formation

Question 15

What is an antiplatelet drug?

Answer 15

low dose aspirin

Question 16

What is a low dose of aspirin (range)?

Answer 16

75-150 mg/day

Question 17

What is the mechanism of action for aspirin?

Answer 17

• irreversibly and non-selectively inhibits COX enzymes
• inhibiting COX1 reduces TXA2 production
• TXA2 is a chemotactic agent recruiting more platelets to endothelial injury site

Question 18

Why is it important to use low dose aspirin in antiplatelet treatment?

Answer 18

low dose only has effect on the platelets (COX1) in the portal circulation
high dose will be able to reach systemic circulation where it will effect platelets (COX1) AND vascular endothelium (COX2)

Question 19

What are the effects of COX1 in the clot formation?

Answer 19

COX1 produces TXA2 which promotes platelet aggregation and vasoconstriction
this initiates thrombus/clot formation
- good to inhibit with antiplatelet

Question 20

What are the effects of COX2 in clot formation?

Answer 20

• COX2 produces PGI2 (prostacyclin)
• PGI2 is an endogenous antiplatelet mediator as it reduces COX activity
• PGI2 inhibits platelet aggregation and promotes vasodilation thus inhibits thrombus/clot formation
• not good to inhibit with antiplatelet

Question 21

What are the side effects of aspirin?

Answer 21

• well tolerated
• not for people allergic to NSAIDs
• can increase risk of gastric bleeding
• not associated with significant oerative bleeding (dental procedures)

Question 22

What is an anticoagulant drug?

Answer 22

heparin and warfarin

Question 23

What is the mechanism of action for heparin?

Answer 23

• increases the action of anti-thrombin III (AT-III)
• increased AT-III binding to prothrombin and thrombin, and factor Xa
• this prevents fibrin formation = prevents clot formation

Question 24

What is the antagonist for heparin? How does it work?

Answer 24

protamine sulphate

• it binds with heparin to form an inactive complex
• prevents binding to substrates

Question 25

What are the adverse effects of heparin?

Answer 25

haemorrhage

Question 26

What is the mechanism of action for warfarin?

Answer 26

• inhibits vitamin K epoxide reductase
• prevents reduction of vitamin K to active form
• prevents vitamin K from activating clotting factors e.g. prothrombin
• reduces fibrin formation

Question 27

How is warfarin administered and duration of action?

Answer 27

• orally

- 2-5 days (given with heparin because it has instant effect while waiting for warfarin effect)

Question 28

How is the effect of warfarin able to be reversed? (4)

Answer 28

• withdraw therapy (but has persistent action)
  reversal therapy:
• vitamin K administration (slow acting)
• fresh frozen plasma (fast acting, large volume required)
• prothrombinex-VF (freeze dried factors, small volume required, expensive)

Question 29

What are the side effects of anticoagulants?

Answer 29

- narrow TI
due to reduced clotting:
- haemorrhage
- GI bleeding
- bruising
- bleeding noses
metabolised via CYP450 drugs 
- many drug interactions (elderly)

Question 30

How is the development of adverse effects of anti-coagulants reduced?

Answer 30

INR - compare patient clotting time to normal healthy individual (~1)
- should be 2-4

Question 31

When are fibrinolytics used? How do they work?

Answer 31

when thrombus/clot already formed e.g.

• MI: must give within 6 hours
• stroke: must give within 4 hours

Question 32

What is an example of a fibrinolytic?

Answer 32

Recombinant Tissue Plasminogen Activator (rtPA)

e.g. alteplase

Question 33

What is the mechanism of action of alteplase?

Answer 33

it is a serine protease

• converts plasminogen to plasmin
• plasmin breaks down the clot (fibrin)

Question 34

How do fibrinolytics produce their effect?

Answer 34

• increase thrombus/clot breakdown

Question 35

What is the adverse effect of fibrinolytics?

Answer 35

bleeding