Antiplatelets and Anticoagulation

Question 1

Outline the steps of endothelial injury and subsequent haemostasis

Answer 1

• Vascular wall damage exposes collagen and tissue factor
• Primary haemostasis occurs -> local vasoconstriction + platelet adhesion
• Activation of the coagulation cascade enmeshes the platelets to form a solid clot

Question 2

What do platelets bind to on damaged blood vessels?

Answer 2

Collagen

Question 3

What do platelets do once they have bound collagen and become activated? (2)

Answer 3

• Extend pseudopodia which help them link together

- Release thromboxane A2 (TXA2)

Question 4

What does TXA2 released from platelets do?

Answer 4

Binds to GPCR TXA2 receptors, resulting in release of ADP from the platelets

Question 5

What does ADP released from platelets do?

Answer 5

Binds to GPCR purine receptors (P2Y12), resulting in…

• activation of more platelets
• increase expression of platelet glycoprotein receptors

Question 6

What do platelet glycoprotein receptors do?

Answer 6

Bind fibrinogen and hold platelets in a ‘soft plug’ at the site of injury

Question 7

How is expression of platelet glycoprotein receptor GPIIb/IIa increased? (2)

Answer 7

By ADP and TXA2

Question 8

Which receptors do ADP and TXA2 bind to? (recap!)

Answer 8

ADP -> P2Y12 receptors

TXA2 -> TXA2 receptors

Question 9

Describe the key steps in the coagulation cascade, occurring at the surface of the platelet plug

Answer 9

• Inactive factor X is converted by tenase (IXa/VIIIa) to active factor X
• Active factor X is used to make prothrombinase (Xa/Va)
• Prothrombinase converts prothrombin (II) to active thrombin (IIa)
• Thrombin converts fibrinogen into fibrin
• Fibrin is used to form a solid clot

Question 10

What drugs are mainly used to treat arterial thrombosis and venous thrombosis?

Answer 10

Arterial thrombosis -> antiplatelets

Venous thrombosis -> anticoagulants

Question 11

How does warfarin target the coagulation cascade?

Answer 11

• It competes with vitamin K for binding with vitamin K reductase
• Vitamin K reductase is essential for gamma-carboxylation which forms factors X and II (prothrombin) in the coagulation cascade

Question 12

How does rivaroxiban target the coagulation cascade?

Answer 12

Directly inhibits factor Xa in the prothrombinase complex

Question 13

How do heparin, LMWH’s and fondaparinux target the coagulation cascade?

Answer 13

They inactivate factor Xa in the prothrombinase complex via antithrombin III

Question 14

How else does heparin target the coagulation cascade?

Answer 14

It inactivates thrombin (IIa) via antithrombin III

Question 15

How does dabigatran target the coagulation cascade?

Answer 15

Directly inhibits thrombin (IIa)

Question 16

What is warfarin’s onset of action?

Answer 16

2-3 days

Question 17

What is warfarin’s half-life?

Answer 17

~40 hours

Question 18

What is the role of antithrombin III (which is what heparin binds to)?

Answer 18

• Blocks the effect of factor Xa

- Blocks the effect of thrombin (factor IIa)

Question 19

How are heparin and LMWHs administered?

Answer 19

Heparin - IV or SC

LMWH’s - SC

Question 20

How can the effects of factor Xa inhibitors (e.g., rivaroxaban and apixaban) be reduced?

Answer 20

Using andexanet

Question 21

How does aspirin target platelets?

Answer 21

It irreversibly blocks the COX (cyclo-oxygenase) enzyme

This prevents TXA2 synthesis from arachidonic acid

Question 22

How does clopidogrel target platelets?

Answer 22

It is a P2Y12 receptor antagonist, so irreversibly binds the P2Y12 receptor and prevents ADP binding

Question 23

Describe the fibrinolytic cascade

Answer 23

• Plasminogen is converted to plasmin by tPA

- Plasmin breaks fibrin down into fibrin fragments, causing lysis of the clot

Question 24

How do fibrinolytic drugs work?

Give examples of these drugs

Answer 24

They mimic tPA and activate plasminogen to plasmin

e.g., Streptokinase, alteplase, duteplase