Essay: Discuss anticoagulants, MOA, evidence, compare new ones to warfarin

Question 1

Warfarin

- Uses and usage

Answer 1

• Most commonly used anticoagulant
• DVT, PE, AF
• Other thrombotic events

Question 2

Warfarin MOA

Answer 2

• CYP2C9 converts warfarin to s-warfarin
• Prevents Vitamin K-dependent synthesis of Ca-dependent clotting factors
• FII, FVII, FIX and FX

also

• Protein C
• Protein S
• Protein Z

Question 3

Warfarin risk, monitoring (and trouble)

Answer 3

Haemorrhage
- Narrow therapeutic window

Problem with plasma warfarin
- Effect is varied in individuals downstream of plasma concentration so it’s useless for monitoring

Monitoring
- INR

Question 4

UF Heparin MOA

Answer 4

• Binds to antithrombin III (AT)
• Conformational change activates AT
• AT inactivates FXa and FIIa (thrombin)*
• Thrombin must also bind the heparin polymer for its inhibition (size dependent)

Question 5

UF Heparin reversal

Answer 5

• Complete reversal with protamine

- Irreversibly binds to heparin and inactivates it

Question 6

NOACs

Answer 6

Non-vitamin K antagonist oral anticoagulants

• Direct inhibitors
• Selective for FIIa (thrombin) or Xa

Question 7

Advantages of NOACs over VKAs

Answer 7

• safety (lower major bleeding incidence)
• wider therapeutic window
• convenience of use
• minor drug/food interactions
• no need for lab monitoring

Question 8

Disadvantages of NOACs vs VKAs

Answer 8

• Contraindications: pregnancy, childhood
• not yet approved for use in some thrombophillic states
• malignancy, mech MV, antiphospholipid syndrome

Question 9

Dabigatran (RE-LY)

Answer 9

• Dabigatran vs warfarin
• similar risk of stroke/ systemic embolism
• lower risk of major haemorrhage

Question 10

Daigatran MOA

Answer 10

• Direct selective FIIa inhibitor

- prevents fibrinogen conversion to fibrin

Question 11

Rivaroxiban (ROCKET-AF)

Answer 11

• as effective at preventing stroke/embolism
• lower risk of intracranial haemorrhage
• lower risk of fatal bleeding

Question 12

Rivaroxiban MOA

Answer 12

• Direct selective inhibitor of FXa

Question 13

Apixaban (ARISTOTLE)

Answer 13

• superior prevention of stroke, systemic embolism

- lower haemorrhage (lower mortality)

Question 14

Thrombin pathway

Answer 14

• FXa converts prothrombin (FII) -> thrombin (FIIa)

- FIIa converts fibrinogen to fibrin

Question 15

Problems with warfarin

Answer 15

• Slow onset of action
• Narrow therapeutic window
• Need for laboratory monitoring
• Drug/food interactions
• High risk of severe bleeding