WARFARIN 

1. INTRODUCTION

Warfarin is an oral vitamin K antagonist (VKA) used for long-term anticoagulation.

  • Narrow therapeutic index
  • Requires INR monitoring

2.  MECHANISM OF ACTION

Warfarin inhibits:

 Vitamin K epoxide reductase complex (VKORC1)

This leads to ↓ activation of vitamin K–dependent clotting factors:

  • Factor II (Prothrombin)
  • Factor VII
  • Factor IX
  • Factor X
  • Proteins C & S (natural anticoagulants)


  • Protein C decreases fastest → transient hypercoagulability
  • Hence → heparin bridging is required initially

3.  PHARMACOKINETICS

Parameter

Details

Route

Oral

Bioavailability

~100%

Half-life

~36–42 hours

Onset

Delayed (36–72 hrs)

Peak effect

5–7 days

Metabolism

Hepatic (CYP2C9)

Protein binding

Highly bound (99%)

  • Effect depends on clearance of existing clotting factors
  • Factor VII declines fastest → early INR rise

4.  MONITORING – INR

Target INR (Guideline-based)

Indication

Target INR

DVT / PE

2.0–3.0

Atrial fibrillation

2.0–3.0

Mechanical aortic valve

2.0–3.0

Mechanical mitral valve

2.5–3.5

Antiphospholipid syndrome

2.0–3.0 (sometimes higher)

5.  INDICATIONS IN ICU

Common CCM Uses

  1. Atrial fibrillation
  2. Deep vein thrombosis / PE
  3. Mechanical heart valve
  4. Antiphospholipid syndrome
  5. LV thrombus

When NOT preferred (DOAC preferred)

  • Non-valvular AF
  • Routine VTE (unless contraindications)

6.  INITIATION & BRIDGING

 Why bridging?

Due to early depletion of Protein C → hypercoagulable state

 Protocol (CHEST guidelines)

  • Start:
    • Warfarin + Unfractionated heparin OR
    • Low molecular weight heparin
  • Continue heparin for:
    • ≥5 days AND INR therapeutic for 24–48 hrs

7.  ADVERSE EFFECTS

 Major

  1. Bleeding (most important)
  2. Warfarin-induced skin necrosis
    • Occurs 3–5 days
    • Due to protein C depletion
  1. Purple toe syndrome (cholesterol embolization)

 Others

  • Teratogenic (contraindicated in pregnancy)
  • Alopecia
  • Hepatic dysfunction (rare)

8.  DRUG & FOOD INTERACTIONS

 Drug interactions

↑ INR (bleeding risk)

  • Antibiotics (e.g., macrolides, fluoroquinolones)
  • Amiodarone
  • Azoles
  • Metronidazole

↓ INR (thrombosis risk)

  • Rifampicin
  • Carbamazepine
  • Phenytoin

 Food interactions

  • Vitamin K rich foods ↓ effect:
    • Spinach, broccoli, cabbage

9. REVERSAL OF WARFARIN

 Based on INR + bleeding (CHEST / ACC guidelines)

Scenario

Management

INR ↑, no bleeding

Hold warfarin

INR > 10

Oral Vitamin K

Serious bleeding

IV Vitamin K + PCC

Life-threatening bleeding

PCC + IV Vitamin K (preferred)

 Drugs used

  • Vitamin K
  • Prothrombin complex concentrate (PCC) (preferredfaster, less volume)
  • Fresh frozen plasma (FFP)

10.  WARFARIN vs DOACs 

Feature

Warfarin

DOACs

Monitoring

INR required

Not required

Onset

Slow

Rapid

Reversal

Available

Limited (some agents)

Use in mechanical valve

 Yes

 No

Renal failure

Preferred

Limited use

11.  SPECIAL ICU SITUATIONS

 Mechanical valve → ONLY warfarin

  • DOACs contraindicated
  • Based on RE-ALIGN trial

Renal failure

  • Warfarin preferred (no renal clearance)

Liver disease

  • INR unreliable → careful interpretation

Peri-procedural management

High thrombotic risk:

  • Mechanical valves
  • Recent VTE

Use heparin bridging


 GUIDELINE REFERENCES 

  • Harrison’s Principles of Internal Medicine
  • CHEST Antithrombotic Guidelines
  • ACC/AHA Valvular Heart Disease Guidelines
  • ESC AF Guidelines