What is the recommended approach for urgent reversal of anticoagulation in patients on warfarin or Direct Oral Anticoagulants (DOACs)?

Urgent Reversal of Anticoagulation in Warfarin and DOAC Patients

Warfarin Reversal

For life-threatening bleeding or urgent surgery in warfarin-anticoagulated patients, administer 4-factor prothrombin complex concentrate (4F-PCC) plus intravenous vitamin K 5-10 mg by slow infusion over 15-30 minutes. 1

Dosing Strategy for 4F-PCC

• INR 2 to <4: 25 units/kg 1
• INR 4 to 6: 35 units/kg 1
• INR >6: 50 units/kg 1
• Maximum dose: 5,000 units (capped at 100 kg body weight) 1

Vitamin K Administration

Always co-administer vitamin K with 4F-PCC for sustained reversal. 1

• For life-threatening bleeding: 10 mg IV slow infusion (over 15-30 minutes in 25-50 mL normal saline) 1
• Onset of action: IV vitamin K reduces INR within 4-6 hours, compared to 18-24 hours for oral administration 1
• Repeat dosing: May give additional 10 mg every 12 hours if INR remains elevated 1

Alternative Agents When 4F-PCC Unavailable

If 4F-PCC is not available, use fresh frozen plasma (FFP) 10-15 mL/kg, though this is significantly inferior. 1

• FFP contains approximately 25 times less vitamin K-dependent factors per unit volume compared to 4F-PCC (1 U/mL vs 25 U/mL) 1
• FFP requires 60-90 minutes for ABO typing and thawing, delaying treatment 1
• FFP carries risks of volume overload, transfusion-related acute lung injury, and allergic reactions 1
• Do not use recombinant factor VIIa (rFVIIa) as first-line therapy 1

Non-Life-Threatening Elevations

For elevated INR without major bleeding:

• INR 5-9 without bleeding: Omit 1-2 warfarin doses; if increased bleeding risk, give oral vitamin K 1-2.5 mg 1
• INR >9 without bleeding: Oral vitamin K 3-5 mg, anticipating INR reduction within 24-48 hours 1
• INR >10 requiring rapid reversal for urgent surgery: Oral vitamin K 2-5 mg 1

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DOAC Reversal

Factor Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban, Betrixaban)

For life-threatening bleeding on Factor Xa inhibitors, administer andexanet alfa as the specific reversal agent. 1, 2

Andexanet Alfa Dosing

Low-dose regimen (for rivaroxaban ≤10 mg or apixaban ≤5 mg taken >8 hours prior, or unknown timing): 1

• IV bolus: 400 mg at 30 mg/min over 15 minutes
• Followed by IV infusion: 480 mg at 4 mg/min over 120 minutes

High-dose regimen (for rivaroxaban >10 mg or apixaban >5 mg taken <8 hours prior, or unknown dose <8 hours prior): 1

• IV bolus: 800 mg at 30 mg/min over 30 minutes
• Followed by IV infusion: 960 mg at 8 mg/min over 120 minutes

For betrixaban or edoxaban: Always use high-dose regimen 1

Alternative When Andexanet Alfa Unavailable

If andexanet alfa is unavailable, administer 4F-PCC 2000 units (or 50 units/kg) as an off-label alternative. 1

• Consider activated charcoal if ingestion occurred within 2-4 hours 1
• Important caveat: No randomized trials compare PCC to specific reversal agents for DOACs 1

Factor IIa Inhibitor (Dabigatran)

For life-threatening bleeding on dabigatran, administer idarucizumab 5 g IV as two consecutive 2.5 g infusions. 1, 3

Alternative When Idarucizumab Unavailable

If idarucizumab is unavailable, administer activated prothrombin complex concentrate (aPCC) 50 units/kg IV. 1

• Consider activated charcoal if ingestion occurred within 2-4 hours 1
• Standard PCC may be used if aPCC is unavailable 1

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Critical Decision Points

When to Withhold vs. Reverse DOACs

Assess DOAC levels if quantitative testing is available before deciding on reversal, as many patients may have subtherapeutic levels. 1

• Administer reversal agents only for: 1
  • Hemorrhagic shock not responding to resuscitation
  • Dosable plasma DOAC levels present
  • Bleeding in critical organs (CNS, pericardial, intraspinal, intraocular, retroperitoneal)

DOAC Half-Life Considerations

For patients with renal impairment, DOAC half-lives are significantly prolonged: 1

• Dabigatran: 13 hours (CrCl >80) to 30 hours (CrCl <15)
• Apixaban/Rivaroxaban/Edoxaban: 6-15 hours (CrCl >30) to 17 hours (CrCl <15)

In hemodynamically stable patients without life-threatening bleeding, supportive care and allowing drug clearance may be appropriate rather than immediate reversal. 1

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Common Pitfalls

1. Using FFP instead of 4F-PCC for warfarin reversal: FFP is 25-fold less concentrated and requires large volumes that risk circulatory overload, particularly in elderly patients 1, 4

2. Giving vitamin K without clotting factor replacement in major bleeding: Vitamin K alone takes 4-24 hours to work; immediate factor replacement is essential 1

3. Subcutaneous vitamin K administration: Absorption is unpredictable and not recommended 1

4. Reversing DOACs without confirming drug levels: Many patients have minimal circulating drug, making reversal unnecessary and exposing them to thrombotic risk 1

5. Excessive vitamin K dosing: High doses (>10 mg) can cause warfarin resistance for up to one week 1

6. Forgetting sustained reversal: Vitamin K must accompany 4F-PCC because the concentrate's half-life is shorter than warfarin's duration of action 1