What is the approach for reversing anticoagulation in a patient with intracranial bleeding?

Reversal of Anticoagulation in Intracranial Bleeding

Immediately discontinue all anticoagulants and initiate urgent reversal therapy without waiting for laboratory confirmation—time to reversal directly impacts mortality and hematoma expansion in anticoagulant-associated intracranial hemorrhage. 1

Warfarin (Vitamin K Antagonist) Reversal

For patients with INR ≥1.4, administer 4-factor prothrombin complex concentrate (PCC) plus vitamin K 10 mg IV immediately—this is superior to fresh frozen plasma and achieves faster, more complete reversal. 1, 2

Specific Dosing Protocol:

• 4-factor PCC: 25-50 IU/kg IV based on weight and INR (preferred over 3-factor PCC due to more complete factor replacement) 1
• Vitamin K 10 mg IV: Administer slowly over 20-30 minutes, given concomitantly with PCC to prevent INR rebound 1, 2
• Fresh frozen plasma (FFP): 10-15 mL/kg IV only if PCC unavailable (less effective, slower reversal) 1

Evidence Supporting PCC Over FFP:

A randomized trial demonstrated that 4-factor PCC achieved INR ≤1.2 within 3 hours in 67% of patients versus only 9% with FFP, and was associated with reduced hematoma expansion (18.3% vs 27.1%). 1 Observational data show that PCC infusion is significantly faster than FFP and provides more complete correction of factor IX deficiency. 3, 4

Critical Monitoring:

• Recheck INR within 30-60 minutes after PCC administration 2
• If INR remains ≥1.4 at 24-48 hours, redose with vitamin K 10 mg IV 1, 2
• Earlier reversal (<4 hours from admission) combined with blood pressure control significantly reduces mortality 1

Important Caveat:

Do NOT reverse anticoagulation if cerebral venous thrombosis is suspected as the cause of intracranial hemorrhage—this represents a contraindication to reversal. 1

Direct Oral Anticoagulant (DOAC) Reversal

Factor Xa Inhibitors (Apixaban, Rivaroxaban, Edoxaban):

First-line: Andexanet alfa 5g IV (low-dose regimen) or 10g IV (high-dose regimen) based on timing and dose of last DOAC intake. 5

• Andexanet alfa is the FDA-approved specific reversal agent that rapidly reduces anti-FXa activity 5
• In clinical trials, 68% of apixaban-treated patients and 53% of rivaroxaban-treated patients achieved >90% reduction in anti-FXa activity 5
• Warning: Thromboembolic events occurred in 18% of patients within 30 days in the ANNEXA-4 study, with median time to event of 7 days 5

Alternative if andexanet alfa unavailable:

• Activated PCC (FEIBA) 50 U/kg IV, OR 1
• 4-factor PCC 50 U/kg IV 1
• Activated charcoal 50g PO if within 2 hours of ingestion 1

Direct Thrombin Inhibitor (Dabigatran):

First-line: Idarucizumab 5g IV (two 2.5g/50mL vials)—this is the specific FDA-approved reversal agent. 1

• Consider hemodialysis or idarucizumab redosing for refractory bleeding 1
• Activated charcoal 50g PO if within 2 hours of ingestion 1

Alternative if idarucizumab unavailable:

• Activated PCC (FEIBA) 50 U/kg IV, OR 1
• 4-factor PCC 50 U/kg IV 1

Heparin Reversal

Unfractionated Heparin:

Protamine 1 mg IV for every 100 units of heparin administered in the previous 2-3 hours (maximum 50 mg single dose). 1

Low Molecular Weight Heparin (LMWH):

For enoxaparin:

• If dosed within 8 hours: Protamine 1 mg IV per 1 mg enoxaparin (max 50 mg) 1
• If dosed within 8-12 hours: Protamine 0.5 mg IV per 1 mg enoxaparin (max 50 mg) 1
• Minimal utility if >12 hours from dosing 1

For dalteparin, nadroparin, tinzaparin:

• If within 3-5 half-lives: Protamine 1 mg IV per 100 anti-Xa units (max 50 mg) 1

Common Pitfalls to Avoid

• Never delay reversal while waiting for INR results—initiate treatment immediately based on medication history alone 1, 2
• Never use vitamin K alone without PCC or FFP—vitamin K takes 12-24 hours to work and does not provide immediate reversal 2
• Never use 3-factor PCC when 4-factor PCC is available—4-factor provides complete factor replacement including factor VII 1, 2
• Never omit vitamin K when giving PCC—this leads to INR rebound within 24-48 hours as PCC factors are consumed 1, 2
• Never use FFP as first-line when PCC is available—FFP is slower, requires larger volumes, and is less effective at achieving target INR 1, 3
• Never use recombinant factor VIIa as first-line therapy—it carries high thrombotic risk and lacks FDA approval for this indication 2

Special Considerations

Patients with Mechanical Heart Valves or High Thrombotic Risk:

Assess individual risk-benefit when considering reversal in patients with concurrent symptomatic thrombosis, ischemia, heparin-induced thrombocytopenia, or DIC. 1 However, in the context of active intracranial hemorrhage, the immediate mortality risk from ongoing bleeding typically outweighs thrombotic risk, and reversal should proceed. 1

Timing of Anticoagulation Resumption:

For intracranial hemorrhage, particularly intracerebral hemorrhage, resume anticoagulation after 1 week—the long-term risk of further intracranial bleeding is lower than the risk of valve thrombosis or thromboembolic events. 1 The 30-day risk of ischemic stroke after anticoagulation discontinuation is 3-5%. 2