What are the reversal agents and doses for anticoagulation in intracranial hemorrhage?

Reversal Agents for Intracranial Hemorrhage

For anticoagulant-associated intracranial hemorrhage, immediately discontinue the offending agent and initiate urgent reversal therapy without waiting for laboratory confirmation, as time to reversal directly impacts mortality and hematoma expansion. 1

Warfarin (Vitamin K Antagonists)

For 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

Dosing Protocol:

• 4-factor PCC: 25-50 IU/kg IV based on weight and INR 1, 2
• Vitamin K: 10 mg IV administered slowly over 20-30 minutes, given concomitantly with PCC 3, 1, 2
• Target INR: <1.4, preferably <1.2 4

If PCC Unavailable:

• Fresh frozen plasma (FFP): 10-15 mL/kg IV plus vitamin K 10 mg IV 3
• Note: FFP is less effective and slower than PCC 2

Monitoring:

• Recheck INR within 15-60 minutes after PCC administration 3, 1
• Monitor serially every 6-8 hours for the next 24-48 hours 3
• If INR remains ≥1.4 after initial treatment, administer additional vitamin K 10 mg IV or consider FFP 3

Critical Pitfall:

Never use vitamin K alone without PCC or FFP—vitamin K takes 12-24 hours to work and does not provide immediate reversal. 2

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Direct Oral Anticoagulants (DOACs)

Dabigatran (Direct Thrombin Inhibitor):

Administer idarucizumab 5g IV (two 2.5g/50mL vials) as first-line treatment—this is the FDA-approved specific reversal agent. 3, 1

Indications for Idarucizumab:

• Dabigatran administered within 3-5 half-lives without renal failure 3
• Renal insufficiency leading to continued drug exposure beyond normal 3-5 half-lives 3

Alternative if Idarucizumab Unavailable:

• Hemodialysis for patients with renal insufficiency or dabigatran overdose 3
• Activated charcoal: 50g PO if within 2 hours of ingestion (for intubated patients or those at low aspiration risk) 3
• Activated PCC (aPCC): 50 U/kg IV 3
• 4-factor PCC: 50 U/kg IV 3

Factor Xa Inhibitors (Apixaban, Rivaroxaban, Edoxaban):

Administer andexanet alfa as the specific FDA-approved reversal agent, with dosing based on timing and dose of last DOAC intake. 1, 5

Andexanet Alfa Dosing:

• Low-dose regimen: 400 mg IV bolus over 15 minutes, followed by 480 mg infusion over 2 hours 5
• High-dose regimen: 800 mg IV bolus over 30 minutes, followed by 960 mg infusion over 2 hours 5
• Use low-dose if last dose was ≤10 mg apixaban or ≤10 mg rivaroxaban taken >8 hours ago 5
• Use high-dose if last dose was >10 mg or unknown, or taken within 8 hours 5

Alternative if Andexanet Unavailable:

• 4-factor PCC: 50 U/kg IV 3
• Activated PCC (aPCC): 50 U/kg IV 3
• Activated charcoal: 50g PO if within 2 hours of ingestion 3

Critical Pitfall:

Do not use recombinant factor VIIa or FFP for DOAC reversal—these are ineffective. 3

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Unfractionated Heparin

Administer protamine sulfate 1 mg IV for every 100 units of heparin given in the previous 2-3 hours (maximum single dose 50 mg). 3, 1

Administration:

• Give by slow IV injection over approximately 10 minutes 3
• If aPTT remains elevated, repeat protamine at 0.5 mg per 100 units of heparin 3

Special Consideration:

• Do not routinely reverse prophylactic subcutaneous heparin unless aPTT is significantly prolonged 3

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Low Molecular Weight Heparin (LMWH)

For therapeutic-dose LMWH with intracranial hemorrhage, protamine reversal is strongly recommended. 3, 6

Enoxaparin Dosing:

• If dosed within 8 hours: Protamine 1 mg IV per 1 mg enoxaparin (maximum 50 mg single dose) 3, 1, 6
• If dosed within 8-12 hours: Protamine 0.5 mg IV per 1 mg enoxaparin (maximum 50 mg single dose) 3, 1, 6
• After 12 hours: Minimal utility for reversal 3

Other LMWHs (Dalteparin, Nadroparin, Tinzaparin):

• Protamine: 1 mg IV per 100 anti-Xa units of LMWH administered in past 3-5 half-lives (maximum 50 mg single dose) 3

Refractory Bleeding:

• If life-threatening bleeding persists or patient has renal insufficiency, redose protamine at 0.5 mg per 100 anti-Xa units or per 1 mg enoxaparin 3, 6

Critical Pitfall:

Do not routinely reverse prophylactic-dose LMWH unless aPTT is significantly prolonged. 6

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Thrombolytic Agents (tPA, Alteplase)

Administer cryoprecipitate 10 units IV as first-line reversal for thrombolytic-related intracranial hemorrhage within 24 hours of administration. 3

Alternative if Cryoprecipitate Unavailable or Contraindicated:

• Tranexamic acid: 10-15 mg/kg IV over 20 minutes 3
• ε-aminocaproic acid: 4-5 g IV 3

Monitoring:

• Check fibrinogen levels after reversal agent administration 3
• If fibrinogen <150 mg/dL, administer additional cryoprecipitate 3

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Antiplatelet Agents

Discontinue antiplatelet agents immediately when intracranial hemorrhage is present or suspected. 3

Platelet Transfusion Recommendations:

Do NOT Transfuse:

• Patients with antiplatelet-associated intracranial hemorrhage who will not undergo neurosurgical procedure 3
• Patients with laboratory-documented normal platelet function or documented antiplatelet resistance 3
• NSAID or glycoprotein IIb/IIIa inhibitor-related intracranial hemorrhage, even with neurosurgical intervention 3

DO Transfuse:

• Patients with aspirin or ADP inhibitor (clopidogrel, prasugrel, ticagrelor)-associated intracranial hemorrhage who will undergo neurosurgical procedure 3

Platelet Transfusion Protocol:

• Perform platelet function testing prior to transfusion if possible 3
• Initial dose: One single donor apheresis unit 3
• Repeat platelet function testing before additional transfusions 3
• Only repeat transfusion for persistently abnormal platelet function tests 3

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Pentasaccharides (Fondaparinux)

Administer activated PCC (aPCC) 20 U/kg IV or recombinant factor VIIa 90 μg/kg IV for reversal. 3

Critical Pitfall:

Protamine is ineffective for pentasaccharide reversal—do not use. 6

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Key Clinical Principles

Timing is Critical:

• Implement reversal immediately without waiting for laboratory confirmation—medication history alone is sufficient to initiate treatment 1, 2
• Time to reversal directly impacts mortality and hematoma expansion 1
• Target correction of coagulopathy within 4 hours of admission 2

Avoid Heparin After Andexanet:

• Andexanet may interfere with heparin's anticoagulant effect and cause unresponsiveness to heparin 5
• If anticoagulation is needed after andexanet, use an alternative to heparin 5

Thrombotic Risk Considerations:

• Risk of thromboembolism within 30 days after reversal is 7-12% 2
• In ANNEXA-4 study, 18% of patients experienced thromboembolic events (median time 7 days) 5
• However, the immediate mortality risk from ongoing bleeding typically outweighs thrombotic risk, and reversal should proceed 1

Resuming Anticoagulation:

• Typical timing is around 1 week after intracranial hemorrhage, particularly for intracerebral hemorrhage 1
• Balance rebleeding risk against thrombotic complications (3-5% 30-day ischemic stroke risk after discontinuation) 2, 7