Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 46/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Contributor Disclosures W David Freeman, MD Other Financial Interest: Cambridge [Book royalties]; Oxford [Book royalties]. All of the relevant financial relationships listed have been mitigated. Jeffrey I Weitz, MD Consultant/Advisory Boards: Alnylam [Anticoagulation]; Anthos [Anticoagulation]; Bayer/Janssen [Anticoagulation]; Boehringer- Ingelheim [Anticoagulation]; Bristol Myers Squibb/Janssen [Anticoagulation]; Bristol Myers Squibb/Pfizer [Anticoagulation]; Daiichi-Sankyo [Anticoagulation]; Ionis Pharmaceuticals [Anticoagulation]; Merck [Anticoagulation]; Pfizer [Anticoagulation]; PhaseBio [Anti-platelet drug reversal]; Regeneron Pharmaceuticals [Anticoagulation]; Servier [Anticoagulation]; VarmX [Anticoagulant reversal]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 47/47