INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of 23 [35 percent] receiving FFP versus 5 of 27 [19 percent] receiving PCC) and a lower rate of hematoma expansion [34]. The other trial, which randomly assigned 202 patients who presented with major bleeding associated with a vitamin K antagonist to receive 4-factor PCC or plasma, found that PCC was associated with a trend towards greater hemostatic https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 15/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate efficacy (72 percent with PCC versus 65 percent with plasma) and a greater likelihood of INR correction within the first half hour after the infusion (62 versus 10 percent); serious adverse events were similar [25]. Prospective and retrospective observational studies have consistently shown superior or equivalent outcomes with PCC compared with plasma; in some studies, PCCs were also associated with fewer serious adverse events [22,28,31,35- 39]. Despite the efficacy of PCC in reversing warfarin effect, the mortality of anticoagulant- associated ICH remains high (42 percent in one series) [40]. This is likely due to early hematoma expansion and the delay in anticoagulant reversal during transportation to the hospital, intracranial imaging, and administration of reversal products. 4-factor versus 3-factor PCC These two products have not been compared directly for patients with intracranial bleeding. The rate of INR normalization in patients with systemic bleeding appears higher with 4-factor PCC. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Evidence for efficacy'.) PCC versus rFVIIa or aPCC A case series of 101 patients with warfarin-associated intracranial hemorrhage treated with rFVIIa (mean dose 52 mcg/kg) reported thromboembolic complications in eight patients (seven deep vein thromboses, one stroke) [41]. Similar risks were found in a multicenter randomized trial of rFVIIa in 841 patients with ICH not associated with warfarin [27]. There was no benefit with treatment on the primary clinical outcomes of death and disability, and higher rates of arterial thromboembolic serious adverse events (eg, stroke, MI) were found in patients assigned to the higher dose (80 mcg/kg) treatment group. Other studies have also suggested an association between rFVIIa and serious thromboembolic events. These and other studies are discussed in more detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Thromboembolic complications' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) In a retrospective study comparing outcomes with 4-factor PCC versus aPCC in 342 patients with ICH, treatment with 4-factor PCC was associated with a higher likelihood of an INR 1.5 [42]. Case reports suggest that incomplete INR correction is associated with clinical worsening in patients treated with PCC. Observational studies show that in some cases ICH can continue to expand, even in patients for whom anticoagulation is reversed, although more rapid reversal with a PCC appears to correlate with a lower risk of expansion [4,11,43]. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 16/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional supporting data for PCC are presented separately. (See "Management of warfarin- associated bleeding or supratherapeutic INR", section on 'PCC products'.) Thrombotic events have complicated infusion of PCC, but this risk is difficult to quantify due to varying preparations, doses, and differing patient populations in available reports. Among most series, thrombotic complications occurred in 1.5 to 10 percent of patients [20,31,40,44-46]. The risk may be substantially higher in individuals with prosthetic heart valves or valvular heart disease [43]. Intravenous vitamin K Vitamin K should be given because the half-life of PCC is very short (hours). Vitamin K 10 mg is given by slow intravenous infusion, no faster than 1 mg/min to minimize anaphylactic risk [11,31]. If the INR is 1.5, a lower dose (eg, 5 mg) may be given if desired. The effect of vitamin K on the INR takes approximately 12 to 24 hours; thus, all patients should also receive PCC. (See 'Prothrombin complex concentrate' above.) Intravenous vitamin K administration is preferred over oral or subcutaneous administration because it results in more rapid correction of the INR and because oral administration can be problematic in the setting of neurologic deficits or conditions that affect gastrointestinal absorption. Oral vitamin K may be used in individuals who are awake and have normal gastrointestinal function. Vitamin K administration can be repeated every 12 hours for persistent INR elevation, and daily INR should be obtained to assess for this need [47]. (See 'Laboratory testing' above.) Evidence supporting the efficacy of vitamin K and comparison of the routes of administration are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Vitamin K dose, route, formulation'.) Dabigatran Intracranial bleeding associated with dabigatran can be treated with idarucizumab or aPCC. We make sure that dabigatran has been discontinued and that this is clearly stated in the medical record. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Convincing evidence of dabigatran anticoagulation may be based on a clinical history of ingestion within the previous 3.5 days and/or laboratory evidence of dabigatran effect (eg, prolonged activated partial thromboplastin time [aPTT], thrombin time [TT], diluted thrombin time [dTT], or ecarin clotting time [ECT]). An aPTT in the normal range cannot be used to justify withholding of idarucizumab, because drug effect may still be present. However, idarucizumab should not be given to patients who have a normal TT, dTT, and/or ECT. (See "Direct oral https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 17/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Laboratory testing and monitoring (dabigatran)'.) Idarucizumab Idarucizumab is an emergency reversal agent for dabigatran. It is an anti- dabigatran monoclonal antibody fragment. For patients with acute intracranial hemorrhage and convincing evidence of dabigatran anticoagulation, we suggest idarucizumab if available, rather than clotting factor products (aPCC, PCC, or plasma). The dose of idarucizumab is 5 grams (two 2.5-gram vials), administered either as two consecutive infusions or as a bolus (ie, injecting both vials consecutively via syringe). Repeat dosing is generally not required but may be appropriate in selected cases (eg, overdose, persistently prolonged aPTT), although data are limited. We do not combine idarucizumab with other prohemostatic products such as a PCC, aPCC, or rFVIIa. Treatment with idarucizumab may be associated with thrombosis due to the patient's underlying thrombotic risk factors. Evidence for the efficacy and safety of idarucizumab in dabigatran- associated bleeding is presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Alternative options Activated PCC If idarucizumab is not available, we suggest administering activated prothrombin complex concentrate (aPCC; FEIBA) at a dose of 50 to 80 units/kg. The activated factor VII in this product activates the free factor X and may be sufficient to bypass dabigatran and promote clotting. If aPCC is not available, 4-factor or 3-factor PCC at a dose of 50 units/kg would be reasonable. Three-factor PCC may be supplemented with rFVIIa or plasma. Dosing of these supplements is described above. (See 'Reversal agent' above.) Activated charcoal and dialysis Unabsorbed dabigatran can be removed from the gastrointestinal tract using oral activated charcoal. This is generally appropriate if the last dose was within the previous two hours. Dosing and contraindications are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Dabigatran can also be removed by hemodialysis if the consulting specialist believes this would be useful. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 18/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate These interventions are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Apixaban, edoxaban, and rivaroxaban Intracranial bleeding associated with a direct oral factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban) can be treated with andexanet alfa (a reversal agent for factor Xa inhibitors) or 4-factor PCC ( table 8). We make sure that the factor Xa inhibitor has been discontinued and that this is clearly stated in the medical record. Convincing evidence of factor Xa inhibitor anticoagulation may be based on a clinical history of ingestion within a period of five half-lives and/or laboratory evidence of anticoagulant effect (eg, increased anti-factor Xa activity, ideally calibrated for the specific drug). The PT, aPTT, and anti-Xa calibrated for other drugs may be useful if abnormal but are less reliable. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.) The half-lives of these agents and the number of days elapsed in five half-lives are listed separately (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Interval since last dose'); most are within two to three days. Reversal agent options For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with a factor Xa inhibitor, we suggest andexanet alfa or 4-factor PCC. These agents have not been directly compared in a randomized trial. We prefer andexanet alfa given the drug's specificity and available data [48,49]. However, some experts consider there to be more equipoise in the choice between andexanet alfa and PCC. In a retrospective chart review of 109 adults with intracranial hemorrhage who were taking either apixaban or rivaroxaban at presentation, the rate of effective hemostasis was similar (71 percent for patients who received andexanet alfa and those who received 4-factor PCC) [50]. At baseline, the mean intracerebral hemorrhage score was 1 and Glasgow Coma Scale score was 14. After treatment, the median change in hematoma volume on repeat brain imaging and the rate of thrombotic complications were also similar between groups, but the total cost of treatment was more than three times higher with andexanet alfa. These results are limited by the relative small sample size, the potential of treatment bias, and uncertain applicability to patients with more severe hemorrhagic events. A randomized trial comparing andexanet versus usual care in patients with intracranial bleeding is ongoing [51]. Further discussion of this subject and evidence for the efficacy and safety of andexanet are reviewed separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Andexanet alfa'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 19/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Andexanet alfa Andexanet alfa (andexanet) is an emergency reversal agent for factor Xa inhibitors. It is a recombinantly produced, catalytically inactive form of factor Xa that acts as a "decoy" to bind and sequester the factor Xa inhibitor anticoagulant. Andexanet alfa is given at one of two dose levels based on the dose and timing of the factor Xa inhibitor. The low dose is given as a bolus of 400 mg at 30 mg/min over 15 minutes, followed by an infusion of 480 mg given at 4 mg/min for up to 120 minutes. This is used in patients who received a lower dose of factor Xa inhibitor (eg, rivaroxaban 10 mg, apixaban 5 mg, or edoxaban 30 mg) or if eight hours or more have elapsed since the last dose of factor Xa inhibitor. The high dose is given as a bolus of 800 mg at 30 mg/min over 30 minutes, followed by an infusion at 960 mg given at 8 mg/min for up to 120 minutes. This is used for those who received a higher dose of factor Xa inhibitor (eg, rivaroxaban >10 mg, apixaban >5 mg, edoxaban >30 mg) or unknown dose within the previous eight hours. We do not use anti-factor Xa assays to assess the extent of anticoagulation reversal. Routine anti-factor Xa levels obtained after treatment with andexanet alfa may be falsely elevated due to dilutional effects [52]. We do not combine andexanet with other prohemostatic products such as PCC, aPCC or rFVIIa. 4-factor PCC A 4-factor prothrombin complex concentrate (PCC) is an alternative to andexanet for reversing factor Xa inhibitors. In a retrospective series involving 663 individuals who had an intracranial hemorrhage while receiving apixaban or rivaroxaban, 4-factor PCC was associated with good or excellent hemostasis in 354 of 433 evaluated for efficacy (82 percent) [53]. Thrombosis within 14 days of PCC administration occurred in 22 of the 663 (3.3 percent). These efficacy and safety outcomes are like those seen with andexanet and with 4-factor PCC in other studies of oral factor Xa inhibitor reversal after bleeding in other sites. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of factor Xa inhibitor reversal'.) PCC can be given at a dose of 50 units/kg, or a fixed-dose regimen (2000 or 2500 units) can be used (eg, dosing like that used for warfarin reversal). (See 'Reversal agent' above.) If PCC is used, the patient should not be treated with andexanet. Activated charcoal Unabsorbed anticoagulant can be removed from the gastrointestinal tract using oral activated charcoal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 20/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We use the following intervals from the most recent dose to decide if charcoal may be helpful (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'): Apixaban Within six hours Edoxaban Within two hours Rivaroxaban Within six to eight hours Dosing and contraindications to oral activated charcoal are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Direct factor Xa inhibitors cannot be removed by hemodialysis. Unfractionated heparin For patients with intracranial bleeding associated with therapeutic doses of unfractionated heparin, protamine sulfate can be given for heparin reversal. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.) We make sure that all sources of heparin have been discontinued and that this is clearly stated in the medical record. Protamine sulfate Protamine sulfate (protamine) is an emergency reversal agent for unfractionated heparin. For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with unfractionated heparin (prolonged aPTT and/or administration within the previous two hours), we recommend protamine. A fixed dose of 50 mg or 25 mg may be given; some experts give 50 mg and others give 25 mg followed by an additional dose of 25 mg if needed (eg, based on a prolonged aPTT). The 50 mg dose would be more appropriate for an individual with a greater aPTT prolongation; however, this dose may be associated with a greater risk for relative hypotension. Alternatively, the dose can be calculated as 1 mg protamine per 100 units of heparin. The number of units of heparin is estimated based on the previous dose and the interval since it was administered, with an estimated half-life of heparin in the range of one to two hours (eg, if a dose of 5000 units was given one hour ago, the number of units would be 2500 and the dose of protamine would be 25 mg). Protamine must be given by slow intravenous infusion, as rapid infusion may cause hypotension, particularly at high doses (eg, 50 mg). The infusion rate should not exceed 20 mg/min and the total dose should not exceed 50 mg in any 10-minute period. Repeat doses may be given for a persistently prolonged aPTT. If heparin had been given by subcutaneous injection, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 21/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate repeated small doses of protamine may be required because of prolonged heparin absorption from subcutaneous sites. Protamine is derived from fish sperm and may elicit an allergic reaction, especially in previously exposed individuals. In the United States, the protamine sulfate label contains a boxed warning that the drug can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine or protamine-containing insulin (eg, neutral protamine hagedorn [NPH] or protamine zinc insulin [PZI]), and certain beta-blockers. Allergy to fish, previous vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics also may be risk factors. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Evidence for the efficacy and safety of protamine include a number of preclinical and observational studies that demonstrate effective reversal, as summarized in a 2016 guideline [14]. Studies evaluating clinically significant outcomes are lacking, as discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) LMW heparin Intracranial bleeding associated with low molecular weight (LMW) heparin (eg, enoxaparin, dalteparin, nadroparin, tinzaparin) is uncommon but can occur, particularly in patients with cancer and brain metastases. For intracranial bleeding associated with therapeutic dose LMW heparin, we suggest andexanet alfa rather than protamine sulfate. However, protamine sulfate is a reasonable alternative if andexanet is not available. Evidence of LMW heparin effect may be based on the interval since the last dose and/or anti- factor Xa activity indicating a LMW heparin level of 0.3 international units/mL. (See 'Laboratory testing' above.) We make sure that the LMW heparin has been discontinued and that this is clearly stated in the medical record. Andexanet alfa Despite limited data, andexanet alfa is a reasonable approach for the treatment of intracranial bleeding associated with LMW heparin anticoagulation. Studies evaluating andexanet alfa for reversal of anticoagulation suggested efficacy for achieving hemostasis in a small number of individuals receiving therapeutic dose LMW heparin (16 individuals receiving enoxaparin in the ANNEXA-4 study) [54]. Additional data are needed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 22/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate For patients with bleeding associated with therapeutic dose LMW heparin, the dosing of andexanet alfa in ANNEXA-4 was the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes [54]. The lower dose level (400 mg bolus and 480 infusion at 4 mg/minute) may be sufficient in individuals receiving prophylactic dose LMW heparin, although this has not been demonstrated, and it may be safer to use the higher dose level. If andexanet is unavailable, protamine sulfate should be given. (See 'Protamine sulfate if andexanet alfa is unavailable' below.) Protamine sulfate if andexanet alfa is unavailable For patients with acute intracranial hemorrhage and evidence of LMW heparin anticoagulation (increased anti-factor Xa activity [preferred] or administration within the previous 12 hours), protamine sulfate is a reasonable treatment option if andexanet is not available. Unlike its effect with unfractionated heparin, protamine is less effective in reversing the effect of LMW heparin. This is because protamine acts by reversing the inhibitory effect of LMW heparin on thrombin but only reverses approximately 60 percent of the inhibitory effect on factor Xa due to decreased binding to the shorter heparin chains in LMW heparin. Dosing of protamine sulfate in LMW heparin-associated bleeding is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) Fondaparinux Fondaparinux is a synthetic pentasaccharide analog of the natural pentasaccharide found in heparin. Fondaparinux acts by binding to and inducing a conformational change in antithrombin that causes selective inhibition of factor Xa. The half-life of fondaparinux is 17 to 21 hours. For patients with intracranial hemorrhage associated with fondaparinux anticoagulation, there is little information to guide management. Andexanet alfa is a reasonable option if it is available. Although data are limited, we would use the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes. Protamine sulfate is ineffective for fondaparinux reversal. Other options for reversal and additional information about the use of these agents are presented separately. (See "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 23/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate RESUMPTION OF ANTICOAGULATION In many cases, anticoagulation can be resumed after bleeding resolves, provided the patient remains stable and the risk-benefit calculation clearly favors reinitiating anticoagulation. However, the decision must be individualized. Considerations related to this decision and evidence to support the benefit of restarting anticoagulation are presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Resumption of anticoagulation'.) Likewise, the optimal timing for restarting anticoagulation therapy following an intracranial bleed is unknown. The size and cause of the bleeding (eg, traumatic versus atraumatic) and patient-specific factors that increase bleeding risk may play a role in the calculation. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Prognosis and reinitiation of anticoagulation'.) For individuals treated with high doses of vitamin K, there may be a period of refractoriness after resuming warfarin. The decision process to reinitiate anticoagulation and the timing of reinitiation are discussed separately. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of antithrombotic therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults" and "Society guideline links: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. 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