Anticoagulation Centers of Excellence



Management of Anticoagulant-Associated Bleeding Events Including Reversal StrategiesBackground:Healthcare staff involved in anticoagulant-associated bleeding management, including providers, nurses and pharmacists, should be familiar with available reversal agents and procoagulant therapies, including:Which anticoagulants they will (and will not) reverseBrand and generic namesDosingAdditionally, given high cost and potential for adverse events of some reversal strategies, all healthcare staff should share in stewardship of anticoagulant reversal, including judicious use of reversal agents, to optimize use and patient outcomesRationale:This template was created by the Anticoagulation Forum to aid healthcare institutions in achieving compliance with The Joint Commission National Patient Safety Goal 03.05.01 Element of Performance 2 pertaining to reversal of anticoagulation and management of bleeding events related to each anticoagulant medication1The Anticoagulation Forum developed this clinical tool, which can be modified by individual organizations based on local resources, formularies and agreed-upon approachesThis template is intended as an institutional aid and should not replace sound clinical judgment. The Anticoagulation Forum assumes no medical or legal liability for final versions created by individual organizationsScope: Management of clinically significant bleeding (i.e., requiring intervention) in patients on anticoagulant therapy who present to or are admitted to the hospitalIt does not include guidance for:Reversal of anticoagulation for surgical or procedural interventionsMild or nuisance bleeding (e.g., bruising, hemorrhoidal, mild nosebleed)Asymptomatic elevated INRs in patients on warfarinResource contact information: (list entities most appropriate to your institution)Critical care intensivist on-call X-XXXX Central Pharmacy X-XXXXUnit pharmacist X-XXXX Blood bank X-XXXXUniversal Principles and InformationRisk vs. benefit of anticoagulation reversal in bleedingAnticoagulation reversal strategies should be limited to serious bleeding where the immediate need for anticoagulant reversal outweighs the risk of thrombosis (either from the reversal agent itself or normalization of coagulation in a patient with underlying thromboembolic risk) and only if bleeding is not controlled with maximal supportive measures.2,3High thrombotic riskIn populations at high risk for thrombosis compared to bleeding (e.g., LVAD, mechanical heart valve, recent acute thrombotic event), consider more conservative reversal approaches whenever feasibleMild bleedingDefined as bleeding that does not require urgent (same-day) intervention (e.g., minor nosebleed, hemorrhoidal bleeding, bruising)Immediate reversal is typically not needed and should be avoided Simple measures should be applied, such as:Consideration for holding anticoagulant and antiplatelet medications until mild bleeding resolvesInstitute local measures, as appropriate, such as application of pressure Consider use of decongestant nasal spray for nosebleedsImpaired organ functionElimination half-lives and duration of anticoagulant effect may be prolonged, and last for several days in the presence of organ failure or drug interactions Neuraxial considerationsIf patients have a neuraxial device (e.g., epidural catheter), monitor for signs/symptoms of spinal epidural hematoma (lower back pain, bladder incontinence, lower extremity paresthesia/paralysis)4Prothrombin complex concentrates (PCCs)Inactivated 4-Factor PCC (Kcentra?) contains Factors II, VII, IX, X and trace amounts of heparin (do not use in patients with active confirmed heparin-induced thrombocytopenia [HIT])Activated 4-Factor PCC (FEIBA?) contains Factors II, VIIa, IX and XOptimal dosing strategies have not been identifiedIf giving PCC, no need to co-administer FFP, unless volume resuscitation also desired Adjunctive therapiesTranexamic acid 1 gm IV x 1 for refractory bleedingDDAVP 0.3-0.4 mcg/kg x 1 for patients recently on antiplatelet therapyResumption ofanticoagulation Whenever possible, anticoagulation should be resumed in a timely manner to avoid thromboembolic complications related to the underlying indication for anticoagulation.5Table of Contents - HyperlinkedWarfarinPage 5DabigatranPage 6ApixabanPage 7BetrixabanPage 8EdoxabanPage 9RivaroxabanPage 10ArgatrobanPage 11BivalirudinPage 11FondaparinuxPage 12Unfractionated Heparin Page 13DalteparinPage 14EnoxaparinPage 15Resumption of AnticoagulationPage 16Andexanet alfa dosingPage 16ReferencesPage 17 Note: Actions and components of steps below can and should occur in tandem via multidisciplinary approaches whenever possibleSTEP 1:Patient historyObtain essential information from appropriate persons (primary team, medical chart, patient, family, EMT, pharmacy and other sources)Which antithrombotic agents and dose patient is suspected/confirmed to be taking (including both anticoagulants and antiplatelets)Other medications patient is taking to assess for potential drug interactions that may be potentiating bleedIndication for anticoagulationDate of most recent thrombotic event (if any)Time of last dose of anticoagulant if possibleCurrent renal function, hepatic function, complete blood count (CBC) STEP 2:Severity of bleedDetermine A) severity of bleed, B) urgency of reversal, and C) relevant general approachesCriticalMajorNon-majorCommentsDefined as: Intracranial, intraocular bleed or intraspinal bleed ORBleeding causing hemodynamic instabilitySBP <90 mm HgMAP < 65 mm HgOrthostatic hypotensionUrine output < 0.5 ml/kg/hrDefined as:Overt bleed (e.g. GI/GU/ peritoneal) ANDDrop in Hgb >2g/ dL or transfusion of ≥2 units RBCsANDNot meeting definition of critical bleedingDefined as:Requiring medical attention (e.g. ED visit or urgent clinic visit)ANDNot meeting definition of critical or major bleedingBleed severity:Defined differently by different organizations 3,6,7Not always easily categorizedUrgency of reversal (timeframe)Emergent(minutes)Emergent(minutes to hours)Semi-urgent(hours)General approaches (regardless of specific anticoagulant)□ Hold all anticoagulant and antiplatelet medications□ Institute supportive strategies as needed□ Consider transfer to intensive care unit □ Intubation, fluid resuscitation, transfusion as needed □ Notify other services as needed (e.g.- endoscopy, radiology, surgery, OR) and have them on standby□ Ongoing assessment of vital signs, coagulation parameters, other labs (e.g., Ca++, pH)□ Assess for and manage comorbidities contributing to the bleed (e.g., renal dysfunction, liver disease, thrombocytopenia)□ Identify and control source of bleed (local therapy?/manual compression/ procedural or surgical intervention)□ Consider holding anticoagulant and antiplatelet medications □ Institute local measures as appropriate Apply pressure and use decongestant nasal spray for nosebleeds) STEP 3: Bleed managementDetermine most appropriate management approach(es) based on specific anticoagulant(s) and severity of bleed Oral AnticoagulantsCriticalMajorNon-majorCommentsWarfarin (Coumadin?)Half-life: ~40 hoursElimination:HepaticLab(s) to guide therapy:INR (baseline and q 12 hrs PRN)Drug class: Vitamin K antagonistDraw initial INR STATHold warfarin Supportive measuresIf INR elevated, institute reversal immediately□ Vitamin K 5-10 mg IV STAT3,8PLUS one of the following STATInactivated 4F-PCC IV STATWeight and INR-BASED DOSING3 (using actual body weight, max weight 100 kg, max dose 5000 units)□ INR >1.4 – 4: 25 units/kg□ INR 4.1 – 6: 35 units/kg □ INR >6: 50 units/kg ORFIXED DOSING3□ 1000 units□ 1500 units□ 2000 units4. REPEAT INR within 15-30 minutes after inactivated 4F-PCC administration5. May give repeat inactivated PCC X1 PRN for refractory bleedingDraw initial INR STATHold warfarinSupportive measures If INR elevated, institute reversal if bleeding is not controlled with maximal supportive measures. □ Vitamin K 2-10 mg IV STAT3,8MAY ALSO CONSIDERone of the following STATInactivated 4F-PCC IV STATWeight and INR BASED DOSING3 (using actual body weight, max weight 100 kg, max dose 5000 units)□ INR >1.4 – 4: 25 units/kg□ INR 4.1 – 6: 35 units/kg □ INR >6: 50 units/kg ORFIXED DOSING3□ 1000 units□ 1500 units□ 2000 units4. If inactivated 4F-PCC given, REPEAT INR within 15-30 minutes after administration5. If inactivated 4F-PCC used, may give repeat inactivated PCC X1 PRN for refractory bleedingDraw initial INR STATStop or hold dose(s) if clinically warrantedSupportive measures if neededIf INR elevated and bleed DOES require hospitalization, intervention and/or transfusion, consider reversal Vitamin K 1-5 mg IV or PO3,8 ??? ?Vitamin K: - Vitamin K 1-2 mg provides same INR reduction as higher doses - Higher doses result in longer duration of reversal - IV route provides more rapid reversal than PO - IV formulation of vitamin K may be given orally & provides more dosing flexibilityPCC:Some hospitals may opt to use ACTIVATED PCC. We have provided dosing information for inactivated PCC only, based on available evidence and FDA labelingDabigatran(Pradaxa?)Half-life:12 to 17 hoursProlonged in renal impairmentElimination: Renal (80%)Lab(s) to guide therapy: Thrombin time (TT)More sensitive to presence of drugA normal TT probably excludes clinically relevant dabigatran levels, but a prolonged TT does not discriminate between clinically important and insignificant drug concentrationsaPTT If prolonged, suggests presence of drugNormal aPTT may not exclude presence of clinically relevant drug levelsDrug class: Direct thrombin inhibitor1. Hold dabigatran2. Supportive measures3. ReversalIdarucizumab (Praxbind?) 5 grams IV STAT2,3,5,9 May repeat 5 grams IV x1 PRN for refractory bleedingOR If idarucizumab unavailable:PCC (activated or inactivated) 50 units/kg IV STAT2,3(Optimal dosing of PCC for dabigatran reversal has not been established and may range from 8-50 units/kg10)4. May consider activated charcoal (50g) if known recent ingestion within 2-4 hours31. Hold dabigatran2. Supportive measures3. ReversalPursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding Hold dabigatranSupportive measures if neededDialysis may be considered in patients with continued clinically significant bleeding after reversal administration.In patients with severe renal dysfunction, laboratory evaluation to detect residual anticoagulant activity is recommended following administration of a reversal agent and consideration of redosing if bleeding persists or recursThe risks and benefits of repeat idarucizumab administration are not known.Apixaban(Eliquis?)Half-life:~12 hoursElimination: Renal (27%)Hepatobiliary/Direct intestinal Lab(s) to guide therapy: Apixaban-specific anti-Xa assay or LC-MS/MS* may be used to measure apixaban levels.UFH or LMWH anti-Xa assay is not suitable for measuring apixaban levels. However, a result below the lower limit of quantitation probably excludes clinically relevant apixaban levels.PT and APTT are not useful for apixaban monitoring. A normal PT and/or APTT does not exclude the presence of clinically relevant apixaban levels. Drug class: Factor Xa inhibitor1. Hold apixaban2. Supportive measures 3. Reversal□ Andexanet alfa (ANDEXXA?) IV STAT2,3,5(see andexanet alfa dosing table below)ORFIXED DOSE inactivated 4F-PCC 2000 units IV STAT2ORWEIGHT-BASED DOSING Inactivated 4F-PCC 50 units/kg IV STAT3(Other 4F-PCC doses, such as 25 units/kg, have been tested and may be appropriate based on the literature; optimal dose has not been defined)4. May consider activated charcoal (50g) if known recent ingestion within 2-4 hours3 1. Hold apixaban2. Supportive measures 3. ReversalPursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding 1. Hold apixaban2. Supportive measures if needed Andexanet alfa is FDA-approved for apixaban reversalBetrixaban(Bevyxxa?)Half-life:19-27 hrsElimination:Renal (11%)Hepatobiliary/Direct intestinal Lab(s) to guide therapy: Betrixaban-specific anti-Xa assay or LC-MS/MS* may be used to measure betrixaban levels.UFH or LMWH anti-Xa assay is not suitable for measuring betrixaban levels. However, a result below the lower limit of quantitation probably excludes clinically relevant betrixaban levels.A prolonged PT suggests the presence of clinically relevant betrixaban levels. However, a normal PT does not exclude the presence of clinically relevant betrixaban levels.Drug class: Factor Xa inhibitorHold betrixabanSupportive measures Reversal**Andexanet alfa IV STAT(see andexanet alfa dosing table below)2,3,5ORFIXED DOSE inactivated 4F-PCC 2000 units IV STAT2ORWEIGHT-BASED DOSING Inactivated 4F-PCC 50 units/kg IV STAT3(Other 4F-PCC doses, such as 25 units/kg, have been tested and may be appropriate based on the literature; optimal dose has not been defined)4. May consider activated charcoal (50g) if known recent ingestion within 2-4 hoursHold betrixabanSupportive measures Reversal**Pursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding.Hold betrixabanSupportive measures if needed** There are no approved reversal agents for betrixaban. Evidence supporting reversal is limited. Recommend consulting available clinicians with expertise in reversal if indicatedEdoxaban(Savaysa?)Half-life:10-14 hrsElimination: Renal (50%)Hepatobiliary/Direct intestinal Lab(s) to guide therapy: Edoxaban-specific anti-Xa assay or LC-MS/MS* may be used to measure edoxaban levels.UFH or LMWH anti-Xa assay is not suitable for measuring edoxaban levels. However, a result below the lower limit of quantitation probably excludes clinically relevant edoxaban levels.A prolonged PT suggests the presence of clinically relevant edoxaban levels. However, a normal PT does not exclude the presence of clinically relevant edoxaban levels.Drug class: Factor Xa inhibitorHold edoxabanSupportive measuresReversal**Andexanet alfa IV STAT(see andexanet alfa dosing table below)2,3,5ORFIXED DOSE inactivated 4F-PCC 2000 units IV STAT2ORWEIGHT-BASED DOSING Inactivated 4F-PCC 50 units/kg IV STAT3(Other 4F-PCC doses, such as 25 units/kg, have been tested and may be appropriate based on the literature; optimal dose has not been defined)May consider activated charcoal (50g) if known recent ingestion within 2-4 hoursHold edoxabanSupportive measuresReversal**Pursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding.Hold edoxabanSupportive measures if needed** There are no approved reversal agents for edoxaban. Evidence supporting reversal is limited. Recommend consulting available clinicians with expertise in reversal if indicatedRivaroxaban(Xarelto?)Half-life: 5-9 hrs (healthy subjects age 20-45 yrs)11-13 hrs (elderly subjects age 60-76 yrs)Elimination:Renal (36%)Hepatobiliary/Direct intestinal Lab(s) to guide therapy: Rivaroxaban-specific anti-Xa assay or LC-MS/MS* may be used to measure rivaroxaban levels.UFH or LMWH anti-Xa assay is not suitable for measuring rivaroxaban levels. However, a result below the lower limit of quantitation probably excludes clinically relevant rivaroxaban levels.A prolonged PT suggests the presence of clinically relevant rivaroxaban levels. However, a normal PT does not exclude the presence of clinically relevant rivaroxaban levels.Drug class: Factor Xa inhibitorHold rivaroxabanSupportive measuresReversalAndexanet alfa IV STAT(see andexanet alfa dosing table below)2,3,5ORFIXED DOSE inactivated 4F-PCC 2000 units IV STAT2ORWEIGHT-BASED DOSING Inactivated 4F-PCC 50 units/kg IV STAT3(Other 4F-PCC doses, such as 25 units/kg, have been tested and may be appropriate based on the literature; optimal dose has not been defined)May consider activated charcoal (50g) if known recent ingestion within 2-4 hoursHold rivaroxabanSupportive measuresReversalPursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding.Hold rivaroxabanSupportive measures if neededAndexanet alfa is FDA-approved for apixaban reversalIV/Injectable Anticoagulants11CriticalMajorNon-majorCommentsArgatroban(Acova?)Half-life:39 to 51 minutes Hepatic Impairment: 181 minutes Elimination: Hepatic Lab(s) to guide therapy: aPTT/plasma diluted thrombin timeDrug class: Direct thrombin inhibitorHold argatrobanSupportive measuresNo established reversal agents**Dialysis may be considered Hold argatrobanSupportive measuresNo established reversal agents**Dialysis may be considered Stop or hold infusion if clinically warrantedSupportive measures if needed** There are no established reversal agents for argatroban. Evidence supporting reversal is limited. Recommend consulting available clinicians with expertise in reversal if indicatedShort half-life of argatroban may preclude need for reversal strategies Bivalirudin(Angiomax?)Half-life:Normal renal function and mild renal impairment: 25 minutesModerate renal impairment: 34 minutesSevere renal impairment: 57 minutesDialysis: 3.5 hoursElimination: Primarily Enzymatic. Urine (20%), glomerular filtration, tubular secretion, and tubular reabsorptionLab(s) to guide therapy: aPTT/ plasma dilute thrombin time Drug class: Direct thrombin inhibitorHold bivalirudinSupportive measuresNo established reversal agents**Dialysis may be considered Hold bivalirudinSupportive measuresNo established reversal agents**Dialysis may be consideredStop or hold infusion if clinically warrantedSupportive measures if needed** There are no established reversal agents for bivalirudin. Evidence supporting reversal is limited. Recommend consulting available clinicians with expertise in reversal if indicatedShort half-life of bivalirudin may preclude need for reversal strategiesFondaparinux(Arixtra?)Half-life:17-21 hrsElimination: RenalLab(s) to guide therapy: Fondaparinux-specific anti-Xa assay may be used to measure fondaparinux levels.PT and aPTT are not useful for fondaparinux monitoring. A normal PT and/or aPTT does not exclude the presence of clinically relevant fondaparinux levels. Drug class: Factor Xa inhibitorHold fondaparinuxSupportive measuresReversal**Andexanet alfa IV STAT-Insufficient evidence to support a specific dose.-May consider similar andexanet dosing as for oral FXa inhibitors -See andexanet alfa dosing table belowORPCC (activated or inactivated)-Insufficient evidence to support a specific dose- May consider similar PCC dosing as for other anticoagulants (e.g., up to 50 units/kg)ORRecombinant Factor VIIa (Insufficient evidence to support a specific dose)Hold fondaparinuxSupportive measuresReversal**Pursue reversal only if bleeding is not controlled with maximal supportive measures. Selection and dosing of reversal agents is same as for critical bleeding.Hold fondaparinuxSupportive measures if needed** There are no established reversal agents for fondaparinux. Evidence supporting reversal is extremely limited. Recommend consulting available clinicians with expertise in reversal if indicatedUnfractionated Heparin (UFH)Half-life:~ 60 minutesElimination:Reticuloendothelial Labs to guide therapy:aPTTanti-Xa assayDrug class: Unfractionated HeparinHold UFHSupportive measuresReversalProtamine SulfateFIXED DOSE50 mg IV over 10 minutes (May repeat x1 for refractory bleeding)12ORCALCULATED DOSE1 mg per 100 units of heparin if < 60 min since last heparin0.5 mg per 100 units of heparin if 61-120 minutes since last heparin0.25 mg per 100 units of heparin if 121-180 minutes since last heparinHold UFHSupportive measuresReversalPursue reversal only if bleeding is not controlled with maximal supportive measures. Dosing of protamine is same as for critical bleeding.Stop or hold infusion if clinically warrantedSupportive measures if neededProtamine will fully reverse UFH1 mg of protamine will neutralize 100 units of UFHMaximum dose 50 mg per infusion/pushGive slowly, no faster than 5mg/minute to avoid hypotensionProtamine is derived from fish sperm, and cautious use in patients with fish allergy is imperativeAlso, caution with protamine use is required in patients with exposure to NPH or protamine-containing insulin, or history of vasectomyDalteparin(Fragmin?)Half-life: 5-7 hours (in normal renal function)Elimination: renalLab(s) to guide therapy: anti-Xa assayDrug class: Low molecular weight heparin (LMWH)Hold dalteparinSupportive measuresReversalProtamine SulfateFIXED DOSE50 mg IV over 10 minutes (May repeat x1 for refractory bleeding)12ORCALCULATED DOSETime from last LMWH administration:< 8 hours: 1 mg per 100 units with maximum 50 mg per administration> 8 hours: 0.5 mg per 100 units with maximum 50 mg per administrationRepeat dose if needed:0.5 mg per 100 units with maximum 50 mg per administrationHold dalteparinSupportive measuresReversalPursue reversal only if bleeding is not controlled with maximal supportive measuresDosing of protamine is same as for critical bleedingStop or hold infusion if clinically warrantedSupportive measures if neededProtamine will only reverse approximately 60% of LMWH anti-Xa activityMaximum dose 50 mg per infusion/pushGive slowly, no faster than 5mg/minute to avoid hypotensionProtamine is derived from fish sperm, and cautious use in patients with fish allergy is imperativeAlso, caution with protamine use is required in patients with exposure to NPH or protamine-containing insulin, or history of vasectomyEnoxaparin(Lovenox?)Half-life: 5-7 hours (in normal renal function)Elimination: renalLab(s) to guide therapy: anti-Xa assayDrug class: Low molecular weight heparin (LMWH)Hold enoxaparinSupportive measuresReversalProtamine SulfateFIXED DOSE50 mg IV over 10 minutes (May repeat x1 for refractory bleeding)12ORCALCULATED DOSETime from last LMWH administration:< 8 hours: 1 mg per 100 units with maximum 50 mg per administration> 8 hours: 0.5 mg per 100 units with maximum 50 mg per administrationRepeat dose if needed:0.5 mg per 100 units with maximum 50 mg per administrationHold enoxaparinSupportive measuresReversalPursue reversal only if bleeding is not controlled with maximal supportive measures Dosing of protamine is same as for critical bleedingStop or hold infusion if clinically warrantedSupportive measures if neededProtamine will only reverse approximately 60% of LMWH anti-Xa activityMaximum dose 50 mg per infusion/pushGive slowly, no faster than 5mg/minute to avoid hypotensionProtamine is derived from fish sperm, and cautious use in patients with fish allergy is imperativeAlso, caution with protamine use is required in patients with exposure to NPH or protamine-containing insulin, or history of vasectomyResumption of Anticoagulation2,3,5,13CriticalMajorNon-majorCommentsAfter extracranial bleed (e.g., gastrointestinal):Balance risk of thromboembolism and bleeding and resume when able After intracranial bleed:If traumatic, balance risk of thromboembolism and bleeding and resume when ableIf spontaneous LOBAR consider alternatives to anticoagulation If spontaneous NON-LOBAR, consider re-initiation of anticoagulation in 1 monthSame as criticalSame as criticalLobar hemorrhage= occurring in the frontal, parietal, temporal or occipital cerebral lobe * LC-MS/MS= Liquid chromatography/tandem mass spectrometryTable: Andexanet alfa dosing Factor Xa inhibitorLast doseTiming of last dose< 8 hours or unknown≥ 8 hoursApixaban≤ 5 mgLow-dose1Low-dose1> 5 mg or unknownHigh-dose2Low-dose1Betrixaban3AnyHigh-dose2High-dose2Edoxaban3AnyHigh-dose2High-dose2Rivaroxaban≤ 10 mgLow-dose1Low-dose1> 10 mg or unknownHigh-dose2Low-dose11Initial 400 mg IV bolus at target rate of 30 mg/min followed by continuous infusion at 4 mg/min for up to 120 min2Initial 800 mg IV bolus at target rate of 30 mg/min followed by continuous infusion at 8 mg/min for up to 120 min3Andexanet alfa is not FDA-approved for reversal of betrixaban or edoxaban and dosing of andexanet alfa for reversal of these agents has not been established References: Accessed 12/11/19Cuker A, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol.?2019 Jun;94(6):697-709Tomaselli GF, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:3042–67Horlocker T, et al. Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Fourth Edition). Regional Anesthesia and Pain Medicine 2018; 43 93): 263–309. doi: 10.1097/AAP.0000000000000763Witt DM, et al. .American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018 Nov 27; 2(22): 3257–3291. doi: 10.1182/bloodadvances.2018024893Schulman S, et al. ?Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients: on behalf of the subcommittee on control of anticoagulation of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost2005;3: 692–4Kaatz S, et al. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost2015;13: 2119–26Holbrook A, et al. Evidence-Based Management of Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e152S–e184SFrontera, JA. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care (2016) 24:6–46 DOI 10.1007/s12028-015-0222-xDager WE, et al. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thrombosis Research 173 (2019) 71–76Garcia DA, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e24S-e43S. doi: 10.1378/chest.11-2291Heparin. In: Lexi-drugs online. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; Last updated 12/13/19. Available at ?Accessed 12/11/19. Subscription required to viewHemphill JC III, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke.?2015 Jul;46(7):2032-60. doi: 10.1161/STR.0000000000000069About the Anticoagulation Forum The Anticoagulation Forum is the largest organization of anticoagulation management specialists in North America. The organization’s mission is to improve the quality of care for patients taking antithrombotic medications by educating healthcare professionals and advocating for clinical best practices. Contributors: This document was created by members of the Anticoagulation Forum Board of Directors, including: Geoffrey Barnes, MD, MS; Allison Burnett, PharmD, PhC, CACP; Adam Cuker, MD, MS; William E. Dager, PharmD, BCPS, MCCM, FCSHP, FACCP, FASHP; Steven Deitelzweig, MD, MMM, FACC, SFHM, FACP, RVT; Scott Kaatz, DO, MSc, FACP, SFHMThis project is funded in part by an educational grant from Portola Pharmaceuticals, Inc. ................
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