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University ..- Health System

Reversal of and Management of Bleeding Guideline Patients with trauma and/or life-threatening hemorrhage (ICH, intra-abdominal, intra-thoracic) or needs emergent operative intervention

Warfarin (Coumadin®)

Check INR

INR 1.4 - 3.9 INR 4 - 6 INR > 6 Kcentra® 25 units/kg IV x 1 Kcentra® 35 units/kg IV x 1 Kcentra® 50 units/kg IV x 1 Max dose: 2500 units Max dose: 3500 units Max dose: 5000 units

5-10 mg Vitamin K IV over 30 minutes x 1 Recheck INR 30 minutes after Kcentra® dose Kcentra®=4-Factor PCC Dose based on actual body weight up to 100 kg. Cannot re-dose Kcentra®

Direct Oral Anticoagulants (DOAC)

Rivaroxaban (Xarelto®), (Eliquis®) (Pradaxa®) or (Savaysa®)

Check Time (TT) Last dose taken within 3-5 half-lives of DOAC (A normal thrombin time excludes clinically significant levels of dabigatran )

Yes or Unknown No Kcentra® Dabigatran taken Dabigatran taken 50 units/kg IV x 1 Provide supportive within 24 hrs: 24 - 48 hrs ago Max dose: 5000 units care Praxbind® AND TT is elevated: 5 grams IV x 1 Praxbind® Kcentra®=4-Factor PCC 5 grams IV x 1 If signs/symptoms of allergic reaction to infusion – stop infusion. Avoid Kcentra® in patients with history of HIT or allergy to albumin. Praxbind®= Idarucizumab May consider an additional 5 gram dose if: Given as 2 consecutive 2.5 gram infusions  Re-bleeding and TT is elevated Praxbind contains 4 grams sorbitol. Consider this if calculating total daily  2nd emergent surgery is needed and TT amount of sorbitol/fructose in patients with hereditary fructose intolerance. is elevated

Origination date: 5/2014 Revisions: 5/2015, 1/2016, 2/2019 Approved by Anticoagulation Safety Committee: 3/2019 1 Approved by P&T: 5/2019 Unfractionated (UFH)

Time since UFH last given

Time elapsed: Immediate Time elapsed: 30 - 60 minutes Time elapsed: >2 hours Protamine 1–1.5 mg slow IV Protamine 0.5–0.75 mg slow IV Protamine 0.25– 0.375 mg slow IV for every 100 units of UFH the for every 100 units of UFH the for every 100 units of UFH the patient has received* patient has received * patient has received * Max dose: 50 mg in a 10 minute period Max dose: 50 mg in a 10 minute period Max dose: 50 mg in a 10 minute period

* If patient was on a continuous infusion, only consider heparin given in the preceding 2 - 3 hours Additional protamine dose should be guided by clinical bleeding. May repeat dose x 1 (≤ 0.5 mg of protamine for every 100 units of heparin) if bleeding continues and if the heparin assay (AntiXa level) remains elevated Repeat dosing of protamine can elevate the aPTT and ACT. A normal thrombin time is useful to confirm reversal of heparin

I Enoxaparin (Lovenox ®) 'I Time since enoxaparin last given I I I Time elapsed: 8 -12 hours Time elapsed: < 8 hours or Time elapsed: >12 hours a 2nd dose of Protamine needed* i l l 1 mg of Protamine per 0.5 mg Protamine per 1 mg of enoxaparin the patient 1 mg of enoxaparin the Protamine likely not has received patient has received needed if 3 – 5 half-lives Max dose: 50 mg in a 10 minute period Max dose: 50 mg in a 10 minute have elapsed

* Additional protamine dose should be guided by clinical bleeding. May repeat dose x 1 if bleeding continues and if the LMW heparin assay (AntiXa level) remains elevated. Protamine neutralizes 60% - 75% of anti-Xa activity of enoxaparin (Arixtra®) o There is no FDA-approved reversal agent for Fondaparinux o Reversal agent is likely not needed if 3 – 5 half-lives have elapsed (half-life 17 - 21 hours) o Recombinant factor VIIa (NovoSeven ®) 90 mcg/kg has been shown to partially normalize a prolonged aPTT, endogenous thrombin potential, and prothrombin activation in vivo. and Bivalirudin (Angiomax®) o There is no FDA-approved reversal agent for Argatroban or Bivalirudin o Reversal agent is likely not needed if 3 – 5 half-lives have elapsed o Argatroban half-life 40 - 50 minutes o Bivalirudin half-life 25 minutes, extended up to 3.5 hour in patients on dialysis o Recombinant factor VIIa (NovoSeven ®) 90 mcg/kg has been shown to reverse the anticoagulation effect of direct thrombin inhibitors

Origination date: 5/2014 Revisions: 5/2015, 1/2016, 2/2019 Approved by Anticoagulation Safety Committee: 3/2019 2 Approved by P&T: 5/2019 Management of Bleeding

Name of Dialysis Management Reversal Agent Not dialyzable - Hold warfarin Kcentra ® and (Coumadin ®) - Supportive measures* Vitamin K

Rivaroxaban Not dialyzable - Discontinue anticoagulant Kcentra ® (Xarelto ®) - Supportive measures* - Overdose: Charcoal by mouth if Apixaban ingested within 1 – 2 hours (Eliquis ®)

Edoxaban (Savaysa®)

Dabigatran Hemodialysis removes - Discontinue anticoagulant Praxbind ® (Pradaxa ®) ~57% over 4 hours - Supportive measures* - Overdose: Charcoal by mouth if ingested within 1 – 2 hours

Unfractionated Not dialyzable - Discontinue anticoagulant Protamine Heparin (UFH) - Supportive measures*

Enoxaparin Not dialyzable - Discontinue anticoagulant Protamine (Lovenox ®) - Supportive measures*

Fondaparinux Clearance increased by - Discontinue anticoagulant NovoSeven ® (Arixtra ®) 20% - Supportive measures*

Argatroban Hemodialysis removes - Discontinue anticoagulant NovoSeven ® ~20% over 4 hours - Supportive measures*

Bivalirudin Hemodialysis removes - Discontinue anticoagulant NovoSeven ® (Angiomax ®) ~25% over 4 hours - Supportive measures*

* Supportive measures include management of airway, breathing, circulation, transfusions, compression, surgical hemostasis

References: 1. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Therapy. CHEST 2012;141;e326S-e350S 2. Woo CH, Patel N, Conell C, et al. Rapid Warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate.World Neurosurg 2014;81(1):110-15 3. Kuamatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulation reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage JAMA 2015;313(8):824-36 4. Idarucizumab (PRAXABIND®) package insert, Boehringer Ingelheim, December 2015 5. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of in Intracranial Hemorrhage: A Satement for Healthcare Professionals from the Neurocritical Care Society of Critical Care Medicine. Neurocrit Care 2016;24(1):6-46 6. Christos S, Naples R. Anticoagulation Reversal and Treatment Strategies in Major Bleeding: Update 2016. West J Emerg Med. 2016;17(3):264-70 7. Lexi-Comp OnlineTM [database online]. Hudson, OH: Lexi-Comp, Inc.; 2016. Available at: http://online.lexi.com/lco/action/home 8. Raval AN, Cigarroa JE, Chung MK, et al. Management of Patients on Non- Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation 2017;135:e604-e633 9. Cuker A, Burnett A, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 2019;1-13

Origination date: 5/2014 Revisions: 5/2015, 1/2016, 2/2019 Approved by Anticoagulation Safety Committee: 3/2019 3 Approved by P&T: 5/2019