Anti-Coagulant Reversal
Original Date: 01/2012 | Last Review Date: 07/2025
Purpose: To simplify the choice and dosing of reversal agents and strategies in the setting of traumatic bleeding in patients taking anticoagulants and antiplatelet therapy
Introduction:
Anticoagulants and antiplatelet agents are increasingly common among injured patients. Below is a summary of reversal agents available and used for common anticoagulants and antiplatelet agents.
The primary decision point is whether reversal is needed. Patients should have their anticoagulant or antiplatelet agents reversed depending on the severity of the bleeding, the site of bleeding, and hemodynamic status. When assessing patients for the need for reversal, it is imperative to detail the dose and time of last dose of the anticoagulant or antiplatelet.
Critical site bleeding:
- Intracranial hemorrhage
- Pericardial tamponade
- Airway
- Intraspinal hemorrhage
- Intraocular hemorrhage
- Retroperitoneal or intra-abdominal hemorrhage
- Intra-articular hemorrhage
- Intramuscular hemorrhage with compartment syndrome
Critical major bleeding:
- Hemorrhagic shock with transfusion requirement
- Evidence of decreased organ perfusion (e.g. acute kidney injury)
- Overt bleeding with a hemoglobin drop of ≥2 g/dL
Prothrombin Complex Concentrate (PCC):
Four factor prothrombin complex concentrate (PCC) (Kcentra®) is used for the reversal of warfarin, rivaroxaban, edoxaban, and apixaban. All PCC orders require review and approval by pharmacy prior to dispensing. Ordering information is at the bottom of this page. Indications for use of PCC to reverse medication-induced coagulopathy are limited to the following:
- Serious or life-threatening bleeding (i.e. intracranial, gastrointestinal, retroperitoneal)
- Trauma
- Patients who require emergency surgery or invasive procedure
- Large hematoma
Below is a table that summarizes the above recommendation and specifies dosages:
| Class | Drug | MOA | Measurement | Half-life | Clearance | Reversal |
|---|---|---|---|---|---|---|
| Vitamin K antagonists | Warfarin (Coumadin) | Inhibits vitamin K-dependent g-carboxylation of factors (II, VII, XI, X) | PT/INR, r-TEG-ACT (>136 sec) |
2-5 days | Hepatic metabolism, renal elimination | Administer PCC according to INR level:
Recommend administration of Vitamin K (10mg IV once) if persistent reversal is desired. Add plasma (10-15cc/kg) if volume resuscitation also needed or if INR remains 1.5-2. Max PCC in a 24 hour period is 50 units/kg. |
| Direct thrombin inhibitors | Dabigatran (Pradaxa) | Direct thrombin inhibitor (prevents fibrinogen conversion to fibrin) | Dilute thrombin time, ecarin clotting time, r-TEG ACT (>128 sec) |
12-17 hrs | 80% Renal 20% hepatic |
Administer Idarucizumab (PraxBind) (irreversible mab 350x affinity) – 5g administered as 2 doses of 2.5g IV over 5–10 min, 15 min apart Add activated charcoal (50 g) if within 2 h of known ingestion* Hemodialysis (~60% effective) if PraxBind not available |
| Argatroban | aPTT | 40-50 mins | Stop the infusion (short half-life). PCC in case of life threatening hemorrhage |
|||
| Bivalirudin (Angiomax) | aPTT | 25 mins | Stop the infusion (short half-life). PCC in case of life threatening hemorrhage |
|||
| Factor Xa inhibitors | Rivaroxaban (Xarelto) | Direct factor Xa inhibitor (prevents formation of new thrombin) | Chromogenic anti-FXa assay, r-TEG ACT (>128 sec) |
5-9 hrs healthy 9-13 hrs elderly |
2/3 metabolic degradation (hepatic) 1/3 unchanged in urine |
Andexanet alfa is not available at MH Katy. If known use of rivaroxaban or apixaban in the last 18 hours and emergency reversal is needed: PCC 2,500 units Add activated charcoal (50 g) if within 2 h of known ingestion* |
| Apixaban (Eliquis) | 8-15 hrs | 35% renal 65% Hepatic | ||||
| Edoxaban (Lixiana, Savaysa) | 10-14 hrs | 50% renal | ||||
| Heparins | Heparin | Activates antithrombin which inhibits thrombin | aPTT | 60-90 mins | Renal | Administer protamine 1 mg IV for every 100 units of heparin administered in the previous 2–3 h (max 50mg) |
| LMWH, enoxaparin (Lovenox) | Anti Xa | 4.5hrs | 40% renal | Dosed within 8 h: administer protamine 1 mg IV per 1 mg enoxaparin (max 50mg) Dosed within 8–12 h: administer protamine 0.5 mg IV per 1 mg enoxaparin (max 50mg) |
||
| antiplatelets | ASA | COX-1 and -2 inhibitor | TEG-MA, TEG-PM, platelet function assay, bleeding time |
20 mins, but effect irreversible | Platelet apheresis transfusion** (COLD STORED PLATELETS AVAIILABLE FOR EMERGENCY USE IN TRAUMA BAY FRIDGE) Consider DDAVP 0.4mcg/kg as a one-time reversal, especially in renally impaired. |
|
| Clopidogrel (Plavix) | Irreversible inhibition of P2Y12 ADP receptor | 6-8 hrs but effect irreversible | 50% renal | |||
| Prasugrel (Effient) | 2-15 hrs | 70% renal | ||||
| Ticagrelor (Brilinta) | 7 hrs | 30% renal | ||||
| Pentasaccharides | Fondaparinux (Arixtra) | Binds with antithrombin and potentiates inhibition of free factor Xa, preventing formation of the prothrombinase complex |
17-21 hrs | 75% Renal | No known reversal agents | |
| Thrombolytics | Alteplase | Catalyzes conversion of fibrin-bound plasminogen to plasmin, which cleaves fibrin |
Fibrinogen levels, TEG (Lys) |
3-6 mins | Hepatic | Transfuse cryoprecipitate (10 units) to goal fibrinogen level >150 Consider anti-fibrinolytics (TXA, Amiocaproic Acid) |
*When considering activated charcoal administration, assess the patient’s mental status and ability to protect their airway. Consider NGT placement for administration. Avoid if patient is going to the OR soon to avoid delaying operative interventions
**NOT indicated for TBI or ICH unless neurosurgical intervention planned
Ordering PCCs:
Utilize the “Kcentra” order panels for the specific anticoagulant trying to reverse (“warfarin” or “bleeding reversal” for novel anticoagulants)
- Factor 2-7-9-10 (KCENTRA) Oral Anticoagulant Reversal Orders Panel
- Factor 2-7-9-10 (KCENTRA) Warfarin Reversal Orders Panel
For both, select the “Fixed Dose PCC” option.
Notify Central Pharmacy (7288) at the time the order is entered to expedite delivery of PCCs
Monitoring:
Both fatal and nonfatal arterial and venous thromboembolic complications have been reported with Kcentra® in clinical trials and post marketing surveillance. Patients initiated on this product should be monitored for these complications of thromboembolic events.
For patients taking warfarin, an INR should be obtained immediately and should be repeated 2 hours after administration of Kcentra® and then as indicated for ongoing or recurrent bleeding.
References:
- Wood B, Nascimento B, Rizoli S, Sholzberg M, McFarlan A, Phillips A, Ackery AD. The Anticoagulated trauma patient in the age of the direct oral anticoagulants: a Canadian perspective. Scand J Trauma Resusc Emerg Med. 2017 Aug 2;25(1):76. doi: 10.1186/s13049-017-0420-y. PubMed PMID: 28768548; PubMed Central. PMCID: PMC5541703.
- Maung AA, Bhattacharya B, Schuster KM, Davis KA. Trauma patients on new oral anticoagulation agents have lower mortality than those on warfarin. J Trauma Acute Care Surg. 2016 Oct;81(4):652-7. doi: 10.1097/TA.0000000000001189. PubMed. PMID: 27438683.
- Kobayashi L, Barmparas G, Bosarge P, Brown CV, Bukur M, Carrick MM, Catalano RD, Holly-Nicolas J, Inaba K, Kaminski S, Klein AL, Kopelman T, Ley EJ, Martinez EM, Moore FO, Murry J, Nirula R, Paul D, Quick J, Rivera O, Schreiber M, Coimbra R; AAST Multicenter Prospective Observational Study of Trauma Patients on Novel Oral Anticoagulants Study Group. Novel oral anticoagulants and trauma: The results of a prospective American Association for the Surgery of Trauma Multi-Institutional Trial. J Trauma Acute Care Surg. 2017 May;82(5):827-835. doi: 10.1097/TA.0000000000001414. PubMed PMID: 28431413.
- Ruff CT, Giugliano RP, Antman EM. Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. 2016 Jul 19;134(3):248-61. doi: 10.1161/CIRCULATIONAHA.116.021831. Review. PubMed PMID: 27436881.
- Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015 Nov;13(11):2012-20. doi: 10.1111/jth.13139. Epub 2015 Oct 5. Review. PubMed PMID: 26356595.
- Feeney JM, Neulander M, DiFiori M, Kis L, Shapiro DS, Jayaraman V, Marshall WT 3rd, Montgomery SC. Direct oral anticoagulants compared with warfarin in patients with severe blunt trauma. 2017 Jan;48(1):47-50. doi: 10.1016/j.injury.2016.08.016. Epub 2016 Aug 27. PubMed PMID: 27582383.
- Bonville DJ, Ata A, Jahraus CB, Arnold-Lloyd T, Salem L, Rosati C, Stain SC. Impact of preinjury warfarin and antiplatelet agents on outcomes of trauma patients. 2011 Oct;150(4):861-8. doi: 10.1016/j.surg.2011.07.070. PubMed PMID: 22000201.
- Johansen M, Wikkelsø A, Lunde J, Wetterslev J, Afshari A. Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients. Cochrane Database Syst Rev. 2015 Jul 7;(7):CD010555. doi: 10.1002/14651858.CD010555.pub2. Review. PubMed PMID: 26151108.
- Milling TJ Jr, Clark CL, Feronti C, Song SS, Torbati SS, Fermann GJ, Weiss J, Patel D. Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis. Am J Emerg Med. 2017 Aug 19. pii: S0735-6757(17)30691-5. doi: 10.1016/j.ajem.2017.08.042. [Epub ahead of print] PubMed PMID: 28843518.
- Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11. PubMed PMID: 28693366.
- Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, del Zoppo GJ, Kumar MA, Peerschke EI, Stiefel MF, Teitelbaum JS, Wartenberg KE, Zerfoss CL. 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 Feb;24(1):6-46. doi:10.1007/s12028-015-0222-x. Review. PubMed PMID: 26714677.
- Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Arch Surg. 2011 May;146(5):565-70. doi: 10.1001/archsurg.2010.313. Epub 2011 Jan 17. PubMed PMID: 21242422.