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Anticoagulant reversal


Anticoagulant reversal is a critical step in the management of patients with life-threatening bleeding who are taking an anticoagulant. The reversal agents indicated depend on the specific anticoagulant taken by the patient. The risk of thromboembolic events is increased by most reversal agents. For this reason, their use should be limited to cases of serious or life-threatening bleeding. All patients who undergo anticoagulation reversal should be monitored closely.

Overview of anticoagulant reversal

Drug class Drug names Monitoring parameters [1] Half-life [1] Reversal agents [2][1]
Oral vitamin K antagonists
  • 36–48 hours
Heparins Unfractionated heparin
  • 60–90 minutes
Low molecular weight heparin
  • 3–6 hours
Synthetic pentasaccharide factor Xa inhibitors
  • 17–21 hours
Direct oral anticoagulants Direct thrombin inhibitors
  • 12–14 hours
Direct Xa inhibitors

Nonspecific reversal agents like 4-factor prothrombin complex concentrate (PCC), activated PCC, recombinant activated factor VII, thrombocyte concentrates, and fresh frozen plasma have procoagulatory effects! Before these drugs are administered, the increased risk of thrombosis should be carefully weighed against the risk of ongoing bleeding. [3]

Warfarin reversal

The treatment strategy depends on whether the patient is symptomatic and if there is serious or life-threatening bleeding present. [2][4][5][6]

Active hemorrhage (regardless of INR) [2]

The large fluid volumes of FFP and the fact that it must be transfused shortly after thawing can cause fluid overload and TRALI.

Asymptomatic patient with elevated INR

Serum INR Recommended management [2][6]
INR greater than therapeutic range but < 5.0
  • Decrease dose or stop warfarin.
  • Monitor INR every 24 hours.
  • Once INR is within the therapeutic range, restart warfarin at the same or lower dose.
INR ≥ 5 but < 10
  • Stable patient with no increased risk of bleeding:
    • Stop warfarin.
    • Monitor INR every 24 hours.
    • Once INR is within the therapeutic range, restart warfarin at a 10–15% lower dose.
  • Stable patient at increased risk of bleeding:
INR ≥ 10
  • Stop warfarin.
  • Give high-dose oral vitamin K. [2]
  • Monitor INR every 24 hours.
  • Repeat oral vitamin K if INR remains elevated at 24 hours.
  • When INR is in the therapeutic range, restart warfarin at a dose that is 15–20% lower.

Heparin reversal

General principles [2]

Reversal of unfractionated heparin and LMWH [2]

Protamine dosing for unfractionated heparin [2]

Time since last heparin dose Recommended IV protamine dose
< 30 minutes
30–60 minutes
> 120 minutes

Protamine dosing for LMWH [2]

  • Enoxaparin
    • Give IV protamine (dose per the table below).
    • If PTT remains elevated after 2–4 hours or bleeding persists, give a second, lower dose of protamine.
Time since enoxaparin dose Recommended IV protamine dose
< 8 hours
8–12 hours
> 12 hours

The total dose of protamine should never exceed 50 mg.

Reversal of fondaparinux

Both aPCC and recombinant activated factor VII increase the risk of thrombosis.

Direct oral anticoagulant reversal

Reversal of dabigatran [2]

Reversal of factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban) [2]

PCC and aPCC increase the risk of thrombosis.

Acute management checklist

  • 1. Sartori MT, Prandoni P. How to effectively manage the event of bleeding complications when using anticoagulants. Expert Review of Hematology. 2015; 9(1): pp. 37–50. doi: 10.1586/17474086.2016.1112733.
  • 2. Yee J, Kaide C. Emergency Reversal of Anticoagulation. West J Emerg Med. 2019; 20(5): pp. 770–783. doi: 10.5811/westjem.2018.5.38235.
  • 3. Frontera JA, Lewin III JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Neurocrit Care. 2015; 24(1): pp. 6–46. doi: 10.1007/s12028-015-0222-x.
  • 4. Shoeb M, Fang MC. Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis. 2013; 35(3): pp. 312–319. doi: 10.1007/s11239-013-0899-7.
  • 5. Garcia DA, Crowther MA. Reversal of Warfarin. Circulation. 2012; 125(23): pp. 2944–2947. doi: 10.1161/circulationaha.111.081489.
  • 6. Cushman M, Lim W, Zakai NA. 2011 Clinical Practice Guide on Anticoagulant Dosing and Management of Anticoagulant Associated Bleeding Complications in Adults. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/525.aspx. Updated January 1, 2011. Accessed December 10, 2019.
  • 7. Awad NI, Cocchio C. Activated prothrombin complex concentrates for the reversal of anticoagulant-associated coagulopathy. P T. 2013; 38(11): pp. 696–701. pmid: 24391389.
  • Thomas S, Makris M. The reversal of anticoagulation in clinical practice . Clin Med. 2018; 18(4): pp. 314–319. doi: 10.7861/clinmedicine.18-4-314.
  • Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Antithrombotic Therapy. Chest. 2012; 141(2): pp. e326S–e350S. doi: 10.1378/chest.11-2298.
  • Sunkara T, Ofori E, Zarubin V, Caughey ME, Gaduputi V, Reddy M. Perioperative Management of Direct Oral Anticoagulants (DOACs): A Systemic Review. Health Serv Insights. 2016; 9s1: pp. s25–36. doi: 10.4137/hsi.s40701.
last updated 06/11/2020
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