Anticoagulant reversal

Last updated: August 10, 2022

Summary

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 ^[1]^[2]
Oral vitamin K antagonists		Warfarin	PT/INR	36–48 hours	Vitamin K 4-factor prothrombin complex concentrate (PCC; rapid reversal) Fresh frozen plasma (FFP)
Heparins	Unfractionated heparin	Heparin	aPTT	60–90 minutes	Protamine
	Low molecular weight heparin	Enoxaparin Dalteparin Tinzaparin	Anti-factor Xa activity level	3–6 hours	Protamine
	Synthetic pentasaccharide factor Xa inhibitors	Fondaparinux	Anti-factor Xa activity level	17–21 hours	Activated prothrombin complex concentrate (aPCC) Recombinant activated factor VII
Direct oral anticoagulants	Direct thrombin inhibitors	Dabigatran	aPTT dTT	12–14 hours	Idarucizumab (monoclonal antibody Fab fragments) Activated prothrombin complex concentrate (aPCC) Dialysis
Direct oral anticoagulants	Direct Xa inhibitors	Rivaroxaban Apixaban Edoxaban Betrixaban	PT (rivaroxaban) Anti-factor Xa activity level	Rivaroxaban: 5–9 hours (11–13 hours in elderly) Apixaban: 12 hours Edoxaban: 10–14 hours	Andexanet alfa (inactive, recombinant factor Xa) 3- or 4-factor PCC aPCC

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]

Mechanism of action: anticoagulants that prevent secondary hemostasis

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]

Stop warfarin.
Administer IV vitamin K PLUS 4-factor prothrombin complex concentrate (PCC)
- Fixed-dose PCC regimen
- OR PCC regimen based on INR and weight
  - Pretreatment INR 2–4
  - Pretreatment INR 4–6
  - Pretreatment INR > 6
- If PCC is unavailable, give fresh frozen plasma (FFP)
Monitor INR every 6 hours until warfarin has been fully reversed (INR ≤ 1.1)

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: Stop warfarin. Give oral vitamin K. ^[2] Monitor INR. Once INR is within the therapeutic range, restart warfarin at a dose that is 10–15% lower.
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]

Stop heparin.
Protamine is the mainstay of heparin reversal but has variable effects depending on the type of heparin. ^[2]^[7]
- Completely reverses unfractionated heparin
- Partially reverses LMWH ^[2]
- No effect on fondaparinux
- Because protamine has weak anticoagulant effects, the dose should be adjusted (dependent on time since heparin was last administered) to prevent a net anticoagulant effect.
Check platelets if the patient is on unfractionated or LMWH and has serious bleeding to rule out heparin-induced thrombocytopenia.

Reversal of unfractionated heparin and LMWH ^[2]

Protamine dosing for unfractionated heparin ^[2]

Time since last heparin dose	Recommended IV protamine dose
< 30 minutes	1–1.5 mg protamine per 100 units of heparin given
30–60 minutes	0.5–0.75 mg protamine per 100 units of heparin given
> 120 minutes	0.25–0.375 mg protamine per 100 units of heparin given

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	1 mg protamine per 1 mg of enoxaparin given
8–12 hours	0.5 mg protamine per 1 mg enoxaparin given
> 12 hours	No protamine required

Tinzaparin or dalteparin
- Give IV protamine.
- If PTT remains elevated after 2–4 hours or bleeding persists, give a second, lower dose of protamine.

The total dose of protamine should never exceed 50 mg.

Reversal of fondaparinux

Hold fondaparinux.
No specific antidote exists.
Consider aPCC or recombinant activated factor VII.

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

Direct oral anticoagulant reversal

Reversal of dabigatran ^[2]

Stop dabigatran.
Administer idarucizumab.
If idarucizumab is not available, administer aPCC.
Consider hemodialysis.

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

Stop the factor Xa inhibitor.
Administer one of the following:
- Andexanet alfa
  - High-dose regimen of andexanet alfa indicated if:
    - Rivaroxaban dose ≥ 10 mg
    - Apixaban dose ≥ 5 mg
    - Unknown dose of either rivaroxaban or apixaban taken within the last 8 hours
  - Low dose regimen of andexanet alfa indicated if:
    - Rivaroxaban dose < 10 mg
    - Apixaban dose < 5 mg
    - Unknown dose of either rivaroxaban or apixaban taken > 8 hours ago
- 3-factor or 4-factor PCC
- aPCC

PCC and aPCC increase the risk of thrombosis.

Acute management checklist

Stop the anticoagulant.
Provide hemodynamic support.
Consider local and interventional hemostatic methods.
Check labs
- CBC
- Coagulation panel (e.g., INR, PTT, PT, anti-factor Xa activity level)
- Serum BUN, creatinine, LFTs
- Blood type and screen
Obtain patient consent for blood transfusion.
Transfuse if necessary (see transfusion).
Consider imaging, depending on the suspected site of bleeding.
Give anticoagulant reversal agent, if available (see overview of anticoagulant reversal agents).

References

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Yee J, Kaide C. Emergency Reversal of Anticoagulation. West J Emerg Med. 2019; 20 (5): p.770-783. doi: 10.5811/westjem.2018.5.38235 . | Open in Read by QxMD
Frontera JA, Lewin III JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Neurocrit Care. 2015; 24 (1): p.6-46. doi: 10.1007/s12028-015-0222-x . | Open in Read by QxMD
Shoeb M, Fang MC. Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis. 2013; 35 (3): p.312-319. doi: 10.1007/s11239-013-0899-7 . | Open in Read by QxMD
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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.
Awad NI, Cocchio C. Activated prothrombin complex concentrates for the reversal of anticoagulant-associated coagulopathy.. P T. 2013; 38 (11): p.696-701.
Thomas S, Makris M. The reversal of anticoagulation in clinical practice .. Clin Med. 2018; 18 (4): p.314-319. doi: 10.7861/clinmedicine.18-4-314 . | Open in Read by QxMD
Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Antithrombotic Therapy. Chest. 2012; 141 (2): p.e326S-e350S. doi: 10.1378/chest.11-2298 . | Open in Read by QxMD
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 : p.s25–36. doi: 10.4137/hsi.s40701 . | Open in Read by QxMD

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