Anticoagulant Reversal

Introduction

Anticoagulants reduce the risk of thrombosis but can lead to life-threatening bleeding. Reversal is indicated when there’s major bleeding, bleeding in critical sites (e.g., brain), or emergency surgery.

This guide reviews how common anticoagulants work, how they’re reversed, what lab values they affect, and how reversal works physiologically.

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Vitamin K Antagonists (e.g., Warfarin)

• Mechanism: Inhibits vitamin K–dependent clotting factors (II, VII, IX, X)
• Lab Effects: Increase INR (very reliable)
• Reversal: Replace clotting factors with PCC or FFP + give vitamin K to restore production.¹

Factor Xa Inhibitors (e.g., Apixaban, Rivaroxaban)

• Mechanism: Directly inhibit factor Xa → decrease thrombin generation
• Lab Effects: PT/INR may be slightly increased; anti-Xa assay (if available) is most accurate
• Reversal: Andexanet alfa (preferred), or PCC if unavailable.²

Direct Thrombin Inhibitors (e.g., Dabigatran, Bivalirudin, Lepirudin)

• Mechanism: Directly inhibit thrombin (factor IIa)
• Lab Effects: Increase aPTT and thrombin time (TT); dilute thrombin time or ecarin clotting time most specific
• Reversal: Idarucizumab; dialysis also effective due to renal clearance.³

Unfractionated Heparin (UFH)

• Mechanism: Binds antithrombin → inhibits thrombin and Xa
• Lab Effects: Increases aPTT (reliable); ACT* used during procedures
• Reversal: Protamine sulfate (fully reverses if recent)⁴

Low Molecular Weight Heparin (e.g., Enoxaparin)

• Mechanism: Primarily inhibits factor Xa via antithrombin
• Lab Effects: aPTT minimally affected; anti-Xa assay best if available
• Reversal: Protamine sulfate (partial reversal only)⁴

Fondaparinux

• Mechanism: Indirect Xa inhibitor via antithrombin; long half-life
• Lab Effects: Anti-Xa level elevated; PT/INR and aPTT usually normal
• Reversal: No direct antidote; PCC or aPCC may offer partial effect⁵

Direct Thrombin Inhibitors (IV) — Argatroban, Bivalirudin

• Mechanism: Directly inhibit thrombin (IIa)
• Lab Effects: Increase aPTT, increase INR (especially argatroban)
• Reversal: None needed — short half-life (~1 hr); stop infusion⁶

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Anticoagulant Rapid Reversal Summary

Anticoagulant	Reversal Agent	Dose / Notes	Other Options
Warfarin	Vitamin K + PCC	Vit K 5–10 mg IV slow + PCC 25–50 U/kg (max 3000 U)¹	FFP if PCC unavailable
Apixaban / Rivaroxaban	Andexanet alfa	400–800 mg IV bolus, then 4–8 mg/min infusion²	PCC 50 U/kg if Andexanet not available²
Dabigatran	Idarucizumab (Praxbind)	5 g IV (2 × 2.5 g vials)³	Dialysis if renal failure³
Heparin (UFH)	Protamine sulfate	1 mg per 100 U UFH (max 50 mg)⁴	Best if given <2 hrs from last dose; monitor ACT*
Enoxaparin (LMWH)	Protamine (partial)	1 mg protamine per 1 mg enoxaparin (if <8 hrs)⁴	Second dose: 0.5 mg/mg if bleeding continues⁴
Fondaparinux	None specific	PCC or aPCC empirically⁵	Supportive measures⁵
Argatroban / Bivalirudin	None	Short half-life; discontinue → clearance in 1–2 hrs⁶	Supportive only⁶

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ACT Footnote

ACT* = Activated Clotting Time

• Point-of-care test used to monitor high-dose heparin during procedures like cardiopulmonary bypass, cath lab, or ECMO
• Faster but less sensitive than aPTT
• Normal: ~70–120 sec; therapeutic often >250–300 sec

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References

1. Holbrook A, et al. Evidence-based management of anticoagulant therapy. Chest. 2012;141(2_suppl):e152S-e184S. doi:10.1378/chest.11-2295
2. Connolly SJ, et al. Andexanet alfa for bleeding with factor Xa inhibitors. NEJM. 2016;375(12):1131–1141. doi:10.1056/NEJMoa1607887
3. Pollack CV Jr, et al. Idarucizumab for dabigatran reversal. NEJM. 2015;373(6):511–520. doi:10.1056/NEJMoa1502000
4. Smythe MA, et al. Reversal of oral and parenteral anticoagulants. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S27–S48. doi:10.2146/ajhp150658
5. Spina M, et al. Reversal agents for NOACs: rapid evidence review. J Thromb Thrombolysis. 2020;49(2):220–231. doi:10.1007/s11239-019-01916-x
6. Siegal DM, et al. Andexanet for reversal of Xa inhibitor activity. NEJM. 2015;373(25):2413–2424. doi:10.1056/NEJMoa1510991