Anticoagulant Reversal

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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.

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. [4]

Reversal of dabigatran [3]

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

Reversal of factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban) [3]

• 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.

The treatment strategy depends on whether the patient is symptomatic and if there is serious or life-threatening bleeding present. [3][5][6][7]

Active hemorrhage (regardless of INR) [3]

• Stop warfarin.
• Administer IV vitamin K PLUS 4-factor prothrombin complex concentrate (PCC)
  • Fixed-dose regimen: PCC 1500 units IV once
  • OR weight-based regimen depending on pretreatment INR, i.e.:
    • INR 2–4: Give PCC 25 units/kg IV once (max. 2500 units).
    • INR 4–6: Give PCC 35 units/kg IV once (max. 3500 units).
    • INR > 6: Give PCC 50 units/kg IV once (max. 5000 units).
  • If PCC is unavailable, give fresh frozen plasma (FFP): 10–15 mL/kg IV once
• 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

General principles [3]

• Stop heparin.
• Protamine is the mainstay of heparin reversal but has variable effects depending on the type of heparin. [3][8]
  • Completely reverses unfractionated heparin
  • Partially reverses LMWH [3]
  • 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 [3]

Protamine dosing for unfractionated heparin [3]

Protamine dosing for LMWH [3]

• 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.

• 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.

• 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).