Anti-Coagulant Reversal

Original Date: 01/2012 | Last Review Date: 07/2024
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:

  • INR <4 – 25 units/kg
  • INR 4-6 – 35 units/kg
  • INR ≥6 – 50 units/kg

Recheck INR 2 hours after administration and then as indicated for ongoing or recurrent bleeding. If INR unknown, standard dose is 35 units/kg. Recommend administration of Vitamin K (10mg IV) 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
PCC in case of life threatening hemorrhage
Factor Xa inhibitor 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		 If known use of rivaroxaban or apixaban in the last 18 hours and emergency reversal is needed: andexanet alfa
Apixaban (Eliquis) 8-15 hrs 35% renal 65% Hepatic Low dose = 400 mg IV bolus 30 mg/minute, then infusion of 4 mg/min up to 120 minutes.
High dose = 800 mg IV bolus 30 mg/minute, then infusion of 8 mg/min up to 120 minutes.
Apixaban:
≤5 mg or ≥8 hours since last dose: low dose
>5 mg AND <8 hours since last dose: high dose
Rivaroxaban:
≤10 mg or ≥8 hours since last dose: low dose
>10 mg AND <8 hours since last dose: high dose
If andexanet alfa not available: PCC 35 units/kg
Add activated charcoal (50 g) if within 2 h of known ingestion*
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:

  1. Utilize the “Kcentra” MPP for the specific anticoagulant trying to reverse (“warfarin” or “bleeding reversal” for novel anticoagulants)
  2. Notify ED Pharmacy (43540) at the time the order is entered to expedite delivery of PCCs
  3. For patients located in the ICU or in the Operating Room, call O.R. Pharmacy (42838).
  4. No order will be overridden or cancelled by a pharmacy phone call to the attending.  Such a process requires a direct phone-to-phone (or face-to-face) discussion between ordering Faculty and Hematology Faculty on call.
  5. Should delivery of the drug be delayed, the Main Pharmacy should be contacted (43568)

kcentra

Monitoring:

  1. 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.
  2. 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.
  3. In patients taking dabigatran, rivaroxaban or apixaban, the use of rapid TEG (thrombelastography) may be more appropriate but further data is needed before it can be standardized. ACT is usually prolonged (>128 sec) with these newer oral anticoagulants in the presence of bleeding. However, until standardized, in patients receiving PCC for reversal of rivaroxaban or apixaban (and in those taking dabigatran receiving FEIBA), a TT should also be obtained if possible and repeated 2 hours after administration and in the face of continued clinical bleeding.

** While the r-TEG can be run in the ED Stat Lab, a TT must be sent to main lab for processing.

**Understanding this, the processing and results of TT should NOT delay preparation and administration of the drugs above

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