Anti-Coagulant Reversal

Original Date: 01/2012 | Supersedes: 04/2013 | Last Review Date: 12/2018
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:
The number of trauma patients on anticoagulant and antiplatelet therapy is increasing steadily, especially those on novel oral anticoagulants (NOACs).(1) Those patients are generally older with multiple medical comorbidities. Pre-injury anticoagulation has been shown to be an independent predictor of mortality.(7, 12) It is important to recognize the impact of such agents on patient outcome and administer early reversal when clinically indicated to prevent further complications. Interestingly, multiple studies have demonstrated that the worst outcomes were observed with patients on vitamin K antagonists (warfarin).(1, 2, 5-7) This could be attributed to the long half-life of these drugs as well as the propensity to have supra-therapeutic levels due to non-standardized dosing.

Classical strategies for warfarin reversal include administration of vitamin K and fresh frozen plasma (FFP). Recently, the introduction of prothrombin complex concentrates (PCC) have allowed for much quicker and reliable reversal of vitamin K antagonists.(4) Multiple studies have demonstrated the superiority of PCC over FFP in quick reversal and achieving INR<1.4 within 30-60 minutes of administration.(4, 11) This has become the new standard of care and is recommended by multiple societies. Concomitant administration of vitamin K ensures prolonged and sustained reversal of anticoagulation as well.(11)

The challenge arises when dealing with patients taking NOACs because most of these agents don’t have direct reversal agents. The two major classes are direct thrombin inhibitors (e.g. dabigatran AKA Pradaxa) and direct factor Xa inhibitors (e.g. rivaroxaban and apixaban AKA Xarelto and Eliquis). Recently, a reversal agent for dabigatran was approved by the FDA in the form of a monoclonal antibody that binds the drug with 350x affinity more than the thrombin molecule.(4) Multiple clinical trials demonstrated the effective reversal of dabigatran with the administration of idarucizumab (PraxBind) making it the reversal agent of choice for patients on Pradaxa.(10)

Unfortunately, no such reversal agent exists yet for direct Xa inhibitors, however, there is one currently being investigated in Phase 3b clinical trials called Andexanet alpha.(4) It is a recombinant factor Xa molecule which acts as a decoy for the drug to bind to. In the meantime, the only available strategy for reversal of such agents is administration of PCC, which has been shown to be partially effective in reversing the effects of direct Xa inhibitors in multiple studies.(4)

Finally, reversal of antiplatelet agents is achieved by simply administering platelets transfusion as most of these agents are irreversible.

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, TEG-ACT 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 15-30 minutes after administration.

Add Vitamin K (10mg IV) if persistent reversal is desired,

Add FFP (10-15cc/kg) if PCC did not achieve INR<1.4. 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 time		 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 minutes Stop the infusion (short half-life)
PCC in case of life threatening hemorrhage
Bivalirudin (Angiomax) aPTT 25 minutes Stop the infusion
PCC in case of life threatening hemorrhage
Factor Xa inhibitors Rivaroxaban (Xarelto) Direct factor Xa inhibitor (prevents formation of new thrombin) Chromogenic anti-FXa assay 5-9 hrs healthy

9-13 hrs elderly

 2/3 metabolic degradation (hepatic)
1/3 unchanged in urine		 Administer PCC (25 units/kg)
Add activated charcoal (50 g) if within 2 h of known ingestion*
#Future: Andexanet alpha (modified human recombinant FXa decoy protein)
Apixaban (Eliquis) 8-15 hrs 35% renal 65% Hepatic
Edoxaban (Lixiana, Savaysa) 10-14 hrs 50% renal

 

 

 

Heparins Heparin Activates antithrombin which inhibits thrombin aPTT 60-90 minutes 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, platelet function assay, bleeding time 20 minutes, but effect irreversible Platelet pheresis transfusion**
Consider DDAVP 0.4mcg/kg
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 minutes Hepatic Transfuse cryoprecipitate (10 units) to goal fibrinogen level >150
Consider antifibrinolytics (TXA, Amicar)

*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

References:

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