II. Precaution

  1. Most reversal agents (PCC, rFVIIa) are thrombogenic and a risk for thromboembolic events

IV. Management: General

  1. Consultation
    1. Hematology (if available)
    2. General surgery
    3. Intervention radiology (embolization of bleeding site)
  2. Control bleeding per specific sites
    1. Gastrointestinal Bleeding
    2. Extremity bleeding with Tourniquet
    3. Facial or scalp bleeding with Suture
    4. Pelvic Fracture bleeding with Pelvic Binder
  3. Transfusion
    1. Correct Anemia (Hemoglobin <7-8) with Packed Red Blood Cells
    2. Correct Thrombocytopenia with Platelet Transfusion
    3. Correct other causes of coagulopathy
    4. Fresh Frozen Plasma (FFP) is unlikely to correct bleeding due to Anticoagulant medications listed below
      1. Warfarin (Coumadin) is one exception, however PCC4 is preferred over FFP
  4. Massive Overdose
    1. Consider Activated Charcoal if ingestion within 1-2 hours

V. Management: Reversal

  1. Warfarin and other Vitamin K Antagonists
    1. See Warfarin Reversal
    2. Vitamin K 5-10 mg slowly IV
      1. If mild to moderate bleeding, as little as 2.5 mg orally may be effective
    3. Factor Replacement
      1. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
        1. Preferred if available
        2. FFP-like serum extract that is 25 fold more potent than FFP
        3. Dose: 50 Units/kg once daily
      2. Fresh Frozen Plasma (FFP)
        1. Indicated if PCC unavailable
      3. Factor VIIa (NovoSeven) is no longer recommended
  2. Heparin (unfractionated and LMWH)
    1. Stop Heparin infusion
    2. Protamine (only partially reverses LMWH)
      1. See Protamine for details
  3. Direct Thrombin Inhibitors (e.g. Dabigatran)
    1. Stop offending agent (most have short half-life such as 12-14 hours for Dabigatran)
    2. Bleeding unlikely due to Direct Thrombin Inhibitor if aPTT <37 seconds and Thrombin Time <25 seconds
    3. Consider Activated Charcoal if presenting within 2 hours of suspected Overdose ingestion
    4. Dialysis is unlikely to be beneficial
      1. Risk of placing large bore filtered catheters in actively bleeding, coagulopathic patients
    5. Life threatening bleeding - reversal agents
      1. No known antidotes (all recommendations per expert opinion)
      2. Step 1 (choose 1)
        1. Idarucizumab is highly effective in initial studies and FDA approval
          1. Monoclonal Antibody specific for Dabigatran
          2. Pollack (2015) N Engl J Med 373(6): 511-20 +PMID: 26095746 [PubMed]
          3. Pollack (2017) N Engl J Med 377(5): 531-41 +PMID: 28693366 [PubMed]
        2. Prothrombin Complex Concentrate (PCC): PCC4, PCC3 or Activated PCC
        3. Fresh Frozen Plasma (FFP)
      3. Step 2 (if no response to step 1)
        1. Consult Hematology
        2. Hemodialysis increases clearance (limited benefit)
        3. Other agents previously used
          1. Factor VII Inhibitor Bypass Activity (FEIBA) 50 units/kg IV once (up to 7500 units)
          2. Activated Clotting Factor VII (rFVIIa or NovoSeven) 90 mcg/kg IV once (up to 10 mg)
    6. Other reversal agents to consider
      1. Consider Desmopressin (DDAVP) 0.3 mcg/kg
      2. Consider Cryoprecipitate (from FFP)
      3. Consider Prothrombin Complex Concentrate (PCC)
  4. Factor Xa Inhibitors (e.g. Rivoroxaban or Xarelto, Apixaban or Eliquis)
    1. Stop offending Xa agent
    2. Bleeding unlikely due to Xa agent if Anti-Xa level <0.1 IU/ml
    3. Dialysis is not effective (protein bound)
    4. For serious bleeding (e.g. CNS Hemorrhage)
      1. Specific antidote pending approval in U.S. (all other recommendations per expert opinion)
      2. Step 1 (choose 1)
        1. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex) OR
        2. Andexanet (Factor Xa decoy protein) 400 mg IV bolus
          1. Not available yet as of 2016 (pending FDA approval in U.S.)
        3. Fresh Frozen Plasma (FFP)
      3. Step 2 (if no response to step 1)
        1. Consult Hematology
        2. Factor VII Inhibitor Bypass Activity (FEIBA) 50-75 units/kg IV once (up to maximum 7500 units)
        3. Consider Recombinant activated Clotting Factor VII (rFVIIa or NovoSeven)
          1. Dose: 90 mcg/kg IV once (up to maximum 10 mg)
          2. Improves lab data, but not effective in animal models
    5. Experimental agents as of 2013
      1. r-Antidote or recombinant antidote
  5. Aspirin
    1. Platelet Transfusion 1 unit (6 pack)
    2. Consider Desmopressin (DDAVP) 0.3 mcg/kg (expert opinion)
    3. Consider Recombinant activated Clotting Factor VII (rFVIIa) 30-90 mcg/kg (expert opinion)
  6. ADP Inhibitors (e.g. Clopidogrel)
    1. Platelet Transfusion 2 units (12 pack)
    2. Consider Desmopressin (DDAVP) 0.3 mcg/kg (expert opinion)
    3. Consider Recombinant activated Clotting Factor VII (rFVIIa) 30-90 mcg/kg (expert opinion)
  7. Resources
    1. ACEP: Reversal of NOACs in the Presence of Major Life-Threatening Bleeding
      1. http://www.annemergmed.com/article/S0196-0644(17)31502-0/fulltext
  8. References
    1. Deloughery and Orman in Majoewsky (2013) EM:Rap 13(9): 1
    2. Lex and Orman in Majoewsky (2013) EM:Rap 13(4): 6
    3. Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
    4. Sun (2016) Crit Dec Emerg Med 30(8): 28

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