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Emergent Reversal of Anticoagulation

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Emergent Reversal of Anticoagulation, Anticoagulant Reversal, Anticoagulant Overdose, Hemorrhage in Anticoagulated Patients

  • See Also
  1. Anticoagulation
  2. Warfarin (Coumadin)
  3. Heparin
  4. Low-Molecular Weight Heparin (LMWH)
  5. Dabigatran (Pradaxa)
  6. Rivoroxaban
  7. Aspirin
  8. Clopidogrel
  • Precaution
  1. Most reversal agents (PCC, rFVIIa) are thrombogenic and a risk for thromboembolic events
  • Labs
  1. Partial Thromboplastin Time (aPTT)
  2. International Normalized Ratio (INR, PT)
  3. Complete Blood Count with Platelet Count
  4. Serum Creatinine
  5. Hepatic Panel
  6. Fibrinogen
  7. Anti-Xa (Heparin Level)
  • 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. Overdose
    1. Consider Activated Charcoal if ingestion within 1-2 hours (may be effective with DOACs up to 8 hours)
      1. Ollier (2017) Clin Pharmacokinet 56(7): 793-801 +PMID:27910037 [PubMed]
    2. Intentional Overdose
      1. Observe for bleeding for 24 hours (or per poison control) before medically cleared to psychiatry
    3. Unintentional Overdose
      1. If small quantity (e.g. one extra dose) may discharge home with bleeding precautions
      2. Risk of significant bleeding 5% after Anticoagulant Overdose
    4. References
      1. Swaminathan and Hayes in Herbert (2018) EM:Rap 18(7): 4-5
      2. Levine (2018) Ann Emerg Med 71(3): 273-8 +PMID:29032872 [PubMed]
  • 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. 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)
      2. 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 (most have half-lives of 12 hours)
    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. Andexxa or Andexanet (Inactivated Recombinant Factor Xa decoy protein) 400 mg IV bolus
          1. Cost approaches $50,000 per dose
          2. Ineffective in the 25% of patients who have low anti-Factor Xa Inhibitor
          3. Connolly (2019) N Engl J Med 380(14):1326-35 +PMID:30730782 [PubMed]
        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. Thrombolytic
    1. Not reduced by clot-specific agents
    2. Consider infusing Fibrinogen concentrate or Cryoprecipitate 10 pack
    3. Consider Fresh Frozen Plasma
    4. Consider Tranexamic Acid (TXA)
    5. Swaminathan and Weingart in Herbert (2020) EMRap 20(4):5-6
  8. 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
  9. 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