Emergent Reversal of Anticoagulation

Aka: Emergent Reversal of Anticoagulation, Anticoagulant Reversal, Anticoagulant Overdose, Anticoagulation Reversal, Hemorrhage in Anticoagulated Patients, Early Anticoagulant Reversal After Trauma

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II. Indications: Anticoagulation Reversal

  1. Life Threatening Bleeding
    1. Hemodynamic instability (requiring Blood Transfusion or Vasopressors)
    2. Ongoing Hemorrhage AND
      1. Hemoglobin drops >=2 g/dl or
      2. Blood Transfusion of >=2 units pRBC required or
      3. Surgery or procedural intervention (e.g. Intervention Radiology) required for Hemorrhage Control
  2. Critical-Site Bleeding
    1. Intracranial Bleeding
    2. Spinal canal bleeding (e.g. Epidural Hematoma)
    3. Ocular or periocular Hemorrhage
    4. Pericardial Hemorrhage
    5. Airway compromise due to Hemorrhage (e.g. expanding neck Hematoma)
    6. Extremity Hemorrhage with risk of Compartment Syndrome
    7. Intraabdominal Hemorrhage
    8. Retroperitoneal Hemorrhage
    9. Intrathoracic Hemorrhage

III. Precaution

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

IV. Labs

  1. Complete Blood Count with Platelet Count
  2. ABO Type and Rh, Cross Match for Blood
  3. Partial Thromboplastin Time (aPTT)
  4. International Normalized Ratio (INR, PT)
  5. Serum Creatinine
  6. Hepatic Panel
  7. Fibrinogen
  8. Anti-Xa (Heparin Level)

V. 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]

VI. Management: Reversal

  1. Warfarin and other Vitamin K Antagonists
    1. See Warfarin Reversal
    2. Indicated for INR >2.0
      1. May consider for INR >1.3 to 1.5 with life threatening Hemorrhage (e.g. Intracerebral Hemorrhage)
    3. Vitamin K 5-10 mg slowly IV
      1. If mild to moderate bleeding, as little as 2.5 mg orally may be effective
    4. 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
          1. Consider 10-25 Units/kg if INR <2.0
      2. Fresh Frozen Plasma (FFP)
        1. Indicated if PCC unavailable
        2. Slower reversal due to thawing and cross match prior to infusion
        3. Risk of Fluid Overload (requires larger volume infusions of plasma)
      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. Hemodialysis is unlikely to be beneficial
      1. Risk of placing large bore filtered catheters in actively bleeding, coagulopathic patients
    5. Life threatening or critical site bleeding - reversal agents
      1. Step 1 (choose 1)
        1. Idarucizumab (preferred)
          1. Monoclonal Antibody specific for Dabigatran
          2. Highly effective in initial studies and FDA approval (however may not alter clinical outcomes)
          3. Give 2 doses each of 2.5 g IV
          4. Follow Thrombin Time and PTT
          5. Pollack (2015) N Engl J Med 373(6): 511-20 +PMID: 26095746 [PubMed]
          6. Pollack (2017) N Engl J Med 377(5): 531-41 +PMID: 28693366 [PubMed]
        2. Alternatives if Idarucizumab is not available
          1. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex) OR
          2. Fresh Frozen Plasma (FFP)
          3. Cryoprecipitate (from FFP)
      2. Step 2 (if no response to step 1)
        1. Consult Hematology
        2. Hemodialysis increases clearance (limited benefit)
        3. Consider repeat dosing of agents in step 1
        4. Consider Desmopressin (DDAVP) 0.3 mcg/kg (if on antiplatelet agents)
        5. 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)
  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, unlike Dabigatran)
    4. Life threatening or critical site bleeding - reversal agents
      1. Specific antidote pending approval in U.S. (all other recommendations per expert opinion)
      2. Step 1 (choose 1)
        1. Andexxa or Andexanet Alpha (preferred)
          1. Inactivated Recombinant Factor Xa decoy Protein
          2. Dosing based on Factor Xa Level (use high dose if Xa level unknown)
            1. Low Dose: 400 mg IV bolus over 14 min, then 480 mg infusion over 120 min
            2. High Dose: 800 mg IV bolus over 28 min, then 960 mg infusion over 120 min
          3. Cost approaches $30,000 to 50,000 per dose
          4. Ineffective in the 25% of patients who have low anti-Factor Xa Inhibitor
          5. Connolly (2019) N Engl J Med 380(14):1326-35 +PMID:30730782 [PubMed]
        2. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
          1. Dose 25 to 50 units/kg IV contingent on INR and bleeding severity
        3. Fresh Frozen Plasma (FFP)
      3. Step 2 (if no response to step 1)
        1. Consult Hematology
        2. Consider repeat dosing of agents as above
        3. Other agents previously used
          1. Factor VII Inhibitor Bypass Activity (FEIBA) 50-75 units/kg IV once (up to maximum 7500 units)
          2. 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. Low Molecular Weight Heparin (e.g. Enoxaparin)
    1. Protamine Sulfate
      1. Administer slowly (no more than 50 mg per 10 minute interval) to prevent Hypotension, Anaphylaxis-like reaction
      2. Give 1 mg for every 1 mg Enoxaparin in <8 hours
      3. Give 0.5 mg for every 1 mg Enoxaparin in >8 hours
  6. Aspirin
    1. Platelet Transfusion 1 unit (6 pack) for high risk perioperative reversal (e.g. neurosurgery for Intracerebral Hemorrhage)
    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. 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)
  8. 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

VII. 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

VIII. References

  1. Deloughery and Orman in Herbert (2013) EM:Rap 13(9): 1
  2. Ebersole, Toomey and Baugh (2021) Crit Dec Emerg Med 35(5): 3-9
  3. Lex and Orman in Herbert (2013) EM:Rap 13(4): 6
  4. Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
  5. Marcolini and Swaminathan in Swadron (2023) EM:Rap 23(3): 3-6
  6. Sun (2016) Crit Dec Emerg Med 30(8): 28
  7. Umoga and Eyre (2023) Crit Dec Emerg Med 37(10): 14-5
  8. Peck (2021) J Trauma Acute Care Surg 90(2): 331-6 [PubMed]

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