Emergent Reversal of Anticoagulation

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

advertisement

II. Indications: Anticoagulation Reversal

  1. Life Threatening Bleeding in General (see below for life-threatening GI 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. Life threatening Gastrointestinal Bleeding
    1. Hemodynamic instability
    2. Vasopressor requirement
    3. Ongoing Hemorrhage AND
      1. Hemoglobin drops >=5 g/dl or
      2. Blood Transfusion of >=5 units pRBC required
    4. References
      1. Singer (2025) Int J Emerg Med 17(1): 70 [PubMed]
  3. 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
  4. Emergent surgery
    1. Abdominal surgery
    2. Neurosurgical intervention

III. Physiology

  1. See Hemostasis
  2. Clotting Cascade
    1. pathClottingCascade.png
  3. Full Thrombosis Pathway
    1. ThrombosisPathway.png

IV. Precautions

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

V. Labs

  1. Degree of Anticoagulation
    1. Partial Thromboplastin Time (aPTT)
    2. International Normalized Ratio (INR, PT)
    3. Anti-Xa (Heparin Level)
  2. Other labs that impact Anticoagulation and reversal
    1. Complete Blood Count with Platelet Count
    2. ABO Type and Rh, Cross Match for Blood
    3. Serum Creatinine
    4. Hepatic Panel
    5. Fibrinogen

VI. 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]

VII. Management: Reversal of Warfarin and other Vitamin K Antagonists (VKA)

  1. See Warfarin Reversal
  2. Mechanism
    1. Warfarin and VKAs prevent activation of Factors 2, 7, 9 and 10
  3. Indicated for INR >2.0
    1. May consider for INR >1.3 to 1.5 with life threatening Hemorrhage (e.g. Intracerebral Hemorrhage)
  4. Vitamin K slow IV 2.5-10 mg
    1. Intravenous route is preferred for active Hemorrhage or hemodynamic instability
    2. If mild to moderate bleeding, as little as 2.5 mg orally may be effective
  5. 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 ABO cross match prior to infusion
      3. Risk of Fluid Overload (requires larger volume infusions of plasma)
    3. Factor VIIa (NovoSeven) is no longer recommended

VIII. Management: Reversal of Heparin (unfractionated and LMWH)

  1. Mechanism
    1. See Intrinsic Clotting Pathway
    2. Heparin binds to, and potentiates Antithrombin III (AT III)
      1. Antithrombin III binds to and inhibits Serine proteases, Factor IIa (Thrombin) and Factor Xa
      2. Antithrombin III also binds to and inhibits Factors IXa, XIa and XIIa
      3. Results in decreased Fibrin formation
    3. Unfractionated Heparin
      1. Composed of Polysaccharides of various lengths, resulting in less predictable Pharmacokinetics, requiring close monitoring
      2. Heparin also transiently interacts with Thrombin, independent of its action via Antithrombin 3
    4. Low Molecular Weight Heparin (LMHW, Enoxaparin)
      1. LMHW is a small fragment of the larger Heparin molecule (mucopolysaccharide)
      2. Allows for more predictable Pharmacokinetics, and fewer complications (bleeding, HIT)
  2. Unfractionated Heparin Reversal
    1. Stop Heparin infusion
      1. Short Heparin Half-Life 40-90 minutes results in rapid reversal of Anticoagulation on stopping infusion
      2. Additional reversal agents are rarely needed
    2. Protamine Sulfate (preferred first-line)
      1. See Protamine for dosing details
      2. Give 1 mg Protamine sulfate for every 100 units of Unfractionated Heparin administered within prior 2-3 hours
      3. Administer slowly (no more than 50 mg per 10 minute interval) to prevent Hypotension, Anaphylaxis-like reaction
  3. Low Molecular Weight Heparin (LMWH, Enoxaparin)
    1. Background
      1. LMWH half life is 4 hours (more likely to require reversal than Unfractionated Heparin)
    2. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
      1. First-line agent for LMWH
    3. Protamine Sulfate (second-line)
      1. In contrast with Unfractionated Heparin, Protamine only partially reverses LMWH
      2. Administer slowly (no more than 50 mg per 10 minute interval) to prevent Hypotension, Anaphylaxis-like reaction
      3. Give 1 mg for every 1 mg (100 units) Enoxaparin in <8 hours
      4. Give 0.5 mg for every 1 mg (100 units) Enoxaparin in >8 hours

IX. Management: Reversal of Factor Xa Inhibitors (e.g. Rivoroxaban or Xarelto, Apixaban or Eliquis)

  1. Mechanism: Factor Xa Inhibitors
    1. Directly and reversibly bind the active site on Factor Xa
    2. Block Thrombin formation as a part of the Common Clotting Pathway
  2. Mechanism: Indirect Xa Inhibitors (e.g. Fondaparinux)
    1. Binds Antithrombin III and modifies its form, substantially increasing its activity by 300 fold
    2. Super-charged Antithrombin III neutralizes Factor Xa at a markedly increased rate, resulting in Anticoagulation
  3. Reversal General Guidelines
    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. Hemodialysis is not effective (Protein bound, unlike Dabigatran)
  4. Reversal in Life threatening or critical site bleeding
    1. Step 1
      1. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
        1. Dose 25 to 50 units/kg IV using actual weight, and contingent on bleeding severity
        2. Maximum dose: 2500 to 5000 units
      2. Alternative Agents if PCC4 not available
        1. PCC3 or
        2. Fresh Frozen Plasma (FFP)
    2. 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. Agents not recommended or unavailable
    1. Andexxa or Andexanet Alpha
      1. Released in 2018, and off U.S. market in 2025
      2. Inactivated Recombinant Factor Xa decoy Protein
      3. 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
      4. Cost approaches $30,000 to 50,000 per dose
      5. Ineffective in the 25% of patients who have low anti-Factor Xa Inhibitor
      6. Connolly (2019) N Engl J Med 380(14):1326-35 +PMID:30730782 [PubMed]

X. Management: Reversal of Direct Thrombin Inhibitors (e.g. Dabigatran)

  1. Mechanism: Direct Thrombin Inhibitors
    1. Selectively and reversibly inhibit free and clot-bound Thrombin
    2. Prevent conversion of Fibrinogen to Fibrin (which in turn prevents clot)
  2. Reversal General Guidelines
    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
  3. Reversal in Life threatening or critical site bleeding
    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)

XI. Management: Reversal of Antiplatelet Agents

  1. Aspirin
    1. Mechanism
      1. Aspirin irreversibly inactivates cyclooxygenase (COX)
        1. Blocks Thromboxane and Prostaglandin synthesis
        2. Contrast with NSAIDS which reversibly block COX
      2. Platelet Effects (Thromboxane-related)
        1. Inhibits Platelet aggregation via cyclooxygenase blockade of Thromboxane A2 synthesis
        2. Aspirin Irreversibly poisons Platelets for their remaining life (8-10 days)
        3. New Platelets are generated at a rate of 10% per day (25,000/day for a patient with a 250,000 Platelet Count)
          1. By 2 days off Aspirin, a patient will have 50,000 normal Platelets (enough to counter bleeding)
    2. Reversal
      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)
  2. ADP Inhibitors (Thienopyridine Class, e.g. Clopidogrel)
    1. Mechanism
      1. Inhibits Platelet signal transduction
      2. Inhibits Platelet aggregation
      3. Reversibly binds Adenosine Diphosphate (ADP) P2Y12-Class Receptors (inhibits G-Protein, Adenyl cyclase)
    2. Reversal
      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)

XII. Management: Reversal of Thrombolytic (Tissue Plasminogen Activator or tPA, TNK-tPA or Tenecteplase)

  1. Mechanism
    1. Serine protease binds Fibrin and activates Fibrin-bound plasminogen to plasmin
    2. Plasmin breaks down both Fibrin and Fibrinogen to Fibrin
      1. Fibrin Degradation Products result, which in turn also act to inhibit Fibrin formation
  2. Reversal
    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)
  3. References
    1. Swaminathan and Weingart in Herbert (2020) EMRap 20(4):5-6

XIII. 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

XIV. References

  1. Clemens and Oliver (2026) Crit Dec Emerg Med 40(10): 27-37
  2. Deloughery and Orman in Herbert (2013) EM:Rap 13(9): 1
  3. Ebersole, Toomey and Baugh (2021) Crit Dec Emerg Med 35(5): 3-9
  4. Lex and Orman in Herbert (2013) EM:Rap 13(4): 6
  5. Lemkin (2013) Crit Dec Emerg Med 27(4): 2-9
  6. Marcolini and Swaminathan in Swadron (2023) EM:Rap 23(3): 3-6
  7. Sun (2016) Crit Dec Emerg Med 30(8): 28
  8. Umoga and Eyre (2023) Crit Dec Emerg Med 37(10): 14-5
  9. Peck (2021) J Trauma Acute Care Surg 90(2): 331-6 [PubMed]

Images: Related links to external sites (from Bing)

These images are a random sampling from a Bing search on the term "Emergent Reversal of Anticoagulation." Click on the image (or right click) to open the source website in a new browser window. Search Bing for all related images

Related Studies

Related Topics in Pharmacology

advertisement