Background

  • Around 6 million people in the U.S. are on oral anticoagulants (Ref 1)
  • Common causes for oral anticoagulation uses include:
    • Atrial fibrillation 
    • Venous thromboembolism 
    • Stroke
    • Heart valve replacement
  • The number of patients on direct oral anticoagulants is steadily increasing, and about 3% experience life-threatening bleeding annually (Ref 2) 
  • Anticoagulation status leads to increased mortality despite the availability of reversal agents in patients with severe bleeding (ref 2)

 

Indications for Anticoagulation Reversal

  • Life-threatening bleeding as defined (Ref 1, 5) by a: 
    • Hemoglobin drop of 5 g/dL or more compared to baseline and requiring blood transfusion 
    • Bleeding that requires intervention (surgery, endoscopy, IR) 
    • Vital sign instability requiring vasoactive medications (i.e., pressors) or ongoing volume resuscitation
  • Bleeding at critical site (brain, eye, spine, airway, pericardium, aorta, or closed space with potential for compartment syndrome)
  • Emergent surgery

 

Procedures in the Emergency Room

  • The majority of procedures done in the ED do not require screening with coagulation laboratory tests or reversal due to low bleeding risk (ref 9); these include: 
    • Dialysis access, lumbar puncture, non-tunneled chest tube placement, paracentesis, peripheral nerve blocks, thoracentesis, tunneled venous catheter removal/placement (ref 9)

 

Laboratory Evaluation:

  • Obtain CBC, BMP, LFTs, PT/INR, aPTT, anti-FXa activity, fibrinogen, type and screen 
    • INR will be elevated in patients taking warfarin 
    • PT might be elevated in patients taking rivaroxaban, sensitive but not specific (ref 7, 12)
    • PT and aPTT prolonged by rivaroxaban (Ref 12)
    • Anti-FXa activity will reflect factor Xa inhibitors activity (ref 7)

 

Pathophysiology of Common Anticoagulants

Common Reversible Agents

  • Vitamin K 
    • Used for warfarin reversal 
    • Necessary for hepatic synthesis of factors II, VII, IX, and X 
    • PO and subcutaneous Vitamin K require 12 and 24 hours to work (ref 12); IV is preferred in the emergent/urgent setting
    • IV Vitamin K is associated with non-dose-dependent anaphylaxis and overcorrection of Vitamin K antagonists; as such, its use should be restricted to life-threatening bleeding
  • 4-Factor – PCC
    • Also known as Kcentra 
    • Replaces deficient factors (II, VII, IX, X, protein C, protein S, heparin, albumin)
    • The first line and only therapy that is FDA-approved for warfarin reversal (ref 5)
  • 3-Factor-PCC
    • Contains factors II, IX, and X 
    • Commonly used for Hemophilia B
  • Fresh Frozen Plasma – FFP
    • Plasma proteins, including albumin, all coagulation factors and fibrinogen
    • 250-300 cc
    • Used if PCC is not available 
    • Compared to PCCs, larger volume, longer infusion time, increased pathogen transmission risk (ref 11) 
    • FFP may take up to 3- 6 hours for reversal (Ref 12)
  • Cryoprecipitate 
    • Contains a concentrated version of FFP including Factor VIII, vWF, fibrinogen
    • Requires thawing and cannot be administered as fast as FFP 
    • 10-15 cc of volume per 1 unit
  • Recombinant XIIa
    • Contains Factor VIIa
    • Used for Hemophilia patients 
  • Idarucizumab
    • Reversal for direct thrombin inhibitor (Dabigatran) 
    • Irreversibly binds and inactivates direct thrombin inhibitor 
  • Andexanet alfa (ref 10,11) 
    • Reversal for factor Xa inhibitors 
    • Reversibly binds and inactivates the Xa inhibitors  
    • Considerations:
      • Expensive
      • It may not be available in all hospitals
      • Results in an increased thrombotic state
  • Protamine
    • Reversal for heparin 
    • Binds heparin and makes it inactive 
    • Short half-life and might require re-dosing
  • Tranexamic acid 
    • Inhibits the breakdown of fibrin
    • Thought to be beneficial in hemorrhage control (CRASH-2, WOMAN trials)
  • Desmopressin (DDAVP) 
    • A synthetic analog of vasopressin that acts on endothelial calls via an increase of cAMP to increase circulating vWF and Factor VIII (Ref 13)
    • May be used in life-threatening bleeding with platelet dysfunction (e.x, uremia) or in the setting of anti-platelet therapy
    • Also used in patients with Hemophilia A and Von Willebrand Disease

 

Special Situations

  • If bleeding is not improving despite reversal agents, consider alternative diagnosis such as DIC (ref 5)
  • Use charcoal if ingestion of PO anticoagulant within 2-4 hours (ref 5, 11)
  • Patients with renal disease: (ref 1)
    • Might have platelet dysfunction due to uremia; consider desmopressin
    • Might benefit from hemodialysis for dabigatran reversal
  • Patients with liver disease: (ref 1)
    • Will have coagulation abnormalities, especially vitamin K-dependent factors
  • All PCCs carry a risk of pro-thrombotic side effects (ref 7)
  • Platelet transfusion for a patient bleeding on an anti-platelet is not indicated and might negatively affect outcome (PATCH trial)
    • Consider and discuss with consultants platelet transfusion if platelets <50 and an invasive procedure is planned

 

References:

  1. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. doi:10.1016/j.jacc.2017.09.1085
  2. Gómez-Outes A, Alcubilla P, Calvo-Rojas G, et al. Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants. J Am Coll Cardiol. 2021;77(24):2987-3001. doi:10.1016/j.jacc.2021.04.061
  3. Thomas S, Makris M. The reversal of anticoagulation in clinical practice . Clin Med (Lond). 2018;18(4):314-319. doi:10.7861/clinmedicine.18-4-314
  4. Kuramatsu JB, Sembill JA, Huttner HB. Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage. Crit Care. 2019;23(1):206. Published 2019 Jun 6. doi:10.1186/s13054-019-2492-8
  5. Baugh CW, Levine M, Cornutt D, et al. Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel. Ann Emerg Med. 2020;76(4):470-485. doi:10.1016/j.annemergmed.2019.09.001
  6. Gilbert BW, Morton L, Huffman JB, et al. Modified version of the American College of Cardiology’s recommendation for low-dose prothrombin complex concentrate is effective for warfarin reversal. Am J Emerg Med. 2020;38(4):806-809. doi:10.1016/j.ajem.2019.12.005
  7. Kaide CG, Gulseth MP. Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents. J Emerg Med. 2020;58(2):217-233. doi:10.1016/j.jemermed.2019.10.011
  8. Bitonti MT, Rumbarger RL, Absher RK, Curran LM. Prospective Evaluation of a Fixed-Dose 4-Factor Prothrombin Complex Concentrate Protocol for Urgent Vitamin K Antagonist Reversal. J Emerg Med. 2020;58(2):324-329. doi:10.1016/j.jemermed.2019.10.013
  9. Patel IJ, Rahim S, Davidson JC, et al. Society of Interventional Radiology Consensus Guidelines for the Periprocedural Management of Thrombotic and Bleeding Risk in Patients Undergoing Percutaneous Image-Guided Interventions-Part II: Recommendations: Endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol. 2019;30(8):1168-1184.e1. doi:10.1016/j.jvir.2019.04.017
  10. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131-1141. doi:10.1056/NEJMoa1607887
  11. Milling TJ, Pollack CV. A review of guidelines on anticoagulation reversal across different clinical scenarios – Is there a general consensus?. Am J Emerg Med. 2020;38(9):1890-1903. doi:10.1016/j.ajem.2020.05.086
  12. Thigpen JL, Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013;33(11):1199-1213. doi:10.1002/phar.1270
  13. McCarty TS, Patel P. Desmopressin. [Updated 2023 Jun 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554582/