VKA-related bleeding

  • Vitamin K antagonists (VKAs) are widely used for the primary and secondary prevention of venous and arterial thromboembolic events.
  • VKAs, such as warfarin, interfere with the y-carboxylation of the calcium-active binding sites for vitamin K-dependent proteins (including coagulation factors II, VII, IX and X), resulting in the reduction of clotting factors II, VII, IX, X as well as pro-coagulation proteins C and S.
  • The most common adverse reaction of warfarin is hemorrhage, accounting for approximately 29,000 emergency department visits per year.
  • There are up to 10,000 cases of warfarin-associated intracranial hemorrhage (ICH) in the US annually.
  • Patients on warfarin who experience head injury have a 40% higher risk of incurring ICH and a 2-fold higher risk of 30-day in-hospital mortality.

  • Warfarin reversal strategies include: fresh frozen plasma (FFP), vitamin K, prothrombin complex concentrates (PCC): (3 Factor PCC, non-activated 4 Factor PCC and activated 4F Factor PCC)
Warfarin - Multiple Factors Reversal Agents
  • The prothrombin time (PT) test or International Normalized Ratio (INR), which is a standardized expression of the PT, is most commonly used to monitor VKA therapy.
    • The most common target INR is 2.0–3.0 for patients on warfarin; the INR range can vary depending on the indication when on VKA therapy.
  • In two pivotal clinical trials, the INR reduction target for VKA reversal was ≤1.3 at 0.5 hours after end of infusion

Multiple treatment guidelines recommend the use of 4F-PCC for urgent warfarin reversal in acute major bleeding and need for urgent surgery/invasive procedure including:

  • American College of Chest Physicians (ACCP) 2012 and 2018
  • American Society of Hematology (ASH) 2018
  • American College of Surgeons (ACS) 2018
  • American College of Cardiology Consensus Paper
  • American College of Emergency Physicians (ACEP)/Annals of Emergency Medicine 2019
  • Neurocritical Care Society/Society of Critical Care Medicine 2015
  • American Society of Gastrointestinal Endoscopy ASGE 2016
  • Thrombosis Canada Direct Oral Anticoagulants (DOACs): Management of Bleeding

3 windows with quotes from 3 different medical associations

1. DeAngelo J et al. Am J Ther. 2018;25(3):e326-e332. 2. American Association of Blood Banks. Circular of information for the use of human blood and blood components. Bethesda, MD; November 2017. 3. National Patient Safety Goal for anticoagulant therapy. The Joint Commission website. Accessed June 4, 2020. https://www.jointcommission.org/-/media/tjc/newsletters/r3_19_anticoagulant_therapy_final2pdf.pdf. 4. Frumkin K. Ann Emerg Med. 2013;62:616-626. 5. Cleary JP et al. Ann Transplant. 2016;21:531-537. 5. Frontera JA et al. Neurocrit Care. 2016;24:6-46. 6. Holbrook A et al. Chest. 2012;141:e152S-e184S. 7. Acosta RD et al. Gastrointest Endosc. 2016;83:3-16. 8. Tomaselli GF et al. J Am Coll Cardiol. 2017;70:3042-3067. 9. Witt DM et al. Blood Adv. 2018;2:3257-3291. 10. Baugh CW et al. Ann Emerg Med. 2019;9:1-16. 11. American College of Surgeons. Advanced Trauma Life Support (ATLS) Student Course Manual. 10th ed. Chicago, IL: American College of Surgeons; 2018.