EDUCATION IN THE MANAGEMENT OF BLEEDING

A practical, evidence-based guide for front-line physicians on how to Treat the Bleed

Warfarin reversal - Top 10 questions

1

General approach as follows:

  1. Withdrawal of anticoagulants and supportive care
    • Stop anti-coagulants and determine time of last dose
    • Stop anti-platelet agents
    • Laboratory investigations: CBC, INR/aPTT/fibrinogen, group & screen
    • Consider blood transfusion – if the patient requires ≥3 units of RBCs in 1 hour, consider massive transfusion activation
      • Uncrossmatched blood sent stat if group & screen pending (~10 min) – O negative for women age ≤45, O positive for everyone else
  1. Reversal of warfarin - Both fast and slow reversal required:
    • Fast reversal: Administer Prothrombin Complex Concentrates (PCCs) – dosed based on INR ± Weight (see chart below)
      • If INR is unknown administer 2000 IUs
      • Do not wait for INR results during life-threatening bleeding
    • Slow reversal: Administer Vitamin K – 10 mg IV
      • Lower doses sometimes recommended to prevent difficulty “rewarfarinising” ( see question 5) the patient – but full dose should be given in life-threatening bleeding
    • Frozen plasma transfusion despite being common is not appropriate standard of care, unless PCCs unavailable or heparin “allergy”
  2. Adjunct treatments to stop the bleed
    • Tranexamic Acid - consider up to 2 g IV total
      • Not studied specifically in bleeding patients on warfarin
      • Consult interventional radiology or surgery

Dosing based on NAC recommendations:

INR Based Dosing:

 PCC dose if INR > 5PCC dose if INR 3-5PCC dose if INR <3
 Dose 3000 IU (120 mL) 2000 IU (80 mL) 1000 IU ( 40 mL)

 

Weight plus INR based dosing:

Weight (kg)PCC dose if INR > 6
(40 units/kg)
PCC dose if INR 3-6
(30 units/kg)
PCC dose if INR 2-2.9
(20 units/kg)
35-37 1500 IU (60 mL) 1000 IU ( 40 mL) 500 IU ( 20 mL)
38-41 1500 IU (60 mL) 1000 IU ( 40 mL) 1000 IU ( 40 mL)
42-43 1500 IU (60 mL) 1500 IU (60 mL) 1000 IU ( 40 mL)
44-56 2000 IU (80 mL) 1500 IU (60 mL) 1000 IU ( 40 mL)
57-58 2500 IU (100 mL) 1500 IU (60 mL) 1000 IU ( 40 mL)
59-62 2500 IU (100 mL) 2000 IU (80 mL) 1000 IU ( 40 mL)
63-68 2500 IU (100 mL) 2000 IU (80 mL) 1500 IU (60 mL)
69-75 3000 IU (120 mL) 2000 IU (80 mL) 1500 IU (60 mL)
76-87 3000 IU (120 mL) 2500 IU (100 mL) 1500 IU (60 mL)
88-91 3000 IU (120 mL) 2500 IU (100 mL) 2000 IU (80 mL)
92-112 3000 IU (120 mL) 3000 IU (120 mL) 2000 IU (80 mL)
113-136 3000 IU (120 mL) 3000 IU (120 mL) 2500 IU (100 mL)
137 or greater 3000 IU (120 mL) 3000 IU (120 mL) 3000 IU (120 mL)

2

The general considerations for giving PCC for warfarin reversal include:

Consider the urgency of the procedure and the risk of bleeding:

  • Procedures that are elective should be reversed with vitamin K alone. A meta-analysis demonstrates that ~75% of all patients treated with oral vitamin K reach target INRs at 24 hours post-administration. Vitamin K given IV works within 4-8 hours.
  • PCCs must be given within 6 hours of the urgent procedure. Practically, it's best to order it to be given directly pre-operatively (along with antibiotics, factors, etc.) due to its fast onset of action and short duration of effect (6 hours) unless pre-operative bleeding
  • Link to ISTH bleeding assessment tool.

Potential contraindications to PCCs:

  • See question # 7

References

DeZee KJ, Shimeall WT, Douglas KM, Shumway NM, O’Malley PG. Treatment of Excessive Anticoagulation With Phytonadione (Vitamin K): A Meta-analysis. Arch Intern Med. 2006;166(4):391–397.

Spyropoulos, AC, Al‐Badri, A, Sherwood, MW, Douketis, JD. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost 2016; 14: 875– 85.

Hunt BJ, Levi M. Urgent reversal of vitamin K antagonists. BMJ 2018; 360 :j5424

3

There are several reasons to choose PCCs over frozen plasma including:

  1. Faster correction of the coagulation impairment, particularly pertinent with intracranial bleeding.1,2
  2. Lower volume for infusion (40 mL vs 1000 mL) allowing for faster infusion and more rapid correction of INR
  3. Lower risk of transfusion reactions, particularly respiratory transfusion reactions (transfusion-associated circulatory overload and transfusion-related acute lung injury) 3
  4. No need for blood group testing
  5. There is no increase in the risk of thromboembolic complications compared to plasma.4
  6. Viral inactivation mitigating risk of transfusion-transmissible infections including emerging pathogens.
  7. Use of PCC specifically only replaces the missing coagulation factors missing due to warfarin.

References:

  1. Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 2016;15:566-73.
  2. Frontera JA, Gordon E, Zach V, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 2014;21:397-406.
  3. Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 2016;116:879-90.
  4. Brekelmans MPA, Ginkel KV, Daams JG, Hutten BA, Middeldorp S, Coppens M. Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis. J Thromb Thrombolysis 2017;44:118-29.

4

  • PCCs reverse warfarin for only a short period of time (6 hours)
  • Majority of patients reach target INRs at 24 hours post-Vitamin K administration
  • Vitamin K given intravenously starts to work within 4-8 hours, giving sustained warfarin reversal. 1-4

References:

  1. Meehan R, Tavares M, Sweeney J. Clinical experience with oral versus intravenous vitamin K for warfarin reversal. Transfusion 2013; 53:491-8
  2. Keeling D, Baglin T, Tait C, et al., British Committee for Standards in Haematology Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154:311-24.
  3. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl):7S-47S.
  4. Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS, Australasian Society of Thrombosis and Haemostasis (ASTH). An update of consensus guidelines for warfarin reversal. Med J Aust 2013; 198:198-9

5

No

  • “Warfarin resistance” (inability to resume oral anticoagulation) is observed in <1% of patients on warfarin administered oral and intravenous vitamin K 2-10 mg (adults of all ages and indications for anticoagulation).

References:

  1. Denas G, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J Thromb Thrombolysis (2009) 27:340–347
  1. Tai C, et al. Management of Supratherapeutic International Normalized Ratio without Bleeding after Warfarin Use: An Evaluation of Vitamin K Administration (SUPRA-WAR-K Study). Can J Hosp Pharm. 2017;70(3):207-14)

6

Yes, but it depends on the comparison of the risk (clot severity, location, timing) versus the benefit (bleed severity, treatability).

Therefore:

Consultation with a hematologist/thrombosis expert should be made.

  • If the decision for reversal is made, PCCs should be administered given increased efficacy and no difference in thrombosis risk compared to plasma. Thrombosis risks in different meta-analyses for warfarin reversal in patients who received PCC or plasma and vitamin K are reported to be < 5%.

References:

  1. Kearon, C., & Akl, E. A. (2014). Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood, 123(12), 1794-1801.
  2. Brekelmans MPA, Ginkel KV, Daams JG, et al. Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis. Journal of Thrombosis and Thrombolysis 2017;44: 118-29.
  3. Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-90.
  4. Dentali F, Marchesi C, Pierfranceschi MG, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. Thromb Haemost 2011;106: 429-38.

7

References:

  1. Octaplex® Product Monograph, August 25, 2014
  2. National Advisory Committee on Blood and Blood Products. Recommendations for use of prothrombin complex concentrates in Canada [Internet]. Canada: National Advisory Committee on Blood and Blood Products; 2014 May 16 [cited 2019 Feb 20]. 4 p. Available from: https://www.nacblood.ca/resources/guidelines/PCC.html

9

Basic hematology and coagulation tests should be drawn as soon as possible on any patient who presents bleeding, to ensure a coagulopathy attributable to something other than warfarin is not missed:

For non life-threatening bleeds:

  • CBC (Complete Blood Count, to assess the platelet number)
  • INR (International Normalized Ratio)

For life-threatening bleeds:

    • CBC (Complete Blood Count, to assess the platelet number)
    • INR (International Normalized Ratio)
    • aPTT (activated Partial Thromboplastin Time)
    • Fibrinogen
    • Group and Screen
  • The INR should be retested after treatment to measure effects:
    • After PCC and Vit K – check INR within 10 minutes following administration, with a goal INR <1.5, then after 6 hrs and 24hrs; or 30 min before planned procedure
    • After Vitamin K only – check INR 6 hours after administration or 30 min before planned procedure
  • In life threatening bleeds do not wait for INR results before administering PCC and Vit K
  • In non-life threatening bleed consider waiting for INR to help guide management.

References:

  1. Coumadin® Product Monograph including patient medication information [Internet]. Montreal, Canada: Bristol-Myers Squibb Canada; 2018 Sept 4 [cited 2019 Feb 20]. 44 p. Available from: https://www.bms.com/assets/bms/ca/documents/productmonograph/COUMADIN_EN_PM.pdf
  2. National Advisory Committee on Blood and Blood Products. Recommendations for use of prothrombin complex concentrates in Canada [Internet]. Canada: National Advisory Committee on Blood and Blood Products; 2014 May 16 [cited 2019 Feb 20]. 4 p. Available from: https://www.nacblood.ca/resources/guidelines/PCC.html
  3. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral versus intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003;163:2469–2473.

10

There are 2 PCC brands in Canada. PCC reconstitution depends on the brand being used, so refer to the manufacturer’s instructions for reconstitution. Some transfusion laboratories will reconstitute PCC, but in some hospitals the clinical team performs the reconstitution.

PCC must be administered intravenously and should not be mixed with other products.

Link to NAC guidelines

References

  1. Octaplex  P/N product monograph
  2. Beriplex P/N product monograph

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