Marc Carrier, Alex C. Spyropoulos.

Response/Recommendation: In patients on vitamin K antagonist (VKA) with an elevated international normalized ratio (INR) requiring emergency orthopaedic surgery, we suggest correction to an INR ≤ 1.5.

Strength of Recommendation: Limited.

Rationale: The prothrombin time (PT) test measures the extrinsic and common coagulation pathways. The PT correlates to the degree of inhibition of factors II, V, VII, X, and fibrinogen which are synthesized by the liver. The INR is an expression of the results of a PT in a standardized testing environment allowing for universal standardization of anticoagulant therapy^1-3. The most common reason for an isolated elevated INR is VKA anticoagulation therapy (e.g., warfarin). However, a prolonged PT and elevated INR can also occur in vitamin K deficiency, lupus anticoagulants, extrinsic pathway coagulation factor deficiencies, disseminated intravascular coagulation, bile duct obstruction, malabsorption, malnutrition, and other conditions¹. Furthermore, other anticoagulants, including the direct oral anticoagulants (e.g., rivaroxaban), hirudin, argatroban, and heparin, may also prolong the PT.

VKA are widely used for variety of different clinical indications including primary prevention of stroke for patients with atrial fibrillation and for the acute treatment or secondary prevention of venous thromboembolism (VTE). VKA inhibit hepatic production of the vitamin K-dependent coagulation factors (II, VII, IX, X), protein C and S. The clinical effect is measured by the INR. Previous studies have reported that the use of VKA was associated with a delay in time-to-surgery and higher mortality for patients requiring emergency orthopaedic procedures^4-7. Furthermore, these patients experience increased surgical blood loss and higher risk of red blood cell transfusions⁸, highlighting the importance of reversing the anticoagulation effect prior to emergency surgery.

Current VTE guidelines presented by the American Society of Hematology and the American College of Chest Physicians do not provide direction on the correction of INR for patients on VKA undergoing emergency surgery^2,9. Although current literature still lacks consensus regarding the most appropriate management strategy for VKA reversal in patients undergoing emergency orthopaedic surgery, recommendations for the management of major bleeding episodes related to VKA have been published. In patients on VKA with elevated INR and major bleeding complications, the clinical practice guidelines suggest using 4-factor prothrombin complex concentrates (PCC) rather than fresh-frozen plasma (FFP) in addition to cessation of VKA and administration of intravenous vitamin K².

Vitamin K (phytonadione) may be given orally, intravenously, or subcutaneously depending on the value of the INR and the desired time frame for anticoagulant reversal. In stable, semi-urgent cases (within 24 to 36 hours), low-dose oral administration (1 to 2.5 mg) is preferred^10-13. Although intravenous administration of vitamin K is associated with a risk of anaphylactoid reaction, it has a more rapid effect and may be more effective in the truly emergent case. For urgent surgical procedures that can be delayed for six to 12 hours, the anticoagulant effect of warfarin can be effectively reversed with 10 mg of intravenous vitamin K^14-16. For patients requiring emergent surgical procedures (within less than 6 hours), 4-Factor PCC containing factors II, VII, IX, and X or FFP is required to rapidly reverse the anticoagulant effect of VKA^17,18. The concentration of coagulation factors in PCC is approximately 25 times greater than that available in FFP, allowing for it to be administered in small volumes of fluid¹⁴. The reversal of anticoagulation with PCC or FFP is temporary and decreases after six hours due to the short half-life of factor VII. Therefore, it is recommended that vitamin K be administered concurrently to ensure sustained reversal effect. Previous observational studies have shown that reversing the effect of VKA to an INR ≤ 1.5 using vitamin K and/or PCC or FFP is safe and effective in patients requiring emergency orthopaedic surgery^17,19-23.

Although it is widely recognized that the use of VKA is associated with a delay in time to surgery as well as morbidity and mortality in patients requiring emergency orthopaedic surgery, existing studies have not defined the optimal management strategy to reverse the anticoagulant effect of VKA. Notwithstanding, based on the proven efficacy and safety of vitamin K, 4 factors PCC and FFP in the management of major bleeding episodes and the reassuring observational data in patients requiring emergency orthopaedic surgery, there is some evidence to support the recommendation to correct the INR to ≤ 1.5 in patients on VKA who requires emergency surgery.

References:

1.         Patel IJ, Davidson JC, Nikolic B, Salazar GM, Schwartzberg MS, Walker TG, Saad WA, Standards of Practice Committee wC, Interventional Radiological Society of Europe E. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2012;23(6):727-36.

2.         Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, Shehab N, Mock J, Myers T, Dentali F, Crowther MA, Agarwal A, Bhatt M, Khatib R, Riva JJ, Zhang Y, Guyatt G. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

3.         Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-e50S.

4.         You D, Xu Y, Ponich B, Ronksley P, Skeith L, Korley R, Carrier M, Schneider PS. Effect of oral anticoagulant use on surgical delay and mortality in hip fracture. Bone Joint J. 2021;103-B(2):222-33.

5.         Cafaro T, Simard C, Tagalakis V, Koolian M, Can VN. Delayed time to emergency hip surgery in patients taking oral anticoagulants. Thromb Res. 2019;184:110-4.

6.         Daugaard C, Pedersen AB, Kristensen NR, Johnsen SP. Preoperative antithrombotic therapy and risk of blood transfusion and mortality following hip fracture surgery: a Danish nationwide cohort study. Osteoporos Int. 2019;30(3):583-91.

7.         Gosch M, Jacobs M, Bail H, Grueninger S, Wicklein S. Outcome of older hip fracture patients on anticoagulation: a comparison of vitamin K-antagonists and Factor Xa inhibitors. Arch Orthop Trauma Surg. 2021;141(4):637-43.

8.         Xu Y, You D, Krzyzaniak H, Ponich B, Ronksley P, Skeith L, Salo P, Korley R, Schneider P, Carrier M. Effect of oral anticoagulants on hemostatic and thromboembolic complications in hip fracture: A systematic review and meta-analysis. J Thromb Haemost. 2020;18(10):2566-81.

9.         Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ, American College of Chest Physicians Antithrombotic T, Prevention of Thrombosis P. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):7S-47S.

10.       Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-98S.

11.       Crowther MA, Ageno W, Schnurr T, Manfredi E, Kinnon K, Garcia D, Douketis JD. Oral vitamin K produces a normal INR within 24 hours of its administration in most patients discontinuing warfarin. Haematologica. 2005;90(1):137-9.

12.       Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation. 2012;125(23):2944-7.

13.       Woods K, Douketis JD, Kathirgamanathan K, Yi Q, Crowther MA. Low-dose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin. J Thromb Thrombolysis. 2007;24(2):93-7.

14.       Curtis R, Schweitzer A, van Vlymen J. Reversal of warfarin anticoagulation for urgent surgical procedures. Can J Anaesth. 2015;62(6):634-49.

15.       Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-e84S.

16.       Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M, British Committee for Standards in H. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol. 2011;154(3):311-24.

17.       Grandone E, Ostuni A, Tiscia GL, Marongiu F, Barcellona D. Management of Patients Taking Oral Anticoagulants Who Need Urgent Surgery for Hip Fracture. Semin Thromb Hemost. 2019;45(2):164-70.

18.       Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008;83(2):137-43.

19.       Buecking B, Eschbach D, Bliemel C, Oberkircher L, Struewer J, Ruchholtz S, Sachs UJ. Effectiveness of vitamin K in anticoagulation reversal for hip fracture surgery–a prospective observational study. Thromb Res. 2014;133(1):42-7.

20.       Gleason LJ, Mendelson DA, Kates SL, Friedman SM. Anticoagulation management in individuals with hip fracture. J Am Geriatr Soc. 2014;62(1):159-64.

21.       Jay-Caillierez L, Friggeri A, Viste A, Lefevre M, Decullier E, Bernard L, Piriou V, David JS. Safety and efficacy of a strategy of vitamin K antagonist reversal with prothrombin complex concentrates compared to vitamin K in patients with hip fracture. Can J Surg. 2021;64(3):E330-E8.

22.       Mattisson L, Lapidus LJ, Enocson A. Is fast reversal and early surgery (within 24 h) in patients on warfarin medication with trochanteric hip fractures safe? A case-control study. BMC Musculoskelet Disord. 2018;19(1):203.

23.       Vitale MA, Vanbeek C, Spivack JH, Cheng B, Geller JA. Pharmacologic reversal of warfarin-associated coagulopathy in geriatric patients with hip fractures: a retrospective study of thromboembolic events, postoperative complications, and time to surgery. Geriatr Orthop Surg Rehabil. 2011;2(4):128-34.