Denis Nam, Robert L. Barrack.

Response/Recommendation: The available literature suggests that the administration of warfarin leads to a temporary hypercoagulable state.

Strength of Recommendation: Moderate.

Rationale: Warfarin is an oral anticoagulant medication commonly used to treat and prevent venous thromboembolism (VTE)^1,2.  Warfarin is most commonly indicated for cardiac-related issues such as minimization of embolization in patients with atrial fibrillation or heart valve replacement, and the avoidance of stroke and systemic embolization following a myocardial infarction^2–4.  However, warfarin is also food and drug administration (FDA)-approved for prophylaxis and treatment of VTE following surgical procedures including orthopaedic surgery⁵.  Warfarin competitively inhibits the vitamin K epoxide reductase complex 1, which activates the vitamin K available in the body.  By depleting functional vitamin K reserves, warfarin reduces the synthesis of vitamin K dependent clotting factors II, VII, IX, and X, as well as coagulation regulatory factors protein C and protein S (which also require vitamin K)⁶.  However, patient-specific factors such as drug metabolism, differences in vitamin K availability, quantity of vitamin K dependent clotting factors, concurrent diseases, drug interactions, and the pharmacokinetics of warfarin make safe and effective administration of warfarin difficult^1,6,7.

One potential concern when initiating warfarin therapy is systemic hypercoagulability, which is why in most circumstances, particularly in cardiac cases, warfarin is coadministered with another anticoagulation agent such as heparin until the international normalized ratio (INR) is titrated within therapeutic range^8–10.  Warfarin not only impacts procoagulation factors II, II, IX, and IX, but also protein C and protein S (which act to regulate the coagulation pathway).  The potential for hypercoagulability thus arises due to the differences in half-lives of each of these proteins^1,11.  Protein C selectively inactivates factors Va and VIIIa, and thus if protein C is inhibited, there is a temporary period in which a patient may enter a hypercoagulable state¹².  The rate at which these vitamin K dependent factors decrease is governed primarily by their half-lives^13–15.  As both factor VII (4-6 hours) and protein C (9 hours) typically have the shortest half-lives, these are the factors most rapidly impacted. In contrast, factors II (42-72 hours), IX (18-30 hours), X (27-48 hours), and protein S (60 hours) take a longer time to inhibit¹.  However, the speed at which each of these factors are affected also depends on the initial dose of warfarin.  When administered as a high loading dose (30-40mg) followed by lower doses, factor VII coagulant activity decreases more rapidly than when the starting dose is 10mg or less^1,15.

While based on its mechanism of action and the half-lives of vitamin K dependent coagulation and regulatory factor proteins, there is clearly the potential for hypercoagulability after the initial administration of warfarin, the clinical impact of this remains uncertain.  Binymin et al., presented a case report of a patient diagnosed with atrial fibrillation who was initiated on warfarin therapy without low molecular weight heparin, who was subsequently diagnosed with a deep venous thrombosis (DVT) three days after initial administration.  The authors theorized that it was this unopposed warfarin dose that increased the risk of DVT¹⁶.  Azoulay et al., performed a case-control analysis of 70,766 patients diagnosed with atrial fibrillation, of whom 5,519 patients experienced a stroke during follow-up.  They noted that warfarin was associated with a 71% increased risk of stroke in the first 30 days of use, thus proposing that unopposed use of warfarin may lead to a transient hypercoagulable state that increased the risk of stroke in patients with a diagnosis of atrial fibrillation¹⁷.  While warfarin has been shown to be effective for VTE prophylaxis following orthopaedic procedures, it is also known to be difficult to administer effectively.  Nam et al., analyzed 184 patients who received warfarin for 4 weeks postoperatively following a primary hip and knee arthroplasty and noted that patients were in their therapeutic INR range for only 54.4% of the time during their postoperative course¹⁸.  Cipriano et al., compared preoperative versus postoperative initiation of warfarin therapy for VTE prophylaxis following hip and knee arthroplasty and found no difference in perioperative hemoglobin changes or VTE risk, although patients started on warfarin preoperatively reached their therapeutic range more quickly¹⁹.

In conclusion, while transient hypercoagulability is plausible and likely following the initial administration of warfarin, the clinical impact of this remains uncertain given the limited number of studies specifically addressing this issue.

References:

1.         Stirling Y. Warfarin-induced changes in procoagulant and anticoagulant proteins. Blood Coagul Fibrinolysis Int J Haemost Thromb. 1995;6(5):361-373. doi:10.1097/00001721-199507000-00001

2.         Doliner B, Jaller JA, Lopez AJ, Lev-Tov H. Treatments to prevent primary venous ulceration after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2019;7(2):260-271.e1. doi:10.1016/j.jvsv.2018.12.009

3.         Sharp CR, deLaforcade AM, Koenigshof AM, Lynch AM, Thomason JM. Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 4-Refining and monitoring antithrombotic therapies. J Vet Emerg Crit Care San Antonio Tex 2001. 2019;29(1):75-87. doi:10.1111/vec.12794

4.         Badjatiya A, Rao SV. Advances in Antiplatelet and Anticoagulant Therapies for NSTE-ACS. Curr Cardiol Rep. 2019;21(1):3. doi:10.1007/s11886-019-1090-3

5.         Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-1106. doi:10.1001/archinte.165.10.1095

6.         Singh PS, Preuss CV, Patel N. Warfarin. StatPearls; 2021.

7.         Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1998;114(5 Suppl):445S-469S. doi:10.1378/chest.114.5_supplement.445s

8.         Kuruvilla M, Gurk-Turner C. A review of warfarin dosing and monitoring. Proc Bayl Univ Med Cent. 2001;14(3):305-306. doi:10.1080/08998280.2001.11927781

9.         Chokesuwattanaskul R, Thongprayoon C, Bathini T, et al. Efficacy and safety of anticoagulation for atrial fibrillation in patients with cirrhosis: A systematic review and meta-analysis. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2019;51(4):489-495. doi:10.1016/j.dld.2018.12.001

10.       Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician. 1999;59(3):635-646.

11.       Palareti G, Legnani C. Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations. Clin Pharmacokinet. 1996;30(4):300-313. doi:10.2165/00003088-199630040-00003

12.       Esmon CT, Vigano-D’Angelo S, D’Angelo A, Comp PC. Anticoagulation proteins C and S. Adv Exp Med Biol. 1987;214:47-54. doi:10.1007/978-1-4757-5985-3_4

13.       Loeliger EA, Hensen A, Mattern MJ, Hemker HC. BEHAVIOUR OF FACTORS II, VII, IX AND X IN BLEEDING COMPLICATIONS DURING LONG-TERM TREATMENT WITH COUMARIN. Thromb Diath Haemorrh. 1964;10:278-281.

14.       Dike GW, Griffiths D, Bidwell E, Snape TJ, Rizza CR. A factor VII concentrate for therapeutic use. Br J Haematol. 1980;45(1):107-118. doi:10.1111/j.1365-2141.1980.tb03816.x

15.       Weiss P, Soff GA, Halkin H, Seligsohn U. Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy. Thromb Res. 1987;45(6):783-790. doi:10.1016/0049-3848(87)90088-0

16.       Binymin KA, Nasher M, Patel D. Warfarin-induced deep vein thrombosis. Int Med Case Rep J. 2014;7:123-125. doi:10.2147/IMCRJ.S62100

17.       Azoulay L, Dell’Aniello S, Simon TA, Renoux C, Suissa S. Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J. 2014;35(28):1881-1887. doi:10.1093/eurheartj/eht499

18.       Nam D, Sadhu A, Hirsh J, Keeney JA, Nunley RM, Barrack RL. The use of warfarin for DVT prophylaxis following hip and knee arthroplasty: how often are patients within their target INR range? J Arthroplasty. 2015;30(2):315-319. doi:10.1016/j.arth.2014.08.032

19.       Cipriano C, Erdle N, Li K, Curtin B. Preoperative Versus Postoperative Initiation of Warfarin Therapy in Patients Undergoing Total Hip and Knee Arthroplasty. Orthop Clin North Am. 2017;48(1):9-13. doi:10.1016/j.ocl.2016.08.003