VKORC1 Variant Genotypes Influence Warfarin Response in Patients Undergoing Total Joint Arthroplasty: a Pilot Study

Overview

Journal Clin Orthop Relat Res

Publisher Wolters Kluwer

Specialty Orthopedics

Date 2008 Nov 27

PMID 19034590

Citations 4

Authors

Alejandro Gonzalez Della Valle

Saurabh Khakharia

Charles J Glueck

Nicole Taveras

Ping Wang

Robert N Fontaine

Eduardo A Salvati

Affiliations

Soon will be listed here.

Abstract

Unlabelled: Warfarin dosing algorithms do not account for genetic mutations that can affect anticoagulation response. We retrospectively assessed to what extent the VKORC1 variant genotype would alter the likelihood of being a hyperresponder or hyporesponder to warfarin in patients undergoing total joint arthroplasty. We used the international normalized ratio (INR) on the third postoperative day of 3.0 or greater to define warfarin hyperresponders and 1.07 or less to define hyporesponders. A control group of normal responders was identified. From a cohort of 1125 patients receiving warfarin thromboprophylaxis, we identified 30 free of predisposing factors that could affect warfarin response: 10 hyperresponders, eight hyporesponders, and 12 normal responders. Homozygous carriers of the VKORC1 mutant AA genotype were more likely (compared with carriers of GA or GG genotypes) to be hyperresponders (odds ratio, 7.5; 95% confidence interval, 1.04-54.1). Homozygous carriers of the GG (normal) genotype were more likely (compared with carriers of AA or GA genotypes) to be hyporesponders (odds ratio, 9; 95% confidence interval, 1.14-71). Preoperative screening for the VKORC-1 genotype could identify patients with a greater potential for being a hyperresponder or hyporesponder to warfarin. This may allow an adjusted pharmacogenetic-based warfarin dose to optimize anticoagulation, reducing postoperative risks of bleeding and thrombosis or embolism.

Level Of Evidence: Level III, diagnostic study.

Citing Articles

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies.

Jajosky R, Wu S, Zheng L, Jajosky A, Jajosky P, Josephson C iScience. 2023; 26(1):105798.

PMID: 36691627 PMC: 9860303. DOI: 10.1016/j.isci.2022.105798.

The influence of VKORC1 and CYP2C9 mutations on warfarin response after total hip and knee arthroplasty.

Wise E, Gadomski 2nd S, McMaster Jr W, Wilson R, Nelms J, Hocking K J Orthop. 2016; 12(Suppl 2):S145-51.

PMID: 27047214 PMC: 4796661. DOI: 10.1016/j.jor.2015.10.023.

Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin.

Fung E, Patsopoulos N, Belknap S, ORourke D, Robb J, Anderson J Semin Thromb Hemost. 2012; 38(8):893-904.

PMID: 23041981 PMC: 4134937. DOI: 10.1055/s-0032-1328891.

Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis.

Jorgensen A, FitzGerald R, Oyee J, Pirmohamed M, Williamson P PLoS One. 2012; 7(8):e44064.

PMID: 22952875 PMC: 3430615. DOI: 10.1371/journal.pone.0044064.

References

Gonzalez Della Valle A, Serota A, Go G, Sorriaux G, Sculco T, Sharrock N . Venous thromboembolism is rare with a multimodal prophylaxis protocol after total hip arthroplasty. Clin Orthop Relat Res. 2006; 444:146-53. DOI: 10.1097/01.blo.0000201157.29325.f0. View

Geerts W, Pineo G, Heit J, Bergqvist D, Lassen M, Colwell C . Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126(3 Suppl):338S-400S. DOI: 10.1378/chest.126.3_suppl.338S. View

Greenblatt D, von Moltke L . Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol. 2005; 45(2):127-32. DOI: 10.1177/0091270004271404. View

Imperiale T, Speroff T . A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA. 1994; 271(22):1780-5. View

Friedman R . Optimal duration of prophylaxis for venous thromboembolism following total hip arthroplasty and total knee arthroplasty. J Am Acad Orthop Surg. 2007; 15(3):148-55. DOI: 10.5435/00124635-200703000-00004. View

Amstutz H, Friscia D, dOrey F, Carney B . Warfarin prophylaxis to prevent mortality from pulmonary embolism after total hip replacement. J Bone Joint Surg Am. 1989; 71(3):321-6. View

Memtsoudis S, Gonzalez Della Valle A, Besculides M, Gaber L, Laskin R . Trends in demographics, comorbidity profiles, in-hospital complications and mortality associated with primary knee arthroplasty. J Arthroplasty. 2008; 24(4):518-27. DOI: 10.1016/j.arth.2008.01.307. View

Sharrock N, Go G, HARPEL P, Ranawat C, Sculco T, Salvati E . The John Charnley Award. Thrombogenesis during total hip arthroplasty. Clin Orthop Relat Res. 1995; (319):16-27. View

Beksac B, Gonzalez Della Valle A, Salvati E . Thromboembolic disease after total hip arthroplasty: who is at risk?. Clin Orthop Relat Res. 2006; 453:211-24. DOI: 10.1097/01.blo.0000238848.41670.41. View

10.

Caprini J, Arcelus J, Motykie G, Kudrna J, Mokhtee D, Reyna J . The influence of oral anticoagulation therapy on deep vein thrombosis rates four weeks after total hip replacement. J Vasc Surg. 1999; 30(5):813-20. DOI: 10.1016/s0741-5214(99)70005-4. View

11.

Lieberman J, Sung R, dOrey F, Thomas B, Kilgus D, Finerman G . Low-dose warfarin prophylaxis to prevent symptomatic pulmonary embolism after total knee arthroplasty. J Arthroplasty. 1997; 12(2):180-4. DOI: 10.1016/s0883-5403(97)90064-4. View

12.

Quteineh L, Verstuyft C, Descot C, Dubert L, Robert A, Jaillon P . Vitamin K epoxide reductase (VKORC1) genetic polymorphism is associated to oral anticoagulant overdose. Thromb Haemost. 2005; 94(3):690-1. DOI: 10.1160/TH05-03-0690. View

13.

Reitsma P, van der Heijden J, Groot A, Rosendaal F, Buller H . A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med. 2005; 2(10):e312. PMC: 1251635. DOI: 10.1371/journal.pmed.0020312. View

14.

Momary K, Shapiro N, Viana M, Nutescu E, Helgason C, Cavallari L . Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics. 2007; 8(11):1535-44. DOI: 10.2217/14622416.8.11.1535. View

15.

Wu A . Use of genetic and nongenetic factors in warfarin dosing algorithms. Pharmacogenomics. 2008; 8(7):851-61. DOI: 10.2217/14622416.8.7.851. View

16.

Paavolainen P, Pukkala E, Pulkkinen P, Visuri T . Causes of death after total hip arthroplasty: a nationwide cohort study with 24,638 patients. J Arthroplasty. 2002; 17(3):274-81. DOI: 10.1054/arth.2002.30774. View

17.

Millican E, Lenzini P, E Milligan P, Grosso L, Eby C, Deych E . Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood. 2007; 110(5):1511-5. PMC: 1975838. DOI: 10.1182/blood-2007-01-069609. View

18.

Mesko J, Brand R, Iorio R, Gradisar I, Heekin R, Leighton R . Venous thromboembolic disease management patterns in total hip arthroplasty and total knee arthroplasty patients: a survey of the AAHKS membership. J Arthroplasty. 2001; 16(6):679-88. DOI: 10.1054/arth.2001.25506. View

19.

Li T, Lange L, Li X, Susswein L, Bryant B, Malone R . Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet. 2006; 43(9):740-4. PMC: 2564574. DOI: 10.1136/jmg.2005.040410. View

20.

Wadelius M, Chen L, Downes K, Ghori J, Hunt S, Eriksson N . Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005; 5(4):262-70. DOI: 10.1038/sj.tpj.6500313. View