Research Article
BibTex RIS Cite

Kalp Kapak Cerrahisi Hastalarında Genetik Polimorfizmlerin Warfarin Dozaj Gereksinimleri Üzerine Etkisi

Year 2024, Volume: 7 Issue: 2, 104 - 107, 30.06.2024
https://doi.org/10.36516/jocass.1472877

Abstract

Giriş: Yaygın olarak reçete edilen bir antikoagülan olan varfarin, hasta yanıtında önemli farklılıklar göstererek, dar terapötik pencere nedeniyle klinik kullanımını zorlaştırmaktadır. Bu çalışmanın amacı, kalp kapak ameliyatı geçiren ve warfarin tedavisi alan 87 Türk hastadan oluşan bir kohorttaki CYP2C9 ve VKORC1 gen polimorfizmlerinin prevalansını ve bunların warfarin dozaj gereksinimleri üzerindeki etkisini değerlendirmeyi amaçlamıştır.
Gereç ve Yöntemler: CYP2C9 ve VKORC1 polimorfizmlerinin sıklıkları analiz edildi ve hastalar, warfarin dozunu etkileyen mutasyonların varlığı veya yokluğuna göre sınıflandırıldı.
Bulgular: En az bir CYP2C9 veya VKORC1 polimorfizmi taşıyan hastaların, optimal uluslararası normalleştirilmiş orana (INR) ulaşmak için önemli ölçüde daha düşük haftalık warfarin dozuna ihtiyaç duyduğu ortaya çıktı.
Sonuç: Bu çalışma, warfarin dozajının belirlenmesinde genetik faktörlerin kritik rolünü vurgulamakta ve varfarin tedavisini kişiselleştirmek için farmakogenetik testlerin klinik uygulamaya entegrasyonunu desteklemektedir. Böyle bir yaklaşımın tedavi sonuçlarını iyileştirme ve olumsuz olay riskini en aza indirme potansiyeli vardır. Bu bulguları doğrulamak ve varfarin dozajının genetik belirleyicilerine ilişkin mevcut anlayışı geliştirmek için daha büyük örneklem boyutlarını ve farklı hasta popülasyonlarını içeren daha fazla araştırma yapılması gerekmektedir.

References

  • 1. 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):160-98.
  • 2. Franchini M, Mengoli C, Cruciani M, Bonfanti C, Mannucci PM. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost 2014 Sep;12(9):1480-7.
  • 3. Franchini M, Mannucci PM. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med 2012 Dec;23(8):692-5.
  • 4. Lemesle G, Ducrocq G, Elbez Y, Van Belle E, Goto S, Cannon CP, et al. Vitamin K antagonists with or without long-term antiplatelet therapy in outpatients with stable coronary artery disease and atrial fibrillation: Association with ischemic and bleeding events. Clin Cardiol 2017 Oct;40(10):932-9.
  • 5. Santos PC, Soares RA, Strunz CM, Grinberg M, Ferreira JF, Cesar LA, et al. Simultaneous use of amiodarone influences warfarin maintenance dose but is not associated with adverse events. J Manag Care Spec Pharm 2014 Apr;20(4):376-81.
  • 6. Limdi NA, Brown TM, Yan Q, Thigpen JL, Shendre A, Liu N, et al. Race influences warfarin dose changes associated with genetic factors. Blood 2015 Jul 23;126(4):539-45.
  • 7. International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009 Feb 19;360(8):753-64.
  • 8. Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, et al Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 2017 Sep;102(3):397-404.
  • 9. Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 2009 Jul-Aug;43(1):119-28.
  • 10. Yang J, Chen Y, Li X, Wei X, Chen X, Zhang L, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013 Oct 9;168(4):4234-43.
  • 11. Choonara IA, Cholerton S, Haynes BP, Breckenridge AM, Park BK. Stereoselective interaction between the R enantiomer of warfarin and cimetidine. Br J Clin Pharmacol 1986 Mar;21(3):271-7.
  • 12. Liu Y, Jeong H, Takahashi H, Drozda K, Patel SR, Shapiro NL, et al. Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism. Clin Pharmacol Ther 2012 Apr;91(4):660-5.
  • 13. Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, et al. Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet 1988 Jan;42(1):26-37.
  • 14. Villegas-Torres B, Sánchez-Girón F, Jaramillo-Villafuerte K, Soberón X, Gonzalez-Covarrubias V. Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene 2015 Mar 10;558(2):235-40.
  • 15. Gaikwad T, Ghosh K, Kulkarni B, Kulkarni V, Ross C, Shetty S. Influence of CYP2C9 and VKORC1 gene polymorphisms on warfarin dosage, over anticoagulation and other adverse outcomes in Indian population. Eur J Pharmacol 2013 Jun 15;710(1-3):80-4.
  • 16. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008 Feb;25(1):45-51.
  • 17. Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006 Aug;6(4):223-7.
  • 18. Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A 1974 Jul;71(7):2730-3.
  • 19. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 Feb 5;427(6974):537-41.
  • 20. Marsh S, McLeod HL. Pharmacogenomics: from bedside to clinical practice. Hum Mol Genet 2006 Apr 15;15 Spec No 1:R89-93.
  • 21. van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VH, et al. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium. Clin Pharmacol Ther 2017 Mar;101(3):341-358. 22. Haga SB, Moaddeb J, Mills R, Voora D. Assessing feasibility of delivering pharmacogenetic testing in a community pharmacy setting. Pharmacogenomics 2017 Mar;18(4):327-335.
  • 23. Stanek EJ, Sanders CL, Taber KA, Khalid M, Patel A, Verbrugge RR, etal. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther 2012 Mar;91(3):450-8.
  • 24. Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008 Feb;83(2):312-21.
  • 25. Lima MV, Ribeiro GS, Mesquita ET, Victer PR, Vianna-Jorge R. CYP2C9 genotypes and the quality of anticoagulation control with warfarin therapy among Brazilian patients. Eur J Clin Pharmacol 2008 Jan;64(1):9-15.

The Influence of Genetic Polymorphisms on Warfarin Dosage Requirements in Cardiac Valve Surgery Patients

Year 2024, Volume: 7 Issue: 2, 104 - 107, 30.06.2024
https://doi.org/10.36516/jocass.1472877

Abstract

Aim: Warfarin, a widely prescribed anticoagulant, exhibits considerable variability in patient response, making its clinical use challenging due to a narrow therapeutic window. This study aimed to evaluate the prevalence of CYP2C9 and VKORC1 gene polymorphisms in a cohort of 87 Turkish patients who underwent cardiac valve surgery and received warfarin therapy, as well as to assess their impact on warfarin dosage requirements.
Methods: The frequencies of CYP2C9 and VKORC1 polymorphisms were analyzed, and patients were stratified based on the presence or absence of mutations affecting warfarin dosing.
Results: Revealed that patients carrying at least one CYP2C9 or VKORC1 polymorphism required a significantly lower weekly warfarin dose to achieve the optimal international normalized ratio (INR).
Conclusion: This study highlights the critical role of genetic factors in determining warfarin dosage and supports the integration of pharmacogenetic testing into clinical practice to personalize warfarin therapy. Such an approach has the potential to enhance treatment outcomes and minimize the risk of adverse events. Further research involving larger sample sizes and diverse patient populations is warranted to validate these findings and refine the current understanding of the genetic determinants of warfarin dosing.

References

  • 1. 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):160-98.
  • 2. Franchini M, Mengoli C, Cruciani M, Bonfanti C, Mannucci PM. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost 2014 Sep;12(9):1480-7.
  • 3. Franchini M, Mannucci PM. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med 2012 Dec;23(8):692-5.
  • 4. Lemesle G, Ducrocq G, Elbez Y, Van Belle E, Goto S, Cannon CP, et al. Vitamin K antagonists with or without long-term antiplatelet therapy in outpatients with stable coronary artery disease and atrial fibrillation: Association with ischemic and bleeding events. Clin Cardiol 2017 Oct;40(10):932-9.
  • 5. Santos PC, Soares RA, Strunz CM, Grinberg M, Ferreira JF, Cesar LA, et al. Simultaneous use of amiodarone influences warfarin maintenance dose but is not associated with adverse events. J Manag Care Spec Pharm 2014 Apr;20(4):376-81.
  • 6. Limdi NA, Brown TM, Yan Q, Thigpen JL, Shendre A, Liu N, et al. Race influences warfarin dose changes associated with genetic factors. Blood 2015 Jul 23;126(4):539-45.
  • 7. International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009 Feb 19;360(8):753-64.
  • 8. Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, et al Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 2017 Sep;102(3):397-404.
  • 9. Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 2009 Jul-Aug;43(1):119-28.
  • 10. Yang J, Chen Y, Li X, Wei X, Chen X, Zhang L, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013 Oct 9;168(4):4234-43.
  • 11. Choonara IA, Cholerton S, Haynes BP, Breckenridge AM, Park BK. Stereoselective interaction between the R enantiomer of warfarin and cimetidine. Br J Clin Pharmacol 1986 Mar;21(3):271-7.
  • 12. Liu Y, Jeong H, Takahashi H, Drozda K, Patel SR, Shapiro NL, et al. Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism. Clin Pharmacol Ther 2012 Apr;91(4):660-5.
  • 13. Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, et al. Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet 1988 Jan;42(1):26-37.
  • 14. Villegas-Torres B, Sánchez-Girón F, Jaramillo-Villafuerte K, Soberón X, Gonzalez-Covarrubias V. Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene 2015 Mar 10;558(2):235-40.
  • 15. Gaikwad T, Ghosh K, Kulkarni B, Kulkarni V, Ross C, Shetty S. Influence of CYP2C9 and VKORC1 gene polymorphisms on warfarin dosage, over anticoagulation and other adverse outcomes in Indian population. Eur J Pharmacol 2013 Jun 15;710(1-3):80-4.
  • 16. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008 Feb;25(1):45-51.
  • 17. Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006 Aug;6(4):223-7.
  • 18. Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A 1974 Jul;71(7):2730-3.
  • 19. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 Feb 5;427(6974):537-41.
  • 20. Marsh S, McLeod HL. Pharmacogenomics: from bedside to clinical practice. Hum Mol Genet 2006 Apr 15;15 Spec No 1:R89-93.
  • 21. van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VH, et al. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium. Clin Pharmacol Ther 2017 Mar;101(3):341-358. 22. Haga SB, Moaddeb J, Mills R, Voora D. Assessing feasibility of delivering pharmacogenetic testing in a community pharmacy setting. Pharmacogenomics 2017 Mar;18(4):327-335.
  • 23. Stanek EJ, Sanders CL, Taber KA, Khalid M, Patel A, Verbrugge RR, etal. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther 2012 Mar;91(3):450-8.
  • 24. Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008 Feb;83(2):312-21.
  • 25. Lima MV, Ribeiro GS, Mesquita ET, Victer PR, Vianna-Jorge R. CYP2C9 genotypes and the quality of anticoagulation control with warfarin therapy among Brazilian patients. Eur J Clin Pharmacol 2008 Jan;64(1):9-15.
There are 24 citations in total.

Details

Primary Language English
Subjects Cardiovascular Surgery, Medical Genetics (Excl. Cancer Genetics)
Journal Section Articles
Authors

Tolga Onur Badak 0000-0002-4254-196X

Ferid Cereb 0000-0002-1571-1708

Hacı Ali Uçak 0000-0003-0350-109X

Hasan Uncu 0000-0002-7549-4389

Özge Özalp 0000-0002-7343-3064

Özlem Anlaş 0000-0002-2861-1693

Publication Date June 30, 2024
Submission Date April 25, 2024
Acceptance Date June 9, 2024
Published in Issue Year 2024 Volume: 7 Issue: 2

Cite

APA Badak, T. O., Cereb, F., Uçak, H. A., Uncu, H., et al. (2024). The Influence of Genetic Polymorphisms on Warfarin Dosage Requirements in Cardiac Valve Surgery Patients. Journal of Cukurova Anesthesia and Surgical Sciences, 7(2), 104-107. https://doi.org/10.36516/jocass.1472877

download

You are free to:
Share — copy and redistribute the material in any medium or format The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. NonCommercial — You may not use the material for commercial purposes. NoDerivatives — If you remix, transform, or build upon the material, you may not distribute the modified material. No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.