THE ROLE OF INDIVIDUAL GENETIC CHARACTERISTICS OF PATIENTS IN THE EFFICACY OF ANTICOAGULANT THERAPY

DOI: https://doi.org/None

E.G. Komova (1,2), V.A. Vavilin (1), M.K. Ivanov (2), V.V. Lyakhovich (1) 1 -Research Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk, 630060, Russian Federation; 2 -StockJoint Company «Vector-Best», Pasechnaya str., 3, Novosibirsk, 630128, Russian Federation

The review highlights the problem of the influence of the genetic characteristics of patients in the dosage of anticoagulant drugs, the main adverse reaction of taking of which is the internal bleeding. Therapy with anticoagulant drugs is characterized by a wide interindividual variability in the effective dose (from 0,5 to 20 mg/day of warfarin), accompanied by side effects such as bleeding (15% of the total cases receiving the therapy) or vice versa, resistance (about 1%). Molecular target and drug-metabolizing proteins, the functional significance of polymorphic variants of the genes encoding these proteins and the decisive contribution of genetic factors to the pharmacokinetics and pharmacodynamics of these drugs were established by the studies over the last 20 years. The search for new anticoagulant drugs has not yet given rise in the discovery of compounds that would be free from the activity of these enzymes. Therefore, at this time the way out is the use of pharmacogenetic tests in the administration of anticoagulant drugs to determine the individual dose, depending on the genetic characteristics of the patient. There was well developed the pharmacogenetic approach in the choice of a dose of warfarin, which is safer for patients and pharmaco-effective if compared with the traditional method of dose detection. In the review there are considered key works, including the history of the issue, in terms of the use of this knowledge in aims of predictive genetic testing for personalized anticoagulation therapy.
Keywords: 
anticoagulants, warfarin, cytochromes P450, vitamin K epoxid reductase complex subunit 1, genetic polymorphism

Список литературы: 
  1. Diagnostika i lechenie fibrillyacii predserdiy. Rekomendacii VNOK i VNOA. Racional`naya farmakoterapiya v kardiologii. 2011. Pril. k №4.[Diagnostika i lechenie fibrilljacii pred-serdij. Rekomendacii VNOK i VNOA. Racional’naja farmakoterapija v kardi-ologii. 2011. Pril. k №4 (in Russian)]
  2. Belousov Yu.B. Yavelov I.S., Belousov D.Yu., Afanas`eva E.V. Racional`naya farmakoterapiya v kardiologii. 2011; 7 (5): 561–6.[Belousov Ju.B. Javelov I.S., Belousov D.Ju., Afanasjeva E.V. Racional’naja farmakot-erapija v kardiologii. 2011; 7 (5): 561–6 (in Russian)]
  3. Hallak H.O., Wedlund P.J., Modi M.W. Patel I.H., Lewis G.L., Woodruff B., Trowbridge A.A. High clearance of (S)-warfarin in a warfarin-resistant subject. Br. J. Clin. Phar-macol. 1993; 35 (3): 327–30.
  4. Rosendaal F.R., Cannegieter S.C., van der Meer F.J., Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb. Haemost. 1993; 69 (3): 236–39.
  5. Weiner M., Shapiro S., Axelrod J., Cooper J.R., Brodie B.B. The physiological disposi-tion of dicumarol in man. J. Pharmacol. Exper. Ther. 1950; 99 (4): 409–20.
  6. O`Reilly R.A., Aggeler P.M., Hoag M.S., Leong L.S., Kropatkin M.L. Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs – The First Reported Kindred. New Eng. J. Med. 1964; 271: 809–15.
  7. Lewis R.J., Spivack M., Spaet T.H. Warfarin resistance . Amer. J. Med. 1967; 42 (4): 620–4.
  8. Vesell E.S., Page J.G. Genetic Control of Dicumarol Levels in Man. J. Clin. Invest. 1968; 47 (12): 2657–63.
  9. Chu P.H., Huang T.Y., Williams J., Stafford D.W. Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2. Proc. Natl. Acad. Sci. USA. 2006; 103 (51): 19308–13.
  10. Li T., Chang C.Y., Jin D.Y., Lin P.J., Khvorova A., Stafford D.W. Identification of the gene for vitamin K epoxide reductase. Nature. 2004; 427 (6974): 541–4.
  11. Rost S., Fregin A., Ivaskevicius V., Conzel-mann E., Hörtnagel K., Pelz H.J., Lappe-gard K., Seifried E., Scharrer I., Tuddenham E.G., Müller C.R., Strom T.M., Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation fac-tor deficiency type 2. Nature. 2004; 427 (6974): 537–41.
  12. Eriksson N., Wadelius M. Prediction of war-farin dose: why, when and how? Pharma-cogenomics. 2012; 13 (4): 429–40.
  13. Rieder M.J., Reiner A.P., Gage B.F. Nicker-son DA, Eby C.S., McLeod H.L., Blough D.K., Thummel K.E., Veenstra D.L., Rettie A.E. Effect of VKORC1 Haplotypes on Transcrip-tional Regulation and Warfarin Dose. N Engl. J. Med. 2005; 352 (22): 2285–93
  14. D’Andrea G., D’Ambrosio R.L., Di Perna P., Chetta M, Santacroce R., Brancaccio V., Grandone E., Margaglione M. A polymor-phism in the VKORC1 gene is associated with an inter-individual variability in the dose-anticoagulant effect of warfarin. Blood. 2005; 105 (2): 645–9.
  15. Morris, D. P., Stevens, R. D., Wright, D. J., Stafford, D. W J. Processive post-transla-tional modification. Vitamin K-dependent carboxylation of a peptide substrate. Biol. Chem. 1995; 270 (51): 30491–8.
  16. Glurich I., Berg R.L., Burmester J.K. Does CALU SNP rs1043550 contribute variability to therapeutic warfarin dosing require-ments? Clin. Med. Res. 2013; 11 (2): 73–9.
  17. Rettie A.E., Eddy A.C., Heimark L.D., Gibaldi M., Trager W.F. Characteristics of warfarin hydroxylation catalyzed by human liver microsomes. Drug Metab. Dispos. 1989; 17 (3): 265–70.
  18. Rettie A.E., Korzekwa K.R., Kunze K.L., Lawrence R.F., Eddy A.C., Aoyama T., Gelboin H.V., Gonzalez F.J., Trager W.F. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfa-rin-drug interactions. Chem. Res. Toxicol. 1992; 5 (1): 54–9.
  19. Stubbins M.J., Harries L.W., Smith G., Tarbit M.H., Wolf C.R. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics. 1996; 6 (5): 429–39.
  20. Rettie A.E., Wienkers L.C., Gonzalez F.J., Trager W.F., Korzekwa K.R. Impaired (S)-warfarin metabolism catalyzed by the R144C allelic variant of CYP2C9. Pharma-cogenetics. 1994; 4 (1): 39–42.
  21. Aithal G.P., Day C.P., Kesteven P.J.L., Daly A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999; 353 (9154): 717–9.
  22. Jones D.R., Kim S.Y., Boysen G., Yun C.H., Miller G.P. Contribution of Three CYP3A Isoforms to Metabolism of R- and S-Warfarin. Drug Metab. Lett. 2010; 4 (4): 213–9.
  23. Jones D.R., Kim S.Y., Guderyon M. Yun C.H., Moran J.H., Miller G.P. Hydroxywarfarin metabolites potently inhibit CYP2C9 me-tabolism of S-warfarin. Chem. Res. Toxicol. 2010; 23 (5): 939–45.
  24. McDonald M.G., Rieder M.J., Nakano M., Hsia C.K., Rettie A.E. CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered War-farin Dose in Carriers of the V433M Variant Mol. Pharmacol. 2009; 75 (6): 1337–46.
  25. Caldwell M., Awad T., Johnson J., Gage B, Falkowski M., Gardina P., Hubbard J., Turpaz Y., Langaee T.Y., Eby C, King C.R., Brower A., Schmelzer J.R., Glurich I., Vidaillet H.J., Yale S.H., Qi Zhang K., Berg R.L., Burmester J.K. CYP4F2 genetic variant alters required war-farin dose. Blood. 2008; 111 (8): 4106–12.
  26. Edson K.Z., Prasad B., Unadkat J.D., Suhara Y., Okano T., Guengerich F.P., Rettie AE. Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11. Biochemistry. 2013; 52 (46): 8276–85
  27. Ciccacci C., Falconi M., Paolillo N. Oteri F., Forte V., Novelli G., Desideri A., Borgiani P. Characterization of a novel CYP2C9 gene mutation and structural bioinformatic protein analysis in a warfarin hypersensitive patient. Pharmacogenetics and Genom-ics. 2011; 21 (6): 344–6.
  28. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. www.cypalleles.ki.se.
  29. DeLozier T.C., Lee S-C, Coulter S.J., Goh B.C., and Goldstein J.A. Functional characterization of novel allelic variants of CYP2C9 recently discovered in Southeast Asians. J. Pharmacol. Exp. Ther. 2005; 315 (3): 1085–90.
  30. Herman D., Peternel P., Stegnar M., Breskvar K., Dolzan V. A novel sequence variant in exon 7 of CYP2C9 gene (CYP2C9*24) in a patient on warfarin therapy. Thromb. Haemost. 2006; 95 (1): 192–4.
  31. Kropacheva E.S., Panchenko E.P., Dobrovol`skiy A.B., Saidova M.A. Rezistentnost` k varfarinu u bol`noy s absolyutnymi pokazaniyami k priemu antagonistov vitamina K Aterotromboz. 2009; 1 (2): 99–104. [Kropachjova E.S., Panchenko E.P., Dobrovol’skij A.B., Saidova M.A. Rezistent-nost’ k varfarinu u bol’noj s absoljutnymi pokazanijami k priemu antagonistov vita-mina K Aterotromboz. 2009; 1 (2): 99–104 (in Russian)]
  32. Veenstra D.L., Blough D.K., Higashi M.K., Farin F.M., Srinouanprachan S., Rieder M.J., Rettie A.E. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin. Pharmacol. Ther. 2005; 77 (5): 353–64.
  33. Kramer M.A., Rettie A.E., Rieder M.J. Cabacungan E.T., Hines R.N. Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression. Mol. Pharma-col. 2008; 73 (6): 1751–60.
  34. Cavallari L.H., Perera M., Wadelius M. Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans. Pharmacogenet. Genomics. 2012; 22 (2): 152–8.
  35. Cavallari L.H. and Perera M.A. The future of warfarin pharmacogenetics in under-rep-resented minority groups. Future Cardiol. 2012; 8 (4): 563–76.
  36. Ansell J., Hirsh J., Hylek E., Jacobson A., Crowther M., Palareti G. Pharmacol-ogy and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Prac-tice Guidelines (8th Edition). CHEST. 2008; 133 (6): 160–98.
  37. Klein T.E., Altman R.B., Eriksson N., Gage B.F., Kimmel S.E., Lee M.T., Limdi N.A., Page D., Roden D.M., Wagner M.J., Caldwell M.D., Johnson J.A. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 2009; 360 (8): 753–64.
  38. Bristol-Meyers Squibb Company. Couma-din® tablets (warfarin sodium tablets, USP) crystalline; Coumadin® for injection (warfa-rin sodium for injection, USP). Available at: http:www.accessdata.fda.gov/drugsat-fda_docs/label/2010/009218s108lbl.pdf
  39. Gage B.F., Eby C., Johnson J.A., Deych E., Rieder M.J., Ridker P.M,. Milligan P.E., Grice G., Lenzini P., Rettie A.E., Aquilante C.L., Grosso L., Marsh S., Langaee T., Farnett L.E., Voora D., Veenstra D.L., Glynn R.J., Barrett A., McLeod H.L. Use of pharmacogenetic and clinical factors to predict the thera-peutic dose of warfarin. Clin. Pharmacol. Ther. 2008; 84 (3): 326–31
  40. Grishhenko N.D. Vliyanie polimorfizma genov CYP2C9 i VKORC1 na osobennosti dozirovaniya i antikoagulyantnoe deystvie fenindiona u pacientov s fibrillyaciey predserdiy. Avtoref. diss. na soisk. uch. st. k.m.n. Moskva, 2012.[Grishhenko N.D. Vlijanie polimorfizma genov CYP2C9 i VKORC1 na osobennosti dozirovanija i antikoaguljantnoe dejstvie fenindiona u pacientov s fibrilljaciej pred-serdij. Avtoref. diss. na soisk. uch. st. k.m.n. Moskva, 2012 (in Russian)]
  41. Lacut K., Ayme-Dietrich E., Gourhant L. Poulhazan E., Andro M., Becquemont L., Mottier D., Le Gal G., Verstuyft C. Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation re-sponse to fluindione. Br. J. Clin. Pharmacol. 2011; 73 (3): 428–36.
  42. Cadamuro J., Dieplinger B., Felder T., Kedenko I., Mueller T., Haltmayer M., Patsch W., Oberkofler H. Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. Eur. J. Clin. Pharmacol. 2010; 66 (3): 253–60
  43. Sychev D.A. Farmakogeneticheskie podhody k personalizacii primeneniya antitromboticheskih sredstv. «Itogi raboty Centra personalizirovannoy mediciny po vnedreniyu metodologii personalizirovannoy mediciny v prakticheskoe zdravoohranenie». Materialy VI Mezhdunarodnogo medicinskogo foruma «Industriya zdorov`ya», 22–25 aprelya 2013 g. Moskva.[Sychev D.A. Farmakogeneticheskie podhody k personalizacii primenenija antitromboticheskih sredstv. «Itogi raboty Centra personalizirovannoj mediciny po vnedreniju metodologii personalizirovan-noj mediciny v prakticheskoe zdra-voohranenie». Materialy VI Mezhdunar-odnogo medicinskogo foruma «Industrija zdorov’ja», 22–25 aprelja 2013 g. Moskva. (in Russian)]
  44. Ezekowitz M.D., Connolly S., Parekh A., Reilly P.A., Varrone J., Wang S., Oldgren J., Themeles E., Wallentin L., Yusuf S. Rationale and design of RE-LY: rand-omized evaluation of long-term antico-agulant therapy, warfarin compared with dabigatran. Am. Heart J. 2009; 157 (5): 805–10, 810.e1-2.
  45. Van de Werf F., Brueckmann M., Connolly S.J. Friedman J., Granger C.B., Härtter S., Harper R., Kappetein A.P., Lehr T., Mack M.J., Noack H., Eikelboom J.W. Comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am. Heart J. 2012; 163 (6): 931-37.e1
  46. FDA Drug Safety Communication: 1) Up-date on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigat-ran). http:www.fda.gov/Drugs/DrugSafety/ucm326580.htm. 2) Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. http:www.fda.gov/Drugs/Drug-Safety/ucm332912.htm.
  47. Eikelboom J.W., Connolly S.J., Brueck-mann M. Granger C.B., Kappetein A.P., Mack M.J., Blatchford J., Devenny K., Friedman J., Guiver K., Harper R., Khder Y., Lobmeyer M.T., Maas H., Voigt J.U., Simoons M.L., Van de Werf F. Dabigatran versus Warfarin in Patients with Mechani-cal Heart Valves. N. Engl. J. Med. 2013; 369 (13): 1206–14.
  48. Pradaxa® gains EU approval for treatment and prevention of recurrence of deep vein thrombosis and pulmonary embo-lism. http://www.boehringer-ingelheim.com/news/news_releases/press_releas-es/2014/06_june_2014_dabigatranetexi-late.html.
  49. Stangier J., Clemens A. Pharmacology, pharmacokinetics, and pharmacodynam-ics of Dabigatran Etexilate, an oral direct thrombin inhibitor. Clin. Appl. Thromb. Hemost. 2009; 15 (1): 9–16.
  50. Pare G., Eriksson N., Lehr T. Connolly S., Eikelboom J., Ezekowitz M.D., Axelsson T., Haertter S., Oldgren J., Reilly P., Siegbahn A., Syvanen A.C., Wadelius C., Wadelius M., Zimdahl-Gelling H., Yusuf S., Wallentin L. Ge-netic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding. Circulation. 2013; 127 (13): 1404–12.
  51. Stangier J., Rathgen K., Stahle H., Gan-sser D., Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br. J. Clin. Pharmacol. 2007; 64: 292–303.
  52. Woodahl E.L., Ho R.J.Y. The Role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. Curr. Drug Metab. 2004; 5 (1): 11–9.
  53. Alexander J.H., Lopes R.D., James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 2011; 365 (8): 699–708.
  54. Granger C.B., Alexander J.H., McMurray J.J.V et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation Engl. J. Med. 2011; 365 (11): 981–92.
  55. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halp-erin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N. Engl. J. Med. 2011; 365 (10): 883–91.
  56. The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symp-tomatic Venous Thromboembolism. N. Engl. J. Med. 2013; 369 (15): 1406–15
  57. Kropacheva E.S. Genotipirovanie chuvstvitel`nosti k varfarinu: ot nauchnyh predposylok k klinicheskoy praktike. Materialy XVII Foruma «Nacional`nye dni laboratornoy mediciny Rossii – 2013», 1–3 oktyabrya 2013.[Kropacheva E.S. Genotipirovanie chuvstvitel’nosti k varfarinu: ot nauch-nyh predposylok k klinicheskoj praktike. Materialy XVII Foruma «Nacional’nye dni laboratornoj mediciny Rossii – 2013», 1–3 oktjabrja 2013 (in Russian)]

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