Skip to main content

Advertisement

SpringerLink
Log in

Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients.

Methods

Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20.

Results

A significant correlation was found between age, BMI, and daily AC dose (r = − 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2 or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06–0.60], p = 0.004; ORs* = 0.12 [0.04–0.05], p < 0.001; ORs* = 0.45 [0.24–0.84], p = 0.01; and ORs* = 0.28 [0.06–0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12–5.91], p = 0.013; ORs* = 8.76 [1.07–76.26], p = 0.019; ORs* = 3.12 [1.01–9.63], p = 0.047; and ORs* = 3.96 [1.41–11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement.

Conclusion

The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Buzoianu AD, Militaru FC, Vesa SC, Trifa AP, Crisan S (2013) The impact of the CYP2C9 and VKORC1 polymorphisms on acenocoumarol dose requirements in a Romanian population. Blood Cells Mol Dis 50(3):166–170. https://doi.org/10.1016/j.bcmd.2012.10.010

    Article  CAS  PubMed  Google Scholar 

  2. D’Andrea G, D’Ambrosio R, Margaglione M (2008) Oral anticoagulants: pharmacogenetics relationship between genetic and non-genetic factors. Blood Rev 22(3):127–140. https://doi.org/10.1016/j.blre.2007.11.004

    Article  PubMed  Google Scholar 

  3. Van Geest-Daalderop JH, Hutten BA, Péquériaux NC, Levi M, Sturk A (2009) Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model. J Thromb Thrombolysis 27(2):207–214. https://doi.org/10.1007/s11239-008-0203-4

    Article  CAS  PubMed  Google Scholar 

  4. Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, Nalysnyk L (2004) Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. CHEST J 126(6):1938–1945. https://doi.org/10.1378/chest.126.6.1938

    Article  Google Scholar 

  5. Cannegieter SC, Rosendaal F, Wintzen A, Van der Meer F, Vandenbroucke J, Briet E (1995) Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 333(1):11–17. https://doi.org/10.1056/NEJM199507063330103

    Article  CAS  PubMed  Google Scholar 

  6. Visser LE, Penning-van Beest FJ, Kasbergen AH, De Smet PA, Vulto AG, Hofman A, Stricker BHC (2002) Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 88(5):705–710

    Article  CAS  PubMed  Google Scholar 

  7. Tong HY, Dávila-Fajardo CL, Borobia AM, Martínez-González LJ, Lubomirov R, León LMP, Bañares MJB, Díaz-Villamarín X, Fernández-Capitán C, Barrera JC (2016) A new pharmacogenetic algorithm to predict the most appropriate dosage of acenocoumarol for stable anticoagulation in a mixed Spanish population. PLoS One 11(3):e0150456. https://doi.org/10.1371/journal.pone.0150456

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ragia G, Kolovou V, Kolovou G, Konstantinides S, Maltezos E, Tavridou A, Tziakas D, Maitland-van der Zee AH, Manolopoulos VG (2017) A novel acenocoumarol pharmacogenomic dosing algorithm for the Greek population of EU-PACT trial. Pharmacogenomics 18(1):23–34. https://doi.org/10.2217/pgs-2016-0126

    Article  CAS  PubMed  Google Scholar 

  9. Jiménez-Varo E, Cañadas-Garre M, Gutiérrez-Pimentel MJ, Calleja-Hernández MÁ (2014) Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm. Pharmacogenet Genomics 24(10):501–513. https://doi.org/10.1097/FPC.0000000000000082

    Article  PubMed  Google Scholar 

  10. Yin T, Miyata T (2007) Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1—rationale and perspectives. Thromb Res 120(1):1–10. https://doi.org/10.1016/j.thromres.2006.10.021

    Article  CAS  PubMed  Google Scholar 

  11. Kirchheiner J, Brockmöller J (2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 77(1):1–16. https://doi.org/10.1016/j.clpt.2004.08.009

    Article  CAS  PubMed  Google Scholar 

  12. Verde Z, Ruiz JR, Santiago C, Valle B, Bandrés F, Calvo E, Lucía A, Gómez Gallego F (2010) A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants. PloS one 5. https://doi.org/10.1371/journal.pone.0011210

  13. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106(1):135–140. https://doi.org/10.1182/blood-2005-01-0341

    Article  CAS  PubMed  Google Scholar 

  14. Rost S, Fregin A, Ivaskevicius V, Conzelmann E (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427(6974):537–541. https://doi.org/10.1038/nature02214

    Article  CAS  PubMed  Google Scholar 

  15. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352(22):2285–2293. https://doi.org/10.1056/NEJMoa044503

    Article  CAS  PubMed  Google Scholar 

  16. Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, Muller CR, Wienker TF, Oldenburg J (2005) VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 94(4):773–779. https://doi.org/10.1160/th05-04-0290

    PubMed  Google Scholar 

  17. Lal S, Sandanaraj E, Jada SR, Kong MC, Lee LH, Goh BC, Lee SC, Chowbay B (2008) Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients. Br J Clin Pharmacol 65(2):260–264. https://doi.org/10.1111/j.1365-2125.2007.03053.x

    Article  CAS  PubMed  Google Scholar 

  18. D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105(2):645–649. https://doi.org/10.1182/blood-2004-06-2111

    Article  PubMed  Google Scholar 

  19. Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, Clarke JL, James BC, Anderson JL (2006) Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 22(3):191–197. https://doi.org/10.1007/s11239-006-9030-7

    Article  CAS  PubMed  Google Scholar 

  20. Powell PK, Wolf I, Jin R, Lasker JM (1998) Metabolism of arachidonic acid to 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11. J Pharmacol Exp Ther 285(3):1327–1336

    CAS  PubMed  Google Scholar 

  21. Sontag TJ, Parker RS (2002) Cytochrome P450 ω-hydroxylase pathway of tocopherol catabolism novel mechanism of regulation of vitamin E status. J Biol Chem 277(28):25290–25296. https://doi.org/10.1074/jbc.M201466200

    Article  CAS  PubMed  Google Scholar 

  22. Wypasek E, Branicka A, Awsiuk M, Sadowski J, Undas A (2014) Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms. Thromb Res 134(3):604–609. https://doi.org/10.1016/j.thromres.2014.06.022

    Article  CAS  PubMed  Google Scholar 

  23. McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE (2009) CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol 75(6):1337–1346. https://doi.org/10.1124/mol.109.054833. https://doi.org/10.1124/mol.109.054833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rathore SS, Agarwal SK, Pande S, Singh SK, Mittal T, Mittal B (2014) CYP4F2 1347 G> A & GGCX 12970 C> G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant. Indian J Med Res 139(4):572

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Borgiani P, Ciccacci C, Forte V, Sirianni E, Novelli L, Bramanti P, Novelli G (2009) CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. https://doi.org/10.2217/14622416.10.2.261

  26. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, Hubbard J, Turpaz Y, Langaee TY, Eby C, King CR, Brower A, Schmelzer JR, Glurich I, Vidaillet HJ, Yale SH, Qi Zhang K, Berg RL, Burmester JK (2008) CYP4F2 genetic variant alters required warfarin dose. Blood 111:4106–4112. https://doi.org/10.1182/blood-2007-11-122010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wallin R, Hutson SM, Cain D, Sweatt A, Sane DC (2001) A molecular mechanism for genetic warfarin resistance in the rat. FASEB J 15(13):2542–2544. https://doi.org/10.1096/fj.01-0337fje

    Article  CAS  PubMed  Google Scholar 

  28. Wajih N, Sane DC, Hutson SM, Wallin R (2004) The inhibitory effect of calumenin on the vitamin K-dependent γ-carboxylation system characterization of the system in normal and warfarin-resistant rats. J Biol Chem 279(24):25276–25283. https://doi.org/10.1074/jbc.M401645200

    Article  CAS  PubMed  Google Scholar 

  29. Wajih N, Hutson SM, Wallin R (2006) siRNA silencing of calumenin enhances functional factor IX production. Blood 108(12):3757–3760. https://doi.org/10.1182/blood-2006-02-004671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cadamuro J, Dieplinger B, Felder T, Kedenko I, Mueller T, Haltmayer M, Patsch W, Oberkofler H (2010) Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. Eur J Clin Pharmacol 66(3):253–260. https://doi.org/10.1007/s00228-009-0768-7

    Article  CAS  PubMed  Google Scholar 

  31. Vecsler M, Loebstein R, Almog S, Kurnik D, Goldman B, Halkin H, Gak E (2006) Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost 95(2):205–211. https://doi.org/10.1160/TH05-06-0446

    CAS  PubMed  Google Scholar 

  32. Tzveova R, Dimitrova-Karamfilova A, Saraeva R, Solarova T, Naydenova G, Petrova I, Hristova N, Popov I, Nachev G, Mitev V (2015) Estimation and validation of acenocoumarol dosing algorithms in Bulgarian patients with cardiovascular diseases. Pers Med 12(3):209–220. https://doi.org/10.2217/pme.14.80

    Article  CAS  Google Scholar 

  33. Bourel M, Ardaillou R (2006) Pharmacogenetics and pharmacogenomics. Bull Acad Natl Méd 190(1):9–22 discussion 22-23

    CAS  PubMed  Google Scholar 

  34. Vacheron A (2004) Recommandations concernant les traitements anticoagulants par les antivitamines K. Bulletin de l'Academie Nationale de Med 188(5):867–868

    Google Scholar 

  35. Tremey B (2009) Épidémiologie des accidents hémorragiques survenant chez les patients sous antivitamine K. J Eur Urgences 22:S1–S4. https://doi.org/10.1016/S0993-9857(09)72453-7

    Article  Google Scholar 

  36. Blaise S, Satger B, Fontaine M, Yver J, Rastel D, Toffin L, Seinturier C, Ramos M, Bosson J-L, Pernod G (2009) Évaluation d’un programme d’éducation thérapeutique pour les traitements anticoagulants oraux: expérience du réseau Ville-Hôpital GRANTED du secteur Sud-Isère. J Mal Vasc 34(5):346–353. https://doi.org/10.1016/j.jmv.2009.07.088

    Article  CAS  PubMed  Google Scholar 

  37. Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM (2014) Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics 15(16):1973–1983. https://doi.org/10.2217/pgs.14.153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Metcalfe C (2001) Biostatistics: a foundation for analysis in the health sciences. 7th edn. Wayne W. Daniel, Wiley, 1999. No. of. Pages: xiv+ 755+ appendices. Price:£ 28.95. ISBN 0-471-16386-4. Stat Med 20 (2):324–326. https://doi.org/10.1002/1097-0258(20010130)20:2<324::AID-SIM635>3.0.CO;2-O

  39. Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215. https://doi.org/10.1093/nar/16.3.1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Provenzani A, Notarbartolo M, Labbozzetta M, Poma P, Biondi F, Sanguedolce R, Vizzini G, Palazzo U, Polidori P, Triolo F (2009) The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients. Ann Transplant 14(1):23–23

    CAS  PubMed  Google Scholar 

  41. Moridani M, Fu L, Selby R, Yun F, Sukovic T, Wong B, Cole DE (2006) Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort. Clin Biochem 39(6):606–612. https://doi.org/10.1016/j.clinbiochem.2006.01.023

    Article  CAS  PubMed  Google Scholar 

  42. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106(7):2329–2333. https://doi.org/10.1182/blood-2005-03-1108

    Article  CAS  PubMed  Google Scholar 

  43. Scott SA, Edelmann L, Kornreich R, Desnick RJ (2008) Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations. Am J Hum Genet 82(2):495–500. https://doi.org/10.1016/j.ajhg.2007.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bejarano-Achache I, Levy L, Mlynarsky L, Bialer M, Muszkat M, Caraco Y (2012) Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study. Clin Ther 34(4):811–823. https://doi.org/10.1016/j.clinthera.2012.02.009

    Article  CAS  PubMed  Google Scholar 

  45. Gonzalez-Conejero R, Corral J, Roldan V, Ferrer F, Sanchez-Serrano I, Sanchez-Blanco JJ, Marin F, Vicente V (2007) The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol. J Thromb Haemost 5(8):1701–1706. https://doi.org/10.1111/j.1538-7836.2007.02630.x

    Article  CAS  PubMed  Google Scholar 

  46. Shinnick MA, Woo MA (2015) Learning style impact on knowledge gains in human patient simulation. Nurse Educ Today 35(1):63–67. https://doi.org/10.1016/j.nedt.2014.05.013

    Article  PubMed  Google Scholar 

  47. Yoo J, Lee Y, Kim Y, Rha SY, Kim Y (2008) SNPAnalyzer 2.0: a web-based integrated workbench for linkage disequilibrium analysis and association analysis. BMC Bioinf 9(1):290. https://doi.org/10.1186/1471-2105-9-290

    Article  Google Scholar 

  48. Militaru F, Vesa S, Pop T, Buzoianu A (2015) Pharmacogenetics aspects of oral anticoagulants therapy. J Med Life 8(2):171–175

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Teichert M, Eijgelsheim M, Rivadeneira F, Uitterlinden AG, van Schaik RH, Hofman A, De Smet PA, van Gelder T, Visser LE, Stricker BH (2009) A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 18(19):3758–3768. https://doi.org/10.1093/hmg/ddp309

    Article  CAS  PubMed  Google Scholar 

  50. Lafuente-Lafuente C, Baudry É, Paillaud E, Piette F (2013) Pharmacologie clinique et vieillissement. Presse Med 42(2):171–180. https://doi.org/10.1016/j.lpm.2012.06.023

    Article  PubMed  Google Scholar 

  51. Pautas E, Moreau C, Deverlie C, Golmard J, Lebourgeois F, Le Gal G, Peyron I, Gouin-Thibault I, Loriot M, Siguret V (2011) Facteurs cliniques, thérapeutiques et pharmacogénétiques influençant la dose d’équilibre d’un traitement AVK par fluindione. Rev Méd Interne 32:S59. https://doi.org/10.1016/j.revmed.2011.03.048

    Google Scholar 

  52. Puisieux F (2012) Gériatrie. Lavoisier,

    Google Scholar 

  53. Membrey B, Miranda S, Armengol G, Cailleux N, Levesque H, Benhamou Y (2013) Facteurs prédictifs d’un retard d’équilibration à l’instauration d’un traitement par antivitamine K: étude d’une cohorte de 98 patients. Rev Med Interne 34(34):A120. https://doi.org/10.1016/j.revmed.2013.10.207

    Article  Google Scholar 

  54. Smires FZ, Habbal R, Moreau C, Assaidi A, Loriot MA, Nadifi S (2013) Effect of different genetics variants: CYP2C9*2, CYP2C9*3 of cytochrome P-450 CYP2C9 and 1639G>A of the VKORC1 gene; On acenocoumarol requirement in Moroccan patients. Pathol Biol 61(3):88–92. https://doi.org/10.1016/j.patbio.2012.10.002

    Article  CAS  PubMed  Google Scholar 

  55. Kaur A, Khan F, Agrawal SS, Kapoor A, Agarwal SK, Phadke SR (2013) Cytochrome P450 (CYP2C9* 2,* 3) & vitamin-K epoxide reductase complex (VKORC1-1639G< A) gene polymorphisms & their effect on acenocoumarol dose in patients with mechanical heart valve replacement. Indian J Med Res 137(1):203–209

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet™ systematic review and meta-analysis. Genet Med 7(2):97–104. https://doi.org/10.1097/01.GIM.0000153664.65759.CF

    Article  CAS  PubMed  Google Scholar 

  57. Palareti G, Legnani C, Guazzaloca G, Lelia V, Cosmi B, Lunghi B, Marchetti G, Poli D, Pengo V (2005) Risks factors for highly unstable response to oral anticoagulation: a case-control study. Br J Haematol 129(1):72–78. https://doi.org/10.1111/j.1365-2141.2005.05417.x

    Article  CAS  PubMed  Google Scholar 

  58. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52(4):447–450. https://doi.org/10.1046/j.0306-5251.2001.01460.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wu AH, Wang P, Smith A, Haller C, Drake K, Linder M, Valdes R (2008) Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics 9(2):169–178. https://doi.org/10.2217/14622416.9.2.169

    Article  CAS  PubMed  Google Scholar 

  60. Lee KE, Chang BC, Kim HO, Yoon IK, Lee NR, Park HY, Gwak HS (2012) Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves. Ther Drug Monit 34(3):275–282. https://doi.org/10.1097/FTD.0b013e318256a77c

    Article  CAS  PubMed  Google Scholar 

  61. Cen HJ, Zeng WT, Leng XY, Huang M, Chen X, Li JL, Huang ZY, Bi HC, Wang XD, He YL (2010) CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. Br J Clin Pharmacol 70(2):234–240. https://doi.org/10.1111/j.1365-2125.2010.03698.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Markatos CN, Grouzi E, Politou M, Gialeraki A, Merkouri E, Panagou I, Spiliotopoulou I, Travlou A (2008) VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients. Pharmacogenomics 9(11):1631–1638. https://doi.org/10.2217/14622416.9.11.1631

    Article  CAS  PubMed  Google Scholar 

  63. Van Schie RM, Wadelius M, Kamali F, Daly AK, Manolopoulos VG, De Boer A, Barallon R, Verhoef TI, Kirchheiner J, Haschke-Becher E (2009) Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics 10(10):1687–1695. https://doi.org/10.2217/pgs.09.125

    Article  PubMed  Google Scholar 

  64. van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, Verhoef TI, van Meegen E, Rosendaal FR, Maitland-van der Zee A-H (2011) Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 32(15):1909–1917. https://doi.org/10.1093/eurheartj/ehr116

    Article  PubMed  Google Scholar 

  65. van Schie RM, Verhoef TI, de Boer A, van der Meer FJ, Redekop WK, Schalekamp T, Maitland-van der Zee A-H (2015) Pharmacogenetics of coumarin anticoagulant therapy. In: Preventive and predictive genetics: towards personalised medicine. Springer, pp 307–328. https://doi.org/10.1007/978-3-319-15344-5_11

  66. Borobia AM, Lubomirov R, Ramírez E, Lorenzo A, Campos A (2012) An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in Spanish patients with thromboembolic disease. PLoS One 7(7):e41360. https://doi.org/10.1371/journal.pone.0041360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pengo V, Zambon C-F, Fogar P, Padoan A, Nante G, Pelloso M, Moz S, Frigo AC, Groppa F, Bozzato D (2015) A randomized trial of pharmacogenetic warfarin dosing in naïve patients with non-valvular atrial fibrillation. PLoS One 10(12):e0145318. https://doi.org/10.1371/journal.pone.0145318

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are especially grateful to the study participants. They acknowledge the general director of the Sahloul University Hospital and the excellent technical assistance of members of the Biochemistry Department, the Internal Medicine Department and the Cardilogy Department of the Sahloul University Hospital.

Funding

This study was supported by grants from the Tunisian Ministry of Higher Education, Scientific Research and Technology, and the Ministry of Health [LR12SP11]. Without their extremely generous and strong support, this project would not have happened.

Author information

Authors and Affiliations

  1. LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia

    Marwa Ajmi, Asma Omezzine, Slim Achour, Dorra Amor, Haithem Hamdouni, Nabila Ben Rejeb & Ali Bouslama

  2. Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia

    Marwa Ajmi

  3. Faculty of Pharmacy, University of Monastir, Monastir, Tunisia

    Asma Omezzine, Haithem Hamdouni, Nabila Ben Rejeb & Ali Bouslama

  4. Internal Medicine Department, Sahloul University Hospital, Sousse, Tunisia

    Fatma Ben Fredj Ismaïl & Chedia Laouani Kechrid

  5. Cardiology Department, Sahloul University Hospital, Sousse, Tunisia

    Essia Boughzela

Authors
  1. Marwa Ajmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asma Omezzine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Slim Achour
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dorra Amor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haithem Hamdouni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fatma Ben Fredj Ismaïl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nabila Ben Rejeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chedia Laouani Kechrid
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Essia Boughzela
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ali Bouslama
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Asma Omezzine and Ali Bouslama designed the concept. Marwa Ajmi, Slim Achour, Fatma Ben Fredj Ismaïl, Chedia Laouani Kechrid, and Essia Boughzela acquired the data. Marwa Ajmi, Dorra Amor and Nabila Ben Rejeb performed the analysis of the data. Asma Omezzine executed the interpretation of the data. Marwa Ajmi drafted the manuscript. Asma Omezzine, Fatma Ben Fredj Ismaïl, and Chedia Laouani Kechrid provided a critical revision of the manuscript for important intellectual content. Asma Omezzine, Marwa Ajmi, Slim Achour, and Haithem Hamdouni performed the statistical analysis. Asma Omezzine and Ali Bouslama provided the study supervision.

Corresponding author

Correspondence to Marwa Ajmi.

Ethics declarations

Ethical approval

This study was approved by the local ethic committee of the Sahloul University Hospital, Sousse, Tunisia.

Informed consent

An informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ajmi, M., Omezzine, A., Achour, S. et al. Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population. Eur J Clin Pharmacol 74, 711–722 (2018). https://doi.org/10.1007/s00228-018-2423-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-018-2423-7

Keywords

Search

Navigation