{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:04:12Z","timestamp":1782187452016,"version":"3.54.5"},"reference-count":117,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T00:00:00Z","timestamp":1571616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and\/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.<\/jats:p>","DOI":"10.3390\/jcm8101747","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T11:37:55Z","timestamp":1571657875000},"page":"1747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Oral Anticoagulant Therapy\u2014When Art Meets Science"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-1642","authenticated-orcid":false,"given":"Patricia Lorena","family":"C\u00eempan","sequence":"first","affiliation":[{"name":"Department of Cardiology, Heart Institute, 40001 Cluj Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-5938","authenticated-orcid":false,"given":"Romeo Ioan","family":"Chira","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Emergency Clinical County Hospital, 40006 Cluj Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5906-8024","authenticated-orcid":false,"given":"Mihaela","family":"Mocan","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Emergency Clinical County Hospital, 40006 Cluj Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin Petru","family":"Anton","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Emergency Clinical County Hospital, 40006 Cluj Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca Daniela","family":"Farca\u015f","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Emergency Clinical County Hospital, 40006 Cluj Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.2165\/00003088-200847090-00002","article-title":"Pharmacogenetics of oral anticoagulants: A basis for dose individualization","volume":"47","author":"Stehle","year":"2008","journal-title":"Clin. Pharmacokinet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1136\/hrt.2004.042465","article-title":"Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: A record linkage study in a large British population","volume":"91","author":"Jones","year":"2005","journal-title":"Heart"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.2217\/14622416.9.11.1631","article-title":"VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients","volume":"9","author":"Markatos","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_4","first-page":"1","article-title":"The 2018 European Heart Rhythm Association Practical Guide on the use ofnon-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation","volume":"60","author":"Steffel","year":"2018","journal-title":"Eur. Heart. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1016\/j.jacc.2016.08.010","article-title":"Transcatheter aortic valve thrombosis: Incidence, predisposing factors, and clinical implications","volume":"68","author":"Hansson","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1016\/j.jacc.2016.09.958","article-title":"Prosthetic heart valve thrombosis","volume":"68","author":"Dangas","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"335","DOI":"10.14740\/cr789","article-title":"Bioprosthetic valve thrombosis","volume":"9","author":"Sachdev","year":"2018","journal-title":"Cardio. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1055\/s-0037-1607457","article-title":"Antithrombotic treatment after transcatheter heart valves implant","volume":"44","author":"Sorrentino","year":"2018","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1093\/eurheartj\/ehx391","article-title":"2017 ESC\/EACTS guidelines for the management of valvular heart disease. The task force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European","volume":"38","author":"Baumgartner","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1111\/jth.14017","article-title":"Use of direct oral anticoagulants in antiphospholipid syndrome","volume":"16","author":"Cohen","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1056\/NEJMra1705454","article-title":"Diagnosis and management of the antiphospholipid syndrome","volume":"378","author":"Garcia","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1093\/rheumatology\/kev445","article-title":"Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome","volume":"55","author":"Sciascia","year":"2016","journal-title":"Rheumatology (Oxford)"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Erkan, D., and Lockshin, M.D. (2017). Antiphospholipid Syndrome: Current Research Highlights and Clinical Insights, Springer.","DOI":"10.1007\/978-3-319-55442-6"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1111\/jth.14398","article-title":"Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta-analysis","volume":"17","author":"Elsebaie","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2019044","DOI":"10.4084\/mjhid.2019.044","article-title":"Direct oral anticoagulants in patients affected by major congenital thrombophilia","volume":"11","author":"Serrao","year":"2019","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.joa.2015.04.004","article-title":"Persistence of non-vitamin K antagonist oral anticoagulant use in Japanese patients with atrial fibrillation: A single-center observational study","volume":"31","author":"Shiga","year":"2015","journal-title":"J. Arrhythm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1365-2125.2006.02806.x","article-title":"Warfarin: Almost 60 years old and still causing problems","volume":"62","author":"Pirmohamed","year":"2006","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/toxsci\/66.1.4","article-title":"The missing link: The story of Karl Paul Link","volume":"66","author":"Last","year":"2002","journal-title":"Toxicol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2174\/1570163811209020083","article-title":"Discovery of anticoagulant drugs: A historical perspective","volume":"9","author":"Lecumberri","year":"2012","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1111\/j.1365-2141.2008.07119.x","article-title":"The story of the discovery of heparin and warfarin","volume":"141","author":"Wardrop","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2174\/138161210790112737","article-title":"Pharmacogenetics of oral anticoagulant therapy","volume":"16","author":"Schalekamp","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0163-7258(96)00140-4","article-title":"Human P450 metabolism of warfarin","volume":"73","author":"Kaminsky","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"587","DOI":"10.2165\/00003088-200140080-00003","article-title":"Pharmacogenetics of warfarin elimination and its clinical implications","volume":"40","author":"Takahashi","year":"2001","journal-title":"Clin. Pharmacokinet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2165\/00003088-200544120-00003","article-title":"Comparative pharmacokinetics of vitamin K antagonists","volume":"44","author":"Ufer","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/bcp.12220","article-title":"Pharmacogenetic-guided dosing of coumarin anticoagulants: Algorithms for warfarin, acenocoumarol and phenprocoumon","volume":"77","author":"Verhoef","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2217\/fca-2017-0025","article-title":"VKORC1-1639A allele influences warfarin maintenance dosage among Blacks receiving warfarin anticoagulation: A retrospective cohort study","volume":"14","author":"Mili","year":"2018","journal-title":"Future Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.clpt.2006.04.006","article-title":"VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: Interaction between both genotypes affects overanticoagulation","volume":"80","author":"Schalekamp","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"421","DOI":"10.2147\/TCRM.S130198","article-title":"Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population","volume":"13","author":"Jia","year":"2017","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1097\/00008571-200305000-00002","article-title":"Pharmacogenetics of oral anticoagulants","volume":"13","author":"Daly","year":"2003","journal-title":"Pharmacogenetics"},{"key":"ref_30","first-page":"498","article-title":"AICE Working Group. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management","volume":"13","author":"Franchini","year":"2015","journal-title":"Blood Transfus."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s40800-016-0031-y","article-title":"Anticoagulation therapy considerations in factor VII deficiency","volume":"3","author":"Paulus","year":"2016","journal-title":"Drug Saf. Case Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1177\/1358863X17704713","article-title":"Warfarin management in the setting of FVII deficiency and mechanical circulatory support","volume":"22","author":"DeStefano","year":"2017","journal-title":"Vasc. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"490","DOI":"10.5858\/2009-0474-OA.1","article-title":"International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy","volume":"135","author":"Gulati","year":"2011","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1021\/tx00025a009","article-title":"Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: A role for P-4502C9 in the etiology of (S)-warfarin-drug interactions","volume":"5","author":"Rettie","year":"1992","journal-title":"Chem. Res. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nature02254","article-title":"Identification of the gene for vitamin K epoxide reductase","volume":"427","author":"Li","year":"2004","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature02214","article-title":"Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2","volume":"427","author":"Rost","year":"2004","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Scharrer, I., and Schramm, W. (2006). A novel mutation (Asp36Tyr) in the Vitamin K Epoxide Reductase Complex Subunit 1 Gene (VKORC1) causes increased phenprocoumon requirement. 35th Hemophilia Symposium, Springer. Hamburg, 2004.","DOI":"10.1007\/3-540-28546-6"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"724","DOI":"10.3949\/ccjm.76a.09062","article-title":"An algorithm for managing warfarin resistance","volume":"76","author":"Osinbowale","year":"2009","journal-title":"Cleve. Clin. J. Med."},{"key":"ref_39","unstructured":"Jim\u00e9nez-Var, E., Ca\u00f1adas-Garre, M., Aguilera, M., Callejas, D.G., Ramirez, C.P., and Hern\u00e1ndez, M.A.C. (2013). Omics for Personalized Medicine, Springer."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/00008571-200204000-00010","article-title":"Cytochrome P450 2C9 polymorphisms: A comprehensive review of the in-vitro and human data","volume":"12","author":"Lee","year":"2002","journal-title":"Pharmacogenetics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/01.GIM.0000153664.65759.CF","article-title":"CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet systematic review and meta-analysis","volume":"7","author":"Sanderson","year":"2005","journal-title":"Genet. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1111\/j.1582-4934.2012.01606.x","article-title":"Analysis of CYP2C9*2, CYP2C9*3 and VKORC1-1639 G>A polymorphisms in a population from South-Eastern Europe","volume":"16","author":"Buzoianu","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1067\/mcp.2002.129321","article-title":"Influence of CYP2C9 and CYP2C19 please genetic polymorphisms on warfarin maintenance dose and metabolic clearance","volume":"72","author":"Scordo","year":"2002","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1097\/00008571-199810000-00001","article-title":"Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: Catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes","volume":"8","author":"Takahashi","year":"1998","journal-title":"Pharmacogenetics"},{"key":"ref_45","first-page":"399","article-title":"Integrating genomic based information into clinical Warfarin (Coumadin\u00ae) management: An illustrative case report","volume":"72","author":"LaSala","year":"2008","journal-title":"Conn. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1007\/s00228-013-1551-3","article-title":"An acenocoumarol dose algorithm based on a south-eastern European population","volume":"69","author":"Pop","year":"2013","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.2217\/pgs.12.101","article-title":"Validation of the acenocoumarol EU-PACT algorithms: Similar performance in the Rotterdam Study cohort as in the original study","volume":"13","author":"Verhoef","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.clpt.2004.01.008","article-title":"Pharmacogenetics of acenocoumarol pharmacodynamics","volume":"75","author":"Morin","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Borobia, A.M., Lubomirov, R., Ram\u00edrez, E., Lorenzo, A., Campos, A., Mu\u00f1oz-Romo, R., Fern\u00e1ndez-Capit\u00e1n, C., Fr\u00edas, J., and Carcas, A.J. (2012). An Acenocoumarol dosing algorithm using clinical and pharmacogenetic data in Spanish patients with thromboembolic disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041360"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.0902-4441.2006.t01-1-EJH2957.x","article-title":"Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: The need for a more tailored dosing regimen","volume":"77","author":"Sconce","year":"2006","journal-title":"Eur. J. Haematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/clpt.2011.185","article-title":"Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing","volume":"90","author":"Johnson","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/S0140-6736(98)04474-2","article-title":"Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications","volume":"353","author":"Aithal","year":"1999","journal-title":"Lancet"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.clpt.2003.09.015","article-title":"CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy","volume":"75","author":"Peyvandi","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.clpt.2003.12.017","article-title":"Acenocoumarol stabilization is delayed in CYP2C9*3 carriers","volume":"75","author":"Schalekamp","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/00008571-200401000-00003","article-title":"The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon","volume":"14","author":"Visser","year":"2004","journal-title":"Pharmacogenetics"},{"key":"ref_56","first-page":"1185","article-title":"Pharmacogenetics of Acenocoumarol: Cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation","volume":"87","author":"Freire","year":"2002","journal-title":"Haematologica"},{"key":"ref_57","first-page":"397","article-title":"Cytochrome P450 2C9 polymorphism and acenocoumarol therapy","volume":"64","author":"Mark","year":"2006","journal-title":"Kardiol. Pol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1182\/blood.V99.11.4237","article-title":"Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol","volume":"99","author":"Hermida","year":"2002","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1097\/00008571-200011000-00010","article-title":"The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol","volume":"10","author":"Thijssen","year":"2000","journal-title":"Pharmacogenetics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2217\/pgs-2018-0189","article-title":"Extremely low therapeutic doses of acenocoumarol in a patient with CYP2C9*3\/*3 and VKORC1-1639A\/A genotype","volume":"20","author":"Chaidaroglou","year":"2019","journal-title":"Pharmacogenomics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2217\/fca.12.31","article-title":"The future of warfarin pharmacogenetics in under-represented minority groups","volume":"8","author":"Cavallari","year":"2012","journal-title":"Future Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1056\/NEJMoa044503","article-title":"Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose","volume":"352","author":"Rieder","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1182\/blood-2004-06-2111","article-title":"A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin","volume":"105","author":"Chetta","year":"2005","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.clinbiochem.2012.01.002","article-title":"Evaluation of the warfarin-resistance polymorphism, VKORC1 Asp36Tyr, and its effect on dosage algorithms in a genetically heterogeneous anticoagulant clinic","volume":"45","author":"Shuen","year":"2012","journal-title":"Clin. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1160\/TH05-04-0290","article-title":"VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation","volume":"94","author":"Geisen","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1160\/TH07-07-0454","article-title":"Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORC1 and CYP2C9 alleles","volume":"98","author":"Oldenburg","year":"2007","journal-title":"Thromb. Haemost."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1182\/blood-2008-01-134247","article-title":"A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose","volume":"112","author":"Cooper","year":"2008","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Takeuchi, F., McGinnis, R., Bourgeois, S., Barnes, C., Eriksson, N., Soranzo, N., Whittaker, P., Ranganath, V., Kumanduri, V., and McLaren, W. (2009). A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000433"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.1182\/blood-2009-12-255992","article-title":"Warfarin pharmacogenetics: A single VKORC1 polymorphism is predictive of dose across 3 racial groups","volume":"115","author":"Limdi","year":"2010","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/sj.clpt.6100290","article-title":"Influence of CYP2C9 and VKORC1 1173C\/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on Warfarin","volume":"83","author":"Limdi","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1093\/eurheartj\/ehr116","article-title":"Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data","volume":"32","author":"Wessels","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1182\/blood-2008-04-149070","article-title":"The largest prospective warfarin-treated cohort supports genetic forecasting","volume":"113","author":"Wadelius","year":"2009","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2217\/pgs-2016-0126","article-title":"A novel acenocoumarol pharmacogenomic dosing algorithm for the Greek population of EU-PACT trial","volume":"18","author":"Ragia","year":"2017","journal-title":"Pharmacogenomics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1161\/CIRCULATIONAHA.107.737312","article-title":"Randomized trial of genotype-guied versus standard warfarin dosing in patients initiating oral anticoagulation","volume":"116","author":"Anderson","year":"2007","journal-title":"Circulation"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1160\/TH11-06-0388","article-title":"Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy","volume":"107","author":"Horne","year":"2012","journal-title":"Thromb. Haemost."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3349\/ymj.2016.57.3.635","article-title":"Development and comparison of Warfarin dosing algorithms in stroke patients","volume":"57","author":"Cho","year":"2016","journal-title":"Yonsei Med. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1160\/TH11-12-0848","article-title":"A new algorithm to predict warfarin dose from polymorphisms of CYP4F2, CYP2C9 and VKORC1 and clinical variables: Derivation in Han Chinese patients with non valvular atrial fibrillation","volume":"107","author":"Wei","year":"2012","journal-title":"Thromb. Haemost."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.clinthera.2011.09.004","article-title":"Development and comparison of a Warfarin-dosing algorithm for Korean patients with atrial fibrillation","volume":"33","author":"Cho","year":"2011","journal-title":"Clin. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Bernaitis, N., Clark, G., Kohja, S., Leong, S., and Anoopkumar-Dukie, S. (2019). The SAMe-TT2R2 score predicts Warfarin control in an Australian population with atrial fibrillation. J. Clin. Med., 8.","DOI":"10.3390\/jcm8060882"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1371\/journal.pone.0037844","article-title":"Therapeutic dosing of Acenocoumarol: Proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians","volume":"7","author":"Rathore","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_81","first-page":"135","article-title":"Genotypes as determinants of Acenocoumarol sensitivity","volume":"106","author":"Bodin","year":"2005","journal-title":"Pharmacogenetics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1309\/AJCPAO82OTNPUBLW","article-title":"Education Committee of the Academy of Clinical Laboratory Physicians and Scientists. Pathology consultation on Warfarin pharmacogenetic testing","volume":"135","author":"Stack","year":"2011","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.2217\/pgs.14.153","article-title":"Genotype and risk of major bleeding during warfarin treatment","volume":"15","author":"Kawai","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/clpt.2010.13","article-title":"Integration of genetic, clinical, and INR data to refine Warfarin dosing","volume":"87","author":"Lenzini","year":"2010","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1161\/CIRCULATIONAHA.111.070920","article-title":"A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II)","volume":"125","author":"Anderson","year":"2012","journal-title":"Circulation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1056\/NEJMoa1310669","article-title":"A pharmacogenetic versus a clinical algorithm for warfarin dosing","volume":"36","author":"Kimmel","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1093\/eurheartj\/ehu283","article-title":"2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism: The task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) endorsed by the European Respiratory Society (ERS)","volume":"35","author":"Konstantinides","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.amjcard.2017.12.023","article-title":"Meta-analysis of genotype-guided versus standard dosing of vitamin K antagonists","volume":"121","author":"Kheiri","year":"2018","journal-title":"Am. J. Cardiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"429","DOI":"10.2217\/pgs.11.184","article-title":"Prediction of warfarin dose: Why, when and how?","volume":"13","author":"Eriksson","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Reitsma, P.H., van der Heijden, J.F., Groot, A.P., Rosendaal, F.R., and B\u00fcller, H.R. (2005). A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med., 2.","DOI":"10.1371\/journal.pmed.0020312"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1056\/NEJMoa0708078","article-title":"Genetic determinants of response to warfarin during initial anticoagulation","volume":"358","author":"Schwarz","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1538-7836.2009.03677.x","article-title":"Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy","volume":"8","author":"Ferder","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1160\/TH07-09-0552","article-title":"An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients","volume":"100","author":"Meckley","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1007\/s00228-009-0710-z","article-title":"Therapeutic efficacy of acenocoumarol in a warfarin-resistant patient with deep venous thrombosis: A case report","volume":"65","author":"Marusic","year":"2009","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1182\/blood-2006-08-038984","article-title":"A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance","volume":"109","author":"Loebstein","year":"2007","journal-title":"Blood"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ajhg.2007.10.002","article-title":"Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations","volume":"82","author":"Scott","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0064469","article-title":"Novel associations of VKORC1 variants with higher acenocoumarol requirements","volume":"8","author":"Anton","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_98","unstructured":"Pratt, V., McLeod, H., Rubinstein, W., Dean, L., Kattman, B., and Malheiro, A. (2012). Warfarin therapy and VKORC1 and CYP genotype. Medical Genetics Summaries, National Center for Biotechnology Information (US)."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/clpt.2008.10","article-title":"Use of pharmacogenetic and clinical factors to predict the therapeutic dose of Warfarin","volume":"84","author":"Gage","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0140-6736(13)62343-0","article-title":"Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials","volume":"383","author":"Ruff","year":"2014","journal-title":"Lancet"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1161\/STROKEAHA.117.017549","article-title":"Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation","volume":"48","author":"Ntaios","year":"2017","journal-title":"Stroke"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1160\/TH17-10-0733","article-title":"Effectiveness and safety of non\u2013vitamin K oral anticoagulants in comparison to Phenprocoumon: Data from 61,000 patients with atrial fibrillation","volume":"118","author":"Hohnloser","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Joppa, S., Salciccioli, J., Adamski, J., Patel, S., Wysokinski, W., McBane, R., Al-Saffar, F., Esser, H., and Shamoun, F. (2018). A practical review of the emerging direct anticoagulants, laboratory monitoring, and reversal agents. J. Clin. Med., 7.","DOI":"10.3390\/jcm7020029"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/MOH.0b013e328363c170","article-title":"Treatment with novel oral anticoagulants","volume":"20","author":"Ghanny","year":"2013","journal-title":"Curr. Opin. Hematol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1161\/CIRCULATIONAHA.112.001233","article-title":"Genetic determinants of Dabigatran plasma levels and their relation to bleeding","volume":"127","author":"Eriksson","year":"2013","journal-title":"Circulation"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1515\/dmdi-2014-0009","article-title":"The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect","volume":"29","author":"Merali","year":"2014","journal-title":"Drug Metabol. Drug Interact."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1055\/s-0035-1546465","article-title":"Which patients may benefit from dose adjustment of non-vitamin K antagonist oral anticoagulants?","volume":"41","author":"Chin","year":"2015","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/jth.13577","article-title":"Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin","volume":"15","author":"Delavenne","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/j.jacc.2013.02.058","article-title":"The P-glycoprotein transport system and cardiovascular drugs","volume":"61","author":"Wessler","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.thromres.2016.05.025","article-title":"Pharmacogenetics of dabigatran etexilate interindividual variability","volume":"144","author":"Dimatteo","year":"2016","journal-title":"Thromb. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40262-013-0100-7","article-title":"Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban","volume":"53","author":"Mueck","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3810\/pgm.2014.01.2725","article-title":"Cardioembolic stroke: Practical considerations for patient risk management and secondary prevention","volume":"126","author":"Amin","year":"2014","journal-title":"Postgrad. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1124\/jpet.111.180240","article-title":"In vitro and in vivo P-Glycoprotein transport characteristics of rivaroxaban","volume":"338","author":"Gnoth","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s00059-014-4188-9","article-title":"Relevanz von P-Glykoprotein in der schlaganfallpr\u00e4vention mit Dabigatran, rivaroxaban und Apixaban","volume":"40","author":"Finsterer","year":"2015","journal-title":"Herz"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.cjca.2013.04.002","article-title":"Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban","volume":"29","author":"Gong","year":"2013","journal-title":"Can. J. Cardiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/imj.12448","article-title":"New oral anticoagulants: A practical guide on prescription, laboratory testing and peri-procedural\/bleeding management","volume":"44","author":"Tran","year":"2014","journal-title":"Intern. Med. J."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1124\/dmd.112.050260","article-title":"Characterization of efflux transporters involved in distribution and disposition of Apixaban","volume":"41","author":"Zhang","year":"2013","journal-title":"Drug Metab. Dispos."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:28:08Z","timestamp":1760189288000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,21]]},"references-count":117,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["jcm8101747"],"URL":"https:\/\/doi.org\/10.3390\/jcm8101747","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,21]]}}}