Lippi Giuseppe, Franchini Massimo, Favaloro Emmanuel J
Sezione di Chimica Clinica, Dipartimento di Scienze Biomediche e Morfologiche, Università di Verona, and Ospedale Policlinico G.B. Rossi, Verona, Italy.
Clin Chem Lab Med. 2009;47(5):503-15. doi: 10.1515/CCLM.2009.140.
Oral anticoagulant therapy (OAT) based on vitamin K antagonists (VKAs; coumarin derivatives) is the current mainstay for the prevention and long-term treatment of a variety of thromboembolic disorders. Care of patients on OAT is challenging due to considerable variability in the response to a particular dose. This has been attributed to environmental, demographic, clinical and genetic variables. Individualized responses represent a major clinical challenge because patients may experience adverse health outcomes from bleeding or thrombosis as a result of over- or under-coagulation, respectively. Growing evidence indicates that up to 60% of the individual pharmacological response to coumarins might be due to genetic variables and affected by polymorphisms in the genes encoding two enzymes, namely, vitamin K epoxide reductase (VKOR) and cytochrome P450 CYP2C9. Genetic testing has been proposed as a useful tool for allowing prediction of the dose response during initial anticoagulation therapy, to assess variability in dose maintenance and to identify warfarin 'resistance'. However, genetic testing is not a panacea. Limitations include the optimal composition of test panels, still largely unknown, information concerning inter-individual variability, lack of analytical and quality specifications, lack of comprehensive outcome analyses to enable assessment of cost-effectiveness, lack of universal agreement related to reliable dosing algorithms and other ethical and social issues. The aim of this article is to provide a comprehensive overview of our current understanding of the pharmacogenetics of VKAs, as well as assessing potential advantages and limitations. Although it might be premature to recommend routine genetic testing, the future development and clinical validation of simple but comprehensive algorithms integrating the most informative gene polymorphisms (VKORC1 and CYP2C9) with some demographic information (age, race, body mass index) and clinical variables (comorbidities, drugs interference), and standardized dietary intake of vitamin K may provide a valuable tool in the care of patients on OAT with conventional VKAs. However, the ongoing development of new anticoagulant drugs targeting thrombin and factor X will introduce a paradigm shift in long-term anticoagulation therapy, so that consideration could be given to demise pharmacogenetics testing for VKAs.
基于维生素K拮抗剂（VKA；香豆素衍生物）的口服抗凝治疗（OAT）是目前预防和长期治疗各种血栓栓塞性疾病的主要方法。由于对特定剂量的反应存在很大差异，对接受OAT治疗的患者进行护理具有挑战性。这归因于环境、人口统计学、临床和遗传变量。个体反应是一个主要的临床挑战，因为患者可能分别由于抗凝过度或不足而出现出血或血栓形成等不良健康后果。越来越多的证据表明，对香豆素的个体药理反应中高达60%可能归因于遗传变量，并受编码两种酶（即维生素K环氧化物还原酶（VKOR）和细胞色素P450 CYP2C9）的基因多态性影响。基因检测已被提议作为一种有用的工具，用于预测初始抗凝治疗期间的剂量反应、评估剂量维持的变异性以及识别华法林“抵抗”。然而，基因检测并非万灵药。其局限性包括检测组的最佳组成（仍很大程度上未知）、关于个体间变异性的信息、缺乏分析和质量规范、缺乏全面的结果分析以评估成本效益、缺乏与可靠给药算法相关的普遍共识以及其他伦理和社会问题。本文的目的是全面概述我们目前对VKA药物遗传学的理解，以及评估其潜在的优势和局限性。尽管现在推荐常规基因检测可能为时过早，但将最具信息性的基因多态性（VKORC1和CYP2C9）与一些人口统计学信息（年龄、种族、体重指数）和临床变量（合并症、药物相互作用）以及标准化的维生素K饮食摄入量相结合的简单但全面的算法的未来开发和临床验证，可能为接受传统VKA进行OAT治疗的患者护理提供有价值的工具。然而，针对凝血酶和因子X的新型抗凝药物的不断发展将给长期抗凝治疗带来范式转变，因此可以考虑放弃对VKA的药物遗传学检测。
