Oldenburg J, Watzka M, Rost S, Müller C R
Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
J Thromb Haemost. 2007 Jul;5 Suppl 1:1-6. doi: 10.1111/j.1538-7836.2007.02549.x.
The genetic diagnosis of a single family with combined vitamin K-dependent clotting factor deficiency (VKCFD2, OMIM #607473) finally led to the identification and molecular characterization of vitamin K epoxide reductase (VKORC1). VKORC1 is the key enzyme of the vitamin K cycle and the molecular target of coumarins, which represent the most commonly prescribed drugs for therapy and prevention of thromboembolic conditions. However, coumarins are known to have a narrow therapeutic window and a considerable risk of bleeding complications caused by a broad variation of intra- and inter-individual drug requirement. Now, 3 years after its identification, VKORC1 has greatly improved our understanding of the vitamin K cycle and has led to the translation of basic research into clinical practise in at least three directions: (i) Mutations within VKORC1 have been shown to cause a coumarin-resistant phenotype and a single SNP (rs9923231) within the VKORC1 promoter region has been identified as the major pharmacodynamic determinant of coumarin dose. Together with the previously described CYP2C9 variants and other dose-influencing factors, such as age, gender and weight, individualized dosing algorithms have become available. (ii) Preliminary studies indicate that concomitant application of low-dose vitamin K (80-100 microg day(-1)) and warfarin significantly improves INR stability and time of INR within the therapeutic range. (iii) Co-expression studies of FIX and FX with VKORC1 have shown that VKOR activity is the rate-limiting step in the synthesis of biologically active vitamin K-dependent factors. Thus, co-expression of VKORC1 leads to a more efficient production of recombinant vitamin K-dependent coagulation factors such as FIX and FVII. This could improve production of recombinant factor concentrates in the future.
对一个患有联合维生素K依赖凝血因子缺乏症（VKCFD2，OMIM编号#607473）的单一家系进行的基因诊断，最终促成了维生素K环氧化物还原酶（VKORC1）的鉴定及其分子特征分析。VKORC1是维生素K循环的关键酶，也是香豆素类药物的分子靶点，香豆素类药物是治疗和预防血栓栓塞性疾病最常用的处方药。然而，已知香豆素类药物的治疗窗较窄，且个体内和个体间药物需求差异很大，存在出血并发症的显著风险。如今，在VKORC1被鉴定出来3年后，它极大地增进了我们对维生素K循环的理解，并至少在三个方向上推动了基础研究向临床实践的转化：（i）已证明VKORC1内的突变会导致香豆素耐药表型，并且VKORC1启动子区域内的一个单核苷酸多态性（rs9923231）已被确定为香豆素剂量的主要药效学决定因素。连同先前描述的CYP2C9变体和其他剂量影响因素，如年龄、性别和体重，个体化给药算法已经可用。（ii）初步研究表明，低剂量维生素K（80 - 100微克/天）与华法林联合应用可显著提高国际标准化比值（INR）的稳定性以及INR在治疗范围内的时间。（iii）FIX和FX与VKORC1的共表达研究表明，VKOR活性是生物活性维生素K依赖因子合成中的限速步骤。因此，VKORC1的共表达可导致重组维生素K依赖凝血因子如FIX和FVII的生产效率更高。这可能会在未来改善重组因子浓缩物的生产。
