中国胸心血管外科临床杂志

中国胸心血管外科临床杂志

机械瓣膜置换术后稳定期华法林抗凝治疗质量评价及其基因学研究

查看全文

目的 评价机械瓣膜置换手术后稳定期患者的华法林抗凝治疗质量,观察复方丹参片对机械瓣膜置换术后患者华法林抗凝治疗效果的影响,了解 VKORC1、CYP2C9 及 CYP4F2 的基因多态性对机械瓣膜置换术患者术后稳定期华法林敏感及华法林抵抗的影响。 方法 2011 年 7 月至 2014 年 2 月在门诊随访时登记我们所施行的机械瓣膜置换手术后≥6 个月的患者 1 831 例,记录患者基本临床资料。抗凝治疗采用目标国际标准化比值(INR,1.60~2.20)及以每周为单位的华法林剂量调整策略。筛选 46 例需加用复方丹参片的患者,记录服用复方丹参片前后 INR 检测值并比较其差异。将本研究纳入患者按华法林服用剂量的百分位数进行分组,即华法林敏感患者、对照患者、华法林抵抗患者,筛选其中 101 例患者,采用 TIANGEN Blood DNA Kit 血液基因组 DNA 提取试剂盒提取样本,以聚合酶链限制性片段-长度多态性分析法(PCR-RELP)测定患者基因型。检测的基因位点为:CYP4F2:rs2108622C>T 位点;VKORC1:1639G>A 位点;VKORC1:1173C>T 位点;CYP2C9*2:rs1799853C>T 位点;CYP2C9*3:1061A>C 位点。 结果 (1)本研究观察期间内所纳入患者目标 INR 范围内的治疗范围时间(time in therapeutic range,TTR)和治疗范围时间分数(fraction of time in therapeutic range,FTTR)分别为 27.2%、49.4%,可接受 INR 范围内的 TTR 和 FTTR 分别为 34.25%、63.36%。(2)加用复方丹参片的患者在加用前及加用后,INR 检测值分别为 1.55±0.03、1.69±0.30,差异有统计学意义(P<0.05)。(3)基因检测患者共 101 例,其中 VKORC1:1173C>T 基因位点中 C/T 构成比在华法林敏感、对比及华法林抵抗患者中依次升高,而 CYP2C9*3:1061A>C 基因位点中 C/T 的等位基因位点构成比依次降低。CYP4F2 基因、VKORC1639 基因、CYP2C9*2 基因位点无差异。(4)IWPC 模型预测服用华法林剂量仅与华法林敏感患者实际服用华法林剂量吻合。 结论 机械瓣膜置换术后稳定期患者相对较低的 TTR 及 FTTR 是可以接受的。在合适的情况下,患者加用复方丹参片有益。VKORC1:1173C>T 位点及 CYP2C9*3:1061A>C 位点的突变是机械瓣膜置换术后稳定期华法林剂量敏感及华法林抵抗的主要药物基因学因素。IWPC 剂量预测模型仅与华法林敏感患者的实际服用剂量吻合。

Objective To evaluate the quality of warfarin anticoagulant therapy in patients with stable stage after mechanical valve replacement surgery, to observe the effect of compound salvia miltiorrhiza tablet on the anticoagulant effect of warfarin in patients after mechanical valve replacement, and to understand the impact of genetic polymorphisms of VKORC1, CYP2C9 and CYP4F2 on warfarin resistance in patients with mechanical valve replacement in the stable period. Methods From July 2011 to February 2014, 1 831 patients who had ≥ 6 months after mechanical valve replacement surgery were enrolled at the outpatient follow-up. The basic clinical data were recorded. Anticoagulant therapy uses a target international normalized ratio(INR, 1.60–2.20) and a weekly warfarin dose adjustment strategy. Forty-six patients who needed compound salvia miltiorrhiza tablet were screened and the INR values. Before and after taking tablets were recorded and compared. The patients were divided into three groups according to the percentile of warfarin dosage including a warfarin sensitive patients group, a control patients group, and a warfarin resistance patients group. And 101 of them were selected. TIANGEN Blood DNA Kit blood genomic DNA extraction kit was used to extract samples and polymerase chain restriction fragment length polymorphism (PCR-RELP) was used to determine the genotypes of patients. The detected gene loci included CYP4F2: rs2108622C>T locus; VKORC1:1639G>A locus; VKORC1:1173C>T locus; CYP2C9*2: rs1799853C>T locus; CYP2C9*3:1061A>C locus. Results The time in therapeutic range (TTR) and fraction of time in therapeutic range (FTTR) in the target INR range of the patients included in the study period was 27.2% and 49.4%, respectively, and the TTR and FTTR in the acceptable INR range was 34.25% and 63.36%, respectively. Before and after the addition of compound salvia miltiorrhiza tablets, the INR value was 1.55±0.03 and 1.69±0.30, respectively, and the difference was statistically different (P<0.05). A total of 101 patients with genetic testing, in which the C/T composition of the VKORC1:1173C>T locus increased in the warfarin sensitivity, contrast and warfarin resistance patients, while the ratio of allelic loci of C/T in CYP2C9*3:1061A>C loci decreased in turn. There was no difference in the CYP4F2 gene, VKORC1639 gene, and CYP2C9*2 locus. The IWPC model predicts that warfarin dose is only consistent with the actual warfarin dose in warfarin sensitive patients. Conclusion Relatively low TTR and fraction of time in therapeutic range (FTTR) are acceptable in patients with stable stage after mechanical valve replacement. It is beneficial to the patients with compound salvia miltiorrhiza tablets in terms of some appropriate patients. VKORC1:1173C>T site and CYP2C9*3:1061A>C site mutation is the main pharmacological gene factor of warfarin dose sensitivity and warfarin resistance in stable period after mechanical valve replacement. The IWPC dose prediction model is only consistent with the actual dose of warfarin sensitive patients.

关键词: 机械瓣膜置换; 抗凝治疗质量; 治疗范围时间; 华法林敏感; 华法林抵抗; 基因; 剂量预测

Key words: Mechanical valve replacement; anticoagulant therapy quality; treatment range time; warfarin sensitivity; warfarin resistance; gene; dose prediction

登录后 ,请手动点击刷新查看全文内容。 没有账号,
登录后 ,请手动点击刷新查看图表内容。 没有账号,
1. Rosendaal FR, Cannegieter SC, Fj VDM, et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost, 1993, 69(3): 236-239.
2. Pengo V, Pegoraro C, Cucchini U, et al. Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis, 2006, 21(1): 73-77.
3. Shalev V, Rogowski O, Shimron O, e t. The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation. Thromb Res, 2007, 120(2): 201-206.
4. Grzymala B. Mechanical heart valve prosthesis and warfarin – Treatment quality and prognosis. Thromb Res, 2014, 133(5): 795-798.
5. Meijer K, Kim YK, Schulman S. Decreasing warfarin sensitivity during the first three months after heart valve surgery: implications for dosing. Thromb Res, 2010, 125(3): 224-229.
6. Tekkesin AI, Cakilli Y, Turkkan C, et al. OP-005 Assessment of warfarin TTR (time in therapeutic range ) results in a tertiary reference center. Am J Cardiol, 2015, 115: S2-S3.
7. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med, 2005, 352(22): 2285-2293.
8. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy 1. J Am Coll Cardiol, 2003, 41(9): 1633-1652.
9. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis, 2008, 25(1): 45-51.
10. Asarcıklı LD, Şen T, İpek EG, et al. Time in therapeutic range (TTR) value of patients who use warfarin and factors which influence TTR. J Am Coll Cardiol, 2013, 62(18): C127-C128.
11. 王晓蕊, 毛静远. 中药影响华法林抗凝作用的研究进展. 中西医结合心脑血管病杂志, 2016, 14(20): 2379-2383.
12. S. S, B. EB, W. EJ, et al Clinical factors influencing the sensitivity to warfarin when restarted after surgery. J Intern Med, 2008, 263(4): 412-419.
13. Valentin II, Vazquez J, Rivera-Miranda G, et al. Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. Ann Pharmacother, 2012, 46(2): 208-218.
14. 谭胜蓝, 周新民, 李智, 等. 华法林抵抗的诊断及处理. 中南大学学报:医学版, 2013, 38(3): 313-317.
15. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood, 2009, 113(4): 784-792.
16. Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet, 2007, 121(1): 23-34.
17. Nastasi-Catanese JA, Padilla-Gutierrez JR, Valle Y, et al. Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response. Genet Mol Res, 2013, 12(4): 4413-4421.
18. 肖锡俊, 刘关键, 梁茂植, 等. 机械瓣置换术后患者目标 INR 1.60~2.20 及以每周为单位华法林剂量调整合理性的初步评价. 中国循证医学杂志, 2014, 14(1): 16-20.
19. Detlef H, Cornelia P, Rito B, et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience with low-intensity anticoagulation study. Chest, 2005, 127(1): 53-59.
20. Koertke H, Zittermann A, Minami K, et al. Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg, 2005, 79(6): 1909-1914.
21. Kuntze CE, Eijgelaar A, Ebels T, et al. Rates of thromboembolism with three different mechanical heart valve prostheses: randomised study. The Lancet, 1989, 333(8637): 514-517.
22. Cannegieter S, Rosendaal F, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation, 1994, 89(2): 635-641.
23. Butchart E, Lewis P, Bethel JA, et al. Adjusting anticoagulation to prosthesis thrombogenicity and patient risk factors. Recommendations for the Medtronic Hall valve. Circulation, 1991, 84(5 Suppl): III61-69.
24. Butchart E, Lewis P, Kulatilake E, et al. Anticoagulation variability between centres: implications for comparative prosthetic valve assessment. Eur J Cardio-thorac Surg, 1987, 2(2): 72-81.
25. Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis, 2000, 9(3): 283-292.
26. Schmitt L, Speckman J, Ansell J. Quality assessment of anticoagulation dose management: comparative evaluation of measures of time-in-therapeutic range. J Thromb Thrombolysis, 2003, 15(3): 213-216.
27. Koertke H, Zittermann A, Minami K, et al. Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg, 2005, 79(6): 1909-1914.
28. 28s Rosendaal FR, Cannegieter SC, Meer FJ, Van Der, et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost, 1993, 69(3): 236-239.
29. 谢红娟, 付海英, 朱彩凤, 等. 丹参注射液对大鼠体内稳态华法林药动学和药效学参数的影响. 医药导报, 2009, 28(1): 36-39.
30. Qiu F, Wang G, Zhang R, et al. Effect of danshen extract on the activity of CYP3A4 in healthy volunteers. Br J Clin Pharmacol, 2010, 69(6): 656-662.
31. Chan T. Interaction between warfarin and danshen (Salvia miltiorrhiza). Ann Pharmacother, 2001, 35(4): 501-504.
32. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2): 1513-1514.
33. Meijer K, Kim YS. Decreasing warfarin sensitivity during the first three months after heart valve surgery : Implications for dosing. Thromb Res, 2010, 125(3): 224-229.
34. Eriksson N, Wadelius M. Prediction of warfarin dose: why, when and how? Pharmacogenomics, 2012, 13(4): 429-440(412).
35. Grzymala-Lubanski B, Labaf A, Englund E, et al. Mechanical heart valve prosthesis and warfarin – Treatment quality and prognosis. Thrombosis Research, 2014, 133(5): 795-798.
36. Borgiani P, Ciccacci C, Forte V, et al. Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics, 2007, 8(11): 1545-1550.
37. Carlquist JF, Horne BD, Mower C, et al. An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction. J Thromb Thrombolysis, 2010, 30(3): 358-364.
38. Yoshizawa M, Hayashi H, Tashiro Y. Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res, 2009, 124(2): 161-166.
39. Teh LK, Langmia IM, Fazleen Haslinda MH, et al. Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. J Clin Pharm Ther, 2012, 37(2): 232-236.
40. Redman AR. Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy, 2001, 21(2): 235-242.
41. Sagreiya H, Berube C, Wen A, et al. Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenetics & Genomics, 2010, 20(7): 407-413.
42. Wadelius M, Chen L, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J, 2005, 5(4): 262-270.
43. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther, 2008, 84(3): 326-331.