SUBSCRIBE
Search JIM Advanced Search

Journal of Chinese Integrative Medicine ›› 2012, Vol. 10 ›› Issue (6): 647-654.doi: 10.3736/jcim20120608

• Original Clinical Research • Previous Articles     Next Articles

Relationship between cytochrome P450 2C19*17 genotype distribution platelet aggregation and bleeding risk in patients with blood stasis syndrome of coronary artery disease treated with clopidogrel

Ze-long Dai, Hui Chen, Xiao-ying Wu#br#   

  1. Department of Cardiovascular Diseases, Provincial Clinical College of Fujian Medical University, Fujian Provincial Institute of Cardiovascular Diseases, Fuzhou 350001, Fujian Province, China
  • Received:2012-01-28 Accepted:2012-02-16 Online:2012-06-20 Published:2018-06-15
  • Contact: Hui Chen

RichHTML

1

PDF (PC)

64

Like

Objective: To assess the impact of cytochrome P450 (CYP) 2C19 *17 allelic variant on platelet aggregation and bleeding risk in Chinese patients with blood stasis syndrome undergoing percutaneous coronary intervention (PCI) and treated with clopidogrel.
Methods: A total of 520 patients with blood stasis syndrome undergoing PCI after pretreatment with 300 mg clopidogrel and aspirin were studied from July 2009 to April 2011 in Fujian Provincial Institute of Cardiovascular Diseases. CYP2C19 *17 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Platelet aggregation induced by 5 μmol/L of adenosine diphosphate (ADP) was analyzed with platelet-rich plasma and platelet-poor plasma by turbidimetry method before and after 10 d of treatment with clopidogrel.
Results: Bleeding events were observed in 5.96% of patients after thrombolysis for myocardial infarction, and the ratio of patients with CYP2C19 *17 allele was 7.98%. The bleeding rate in patients carrying CYP2C19 *17 allele, heterozygous (wt/ * 17) and homozygous ( * 17/ * 17), was higher than that in patients with wild-type homozygotes (wt/wt) (P<0.01). At baseline, ADP-induced light transmission at maximal aggregation, 5-min aggregation and disaggregation showed no significant difference among patients with the three different CYP2C19 *17 genotypes. However, after 10-day administration of clopidogrel, values of ADP-induced platelet aggregation in * 17/ * 17 and wt/ * 17 carriers were significantly decreased compared with the wild-type homozygotes (P<0.05, P<0.01); the inhibition rate of platelet aggregation was higher in patients carrying * 17/ * 17 and wt/ * 17 than those only carrying wt/wt, and the same result was found in disaggregation of platelet after 10-day treatment (P<0.05, P<0.01). Patients with wt/ * 17 and * 17/ * 17 allele of CYP2C19 showed a higher risk of bleeding than those with wild-type allele (P<0.01), and the occurrence of bleeding was highest in patients with CYP2C19 *17 homozygotes.
Conclusion: CYP2C19 *17 allele is associated with enhanced response to clopidogrel and an increased risk of bleeding in patients with blood stasis syndrome of coronary artery disease treated by clopidogrel.

Key words: cytochrome P-450 enzyme system, bleeding, platelet aggregation inhibitors, blood stasis

"

Genotype Actual frequency Expected frequency Gene frequency
Wt/wt (CC) 443 (85.19%) 440.31 –
Wt/* 17 (CT) 71 (13.65%) 76.37 –
* 17/* 17 (TT) 6 (1.15%) 3.31 –
Wt (C) – – 957 (92.02%)
* 17 (T) – – 83 (7.98%)

"

Variable CYP2C19 wt/wt
(n=443)		 CYP2C19 wt/* 17
(n=71)		 CYP2C19 * 17/* 17
(n=6)
Age (mean±standard deviation, years) 63.5±10.7 63.7±10.8 63.1±10.2
Gender (male/female) 261/172 41/30 3/3
Body mass index (mean±standard deviation, kg/m2) 25.4±4.4 25.1±4.9 27.1±5.4
Serum creatinine (mean±standard deviation, mg/L) 10.6±5.0 10.5±4.0 10.3±6.0
Ejection fraction (mean±standard deviation, %) 56.2±10.3 55.7±11.3 54.6±11.5
Active smoker (n, %) 110 (24.83) 23 (32.39) 2 (33.33)
Diabetes mellitus (n, %) 119 (26.86) 21 (29.57) 2 (33.33)
Hypertension (n, %) 376 (84.87) 62 (87.32) 5 (83.33)
Hypercholesterolemia (n, %) 318 (71.78) 52 (73.23) 4 (66.67)
Previous MI (n, %) 172 (38.82) 28 (39.43) 3 (50)
Non-STEMI/STEMI (n, %) 57 (12.86) 7 (9.85) 1 (16.67)
Platelet count (mean±standard deviation, ×109/L) 207±53 205±55 203±58
Use of PPI (n, %) 94 (21.4) 13 (18.31) 1 (16.67)

"

Genotype n Aggmax Agglate
Basline value After 10 d of treatment Baseline value After 10 d of treatment
Wt/wt (CC) 443 58.02±12.79 41.45±10.27 48.92±14.69 35.87±11.50
Wt/* 17 (CT) 71 55.59±11.43 37.66±8.62** 47.45±11.98 29.12±9.75**
* 17/* 17 (TT) 6 54.32±9.45 31.33±7.86* 47.55±9.54 24.87±8.20*
Genotype n IPAmax IPAlate Disaggregation
Baseline value After 10 d of treatment
Wt/wt (CC) 443 29.76±15.18 26.77±9.18 20.72±14.10 25.54±13.88
Wt/* 17 (CT) 71 35.33±15.99** 39.68±8.26** 19.32±12.51 30.46±12.02**
* 17/* 17 (TT) 6 45.35±9.77* 46.32±8.79** 19.25±10.12 31.35±11.24

"

Genotype n TIMI major bleeding events TIMI minor bleeding events TIMI total bleeding events
Wt/wt (CC) 443 9 (2.03) 11 (2.48) 20 (4.51)
Wt/* 17 (CT) 71 5 (7.04)** 5 (7.04)* 10 (14.08)**
* 17/* 17 (TT) 6 1 (16.67)** 0 1 (16.67)
Total 520 15 (2.88) 16 (3.08) 31 (5.96)

"

Variable OR (95% CI)
CYP2C19*17 allele carriage 1.95 (1.31 to 3.16)
Gender 1.31 (0.68 to 2.54)
Age (per 10 years increment) 1.57 (1.13 to 2.17)
BMI (per 5 kg/m2 increment) 0.87 (0.61 to 1.25)
Serum creatinine (per 1 mg/L increment) 0.97 (0.88 to 1.06)

Figure 1

Observation of bleeding risk in different groups Data are expressed as the rate of TIMI bleeding events in different groups of the total patients, and analyzed by Chi-square test. **P<0.01, vs wt/wt genotype; △△P<0.01, vs total risk group. TIMI: thrombolysis in myocardial infarction; EM: extensive metabolization."

[1] Du JP, Shi DZ, Li TC, Xu H, Chen H . Correlation between blood stasis syndrome and pathological characteristics of coronary artery in patients with coronary heart disease[J]. J Chin Integr Med, 2010,8(9):848-852
doi: 10.3736/jcim20100908
杜健鹏, 史大卓, 李田昌, 徐浩, 陈浩 . 冠心病稳定期血瘀证与冠状动脉病变特点的相关性[J]. 中西医结合学报, 2010,8(9):848-852
doi: 10.3736/jcim20100908
[2] Xu H, Lu XY, Chen KJ, Shi DZ . Study on correlation of blood-stasis syndrome and its accompanied syndromes with pathological changes showed in coronary angiography and restenosis after percutaneous coronary intervention[J]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2007,27(1):8-13
doi: 10.3321/j.issn:1003-5370.2007.01.002
徐浩, 鹿小燕, 陈可冀, 史大卓 . 血瘀证及其兼证与冠脉造影所示病变及介入治疗后再狭窄的相关性研究[J]. 中国中西医结合杂志, 2007,27(1):8-13
doi: 10.3321/j.issn:1003-5370.2007.01.002
[3] Chen H, Zhang Y, Wu XY, Sun H . Investigation of upper gastrointestinal hemorrhage induced by enteric-coated aspirin in treating coronary heart disease[J]. Zhonghua Lin Chuang Yi Shi Za Zhi Dian Zi Ban, 2010,4(8):1277-1281
陈慧, 张艳, 吴小盈, 孙红 . 肠溶阿司匹林致冠心病患者上消化道出血不良反应调查[J]. 中华临床医师杂志电子版, 2010,4(8):1277-1281
[4] Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M . A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006; 79(1):103-113.
doi: 10.1016/j.clpt.2005.10.002
[5] Mendis S, Thygesen K, Kuulasmaa K, Giampaoli S, Mähönen M, Ngu Blackett K, Lisheng L; Writing group on behalf of the participating experts of the WHO consultation for revision of WHO definition of myocardial infarction. World Health Organization definition of myocardial infarction: 2008-09 revision[J]. Int J Epidemiol, 2011,40(1):139-146
doi: 10.1093/ije/dyq165 pmid: 20926369
[6] Weng WL . Recent research progress of blood stasis syndrome: the proceedings of the Second National Academic Conference on Blood Stasis Syndrome Research[J]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 1987,7(3):190-191
翁维良 . 血瘀证及活血化瘀中西医结合研究新进展——第二届全国活血化瘀研究学术会议纪要[J]. 中国中西医结合杂志, 1987,7(3):190-191
[7] Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA . Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus(OPTIMUS) study[J]. Circulation, 2007,115(6):708-716
doi: 10.1161/CIRCULATIONAHA.106.667741
[8] Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E . Thrombolysis in Myocardial Infarction(TIMI) Trial, Phase Ⅰ: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge[J]. Circulation, 1987,76(1):142-154
doi: 10.1161/01.CIR.76.1.142
[9] Desta Z, Zhao X, Shin JG, Flockhart DA . Clinical significance of the cytochrome P450 2C19 genetic polymorphism[J]. Clin Pharmacokinet, 2002,41(12):913-958
doi: 10.2165/00003088-200241120-00002
[10] Savi P, Herbert JM . Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis[J]. Semin Thromb Hemost, 2005,31(2):174-183
doi: 10.1055/s-2005-869523
[11] Geiger J, Brich J , Hönig-Liedl P, Eigenthaler M Schanzenbächer P, Herbert JM, Walter U. Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel[J]. Arterioscler Thromb Vasc Biol, 1999,19(8):2007-2011
doi: 10.1161/01.ATV.19.8.2007
[12] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA . Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives[J]. J Am Coll Cardiol, 2007,49(14):1505-1516
doi: 10.1016/j.jacc.2006.11.044
[13] mig A, von Beckerath N, Kastrati A . Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement[J]. Circulation, 2010,121(4):512-518
doi: 10.1161/CIRCULATIONAHA.109.885194
[14] Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Baggish JS, Bhatt DL, Topol EJ . Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials[J]. Am J Cardiol, 2005,95(10):1218-1222
doi: 10.1016/j.amjcard.2005.01.049
[15] Gurbel PA, Tantry US, Shuldiner AR, Kereiakes DJ . Genotyping: one piece of the puzzle to personalize antiplatelet therapy[J]. J Am Coll Cardiol, 2010,56(2):112-116
doi: 10.1016/j.jacc.2010.04.008
[1] Chun Li, Yong Wang, Yu-lin Ouyang , Wen-jing Chuo , Qi Qiu , Shu-zhen Guo, Wei Wang. Effects of a compound Chinese herbal medicine Yixin Jiedu Formula on haemodynamic in rats with heart failure of qi-deficiency and blood stasis syndrome. Journal of Chinese Integrative Medicine, 2012, 10(5): 577-583.
[2] Tapas Kumar Sur, Biswajit Auddy, Dipankar Bhattacharyya. Effects of Indian herbal formulation Body Revival on human platelet aggregation and myocardial ischemia in rats. Journal of Chinese Integrative Medicine, 2011, 9(7): 746-751.
[3] Nabeel Ghayur Muhammad, Faraz Kazim Syed, Rasheed Huma, Khalid Asaad, Iqbal Jumani Maliha, Iqbal Choudhary Muhammad, Hassan Gilani Anwarul. Identification of antiplatelet and acetylcholinesterase inhibitory constituents in betel nut. Journal of Chinese Integrative Medicine, 2011, 9(6): 619-625.
[4] Yong Wang, Shu-zhen Guo, Chun Li, Jian-xin Chen, Wen-jing Chuo, Fang Dong, Wei Wang, Ying-feng Wang. Analysis of plasma metabonomics of mini-swines with qi deficiency and blood stasis syndrome due to chronic myocardial ischemia. Journal of Chinese Integrative Medicine, 2011, 9(2): 158-164.
[5] Ming-wei Huang, Huan Wang, Wen-juan Zhong, Xiao-ying Wu, Hui Chen. Chinese herbal medicine Naoxintong capsule combined with dual antiplatelet therapy in a rat model of coronary microembolization induced by homologous microthrombi. Journal of Chinese Integrative Medicine, 2011, 9(1): 38-48.
[6] Jian-peng Du, Da-zhuo Shi , Tian-chang Li, Hao Xu, Hao Chen. Correlation between blood stasis syndrome and pathological characteristics of coronary artery in patients with coronary heart disease. Journal of Chinese Integrative Medicine, 2010, 8(9): 848-852.
[7] Xuan Liu , Qing-qi Wang. Professor Wang Qingqi's experience in treating senile diseases based on the theory of blood stasis. Journal of Chinese Integrative Medicine, 2010, 8(5): 486-488.
[8] Hui Han, Li-min Wu, Wen-ming Yang, Mei-xia Wang, Jing-jing Tang, Han Wang, Zhi-xiu Liu, Rong-zhi Liu, Ting Dong, Juan Zhang , Bo Yang, Ming-xiang Han. Characteristics of traditional Chinese medicine syndromes in post-stroke depression. Journal of Chinese Integrative Medicine, 2010, 8(5): 427-431.
[9] Rui Wu , Wen-wen Xiong, Yi-ping Jiang, Guo-xian Li. Changes of eye signs in chronic hepatitis B patients with blood stasis syndrome. Journal of Chinese Integrative Medicine, 2010, 8(1): 46-48.
[10] Bin Li , Rong Xu, Fu-lun Li, Ke-qin Zhao, Ming Zhang, Zheng-cheng Xu. Study of syndrome differentiation factor of gouty arthritis with blood stasis syndrome based on connection number. Journal of Chinese Integrative Medicine, 2009, 7(8): 724-727.
[11] Mei Xue , Ke-ji Chen, Hui-jun Yin. Relationship between polymorphism of platelet membrane glycoprotein Ⅲa and coronary heart disease with blood-stasis syndrome in Chinese Han population. Journal of Chinese Integrative Medicine, 2009, 7(4): 325-329.
[12] Yong-jun Wang, Qi Shi, Jian-chun Jiang, Qin Bian, Qian-qian Liang, Chen-guang Li, Quan Zhou, Xue-jun Cui, Sheng Lu, Chong-jian Zhou. Mechanism of Yiqi Huayu Bushen Recipe in treating cervical syndrome in rats with qi deficiency, blood stasis and kidney deficiency. Journal of Chinese Integrative Medicine, 2009, 7(1): 53-58.
[13] Dan Zhang, Jing Shu, Yi Wang. Salvia Miltiorrhiza injection relieves peritoneal dialysis solution-induced injuries of peritoneal structure and function in rats. Journal of Chinese Integrative Medicine, 2008, 6(5): 517-523.
[14] Wen-yu Xu, Wei Wang, Shu-zhen Guo, Tao Liu, Lei Liu, Yong-xin Yu. Duplication of an animal model of myocardial ischemia with blood stasis syndrome in mini-swines. Journal of Chinese Integrative Medicine, 2008, 6(4): 409-413.
[15] Chen Yue, Liang Zhu, Yi-ming Qian. Diagnostic value of assay of brain natriuretic peptide in patients with sepsis of blood-stasis syndrome. Journal of Chinese Integrative Medicine, 2008, 6(3): 266-269.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] Jin-zhou Tian, Jing Shi, Xin-qing Zhang, Qi Bi, Xin Ma, Zhi-liang Wang, Xiao-bin Li, Shu-li Shen, Lin Li, Zhen-yun Wu, Li-yan Fang, Xiao-dong Zhao, Ying-chun Miao, Peng-wen Wang, Ying Ren, Jun-xiang Yin, Yong-yan Wang, Beijing United Study Group on MCI of the Capital Foundation of Medical Developments. An explanation on "guiding principles of clinical research on mild cognitive impairment (protocol)". Journal of Chinese Integrative Medicine, 2008, 6(1): 15-21
[2] Yi-ting He, Qing-lin Zha, Jian-ping Yu, Yong Tan, Cheng Lu, Ai-ping Lv. Principal factor analysis of symptoms of rheumatoid arthritis and their correlations with efficacy of traditional Chinese medicine and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 32-36
[3] Jun Cai, Hua Wang, Sheng Zhou, Bin Wu, Hua-rong Song, Zheng-rong Xuan. Effect of Sijunzi Decoction and enteral nutrition on T-cell subsets and nutritional status in patients with gastric cancer after operation: A randomized controlled trial. Journal of Chinese Integrative Medicine, 2008, 6(1): 37-40
[4] Wei Zhang, Xiang-feng Lu, Xiao-mei Zhang, Jian-jun Wu, Liang-duo Jiang. A rat model of pulmonary fibrosis induced by infusing bleomycin quickly through tracheal intubation. Journal of Chinese Integrative Medicine, 2008, 6(1): 60-67
[5] A-gao Zhou, Yong Zhang, Gang Kui, De-Yun Kong, Hai-liang Ge, Qiu-hua Ren, Jia-rong Dong, Sheng Hong, Xu-ming Mao, Yin Wang, Hui-zheng Zhang, Shu-jun Wang. Influence of traditional Chinese compound recipes with different efficacy on body weight, tumor weight and immune function in H22 cancer-bearing mice. Journal of Chinese Integrative Medicine, 2008, 6(1): 77-82
[6] Guo-hong Yuan, Xiao-jing Pang, He-chao Ma. Synergic effects of Danggui Buxue Decoction in reducing toxicity of cytoxan in tumor-bearing mice. Journal of Chinese Integrative Medicine, 2008, 6(1): 83-88
[7] Li Zhou, Hong-xing Zhang, Ling-guang Liu, Wen-jun Wan. Effect of electro-acupuncture at Fenglong (GV 16) on nitric oxide and endothelin in rats with hyperlipidemia. Journal of Chinese Integrative Medicine, 2008, 6(1): 89-92
[8] Jin-zhou Tian, Jing Shi, Xin-qing Zhang, Qi Bi, Xin Ma, Zhi-liang Wang, Xiao-bin Li, Shu-li Shen, Lin Li, Zhen-yun Wu, Li-yan Fang, Xiao-dong Zhao, Ying-chun Miao, Peng-wen Wang, Ying Ren, Jun-xiang Yin, Yong-yan Wang, Beijing United Study Group on MCI of the Capital Foundation of Medical Developments. Guiding principles of clinical research on mild cognitive impairment (protocol). Journal of Chinese Integrative Medicine, 2008, 6(1): 9-14
[9] Xin-jun Wang, Ling-ling Wang . A mechanism of endogenous opioid peptides for rapid onset of acupuncture effect in treatment of depression. Journal of Chinese Integrative Medicine, 2010, 8(11): 1014-1017
[10] Bo Wang , Wei Yan , Li-hui Hou, Xiao-ke Wu. Disorder of Tiangui (kidney essence) and reproductive dysfunction in patients with polycystic ovary syndrome. Journal of Chinese Integrative Medicine, 2010, 8(11): 1018-1022
Journal of Integrative Medicine, ISSN: 2095-4964 CN 31-2083/R
Copyright © Journal of Integrative Medicine
Powered by Beijing Magtech Co. Ltd
沪公网安备31010602003416号      沪ICP备18017633号-3