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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

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

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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."

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