The Clinical And Experimental Study About Gastrointestinal Injury On Antiplatelet Therapy

Objective:(1) Investigate the risk of gastrointestinal injury among different antiplatelet therapies, aspirin and/or clopidogrel, and understand the effect of clopidogrel on the healing of gastrointestinal ulcer by endoscopy in the elderly. (2) Identify the effect of clopidogrel on the gastric ulcer healing in experimental rats and explore the delayed gastric ulcer healing mechanisms.Methods:(1) The dyspepsia symptoms and gastrointestinal bleeding from cases of antiplatelet therapy patients treated with aspirin and/or clopidogrel,and endoscopic follow-up results of patients with gastrointestinal ulcer were reviewed.(2) Acetic acid was introduced into the serosal surface of the gastic bodies to induce ulcers in rats, and then the effect of clopidogrel (10mg/kg,30mg/kg) on healing of the gastric ulcer was observed.The microvessel density (MVD) at the bottom of ulcers was calculated by immunohistochemistry. Protein expression levels of endostatin (ES) and vascular endothelial growth factor - A165 (VEGF-A165) in the gastric mucosa were quantified by ELISA.Results:(1) Total 577(22.6%) cases out of 2550 aged patients were treated with aspirin (≤100mg/d) or clopidogrel(<75mg/d). The incidence of dyspepsia symptoms and gastrointestinal bleeding was 12.48% and 2.43%, respectively. The risk of dyspepsia symptoms and gastrointestinal bleeding in clopidogrel treated group was slightly higher than the aspirin treated group (both P>0.05, and AOR (95% CI):1.10 (0.59-2.06),1.83 (0.50-6.69), respectively). In aspirin + clopidogrel treated group, the risk of dyspepsia symptoms was not significantly different from that in aspirin or clopidogrel treated group, but the risk of gastrointestinal bleeding was significantly higher than in aspirin treated group (P=0.019) and slightly higher than in clopidogrel treated group (Compared to the aspirin treated group, the AOR of gastrointestinal bleeding in the clopidogrel and the combined treated groups were 5.67,1.83, respectively). The risk of dyspepsia symptoms significantly increased [P = 0.000, AOR (95% CI):3.90 (1.5-7.83)] and gastrointestinal bleeding slightly increased [P> 0.05, AOR (95% CI):1.58 (0.31-7.99)] in patients with a history of erosion or ulcer. In this study, the follow-up results of 51 patients with gastrointestinal ulcer(active stage) identified by endoscopy indicated that the healing rate of ulcer in patients accepted clopidogrel (72%) was significantly lower than in those who did not accept clopidogrel(96.2%)(P=0.024). (2) In the rat study,10 days after ulcer induction, the ulcer areas were 7±1.85 mm2,11±3.07 mm2 and 12.5±4.96 mm2 in the NS group, clopidogrel low-dose and high-dose treated groups, respectively. The ulcer areas between clopidogrel low-dose and high-dose treated groups had no significant difference(P>0.05), but both were significantly larger than that in the NS group (P= 0.0151, P= 0.0052, for low-dose group and high-dose group, respectively). Compared to the NS group, the MVD in clopidogrel low-dose and high-dose treated groups were significantly lower (P= 0.02, P= 0.013, for low-dose group and high-dose group, respectively), but no significant difference was detected between two clopidogrel treated groups (P>0.05). The VEGF-A165 concentration of gastric mucosa in clopidogrel low-dose and high-dose groups were significantly lower than that in NS group (P= 0.0016, P=0.0008, for low-dose group and high-dose group, respectively), and the high-dose group was significantly lower than the low-dose group (P= 0.0237). The ES concentration of gastric mucosa in clopidogrel low-dose and high-dose groups had no significant difference(P>0.05), but were both significantly higher than that in NS group (P= 0.012, P= 0.037, for low-dose group and high-dose group, respectively). The MVD at the bottom of ulcers was positively correlated with the VEGF-A165 concentration(r=0.5872, P= 0.0026), but negatively correlated with the ES concentration(r=-0.7646, P= 0.0000).Conclusion:(1) In the elderly the use of clopidogrel alone was not safer than low-dose aspirin for gastrointestinal tract and the combination would increase the risk of gastrointestinal bleeding. The use of clopidogrel in patients with gastrointestinal ulcer would decrease the healing rate of ulcer. (2) Clopidogrel can significantly delay the healing of the gastric ulcer in experimental rats, and one of the mechanisms might relate to the inhibiting of angiogenesis at the bottom of ulcers by regulating the expression of VEGF-A165 and ES in the gastric mucosa.