The Anticoagulation Effects Of Dabigatran Etexilate On A Rabbit Model Of Venous Thrombosis And Patients With Atrial Fibrillation

Purpose: 1.To observe the antithrombotic effects of Dabigatran etexilate on a rabbit model of venous thrombosis and the changes of rabbits’ coagulation indexes based on different dose and time.2.To observe the changes of coagulation indexes of clinical patients with atrial fibrillation at different time after taking dabigatran etexilate.3.Evaluate the correlation and mechanism between selected coagulation indexes and anticoagulation effect of Dabigatran etexilate.Methods: This study is divided into two parts: animal experiments and clinical trials.The experimental animals: 36 male rabbits randomly divided into the control group(n = 6)and the Dabigatran etexilate treated group(doses of 1mg/kg, 5mg/kg, 10mg/kg, 20mg/kg and 40mg/kg, n = 6). 2h after administration, established rabbit thrombus model and collected the rabbit’s thrombus. The selected coagulation indexes were measured before and after treatment. Another 36 rabbits got gavage administration of 10mg/kg Dabigatran etexilate, coagulation indexes were measured before and 1h, 2h, 3h, 5h, 7h and 24 h after treatment, the blood drug concentration was also detected, followed by rabbit thrombus model establishing and rabbit’s thrombus collecting. The clinical trials included 14 patients with non valvular atrial fibrillation. Dabigatran etexilate(110mg 2times/day) was taked orally, blood coagulation detection was performed before and 1d, 3d and 7d after treatment.Results: Animal experiments showed that thrombin time(TT) was significantly increased when Dabigatran etexilate dose was more than 1mg/kg(p<0.05). And activated partial thromboplastin time(APTT) was markedly increased when Dabigatran etexilate dose was more than 5mg/kg(p<0.05). Prothrombin time(PT) was significant increased when when Dabigatran etexilate dose was more than 20mg/kg(p<0.05). FII activity wassignificantly decreased when Dabigatran etexilate dose was more than 10mg/kg(p< 0.05);FX activity was decreased when the dose reached 40mg/kg(p<0.05). With the increase of dose, the thrombus showed a decreasing trend. APTT and TT were increased 1h after administration(p<0.05), and were at the maximum level 2h after administration. PT did not change significantly(p>0.05), FII activity was significantly reduced 2h after administration(p<0.05), and did not change at 7h(p>0.05). The activity of FX did not change significantly(p>0.05). The weight of thrombosis is significantly reduced 1h after administration(p<0.05), and was minimum at 2h, however the thrombus weight was not significantly changed at 24h(p>0.05). There was a high degree of correlation between Dabigatran concentration and selected coagulation indexes(APTT and TT). When the concentration of Dabigatran is lower than 50ng/ml, the correlation with APTT was weakened, and the correlation with TT was still obvious. In addition, there was a negative correlation between the concentration of Dabigatran and FX or FII, while no correlation with PT. The clinical study showed that APTT was increased significantly 3d and 7d after Dabigatran etexilate treatment. With the increase of time, PT and international standardization ratio(INR) also tended to increase, but some patients’ PT did not exceed the normal range 7d after Dabigatran etexilate treatment. TT was significantly increased 1d after treatment, and showed a growth trend. TT was increased to about 8 times at 7d compared with baseline. ATIII was slightly decreased and Fibrinogen(Fbg) and was not significantly changed after Dabigatran etexilate treatment.Conclusion: This study showed that Dabigatran etexilate had a good inhibition against thrombosis in a rabbit model of venous thrombosis and the blood drug concentration of Dabigatran reached its peak 2h after treatment. APTT and TT were significant increased after taking the drug which TT was more sensitive, more suitable for monitoring low concentration anticoagulant Dabigatran etexilate.APTT could be used as a indicator to assess the risk of bleeding,as it was less sensitive in low plasma concentration.There was no linear relationship between PT and serum concentration of Dabigatran.but PT increased slightly in high dose,which could be used for a preliminary assessent ofpatients when significant bleeding, especially when the APTT, TT exceeded the limit of detection.Dabigatran etexilate could inhibit FII and FX activity with a certain dose.Dabigatran etexilate inhibited ATIII sightly but seemed to have no effect on Fbg.