静脉应用高剂量氨甲环酸对新西兰兔股静脉血栓形成的影响

The effects of high-dose intravenous tranexamic acid on thrombosis in New Zealand rabbit femoral vein thrombosis model

目的通过建立新西兰兔股静脉血栓模型,研究高剂量氨甲环酸(tranexamic acid,TXA)对兔股静脉血栓形成的影响,探讨围术期使用高剂量TXA止血的安全性。方法将30只健康新西兰兔应用电脑产生随机数表的方法随机分为TXA组(T组,n=15)和空白组(P组,n=15)。再随机分为5个亚组,即1天、3天、5天、7天、14天组,每组3只。T组于术前30 min给予静注50mg/kg TXA,P组则予以等量生理盐水。应用“缩窄法+凝血酶注射法”建立股静脉血栓模型。彩色多普勒超声及组织病理学比较两组建模前、建模后1天、3天、5天、7天、14天的血栓形成情况。结果(1)超声检查结果:术前两组间管径平均值基线一致,两组管径变化均为建模后1天、3天时较术前管径显著增粗,建模后3~7天时管径逐渐回缩,建模后7~14天时管径基本回缩至术前水平。两组管径变化差异:建模后1天时T组管径平均值较P组略大(P>0.05);术后3天、5天、7天、14天时两组的管径平均值相当,差异无统计学意义(P>0.05)。超声图像表现两组未见明显差异:术后1天、3天时股静脉管腔内充满均匀实质性低回声影,未见明显血流信号通过;术后5天、7天、14天时静脉管腔内逐步出现弱强回声影,静脉管壁增厚,至7天时可见少量血流信号。(2)组织病理学结果:两组间血栓形成、机化及再通过程均未见明显差异。术后1天时,两组均为红色血栓,几乎占满管腔,血栓与血管壁未见明显粘连,血栓内未见机化现象。术后3天时,血栓开始出现少量机化,T组与P组相比血栓机化程度稍强,但血栓与血管壁未见明显粘连。术后5天时,T组与P组均可见血栓机化程度进一步增加,肉芽组织逐步长入血栓内,血栓与管壁产生部分粘连。术后7天时,两组肉芽组织覆盖至血栓周边,血栓内部明显机化,血栓与管壁可见明显粘连。术后14天时,T组与P组两组血栓内明显机化,肉芽组织明显深入血栓内部,血栓已被肉芽组织取代,血栓与管壁严重粘连。结论“缩窄法+凝血酶注射法”联合应用能够成功建立新西兰兔股静脉血栓模型。与对照组相比,高剂量TXA在新西兰兔股静脉血栓形成、机化、再通过程等无明显影响。

Objective To investigate the effects of high-dose intravenous tranexamic acid(TXA)on rabbit femoral vein thrombosis via establishing a New Zealand rabbit femoral vein thrombosis model,aiming to study the safety of high-dose intravenous TXA.Methods A series of 30 healthy New Zealand rabbits were randomly divided into TXA group(T-group,n=15)and placebo-controlled group(P-group,n=15).Furthermore,15 rabbits in each group were randomly divided into 1,3,5,7 and 14-day group with 3 rabbits in each subgroup.T-group received intravenous TXA 50 mg/kg loading dose 30 minute before surgery.The P-group received the same volume of normal saline.The femoral vein thrombosis model was established by narrowing one side of femoral vein and injecting thrombin into the distal.Ultrasound examinations:rabbit femoral vein was examined preoperatively and 1,3,5,7,14days postoperatively.Preoperative and postoperative femoral vein diameter,blood flow and postoperative thrombosis were observed to compare the difference between T-group and P-group.Histopathology examinations:thrombus of femoral venous were taken out according to the scheduled time when color Doppler ultrasonography was conducted.After fixation,embedding,paraffin section making and hematoxylin-eosin(H-E)staining,microscopic pathological study was performed to compare the differences between T-group and P-group.Results The 30 New Zealand rabbit femoral vein thrombosis models were successfully established.(1)Results of ultrasound examination:there were no significant differences in preoperative mean femoral vein diameter between the two groups(P>0.05).The change trends of the diameter in the two groups were similar:the femoral vein diameters 1 and 3 days postoperatively were significantly enlarged compared with those preoperatively;significant retraction of the diameter occurred 3-7 days after establishment;femoral vein diameter restored to the preoperative size 7-14 days postoperatively;the mean diameter of T-group was slightly larger than that of P-group 1 day postoperatively(P>0.05);there were no statistically significant differences in the mean diameter 3,5,7 and 14 days postoperatively(P>0.05).Ultrasonography echo intensities of the two groups were not significantly different;homogeneous substantial hypoecho was observed with no obvious blood flow 1 and 3 days postoperatively;echoes gradually increased 5,7 and 14 days postoperatively,and the venous wall gradually thickened;slight blood flow was observed 7 days postoperatively.(2)Results of pathological examination:microscopic pathological study after H-E staining showed that there were no significant differences in thrombosis,organization and recanalization between the two groups.The femoral venous lumen was filled with red thrombosis in both T-group and P-group 1 day postoperatively;no organization of the thrombus or obvious adhesion between the thrombosis and vessel wall was observed;slight organization phenomenon of the thrombus could be seen 3 days postoperatively;organization in T-group was slightly stronger than that of P-group;however,there was no obvious adhesion between the thrombus and the vessel wall;the organization was further aggravated in both group T and P and granulation tissue gradually grew into the thrombus with partial adhesion between the thrombus 5 days postoperatively;obvious organization of the thrombus in both group T and P could be seen 7 days postoperatively;obvious adhesion between the thrombus and vessel wall appeared;pathological results showed organization of the thrombus and obvious granulation tissue inside the thrombus in both T-group and P-group 14 days postoperatively;the thrombus were replaced by granulation tissue,and the thrombus were seriously adhered to the vessel wall.Conclusions The“narrowing+thrombin injection”was effective to establish the femoral vein thrombosis model of New Zealand rabbits.Compared with the placebo-controlled group,the high-dose intravenous TXA showed no significant effect on the thrombosis,organization and recanalization of the femoral vein.It is proved that high-dose intravenous TXA is safe in clinical practice.