CHVAD动物实验抗凝管理研究

doi:10.3969/j.issn.0258-8021. 2014. 05.09

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摘要 VAD绵羊模型常用来验证装置血液相容性、生物安全性和工作可靠性以及对动物生理状态的影响，且需要有效、安全的抗凝管理方案，以降低血栓和出血风险。研究拟讨论绵羊植入CHVAD后应用肝素和华法林钠的抗凝效果，为后期动物长期存活实验和临床应用提供抗凝数据。选择健康绵羊6只，构建动物左心室→心室辅助装置→降主动脉血流旁路，建立CHVAD动物模型。术中一次性静脉注射肝素250 U/kg。术后前4 d连续静脉滴注肝素50 U/kg〖DK〗·h，使活化全血凝固时间（ACT）和活化部分凝血酶时间（aPTT）15～20倍于基值。术后第3 d开始口服华法林钠，并调整用量使国际标准化比值（INR）在12～20目标范围内。动物存活期间密切观察有无出血并发症。实验终止后，观察血泵内部、人工血管、吻合口等血液流道内有无血栓。宏观检查主要脏器是否充血、梗死，取典型部分做HE染色，观察组织病理学变化。6例绵羊整个实验过程无严重出血并发症。绵羊模型术中ACT值为（326±33）s。术后前4 d ACT基本保持在（157±28）s，在基值的15-20倍内，aPTT上升缓慢，第4 d刚达到目标范围下限。除Sheep4血泵转子背部有小块纤维组织外，其他血泵泵体、出入口、人工血管、吻合口内均无血栓和纤维组织。病理学检查显示在此抗凝方案下绵羊终末期器官基本没有血栓、坏死和微栓子存在。CHVAD绵羊模型中，植入后初期连续静脉滴注肝素保持ACT 15～20倍于基值、后期口服华法林钠使INR值在12～20范围内能够很好的控制血栓和出血并发症，可以作为CHVAD后期动物实验抗凝方案参考。

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关键词 ：心室辅助装置, 动物实验, 抗凝, 肝素, 华法林

Abstract：Sheep models are often used to verify the blood compatibility, biological safety and reliability of VADs as well as the impact on physiological conditions of animals. Effective and safe anticoagulation regimens are strongly needed to reduce risks of thrombosis and bleeding. This study is to evaluate the effect of anticoagulation for animals after implantation of CHVAD with heparin and warfarin, aiming to offer anticoagulation data for longterm survival experiments and clinical applications. CHVAD models were established in six healthy sheep by constructing blood bypass of left ventricular →VAD →descending aorta. Heparin of 250 U/kg was injected through jugular vein during operation. Continuous heparin infusion was used in the prior four days after implantation to keep ACT and aPTT values as 15 to 20 times as the baseline. From the third day, proper dosage of warfarin was used orally to make INR in the target range of 12～20. Bleeding complications were closely monitored through the experiment. At the termination point, we examined whether there was thrombosis in the blood pump, grafts and anastomotic stoma. Macroscopical examinations were performed in major organs to check congestion and infarction. Tissues of the organs were collected to make HE staining to evaluate histopathological changes. Bleeding complications were not found in all animals throughout the experiments. Intraoperative ACT values were (326 ± 33) s. ACT values were（157±28）s in the prior four days, reaching the target range. The aPTT increased slowly and reached the lower limit of the target range at the fourth day. No thrombosis and fibrosis tissue were found in blood flow channel except for Sheep4. Pathological images showed no thrombosis, necrosis and microembolus in endstage organs under the anticoagulation regimen. Under the anticoagulation regimen of continuous intravenous heparin maintaining ACT 15～20 times the baseline and later oral warfarin maintaining INR values within the range of 12～20, thrombosis and bleeding complications could be well controlled in sheep models for CHVAD, providing reference for later animal experiments.

Key words： ventricular assist device (VAD) animal experiment anticoagulant heparin warfarin

基金资助:

国家863计划（2012AA041605）；首都卫生发展科研专项（首发-2011-1005-02）

引用本文:

徐创业^1,2刘修健^1,2吴广辉^1,2侯晓彤¹ . CHVAD动物实验抗凝管理研究[J]. 中国生物医学工程学报, 2014, 33(5): 585-592.
XU Chuang Ye^1,2LIU Xiu Jian^1,2WU Guang Hui^1,2HOU Xiao Tong¹ LI Hai Yang¹YANG Peng³ LIN Chang Yan^1,2#*

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http://cjbme.csbme.org/CN/10.3969/j.issn.0258-8021. 2014. 05.09 或 http://cjbme.csbme.org/CN/Y2014/V33/I5/585

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