Role of Heparin Induced Tissue Factor Pathway Inhibitor Release in Attenuation of Tissue Factor-Dependent Thrombin Generation During Cardiopulmonary Bypass

肝素诱导的组织因子途径抑制剂释放在心肺转流过程中组织因子依赖性凝血酶生成减弱中的作用

• 批准号: 18390374
• 负责人: HIRAMATSU Yuji
• 金额: $ 3.14万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390374/
• 关键词: Cradiac Surgery; Cardionufmon Bypass; Tissue Factor; TFPI; Heparin; ヘパリン; 外科

Background: Administration of high doses of heparin causes massive release of tissue factor pathway inhibitor (TFPI) from vascular endothelial cells. However, it is unclear whether TFPI sufficiently attenuates thrombin generation triggered by tissue factor (TF) during cardiopulmonary bypass (CPB). In this study, we purposed to provide evidence to clarify the role of TFPI in attenuation of TF-dependent thrombin generation during and after simulated CPB and primate CPB using Cynomolgus monkeys (Macaca fascicularis) which may provide high or normal plasma level of TEPI by various pharmacological settings.Methods: Simulated CPB was established by recirculating 250 mL of donor blood for 120 minutes in an oxygenator and a roller pump. Three protocols were evaluated: control (heparin 3. 75 U/mL); TF (heparin + recombinant human TF 1000 pg/mL); and TF plus induced TFPI (heparin + TF, using pre-heparinized donor blood, n=7 fot each group). In the third group, 50 U/kg of heparin was administered … More intravenously five minutes before donation to cause TFPI release. Total plasma TEPI, thrombin antithrombin complex and F_ (1+2) were measured using enzyme immunoassay before and during CPB. For a primate CPB model, we used Cynomolgus monkeys (Macaca fascicularis) for 120 minutes of normothermic CPB. Plasma TFPI was enhanced by pre-heparinization for monkeys, and levels of thrombin generation were compared with control animals. Soluble TF, total plasma TFPI, thrombin antithrombin complex and F_ (1+2) were measured using enzyme immunoassay before and during CPB.Results: In the simulated CPB, significant thrombin generation was observed in all three groups and TF enhanced the generation of F_ (1+ 2). In the TF plus induced TFPI group, pre-heparinization resulted in a 3-fold increase in total TFPI, and thrombin generation was significantly reduced to the control levels during CPB despite the administration of TF. In the primate CPB model, plasma TFPI was enhanced by pre-heparinization for monkeys, and levels of thrombin generation were reduced by inhibition of extrinsic pathway when compared with control group.Conclusions: Although TF enhances thrombin generation in CPB, it is likely that contact and intrinsic pathways still play a considerable role in the thrombin generation. Massive release of plasma TFPI induced by early heparin administration may attenuate TF-dependent thrombin generation during clinical CPB. Less

背景：施用高剂量的肝素会导致血管内皮细胞大量释放组织因子途径抑制剂（TFPI），但尚不清楚 TFPI 是否足以减弱体外循环（CPB）期间组织因子（TF）触发的凝血酶生成。在这项研究中，我们的目的是提供证据来阐明 TFPI 在使用食蟹猴模拟 CPB 和灵长类 CPB 期间和之后减弱 TF 依赖性凝血酶生成的作用(Macaca fasciculis)，它可以通过各种药理学设置提供高或正常的 TEPI 血浆水平。方法：通过在氧合器和滚子泵中再循环 250 mL 供体血液 120 分钟来建立模拟体外循环。评估了三种方案：对照（。肝素 3. 75 U/mL); TF (肝素 + 重组人 TF 1000 pg/mL) 和 TF plus 诱导TFPI（肝素 + TF，使用预先肝素化的供体血液，每组 n=7），在献血前 5 分钟静脉注射 50 U/kg 肝素，以引起 TFPI 总血浆 TEPI 释放。在 CPB 之前和期间使用酶免疫测定法测量凝血酶抗凝血酶复合物和 F_ (1+2) 对于灵长类 CPB 模型，我们使用食蟹猴 (Macaca)。通过对猴子进行预肝素化，进行120分钟的常温CPB，并测量了可溶性TF、总血浆TFPI、凝血酶抗凝血酶复合物和F_(1+2)的凝血酶生成水平。在 CPB 之前和期间使用酶免疫分析。结果：在模拟 CPB 中，所有三组均观察到显着的凝血酶生成，并且 TF 增强在 TF 加诱导 TFPI 组中，预肝素化导致总 TFPI 增加 3 倍，并且尽管给予 TF，CPB 期间凝血酶生成仍显着减少至对照水平。在灵长类CPB模型中，与对照组相比，预肝素化使猴血浆TFPI增加，并且通过抑制外源性途径减少凝血酶生成水平。 结论： TF 增强 CPB 中的凝血酶生成，但早期肝素给药诱导的血浆 TFPI 的大量释放可能会减弱临床 CPB 期间 TF 依赖性凝血酶的生成，因此接触途径和内在途径可能仍发挥重要作用。