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：大剂量肝素可导致血管内皮细胞大量释放组织因子途径抑制物(TFPI)。然而，目前尚不清楚TFPI是否能充分抑制体外循环(CPB)期间由组织因子(TF)触发的凝血酶生成。在这项研究中，我们的目的是为了阐明TFPI在模拟CPB和灵长类CPB过程中和之后对TFP依赖的凝血酶产生的抑制作用。评价3种方案：对照组(肝素3.75U/mL)、TF(肝素+重组人TF 1000pg/mL)和TF+诱导性TFPI(肝素+TF，使用预肝素化供体血液，每组n=7)。第三组给予…，肝素50U/kg。更多的是在捐献前五分钟静脉注射以引起TFPI的释放。采用酶免疫法测定CPB术前、术中血浆总TEPI、凝血酶抗凝血酶复合体和F_(1+2)。对于灵长类体外循环模型，我们使用食蟹猴(猕猴)进行120分钟的常温体外循环。通过预肝素化提高猴子的血浆TFPI，并与对照组动物的凝血酶生成水平进行比较。结果：在模拟体外循环中，3组动物均有明显的凝血酶生成，且TF促进F1+2的生成。在Tf加诱导性TFPI组，预肝素化导致总TFPI增加3倍，而凝血酶的生成在CPB期间显著减少到对照水平，尽管使用了Tf。在灵长类CPB动物模型中，与对照组相比，预先肝素化可使猕猴血浆TFPI升高，抑制外源性途径可降低凝血酶生成水平。结论：虽然Tf促进CPB中凝血酶的生成，但接触途径和内在途径在凝血酶生成中可能仍起着相当大的作用。在临床体外循环中，早期应用肝素引起的血浆TFPI的大量释放可能会减弱对TF依赖的凝血酶的产生。较少