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

背景：给予高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是否足以减弱在心肺转流（CPB）期间由组织因子（TF）触发的凝血酶生成。在这项研究中，我们的目的是提供证据，以阐明TFPI在模拟CPB和灵长类CPB期间和之后使用食蟹猴减弱TF依赖性凝血酶生成中的作用（Macaca fascicularis），其可通过各种药理学设置提供高或正常血浆水平的TEPI。通过在氧合器和滚子泵中再循环250 mL供体血液120分钟建立模拟CPB。评价了三种方案：对照（肝素3. 75 U/mL）; TF（肝素+重组人TF 1000 pg/mL）;和TF加诱导的TFPI（肝素+ TF，使用预肝素化的供体血液，每组n=7）。第三组给予肝素50 U/kg 关于我们 在捐献前五分钟静脉注射，以引起TFPI释放。采用酶联免疫法测定CPB前及CPB中血浆总TEPI、凝血酶-抗凝血酶复合物及F_（1+2）。对于灵长类CPB模型，我们使用食蟹猴（Macaca fascicularis）进行120分钟的常温CPB。血浆TFPI增强预肝素化猴，凝血酶生成水平进行了比较，与对照组动物。采用酶联免疫法测定CPB前及CPB中血浆中可溶性TF、总TFPI、凝血酶-抗凝血酶复合物及F_（1 + 2）的含量。在TF加诱导的TFPI组中，预肝素化导致总TFPI增加3倍，尽管给予TF，但CPB期间凝血酶生成显著降低至对照水平。在灵长类动物CPB模型中，血浆TFPI增强预肝素化的猴子，和水平的凝血酶生成减少抑制外源性途径时，与control group.Conclusions：虽然TF增强凝血酶生成CPB中，它是可能的接触和内在途径仍然发挥相当大的作用，在凝血酶生成。早期肝素给药诱导的血浆TFPI大量释放可能会减弱临床CPB期间TF依赖性凝血酶的生成。少

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