Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model.
Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model.
复制标题
重组人组织因子途径抑制剂对大鼠 DIC 模型中血栓形成及其体内分布的影响。
DOI：
10.1093/ajcp/106.5.574
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发表时间：
1996
影响因子：
3.5
通讯作者：
K. Sueishi
中科院分区：
文献类型：
--
作者：
Y. Elsayed;K. Nakagawa;Y. Kamikubo;K. Enjyoji;H. Kato;K. Sueishi
组织因子途径抑制物（TFPI）在调节组织因子依赖性凝血过程中起关键作用。本研究旨在观察重组人TFPI（recombinant human TFPI，rTFPI）对大鼠弥散性血管内凝血（disseminated intravascular coagulation，DIC）模型血栓形成的抑制作用，以及外源性TFPI在大鼠体内的分布。通过给予引发剂量的角叉菜胶10 mg/kg体重诱导弥散性血管内凝血，24小时后给予激发剂量的脂多糖（LPS）500 mg/kg体重。在LPS处理后立即以1或4 mg/kg体重的剂量静脉内施用rTFPI。外源性rTFPI在4 mg/kg剂量下显著抑制纤维蛋白原、血小板和因子VIIa的消耗（P <0.05），并且还减少肝、肺、肾和脾中形成的纤维蛋白血栓的数量（P <0.05），而rTFPI在1 mg/kg剂量下对这些DIC参数没有显著抑制作用。重组人rTFPI活性从血浆中迅速清除;然而，即使在静脉给药后3至6小时，组织中仍存在大量抑制剂。外源性TFPI主要在枯否细胞、巨噬细胞和不同器官的微血管内皮细胞衬里上被鉴定。在肾脏中，在肾小管的近腔表面和近曲小管的腔表面上鉴定出rTFPI。然而，在肝细胞中未检测到rTFPI。组织因子主要由单核/巨噬细胞表达。这些结果表明，TFPI在调节TF依赖性血栓形成中起着重要作用。因此，阐明rTFPI在体内的分布和相互作用可能为其抑制机制及其在DIC中的治疗意义提供有价值的见解。
Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.