Influence of ADAMTS13 deficiency on venous thrombosis in mice
Influence of ADAMTS13 deficiency on venous thrombosis in mice
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ADAMTS13缺陷对小鼠静脉血栓形成的影响
DOI：
10.1160/th14-08-0656
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Miyata T
中科院分区：
文献类型：
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作者：
Tashima Y;Banno F;Akiyama M;Miyata T
最近对静脉血栓形成的实验性小鼠模型的研究表明，中性粒细胞、单核细胞和血小板有助于静脉血栓形成的启动和扩大（1-4）。在静脉血栓形成的早期阶段，中性粒细胞被募集，并且在激活时，中性粒细胞胞外陷阱（由DNA、组蛋白和颗粒细胞毒性酶组成）被释放，并且在血管腔上形成网状胞外网络。中性粒细胞胞外陷阱为血小板粘附和聚集提供了一个支架，用于招募红细胞（3，5）。单核细胞也被募集到活化内皮的部位，并通过组织因子的血管内表达参与纤维蛋白形成（2）。激活的内皮细胞从招募循环血小板的韦伯-帕拉德小体释放异常大的血管性血友病因子（VWF）多聚体。由于VWF缺陷小鼠的静脉血栓形成模型中的血栓大大减少，因此VWF多聚体对于血小板的募集是重要的，并且对于血栓形成是必需的（1）血小板与VWF的结合受血浆VWF切割蛋白酶ADAMTS 13的负调控。我们和其他人先前已经证明，ADAMTS 13缺陷型小鼠没有表现出任何血小板减少症、溶血性贫血或微血管血栓形成的证据，尽管在其血浆中检测到异常大的VWF多聚体（6-8）。由于ADAMTS 13减少了VWF多聚体的大小，从而降低了其血栓形成的可能性，我们假设ADAMTS 13缺乏可能导致VWF多聚体上血小板的过度募集，并导致静脉血栓形成的加重。为了测试ADAMTS 13缺陷是否促进血栓形成，我们使用电解质下腔静脉（IVC）模型在ADAMTS 13缺陷小鼠中诱导静脉血栓形成（4，9）。
Recent studies of experimental murine models of venous thrombosis revealed that neutrophils, monocytes and platelets contribute to the initiation and amplification of venous thrombosis (1–4). In the early stage of venous thrombosis, neutrophils are recruited and, upon activation, neutrophil extracellular traps (composed of DNA, histones, and granule cytotoxic enzymes) are released and a web-like extracellular network is formed on the vascular lumen. The neutrophil extracellular traps provide a scaffold for platelet adhesion and aggregation for the recruitment of red blood cells (3, 5). Monocytes are also recruited to the site of activated endothelium and are involved in fibrin formation through the intravascular expression of tissue factor (2). Activated endothelium releases unusually large von Willebrand factor (VWF) multimers from Weibel-Palade bodies that recruit circulating platelets. Since thrombi in the venous thrombosis models in VWF-deficient mice were greatly reduced, VWF multimers are important for the recruitment of platelets and essential for thrombus formation (1).The platelet binding to VWF is negatively regulated by a plasma VWF-cleaving protease, ADAMTS13. We and others have previously demonstrated that ADAMTS13-deficient mice do not show any evidence of thrombocytopenia, haemolytic anaemia, or microvascular thrombosis, although unusually large VWF multimers were detected in their plasma (6–8). As ADAMTS13 reduces the size of VWF multimers, thereby decreasing their thrombogenic potential, we hypothesised that ADAMTS13 deficiency could cause an excess recruitment of platelets on VWF multimers and result in an aggravation of venous thrombosis. To test whether ADAMTS13 deficiency promotes thrombus formation, we induced venous thrombosis in ADAMTS13-defficient mice using the electrolytic inferior vena cava (IVC) model (4, 9).