Procoagulant microparticles promote coagulation in a factor XI-dependent manner in human endotoxemia.
Procoagulant microparticles promote coagulation in a factor XI-dependent manner in human endotoxemia.
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DOI：
10.1111/jth.13285
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Key NS
中科院分区：
文献类型：
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作者：
Mooberry MJ;Bradford R;Hobl EL;Lin FC;Jilma B;Key NS
人内毒素血症的特征在于急性炎症和凝血激活，以及循环微粒（MP）数量增加。然而，这些MP是否直接促进凝血以及通过何种途径介导其作用尚未完全探索。在这项研究中，我们的目的是进一步表征内毒素诱导的MP和他们的促凝血性能使用几种方法。使用新一代流式细胞仪进行MP的计数和表征。使用缺乏FVII或FXI或组织因子（TF）或FXIa阻断抗体的血浆评估MP介导的促凝血活性中外源性和内源性途径的相对贡献。在健康人受试者中，在输注内毒素后6小时，血浆中的总MP和血小板MP显著升高。内毒素输注后从血浆中分离的MP也证明在重建的缓冲系统中TF活性增加。当添加到再钙化的贫血小板血浆中时，这些MP还促进凝血，如通过使用校准的自动血栓描记术（CAT）缩短滞后时间和凝血酶峰值时间的凝血时间减少所判断的。然而，使用FVII缺乏血浆或TF阻断抗体并不能抑制这些促凝血作用。相比之下，FXI缺乏血浆中的血浆凝血时间延长，并且在CAT试验中，FXIa的封闭抗体抑制所有MP介导的参数。内毒素血症中由细胞TF引发的凝血作用与循环MP的内在途径介导的促凝作用相反（并可能得到补充）。
Human endotoxemia is characterized by acute inflammation and activation of coagulation, as well as increased numbers of circulating microparticles (MPs). Whether these MPs directly promote coagulation and through which pathway their actions are mediated, however, has not been fully explored. In this study, we aimed to further characterize endotoxin-induced MPs and their procoagulant properties using several approaches. Enumeration and characterization of MPs were performed using a new generation flow cytometer. Relative contributions of the extrinsic and intrinsic pathways in MP-mediated procoagulant activity were assessed using plasmas deficient in FVII or FXI or with blocking antibodies to tissue factor (TF) or FXIa. Total MPs and platelet MPs were significantly elevated in plasma at 6 hours after infusion of endotoxin in healthy human subjects. MPs isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a re-constituted buffer system. When added to re-calcified platelet poor plasma, these MPs also promoted coagulation, as judged by a decreased clotting time with shortening of the lag time and time to peak thrombin using calibrated automated thrombography (CAT). However, the use of FVII deficient plasma or blocking antibody to TF did not inhibit these procoagulant effects. In contrast, plasma clotting time was prolonged in FXI deficient plasma, and a blocking antibody to FXIa inhibited all MP-mediated parameters in the CAT assay. The initiation of coagulation by cellular TF in endotoxemia is in contrast to (and presumably complemented by) the intrinsic pathway-mediated procoagulant effects of circulating MPs.