From the Université Paris Diderot, Sorbonne Paris Cite, Laboratory of Vascular Translational Science, U1148 Institut National de la Santé et de la Recherche Médicale (INSERM), France (C. Ducroux, L.D.M., S.L., S.D., W.B., C. Deschildre, R.B., J.-B.M., M.P., M.M., B.H.-T.-N., J.-P.D.); Department of Interventional Neuroradiology (W.B., R.B., H.R., G.C., S.S., R.F., M.P., M.M., J.-P.D.) and Department of Clinical Research (M.B.M., L.S.), Rothschild Foundation Hospital, Paris, France; and DHU NeuroVasc, Paris, France (M.M.).
Stroke. 2018 Mar;49(3):754-757. doi: 10.1161/STROKEAHA.117.019896. Epub 2018 Feb 8.
Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identified as major triggers and structural factors of thrombosis. A recent study designated extracellular DNA threads from NETs as a potential therapeutic target for improving tissue-type plasminogen activator (tPA)-induced thrombolysis in acute coronary syndrome. The aim of this study was to assess the presence of NETs in thrombi retrieved during endovascular therapy in patients with acute ischemic stroke (AIS) and their impact on tPA-induced thrombolysis.
We analyzed thrombi from 108 AIS patients treated with endovascular therapy. Thrombi were characterized by hematoxylin/eosin staining, immunostaining, and ex vivo enzymatic assay. Additionally, we assessed ex vivo the impact of deoxyribonuclease 1 (DNAse 1) on thrombolysis of AIS thrombi.
Histological analysis revealed that NETs contributed to the composition of all AIS thrombi especially in their outer layers. Quantitative measurement of thrombus NETs content was not associated with clinical outcome or AIS pathogenesis but correlated significantly with endovascular therapy procedure length and device number of passes. Ex vivo, recombinant DNAse 1 accelerated tPA-induced thrombolysis, whereas DNAse 1 alone was ineffective.
This study suggests that thrombus NETs content may be responsible for reperfusion resistance, including mechanical or pharmacological approaches with intravenous tPA, irrespectively of their etiology. The efficacy of a strategy involving an administration of DNAse 1 in addition to tPA should be explored in the setting of AIS.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736.
中性粒细胞胞外诱捕网（NETs）是由活化的中性粒细胞产生的带有组蛋白和颗粒蛋白的细胞外 DNA 网络。NETs 已被确定为血栓形成的主要触发因素和结构因素。最近的一项研究将 NETs 中的细胞外 DNA 线程指定为改善组织型纤溶酶原激活剂（tPA）诱导的急性冠脉综合征溶栓的潜在治疗靶点。本研究旨在评估急性缺血性脑卒中（AIS）患者血管内治疗中取出的血栓中是否存在 NETs 及其对 tPA 诱导的溶栓的影响。
我们分析了 108 例接受血管内治疗的 AIS 患者的血栓。通过苏木精/伊红染色、免疫染色和体外酶测定对血栓进行了特征描述。此外，我们还评估了脱氧核糖核酸酶 1（DNAse 1）对 AIS 血栓溶栓的体外影响。
组织学分析显示，NETs 构成了所有 AIS 血栓的组成部分，尤其是在血栓的外层。血栓 NETs 含量的定量测量与临床结果或 AIS 发病机制无关，但与血管内治疗程序长度和器械通过次数显著相关。体外，重组 DNAse 1 加速了 tPA 诱导的溶栓，而 DNAse 1 本身无效。
本研究表明，血栓 NETs 含量可能是导致再灌注抵抗的原因，包括静脉内 tPA 的机械或药物治疗方法，而与病因无关。应在 AIS 患者中探索在 tPA 基础上加用 DNAse 1 的治疗策略的疗效。
