Celina Ducroux1, Lucas Di Meglio1, Stephane Loyau1, Sandrine Delbosc1, William Boisseau1, Catherine Deschildre1, Malek Ben Maacha1, Raphael Blanc1, Hocine Redjem1, Gabriele Ciccio1, Stanislas Smajda1, Robert Fahed1, Jean-Baptiste Michel1, Michel Piotin1, Laurence Salomon1, Mikael Mazighi1, Benoit Ho-Tin-Noe1, Jean-Philippe Desilles2. 1. 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.). 2. 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.). jpdesilles@gmail.com.
Abstract
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736.
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736.
Authors: Waleed Brinjikji; Sharon Duffy; Anthony Burrows; Werner Hacke; David Liebeskind; Charles B L M Majoie; Diederik W J Dippel; Adnan H Siddiqui; Pooja Khatri; Blaise Baxter; Raul Nogeuira; Matt Gounis; Tudor Jovin; David F Kallmes Journal: J Neurointerv Surg Date: 2016-05-10 Impact factor: 5.836