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Letter: Surgical Performance Determines Functional Outcome Benefit in the Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) Procedure

Feng, Zhou MD; Tan, Qiang MD; Chen, Zhi MD, PhD

Author Information
doi: 10.1093/neuros/nyz533

To the Editor:

We read with great interest the recent article by Awad et al1 which firstly reported the specific thresholds of hematoma evacuation impacting the mortality and functional outcomes in intracerebral hemorrhage (ICH). Their study presents a goal for the future treatment and clinical trial of ICH.

Minimally invasive surgery plus tissue-plasminogen activator (tPA) has been considered as a promising treatment strategy for spontaneous ICH, but the fibrinolytic efficacy in clinical trials was far from satisfactory.2,3 Therefore, enhancing the fibrinolytic effect of tPA might be a potential target to promote the treatment of ICH.

In recent years, neutrophil extracellular traps (NETs) have been identified as crucial players participated in the formation of thrombi of various origins, attracting significant attentions.4 NETs are fibrous networks constituted with extracellular deoxyribonucleic acid (DNA) released by neutrophils chromatin in complex with histones and neutrophil granule proteins.5 A recent study reported that NETs contributed to the resistance of tPA-induced thrombolysis in acute ischemic stroke.6 By modifying the fibrin structure tighter, the NETs scaffold made fibrin more resistant to mechanical and enzymatic destruction, thus impairing tPA-induced thrombolysis.7 What's more, degrading NETs by recombinant deoxyribonuclease 1 (DNAse 1) could improve tPA-induced thrombolysis.6,8

Since neutrophil infiltration is a significant pathophysiology after ICH,9 it is reasonable to suspect that NETs participate in the process of ICH. In our recent study,10 we firstly confirmed that NETs were present within the hematoma following ICH in a rat model, and targeting NETs with DNAse 1 enhanced tPA-induced hematoma fibrinolysis and improved the therapeutic effect of ICH rats. Our findings indicate NETs implicate in the resistance of tPA-induced fibrinolysis in ICH, which is also likely to happen in intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Thus, targeting NETs to enhance tPA-induced fibrinolysis might be a promising therapeutic strategy for ICH, as well as IVH and SAH.


The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.


1. Awad IA, Polster SP, Carrion-Penagos J, et al. Surgical performance determines functional outcome benefit in the minimally invasive surgery plus recombinant tissue plasminogen activator for intracerebral hemorrhage evacuation (MISTIE) procedure. Neurosurgery. 2019;84(6):1157-1168.
2. Hanley DF, Thompson RE, Muschelli J, et al. Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial. Lancet Neurol. 2016;15(12):1228-1237.
3. Hanley DF, Thompson RE, Rosenblum M, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019;393(10175):1021-1032.
4. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-76.
5. Brinkmann V. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-1535.
6. Ducroux C, Di Meglio L, Loyau S, et al. Thrombus neutrophil extracellular traps content impair tPA-Induced thrombolysis in acute ischemic stroke. Stroke. 2018;49(3):754-757.
7. Longstaff C, Varjú I, Sótonyi P, et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288(10):6946-6956.
8. Pena-Martinez C, Duran-Laforet V, Garcia-Culebras A, et al. Pharmacological modulation of neutrophil extracellular traps reverses thrombotic stroke tPA (tissue-type plasminogen activator) resistance. Stroke. 2019;50(11):3228-3237.
9. Kurland DB, Gerzanich V, Simard JM. Heme induces microglial CXCL2 release-a mechanism of neutrophil-mediated injury after intracerebral hemorrhage. Neurosurgery. 2013; 60(CN_suppl_1):183.
10. Tan Q, Guo P, Zhou J, et al. Targeting neutrophil extracellular traps enhanced tPA fibrinolysis for experimental intracerebral hemorrhage. Transl Res. 2019;211:139-146.
Copyright © 2019 by the Congress of Neurological Surgeons