Neutrophil Extracellular Traps Block Fibrinolysis in Ischemic Stroke
Abstract
OBJECTIVES: Intravenous thrombolysis (IVT) failure in acute ischemic stroke (AIS) is frequent, but its causes remain elusive. We investigated whether biologically relevant intrathrombus concentrations of tissue plasminogen activator (tPA) were achieved in failed IVT and whether neutrophil extracellular traps (NETs) contributed to this therapeutic failure. METHODS: In this monocenter cohort study, 205 thrombi from AIS patients were analyzed. A total of 83 of these thrombi were compared for tPA content and 53 for their susceptibility to ex vivo thrombolysis according to IVT status. An additional subset of 69 AIS thrombi was used to decipher if and how NETs interfere with intrathrombus fibrinolysis. RESULTS: Thrombi from IVT patients contained twice as much tPA than those from no-IVT patients (p < 0.0001). Plasminogen and tPA in AIS thrombi were associated with fibrin, leukocytes, and NETs. Although ex vivo addition of plasminogen did not cause lysis of either no-IVT or IVT thrombi, combining plasminogen with deoxyribonuclease 1 (DNase 1) helped translate the increased tPA content of IVT thrombi into increased thrombolysis. We further show that DNase 1 enables tPA- and plasmin-mediated thrombolysis by eliminating fibrinolysis inhibitors from AIS thrombi. INTERPRETATION: These results indicate that intrathrombus tPA concentrations reached in failed IVT bear a therapeutic potential that is impaired by NETs, which favor intrathrombus retention of fibrinolysis inhibitors and may limit the availability of tPA and plasminogen for fibrinolysis. Our results stress the interest of DNase 1 to enhance the efficacy of current IVT tPA regimens. ANN NEUROL 2026;100:964-978.
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BibTeX
@article{nomenjanahary2026neutrophil,
title = {{Neutrophil Extracellular Traps Block Fibrinolysis in Ischemic Stroke}},
author = {Mialitiana Solo Nomenjanahary and Jean‐philippe Desilles and Fatima Zemali and Astride Perrot and Lucas Di Meglio and Sara Zalghout and Jéromine Fasille and Jérémy Neel and Stéphane Loyau and Julien Labreuche and Marie‐charlotte Bourrienne and Dorothée Faille and François Delvoye and Véronique Ollivier and Sébastien Dupont and Jasmina Rogozarski and Nahida Brikci-Nigassa and Robert Medcalf and Nadine Ajzenberg and Mikael Mazighi and Benoît Ho-Tin-Noé},
journal = {Annals of Neurology},
year = {2026},
month = sep,
doi = {10.1002/ana.78346},
url = {https://hal.science/hal-05790371v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neutrophil Extracellular Traps Block Fibrinolysis in Ischemic Stroke
AU - Mialitiana Solo Nomenjanahary
AU - Jean‐philippe Desilles
AU - Fatima Zemali
AU - Astride Perrot
AU - Lucas Di Meglio
AU - Sara Zalghout
AU - Jéromine Fasille
AU - Jérémy Neel
AU - Stéphane Loyau
AU - Julien Labreuche
AU - Marie‐charlotte Bourrienne
AU - Dorothée Faille
AU - François Delvoye
AU - Véronique Ollivier
AU - Sébastien Dupont
AU - Jasmina Rogozarski
AU - Nahida Brikci-Nigassa
AU - Robert Medcalf
AU - Nadine Ajzenberg
AU - Mikael Mazighi
AU - Benoît Ho-Tin-Noé
PY - 2026
DA - 2026/09/15
JO - Annals of Neurology
DO - 10.1002/ana.78346
UR - https://hal.science/hal-05790371v1
AB - OBJECTIVES: Intravenous thrombolysis (IVT) failure in acute ischemic stroke (AIS) is frequent, but its causes remain elusive. We investigated whether biologically relevant intrathrombus concentrations of tissue plasminogen activator (tPA) were achieved in failed IVT and whether neutrophil extracellular traps (NETs) contributed to this therapeutic failure. METHODS: In this monocenter cohort study, 205 thrombi from AIS patients were analyzed. A total of 83 of these thrombi were compared for tPA content and 53 for their susceptibility to ex vivo thrombolysis according to IVT status. An additional subset of 69 AIS thrombi was used to decipher if and how NETs interfere with intrathrombus fibrinolysis. RESULTS: Thrombi from IVT patients contained twice as much tPA than those from no-IVT patients (p < 0.0001). Plasminogen and tPA in AIS thrombi were associated with fibrin, leukocytes, and NETs. Although ex vivo addition of plasminogen did not cause lysis of either no-IVT or IVT thrombi, combining plasminogen with deoxyribonuclease 1 (DNase 1) helped translate the increased tPA content of IVT thrombi into increased thrombolysis. We further show that DNase 1 enables tPA- and plasmin-mediated thrombolysis by eliminating fibrinolysis inhibitors from AIS thrombi. INTERPRETATION: These results indicate that intrathrombus tPA concentrations reached in failed IVT bear a therapeutic potential that is impaired by NETs, which favor intrathrombus retention of fibrinolysis inhibitors and may limit the availability of tPA and plasminogen for fibrinolysis. Our results stress the interest of DNase 1 to enhance the efficacy of current IVT tPA regimens. ANN NEUROL 2026;100:964-978.
SN - 0364-5134
SN - 1531-8249
ER -