Annals of neurology · 2026
Neutrophil Extracellular Traps Block Fibrinolysis in Ischemic Stroke.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Solo Nomenjanahary Mialitiana, Desilles Jean-Philippe, Zemali Fatima, Perrot Astride, Di Meglio Lucas, Zalghout Sara, Fasille Jéromine, Neel Jérémy, Loyau Stéphane, Labreuche Julien, Bourrienne Marie-Charlotte, Faille Dorothée, Delvoye François, Ollivier Véronique, Dupont Sébastien, Rogozarski Jasmina, Brikci-Nigassa Nahida, Medcalf Robert L, Ajzenberg Nadine, Mazighi Mikael, Ho-Tin-Noé Benoît, compoCLOT Study Group
Аннотация
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.
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.