ArticleAnnals of neurology2026
Neutrophil Extracellular Traps Block Fibrinolysis in Ischemic Stroke.
Article in Annals of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectivesIntravenous 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.
methodsIn 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.
resultsThrombi 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.
interpretationThese 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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