RT Journal Article
T1 Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance
A1 Peña Martínez, Carolina Belén
A1 Durán Laforet, Violeta
A1 García Culebras, Alicia
A1 Ostos, Fernando
A1 Hernández Jiménez, Macarena
A1 Bravo-Ferrer, Isabel
A1 Perez-Ruiz, Alberto
A1 Bellenilla, Federico
A1 Díaz Guzmán, Jaime
A1 Lizasoaín Hernández, Ignacio
A1 Moro Sánchez, María Ángeles
AB Background and Purpose- Recanalization of the occluded artery is a primary goal in stroke treatment. Unfortunately, endovascular treatment is not always available, and tPA (tissue-type plasminogen activator) therapy is limited by its narrow therapeutic window; importantly, the rate of early arterial recanalization after tPA administration is low, especially for platelet-rich thrombi. The mechanisms for this tPA resistance are not well known. Since neutrophil extracellular traps (NETs) have been implicated in this setting, our aim was to study whether NET pharmacological modulation can reverse tPA resistance and the role of TLR4 (Toll-like receptor 4), previously related to NET formation, in thrombosis. Methods- To this goal, we have used a mouse photothrombotic stroke model, which produces a fibrin-free thrombus composed primarily of aggregated platelets and thrombi obtained from human stroke patients. Results- Our results demonstrate that (1) administration of DNase-I, which promotes NETs lysis, but not of tPA, recanalizes the occluded vessel improving photothrombotic stroke outcome; (2) a preventive treatment with Cl-amidine, impeding NET formation, completely precludes thrombotic occlusion; (3) platelet TLR4 mediates NET formation after photothrombotic stroke; and (4) ex vivo fresh platelet-rich thrombi from ischemic stroke patients are effectively lysed by DNase-I. Conclusions- Hence, our data open new avenues for recanalization of platelet-rich thrombi after stroke, especially to overcome tPA resistance.
PB AHA Journals
YR 2019
FD 2019-11
LK https://hdl.handle.net/20.500.14352/113573
UL https://hdl.handle.net/20.500.14352/113573
LA eng
NO Peña-Martínez C, Durán-Laforet V, García-Culebras A, Ostos F, Hernández-Jiménez M, Bravo-Ferrer I, Pérez-Ruiz A, Ballenilla F, Díaz-Guzmán J, Pradillo JM, Lizasoain I, Moro MA. Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance. Stroke. 2019 Nov;50(11):3228-3237. doi: 10.1161/STROKEAHA.119.026848. Epub 2019 Sep 17. PMID: 31526124.
NO Instituto de Salud Carlos III
NO Ministerio de Economía y Competitividad, Dirección General de Investigación
DS Docta Complutense
RD 25 abr 2025