Neutrophil extracellular traps in ischemic stroke thrombi

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Ischemic stroke is caused by a blood clot that occludes one or multiple arteries in the brain. Blockade of blood flow by an occlusive thrombus leads to irreversible damage of the associated cerebral tissue. The mainstay of current ischemic stroke treatment is rapid removal of the thrombotic occlusion to establish early vessel recanalization, reducing tissue injury and improving patient outcome.1 Despite recent therapeutic advances, ischemic stroke still remains a leading cause of death and permanent disability worldwide.2 The enormous clinical, economic, and social burden of ischemic stroke is in strong contrast with the limited treatment options that are available. Only 2 causal treatment regimens are currently approved by the U.S. Food and Drug Administration (FDA): (1) pharmacological thrombolysis using tissue plasminogen activator (t‐PA), which promotes degradation of fibrin in the occluding thrombus; and (2) mechanical removal of the thrombus via endovascular thrombectomy. Endovascular treatment is unfortunately not always available, and t‐PA therapy is limited by the narrow therapeutic time window (4.5 hours after stroke onset)3. Strikingly, even when t‐PA treatment is started within hours of symptom onset, recanalization is achieved only in less than half of the patients who receive it.4 The exact reasons for this so‐called "t‐PA resistance" are currently unknown, but thrombus composition is believed to play an important role.5 Although the thrombus itself is the primary target for pharmacological thrombolysis, surprisingly little is known about the composition of thrombi that cause ischemic stroke. However, such information is crucial for designing efficient and safe thrombolytic strategies. With cerebral thrombectomy becoming more routinely used in the clinic, patient thrombi are becoming readily available to study their composition. First insights point toward a diverse thrombus composition, suggesting that many factors could influence thrombolysis success rates.6
Recently, neutrophil extracellular traps (NETs) have been found to be implicated in thrombosis.14 Initially discovered as a novel form of neutrophil‐mediated immunity, NETs form through the release of decondensed chromatin that is lined with granular components, creating fibrous structures with antimicrobial properties.16 A key feature of NET formation is citrullination of histones (eg, citrullinated histone H3 [H3Cit]) allowing decondensation of the nuclear chromatin. Besides their immunological role, NETs also contribute to both venous and arterial thrombosis.14 NETs form a scaffold for platelets and red blood cells15 and influence the coagulation cascade.17 Nothing is currently known about the presence of NETs in ischemic stroke thrombi. The aim of this study, therefore, was to assess whether neutrophils and in particular NETs are present in thrombi retrieved from ischemic stroke patients and to investigate whether targeting extracellular chromatin by DNase 1 could influence thrombus stability.

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