Background: The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rtPA) is favorable in only approximately 35% of acute ischemic stroke (AIS) patients. Neutrophil extracellular traps (NETs), composed of extracellular networks of DNA, histones, and neutrophil granular proteins are important constituents of cerebral thrombi. NETs intercalate to fibrin and create a dense network that impairs fibrinolysis.

Aims: To investigate whether levels of circulating markers of NETs, as assessed in AIS patients before thrombolysis, are associated with therapy failure.

Methods: In this prospective observational study, blood samples of 287 consecutive AIS patients, all undergoing i.v. thrombolysis by rtPA within 4.5 h of their symptom onset, were taken on admission. Levels of human neutrophil elastase-α1 antitrypsin (HNE-AT) complex, cell-free DNA (cfDNA) and histone-complexed-DNA-fragments (DNA-histone complexes) were measured from stored platelet-poor-plasma samples. Detailed clinical, laboratory investigations and imaging data (CT angiography) were obtained from patients on admission. Stroke severity was determined by NIHSS. Therapy-associated intracerebral hemorrhage (ICH) was classified according to ECASSII criteria. Short- and long-term outcomes were defined at 7 days and 3 months post-event according to the change in NIHSS and by the modified Rankin Scale (mRS), respectively. All patients or their relatives provided written informed consent.

Results: Levels of cfDNA on admission showed significant, stepwise elevation in case of more severe stroke. Patients with favorable long-term outcomes (mRS 0-1) had significantly lower cfDNA levels (median:65.8 [IQR:54.7-79.3] ng/mL) as compared to patients with poor outcomes (mRS 2-6: median:74.3 [IQR:59.4-88.7] ng/mL, p=0.027). Similar results were obtained for HNE-AT (mRS 0-1: median:0.49 [IQR:0.34-0.72] ng/mL vs. mRS 6: 0.79 [IQR:0.46-1.60] ng/mL, p=0.002). In patients who suffered therapy-related ICH (n=24), HNE-AT levels were significantly higher as compared to those without hemorrhagic complication (median:0.53 [IQR:0.35-0.84] vs. 0.82 [IQR:0.42-1.62] ng/mL, respectively, p=0.016).

Conclusions: Circulating markers of NETs, particularly cfDNA and HNE-AT might be useful to predict thrombolysis outcomes in AIS patients.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/elevated-levels-of-circulating-markers-of-neutrophil-extracellular-traps-nets-are-associated-with-unfavorable-outcomes-in-acute-ischemic-stroke-patients-undergoing-intravenous-thrombolysis/