Neutrophil extracellular traps in ischemic stroke thrombi: Lessons from the COVID-19 pandemic

Background and Aims: Recent studies have found that COVID-19 patients displayed resistance to fibrinolysis and that neutrophil extracellular traps (NETs) contributed to pulmonary microthrombotic complications of COVID-19.We aimed to analyze and compare AIS thrombi from COVID-19 and non COVID19 patients and to determine whether and how NETs played a role in their resistance to thrombolysis. Methods: A total of 32 thrombi, recovered from COVID-19 AIS patients (N=15) or non-COVID-19 patients (N=17) and treated with endovascular therapy, were analyzed by immunohistology, RT-PCR, or subjected to ex vivo thrombolysis. Results: All analyzed COVID-19 AIS thrombi were rich in neutrophils and NETs. SARS-CoV-2 RNA was not detected in the 3 COVID-19 positive analyzed thrombi. Ex vivo thrombolysis assay revealed a highly resistant pattern to tPA-induced thrombolysis in both groups. The addition of DNase 1 successfully reversed this thrombolysis resistance in a same proportion in both groups. Conclusions: Our results identify NETs as important mediators of fibrinolysis resistance in patients with AIS independently of the COVID-19. NETs-targeting therapy with DNase 1 could offer a therapeutic opportunity to improve the efficacy of tPA in all AIS population regardless of the underlying AIS etiology.