Disturbed regulation of immunothrombosis in cerebral ischemia associated with SARS-CoV-2 infection

Background: During the COVID-19 pandemic, it became evident that an infection with SARS-CoV-2 is associated with an increased predisposition for thrombembolic events. Recent studies suggest an excessive neutrophil extracellular trap (NET)-formation in response to SARS-CoV-2, which is considered a hallmark in immunothrombosis. A better understanding of the (dys)regulation of NET-formation in COVID-19 may provide the basis for new therapeutic strategies.

Methods: We conducted a pilot study with a total of 84 patients in three groups matched in a 1:1:1 fashion: Group 1: patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and SARS-CoV-2 infection, Group 2: patients with AIS and no SARS-CoV-2 infection and Group 3: patients with SARS-CoV-2 infection and no AIS or TIA. Venous blood samples were collected from all patients and subsequently analyzed for NET-specific markers, NET regulators (Deoxyribonuclease (DNase) activity) and a panel of cytokines.

Results: Citrullinated histone3 (H3cit) and elastase levels were higher in groups with SARS-CoV-2 infection (Groups 1 and 3) compared to patients without ((group 1: H3cit = 2.9 (1.11-6.89) ng/mL, elastase = 312.1 (162-435.4) ng/mL and group 3: H3cit = 3.31 (2.03-7.97) ng/mL and elastase = 433.1 (281-783.8) ng/mL) vs. group 2: H3cit = 1.17 (0.61-2.15) ng/mL), elastase = 195.1 (91.99-386.9) ng/mL). No relevant differences were found regarding other measured NET-marker (myeloperoxidase, LL-37). DNase activity was lower in group 1 (6.12 (4.97-6.78) pmol/mL/min) compared to both other groups (group 2: (7.16 (5.88-7.85) pmol/mL/min) (p=0.018) and group 3 (7.19 (5.52-8.54) pmol/mL/min) (p=0.013).

Conclusion: This pilot data suggest that a disturbed regulation of NETs in patients with SARS-CoV-2 infection may play a role in SARS-CoV-2 associated cerebral ischemia. These results highlight the importance of further investigating the role of NETs in immunothrombosis in the context of viral infections, to better understand its potential as a target for therapeutic strategies.