Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke

• Respiratory tract infections with S. aureus or SARS-CoV-2 increase plasma VWF levels and decrease ADAMTS13 activity.

• VWF may have a causal role in worsening stroke outcomes in respiratory tract infections preceding stroke, while ADAMTS13 may be protective.

Respiratory tract infections (RTIs) caused by bacteria or viruses are associated with stroke severity. Recent studies have revealed an imbalance in the von Willebrand factor (VWF)-ADAMTS13 axis in patients with RTIs, including COVID-19. We examined whether this imbalance contributes to RTI-mediated stroke severity. Wild-type (WT), Vwf −/−, or Adamts13−/− mice with respective littermate controls (Vwf +/+, or Adamts13+/+) were infected intranasally with sublethal doses of S. aureus (on days 0, 2, and 5) or mouse-adapted SARS-CoV-2 (on day 0) and subjected to transient (30 or 45 min) cerebral ischemia followed by reperfusion. In S. aureus-infected mice, infarct volumes were assessed on day 2 and functional outcomes on weeks 1 and 4 post-reperfusion. In SARS-CoV-2-infected mice, infarct volumes and functional outcomes (Bederson score) were assessed on day 1 post-reperfusion. We demonstrated that S. aureus or SARS-CoV-2 RTI was accompanied by an imbalance in the VWF-ADAMTS13 axis and an increase in plasma levels of IL-6, CXCL1, and MCP-1, which was associated with larger infarcts and worse functional outcomes (P<0.05 vs. mock-infection). S. aureus- or SARS-CoV-2-infected Vwf −/− mice exhibited reduced infarcts and improved functional outcomes, while infected Adamts13−/− mice displayed greater stroke severity (P<0.05 vs. control). In the models of RTI preceding stroke, VWF contributes to stroke severity, while ADAMTS13 is protective.