PROS1 and infection: These findings suggest that SARS-CoV-2 S protein-associated coagulation and systemic inflammation during infection may contribute to the development of post-acute sequelae of COVID-19.IMPORTANCEOur study investigates the distinctive pathogenic properties of the SARS-CoV-2 spike (S) protein from highly virulent variants, with a particular focus on its delayed pathological effects in mice.