SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy

Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19. One-Sentence Summary SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody. ### Competing Interest Statement KA is a co-founder, scientific advisor and board director of Therini Bio. KA is the inventor of the 5B8 patent. KA, JKR, MM and WCG are inventors on a patent application for 5B8 use in COVID-19. KA, JKR, MM, EGS and WCG are inventors on a patent application related to Spike-induced thromboinflammation model. KA and JKR are inventors on fibrin assay patents. Their interests are managed in accordance with their respective institutions conflict of interest policy.