SARS-CoV-2 spike protein can bind fibrin(ogen), but does not alter plasma fibrin formation, clot structure, or lysis

COVID-19 is associated with dysregulated coagulation, including elevated fibrinogen and Ddimer levels, and a heightened risk of thrombosis. The SARS-CoV-2 viral particle expresses the homotrimeric spike protein that mediates viral entry into host cells primarily by binding to the host angiotensin-converting enzyme 2 (ACE2). Notably, the N-terminal domain (NTD) of the spike protein, which is not involved in binding to the ACE2 receptor, can mediate binding to other host proteins. A recent study reported the binding of spike protein to fibrinogen and suggested this interaction alters fibrin polymerization, fibrin clot structure, and susceptibility of clots to fibrinolysis.5 The fibrin(ogen) binding site for spike protein was suggested to lie within the γ-chain between residues 364-395, which overlaps the same region (γ390-396) that binds coagulation factor XIII (FXIII) in soluble fibrinogen and the αMβ2 integrin receptor in tethered fibrinogen and fibrin. Although computational modeling (HADDOCK, AlphaFold) predicted an interaction between spike protein and (soluble) fibrinogen, experimental methods detected binding only when fibrinogen was immobilized on a surface which resulted in a relatively weak interaction (kD=5300 nM). Moreover, binding was only observed when spike protein was 2-3 orders of magnitude higher than the highest concentration ever observed in blood (up to 2.25 nM [300 ng/mL] from patients with COVID-19, and up to 0.75 nM [0.1 ng/mL] in vaccinated donors).