TO THE EDITOR:
The recent publication by Kangro et al1 in Blood Advances entitled “SARS-CoV-2 spike protein can bind fibrin(ogen), but does not alter plasma fibrin formation, clot structure, or lysis,” demonstrate that full-length native trimeric SARS-CoV-2 spike protein folded to its trimeric prefusion state does not notably influence fibrin(ogen) function. Numerous reports of thrombotic ailments in conjunction with COVID-19, are found in the literature, of which Ryu et al2 and Grobbelaar et al3 are cited in the Kangro et al study. Histological evidence show the presence of spike or spike fragments in COVID-19–associated thrombi.4 Grobbelaar et al showed that the S1 subunit of the spike protein (ie, mainly the folded monomer) could interfere with fibrin structure and induce an amyloid-like fibrin structure.3 Notably Kangro et al used a recombinant stabilized full-length SARS-CoV-2 spike. Ryu et al showed deleterious effects on fibrin structure in human plasma when a similar folded spike construct was used,2 unlike Kangro et al, which did not replicate the spike-induced effect on fibrin formation. Both studies used human plasma as reagent. It is not unusual for the proteolytic activity to vary between plasma samples.
Our hypothesis is that native, properly folded spike protein will be rather inert in fibrin(ogen) clot formation. Although spike protein is readily proteolytically processed in vivo and cleaved, fragmented spike is a different beast. We showed that proteolytic processing of spike, mediated by neutrophil elastase, yielded cleaved protein and short spike-derived peptides that formed amyloid fibrils, whereas intact, folded spike does not.5 We recently showed that specific amyloids from spike affect fibrin formation and fibrinolysis differently.6
Taken together, the above findings and results from our study, support a unified structural hypothesis. Pathological modulation of fibrin(ogen) by SARS-CoV-2 spike protein is not an intrinsic property of the native spike fold. Instead, it requires proteolytic generation of spike fragments assembled into amyloid fibrils. Only in this misfolded, fibrillar state, can spike-derived proteins acquire the ability to dysregulate fibrin structure and impair fibrinolysis.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Acknowledgments
Contribution: P.H. and S.N. wrote the manuscript.
Contributor Information
Per Hammarström, Email: per.hammarstrom@liu.se.
Sofie Nyström, Email: sofie.nystrom@liu.se.
References
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