Altered fibrin clot structure contributes to thrombosis risk in severe COVID

  

View ORCID ProfileMalgorzata Wygrecka, Anna Birnhuber, Benjamin Seeliger, Laura Michalick, Oleg Pak, Astrid-Solveig Schultz, Fabian Schramm, Martin Zacharias, Gregor Gorkiewicz, Sascha David, Tobias Welte, Julius J. Schmidt, Norbert Weissmann, Ralph T Schermuly,  View ORCID ProfileGuillermo Barreto, Liliana Schäfer, Philipp Markart, Markus C. Brack, Stefan Hippenstiel,  View ORCID ProfileFlorian Kurth, Leif E Sander, Martin Witzenrath, Wolfgang M. Kuebler, Grazyna Kwapiszewska, Klaus T Preissner

doi: https://doi.org/10.1101/2021.09.17.460777

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.09.17.460777v1.full.pdf

Abstract

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2021.09.17.460777v1