Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19

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

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.