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

Wygrecka, M.; Birnhuber, A.; Seeliger, B.; Michalick, L.; Pak, O.; Schultz, A.-S.; Schramm, F.; Zacharias, M.; Gorkiewicz, G.; David, S.; Welte, T.; Schmidt, J. J.; Weissmann, N.; Schermuly, R. T.; Barreto, G.; Schäfer, L.; Markart, P.; Brack, M. C.; Hippenstiel, S.; Kurth, F.; Sander, L. E.; Witzenrath, M.; Kuebler, W. M.; Kwapiszewska, G.; Preissner, K. T.

doi:10.1101/2021.09.17.460777

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bioRxiv · 10.1101/2021.09.17.460777

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

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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.

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Wygrecka, M., Birnhuber, A., Seeliger, B., Michalick, L., Pak, O., Schultz, A.-S., Schramm, F., Zacharias, M., Gorkiewicz, G., David, S., Welte, T., Schmidt, J. J., Weissmann, N., Schermuly, R. T., Barreto, G., Schäfer, L., Markart, P., Brack, M. C., Hippenstiel, S., Kurth, F., Sander, L. E., Witzenrath, M., Kuebler, W. M., Kwapiszewska, G., Preissner, K. T.. 2021-09-18. Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19. https://doi.org/10.1101/2021.09.17.460777

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