Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19

• Published in: Blood advances 2022-02, Vol.6 (3), p.1074-1087
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: COVID-19; Fibrin; Fibrinolysis; Humans; Life Sciences; SARS-CoV-2; Thrombosis - etiology; Thrombosis and Hemostasis
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2021004816

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19. •Elevated fibrinogen, in conjunction with accelerated formation of FXIIa, may promote compact fibrin clot architecture in COVID-19.•A dense fibrin network and dysregulated fibrinolysis collectively contribute to a high incidence of thrombotic events in COVID-19. [Display omitted]