Impact of FXIIa on fibrin clot structure in plasma from patients with severe COVID-19. (A-B) Maximum turbidity values of fibrin clots generated in the purified system from increasing concentrations of fibrinogen and/or FXII/FXIIa, in the absence or presence of CTI. Clot formation was induced by thrombin (n = 4-5). (C) Representative laser scanning confocal microscopy images of fibrin fibers in clots formed from FXII-depleted SARS-CoV-2 or influenza plasma supplemented with FXII. Fibrin fibers were stained with an anti-fibrinogen/fibrin antibody followed by an Alexa Fluor 488-conjugated secondary antibody. (D) Fibrin fiber density in ARDS-influenza (n = 10) and COVID-19 (n = 10) clots generated in panel C. Per patient, 3 separate clots were prepared, 5 images were taken in different areas of the clots, and fibril density was determined in all images. Interconnections of paired data are shown. (E) Rate of FXII autoactivation in ARDS-influenza and SARS-CoV-2 plasma. FXII was added to FXII-depleted plasma, and its decay was monitored by Western blot assay, with an antibody directed against FXII. A representative blot is shown. (F) Quantification of FXII decay in ARDS-influenza and SARS-CoV-2 plasma in panel E. FXII signal at time point 0 was considered to be 100% (n = 20 per group). (G) Maximum turbidity values of fibrin clots generated by the addition of batroxobin to hirudin-preincubated plasma in the presence of FXIIa and/or CTI (n = 15 biological replicates). *P < .05; **P < .01; ***P < .001.