According to research published in Blood Advances, a compact fibrin network structure combined with dysregulated fibrinolysis may contribute to a high incidence of thrombotic events in severe COVID-19.

Researchers in Europe assessed the plasma levels of factor XII (FXII) and its activation products in patients with moderate COVID-19, critically ill patients with severe COVID-19, patients with severe acute respiratory distress syndrome related to influenza infection (ARDS-influenza), and donors without either disease. Samples were obtained from Charité-University Medicine, Berlin, Germany (Berlin cohort: severe COVID-19, n=21; ARDS-influenza, n=25; donor, n=21) and Hanover Medical School, Hanover, Germany (Hanover cohort: severe COVID-19, n=15, moderate COVID-19, n=15; donor, n=15). The team also examined lung tissue sections obtained from 10 patients with ARDS (COVID-19, n=5; influenza, n=5) and 5 donors at autopsy.

Across the cohorts, patients had similar median ages, ranging from 56 to 61 years. In the Berlin cohort, 87%-90% of the samples were from males. In the Hanover cohort, 67%-69% of the samples were from males.


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The team found that PKa-like activity was significantly elevated in patients with severe COVID-19 compared with donors and patients with moderate COVID-19 (P <.001; P <.01, respectively); they also found a strong negative correlation between the intact HK/albumin ratio and the PKa-like activity in plasma of patients with severe COVID-19 (P =.0029), indicating contact system activation.

When comparing the two diseases, the investigators found that more FXII was consumed in the plasma of patients with severe COVID-19 than in that of patients with ARDS-influenza (P =.0031), and both had significantly lower FXII in plasma than donors (COVID-19, P =.00012; ARDS-influenza, P =.021). They also observed that the lag phase in fibrin formation, which is triggered by the FXII activator kaolin, was prolonged in ARDS-influenza, compared with donors, but not in severe COVID-19 (donor vs ARDS-influenza, P =.0003; donor vs COVID-19, P =.058; ARDS-influenza vs COVID-19, P =.046).

Using confocal and electron microscopy, the team demonstrated that increased FXII activation rate combined with elevated fibrinogen levels resulted in the formation of dense, compact clots with thin fibers and small pores in severe COVID-19 (fibrin density: donor vs ARDS-influenza, P =2.0 × 10-7; donor vs COVID-19, P =6.7 × 10-8; ARDS-influenza vs COVID-19, P =3.6 × 10-7). They also observed lower rates of clot lysis in patients with severe COVID-19 than in those with ARDS-influenza (30% vs 80%), indicating the formation of fibrinolysis-resistant clots in patients with COVID-19.

“In conclusion, pathological events described in COVID-19 create milieu favoring activation of FXII. In combination with high levels of fibrinogen, FXIIa may contribute to compact, lysis-resistant clot formation in a thrombin-dependent and -independent manner. This prothrombogenic microenvironment is further promoted by dysregulated fibrinolysis,” the authors wrote.

Limitations of the study included a small number of samples collected at a single time point, administration of anticoagulant therapy to most patients, no contact-phase pathway inhibitor supplemented to blood samples, and measurement of plasma function in vitro.

Reference

Wygrecka M, Birnhuber A, Seeliger B, et al. Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19. Blood Adv. 2022;6(3):1074-1087. doi:10.1182/bloodadvances.2021004816