OC 67.3 - Thrombin activatable fibrinolysis inhibitor downregulation prevents fibrinolysis shutdown and improves disease severity in SARS-CoV-2 infected K18-hACE2 mice.

Background: Coagulation is a tightly balanced process with thrombotic and fibrinolytic pathways constantly working against each other. This highly regulated and dynamic system exhibits a maladaptive response in various disease states, including COVID-19, where a fibrinolysis shutdown has been identified as a contributor to COVID-19-associated coagulopathy.

Aims: To characterize the role of thrombin activatable fibrinolysis inhibitor (TAFI) in the pathogenesis of SARS-CoV-2 infection in a mouse model of COVID-19.

Methods: Human angiotensin-converting enzyme 2 (hACE2) transgenic mice (K18-hACE2) and TAFI-deficient K18-hACE2 mice were intranasally infected with 2.5 x 103 FFU of SARS-CoV-2 (USA WA1/2020 strain) and followed for general health outcome, mortality, and plasma biomarkers associated with severe disease in humans.

Results: SARS-CoV-2 infection of K18-hACE2 mice recapitulated many CAC-associated findings observed in human patients, including hypercoagulability, increased plasma concentration of D-Dimers, soluble thrombomodulin, and VWF. The low viral dose used in our study prolongs the symptomatic phase of the infection, highlighting an increased susceptibility of male mice to severe infection. The sex-dependent shift in disease severity correlates with the upregulation of TAFI plasma concentration in male mice but not female mice. Heterozygous deletion of TAFI in K18-hACE2 mice resulted in reduced severity of the disease in males, bringing the mortality to the level observed in females (male: TAFI+/- 34% vs. control 68%; female: TAFI+/- 25% vs. control 22%). Histological analysis of TAFI+/- lungs on day seven post-infection highlights a reduction in the overall infiltration of immune cells and the associated fibrin(ogen) deposition.

Conclusion(s): Our data identify TAFI as a potential driver of the fibrinolytic shutdown contributing to the derangement of the finely tuned interaction between the immune, coagulation, and fibrinolytic systems associated with severe cases of COVID-19.