Coagulation factor XIII: An unrecognized regulator of fibrinolytic phenotypes in trauma-A potential link to cysteine cathepsin degradation of plasminogen.

Abstract

Trauma-induced coagulopathy (TIC) has distinct fibrinolytic phenotypes based on viscoelastic testing. The underlying mechanisms behind differences in fibrinolytic responses to trauma are unclear. We hypothesized that plasma proteins crosslinked into fibrin clots by the transglutaminase activity of factor XIII (FXIII) may explain tissue-type plasminogen activator (tPA) responsiveness observed in fibrinolysis shutdown. Plasma samples from trauma patients were categorized into four fibrinolytic phenotypes (hyperfibrinolysis, hypofibrinolysis, fibrinolysis shutdown, and physiologic fibrinolysis) based on rapid thromboelastography and tPA-enhanced thromboelastography. Plasma underwent liquid chromatography-mass spectrometry proteomics for substrates of FXIII, evaluation for FXIII concentration/activity, and Western blotting to confirm proteomic findings. In vitro studies assessed cysteine cathepsin-mediated proteolysis of fibrinolytic and clot-related proteins. Plasma proteomic analysis identified differences in levels of four proteins known to be crosslinked into fibrin in fibrinolysis shutdown patients. Patients with shutdown exhibited significantly higher plasma FXIII activity compared with other phenotypes. Because FXIII crosslinks protease inhibitors to fibrin, we studied inflammatory cysteine cathepsins' ability to degrade fibrinolytic proteins. Cysteine cathepsins degraded coagulation and fibrinolytic proteins in vitro, including plasminogen, tPA, and fibrinogen. Cathepsin L exposure completely disrupted ex vivo fibrin clot formation and impaired fibrinolytic enzyme function, highlighting its potential multifaceted role in TIC pathophysiology. Elevated FXIII activity and protease inhibitor incorporation into fibrin clots may regulate fibrinolysis shutdown in trauma patients with fibrinolysis shutdown by inhibiting cysteine cathepsin activity. These findings identify FXIII and cysteine cathepsins as possible contributors to TIC that should be studied further.