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

Authors

Peter K Moore, Ernest E Moore, Raleigh Garner, Kirk Hansen, Christopher D Barrett, Angela Sauaia, James Chandler, William J Janssen, Hunter B Moore

Published in

The journal of trauma and acute care surgery. Jul 25, 2025. Epub Jul 25, 2025.

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, including increase in MENT, a cysteine cathepsin inhibitor. Patients with shutdown exhibited significantly higher plasma FXIII activity compared with other phenotypes. Western blotting confirmed that MENT was increased in shutdown and is crosslinked into fibrin clots. The targets of MENT, 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 MENT incorporation into fibrin clots may regulate fibrinolysis shutdown in trauma patients with fibrinolysis shutdown by inhibiting cysteine cathepsin activity. These findings identify FXIII, MENT, and cysteine cathepsins as possible contributors to TIC that should be studied further.
Basic Science; N/A.

PMID:
40712062
Bibliographic data and abstract were imported from PubMed on 26 Jul 2025.

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