Inflammation contributes to trauma-induced coagulopathy by oxidation of multiple clotting factors.

Abstract

Trauma-induced coagulopathy (TIC) induces anticoagulation and increases bleeding mortality. Inflammation and oxidative stress play an unknown role in TIC. We examined plasma from injured human trauma patients presenting to the Emergency Department compared to healthy controls to elucidate the contribution of inflammation and oxidative stress to anticoagulation during TIC. Trauma patients demonstrated coagulopathy by prolongation of clotting time assays and decreased thrombin generation in addition to increased pro-inflammatory cytokines and increased markers of oxidative stress. Clotting factors seven (FVII), ten (FX), and twelve (FXII) were oxidatively modified without quantitative changes, displaying decreased activity after trauma. Factor five (FV) was decreased in concentration and retained normal activity. Factor eight (FVIII) concentration and activity were increased after trauma. Clotting factor oxidation after exposure to activated human leukocytes in vitro also impaired thrombin generation and reproduced the oxidative and functional changes seen in trauma patients. Both antioxidant and anti-inflammatory treatments prevented clotting factor oxidation and TIC after trauma in vivo using a rodent TIC model. These results suggest that inflammation and oxidative stress contribute directly to anticoagulation during TIC by direct and selective oxidation of clotting factors. FXII may make a novel contribution to the pathophysiology of TIC by its oxidation.