Thromboinflammatory mediators produced by hyperfibrinolysis following injury

Fibrinolysis phenotypes are integral in the pathogenesis of trauma-induced coagulopathy and its sequelae. Of the various phenotypes of dysregulated fibrinolysis, hyperfibrinolysis (HF) is most associated with the highest mortality and has been implicated directly in death due to bleeding. While the dominant regulators of fibrinolysis are well established, additional yet crucial candidate biomediators of HF are less known. Thus, our hypothesis is that the early proteomic signature of HF would expand our comprehension of this dysregulated pathway after severe trauma.

Mass spectrometry-based proteomics methods were leveraged to characterize plasma samples from trauma patients enrolled in the Control of Major Bleeding After Trauma randomized control trial. In this post hoc analysis, the plasma fraction of samples collected at the emergency department from highly injured, hypotensive patients in HF was subjected to proteomics workflows. Projection to latent structures and principal component analyses were performed using rapid thromboelastogram-based percent decrease in clot strength 30 minutes after it reaches its maximum amplitude to identify statistically significant proteins.

Fibrinogen γ' (odds ratio [OR], 21.85; p = 0.001) and Golgi casein kinase (FAM20C) (OR, 4.25; p = 0.025) were among the top proteins most associated with HF. Other significant proteins included phospholipid transfer protein (OR, 2.39; p = 0.025) and 3-hydroxy-3-methylglutaryl coenzyme A synthase (OR, 217.36; p = 0.003). Proteins least associated with decreased HF included complement proteins, coagulation factors, and other procoagulant proteins such as thrombin-activatable fibrinolysis inhibitor (OR, 0.394; p = 0.011) and actin β (OR, 0.732; p = 0.027).

Cutting-edge proteomic analyses have uncovered potential biomediators of HF, a novel yet crucial next step in understanding these maladaptive syndromes. This provides a platform to characterize numerous additional proteins associated with HF from where we can start investigating potential therapeutic targets as the next step in treating HF and thus trauma-induced coagulopathy.

Prognostic and Epidemiological; Level IV.