Fibrinolysis shutdown following injury : pathologic hypercoagulability driving delayed morbidity and mortality
Year: 2017
Type: dissertation
Study design: Observational Study
Abstract: Trauma patients appear to manifest unique coagulation phenotypes post-injury, and >50% of all severely injury trauma patients present with impairment of their fibrinolytic system. Fibrinolysis shutdown, defined by thrombelastography (TEG) LY30 (percent of clot degraded 30-minutes after achieving maximum clot strength) <0.9%, has been associated with increased mortality compared to trauma patients with moderate level fibrinolysis (LY30 0.9-2.9%). To date, there is a poor understanding of the incidence and mechanisms that drive fibrinolysis resistance. We hypothesized that tissue injury drives fibrinolysis shutdown, shutdown is associated with increased mortality after risk adjustment for confounders, and shutdown is attributable to tissue plasminogen activator (t-PA) resistance. To test these hypotheses, we conducted an initial animal experiment contrasting hemorrhagic shock to tissue injury. Tissue injury suppressed fibrinolysis, while hemorrhagic shock increased fibrinolysis. The next experiment translated these animal findings to a large retrospective study of 2,540 patient. Fibrinolysis shutdown was associated with blunt injury while, hyperfibrinolysis was associated with a low blood pressure, supporting the animal results. This study also confirmed that fibrinolysis was the most common phenotype following injury and independently associated with increased mortality after risk adjustment. The final project was to determine if fibrinolysis shutdown was caused by resistance to t-PA. Whole blood from 400 trauma patients was challenged with t-PA, and a phenotype of fibrinolysis shutdown was identified, which was sensitive to t-PA-mediated clot degradation. Proteomic analysis identified that these patients had normal to low anti-fibrinolytic circulating protease, and an alternative mechanism to explain a low fibrinolytic activity following injury was also present. This data demonstrated that fibrinolysis resistance is associated with tissue injury in vivo, and in clinical series confirmed a pathologic association of early fibrinolysis resistance post-injury in a severely injured patient population. These findings have important clinical implications because delivering an empiric use of antifibrinolytics to a trauma patient early after injury, has the potential to cause increased mortality. Further studies are needed to assess the impact of fibrinolysis phenotypes with the use of antifibrinolytics, and to understand the mechanisms driving early fibrinolysis resistance to assess for therapeutic potentials to reduce mortality in trauma.
DOI: 10.25677/snkg-se33
Author: Moore, Hunter Burroughs
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2893350814