Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown

Abstract

BACKGROUND Fibrinolysis is a physiologic process maintaining patency of the microvasculature. Maladaptive overactivation of this essential function (hyperfibrinolysis) is proposed as a pathologic mechanism of trauma-induced coagulopathy. Conversely, the shutdown of fibrinolysis has also been observed as a pathologic phenomenon. We hypothesize that there is a level of fibrinolysis between these two extremes that have a survival benefit for the severely injured patients. METHODS Thrombelastography and clinical data were prospectively collected on trauma patients admitted to our Level I trauma center from 2010 to 2013. Patients with an Injury Severity Score (ISS) of 15 or greater were evaluated. The percentage of fibrinolysis at 30 minutes by thrombelastography was used to stratify three groups as follows: hyperfibrinolysis (Q3%), physiologic (0.081-2.9%), and shutdown (0-0.08%). The threshold for hyperfibrinolysis was based on existing literature. The remaining groups were established on a cutoff of 0.8%, determined by the highest point of specificity and sensitivity for mortality on a receiver operating characteristic curve. RESULTS One hundred eighty patients were included in the study. The median age was 42 years (interquartile range [IQR], 28Y55 years), 70% were male, and 21% had penetrating injuries. The median ISS was 29 (IQR, 22-36), and the median base deficit was 9 mEq/L (IQR, 6-13 mEq/L). Distribution of fibrinolysis was as follows: shutdown, 64% (115 of 180); physiologic, 18% (32 of 180); and hyperfibrinolysis, 18% (33 of 180). Mortality rates were lower for the physiologic group (3%) compared with the hyperfibrinolysis (44%) and shutdown (17%) groups (p = 0.001). CONCLUSION We have identified a U-shaped distribution of death related to the fibrinolysis system in response to major trauma, with a nadir in mortality, with level of fibrinolysis after 30 minutes between 0.81% and 2.9%. Exogenous inhibition of the fibrinolysis system in severely injured patients requires careful selection, as it may have an adverse affect on survival. LEVEL OF EVIDENCE Prognostic study, level III.

Tissue injury suppresses fibrinolysis after hemorrhagic shock in nonhuman primates (rhesus macaque)

“…15 Furthermore, in a clinical study evaluating trauma patients within 12 hours of injury, 63% of trauma patients with an ISS greater than 15 exhibited fibrinolysis shutdown which was associated with an almost sixfold increase in mortality rate compared to patients with physiologic fibrinolysis. 6 Interestingly, in that study, the difference in TEG LY30 values was only 3% between patients that exhibited hyperfibrinolysis and patients that exhibited fibrinolysis shutdown phenotypes. Yet this stratification, based on such seemingly subtle differences in lysis, was associated with a higher frequency of organ failure-related mortality in the fibrinolysis shutdown phenotype, and a high frequency of hemorrhage-related mortality in the hyperfibrinolysis phenotype.…”

“…Yet this stratification, based on such seemingly subtle differences in lysis, was associated with a higher frequency of organ failure-related mortality in the fibrinolysis shutdown phenotype, and a high frequency of hemorrhage-related mortality in the hyperfibrinolysis phenotype. 6 In a more recent multicenter analysis of 2,450 injured patients, using the same LY30 parameters to define fibrinolysis phenotypes, fibrinolysis shutdown was confirmed as the most common phenotype, and associated with 100 more deaths than patients with hyperfibrinolysis. 8 That study also indicated that patients with blunt trauma were more likely to have a shutdown phenotype.…”

“…6,7,9,10,15,16,21 Previous work in rats has revealed an innate resistance to tPA-mediated fibrinolysis, which is decreased after HS but increased with tissue injury. 16 This is further supported in a swine model of a severe blast injury which produces a hypercoagulable state rather than a bleeding coagulopathy.…”

“…5 Although the majority of work related to TIC has focused on impairment of clot formation, abnormalities of clot degradation (i.e., fibrinolysis) have also been associated with increased mortality in trauma and sepsis. 3,6–8 Hyperfibrinolysis (i.e., excessive clot degradation) is associated with early death from exsanguination, 9,10 whereas impaired fibrinolysis (i.e., fibrinolysis shutdown) is associated with delayed death due to organ failure. 6,11 …”

“…14 On the other hand, a cohort of trauma patients exhibiting fibrinolysis shutdown had increased mortality associated with organ failure. 6 Moreover, tissue injury has not been shown to promote fibrinolysis in rodents and swine and may, in fact, stimulate fibrinolysis shutdown. 15,16 Recent advances in human cell/tissue-derived therapeutics (e.g., infusible human platelet-derived hemostatic agents [hPDHA]) have necessitated preclinical evaluations in a nonhuman primate (NHP) model due to xenogeneic compatibility, 17 thus, a more thorough examination of coagulation system function in NHPs is prudent.…”