Background Fibrinolysis shutdown(SD) is an independent risk factor for increased mortality in trauma. High levels of plasminogen activator inhibitor-1(PAI-1) directly binding tissue plasminogen activator(tPA) is a proposed mechanism for SD, however patients with low PAI-1 levels present to the hospital with a rapid TEG(rTEG) LY30 suggestive SD. We therefore hypothesized that two distinct phenotypes of SD exist, one, which is driven by tPA inhibition, while another is due to an inadequate tPA release in response to injury. Methods Trauma activations from our level-1 center between 2014 to 2016 with blood collected within an hour of injury were analyzed with r-TEG and a modified TEG assay to quantify fibrinolysis sensitivity using exogenous tPA(t-TEG). Using the existing rTEG thresholds for SD(<0.9%), physiologic(LY30 0.9–2.9%), and hyperfibrinolysis(LY30 >2.9%) patients were stratified into phenotypes. A t-TEG LY30 > 95th percentile of healthy volunteers(n=140) was classified as tPA hypersensitive and used to sub-divide phenotypes. A nested cohort had tPA and PAI-1 activity levels measured in addition to proteomic analysis of additional fibrinolytic regulators. Results This study included 398 patients (median NISS 18), tPA-Sen was present in 27% of patients. Shutdown had the highest mortality rate(20%) followed by hyperfibinolysis(16%) and physiologic(9% p=0.020). In the non-tPA hypersensitive cohort, SD had a 5-fold increase in mortality(15%) compared to non-SD patients(3% p=0.003 figure) which remained significant after adjusting for ISS and age (p=0.033). Overall tPA activity (p=0.002) PAI-1 (p<0.001) and tPA/PAI-1 complex levels (p=0.006) differed between the six phenotypes and 54% of fibrinolytic regulator proteins analyzed (n=19) were significantly different. Conclusion In conclusion, acute fibrinolysis shutdown is not caused by a single etiology, and is clearly associated with PAI-1 activity. The differential phenotypes require an ongoing investigation to identify the optimal resuscitation strategy for these patients.

INTRODUCTION: Fibrinolysis was initially defined using rapid thrombelastography (rTEG). The cutoffs for the pathologic extremes of the fibrinolytic system, hyperfibrinolysis and shutdown, were both defined based on association with mortality. We propose to redefine these phenotypes for both TEG and for rotational thrombelastometry, the other commonly used viscoelastic assay. METHODS: Rotational thrombelastometry, rTEG, and clinical data were prospectively collected on trauma patients admitted to an urban Level I trauma center from 2010 to 2016. Hyperfibrinolysis was defined as the Youden index from EXTEM-clot lysis index 60 minutes after clotting time (CLI60) and rTEG-fibrinolysis 30 minutes after achieving MA (LY30) for predicting massive transfusion (>10 red blood cell units, or death per 6 hours after injury) as a surrogate for severe bleeding. Patients identified as having hyperfibrinolysis were then removed from the data set, and the cutoff for fibrinolysis shutdown was derived as the optimal cutoff for predicting mortality in the remaining patients. RESULTS: Overall, 216 patients (median age, 36 years (interquartile range, 27–49 years), 82% men, 58% blunt injury) were included. Of these, 16% required massive transfusion, and 12.5% died. Rapid thrombelastography phenotypes were redefined as hyperfibrinolysis: rTEG-LY30 greater than7.7%, physiologic rTEG-LY30 0.6% to7.6%, and shutdown rTEG-LY30 less than 0.6%. EXTEM-CLI60 fibrinolysis phenotypes were hyperfibrinolysis CLI60 less than 82%, physiologic (CLI60, 82–97.9%), and shutdown (CLI60 > 98%). Weighted kappa statistics revealed moderate agreement between rotational thrombelastometry– and rTEG-defined fibrinolysis (k = 0.51; 95% confidence interval, 0.39–0.63), with disagreement mostly in the shutdown and physiologic categories. CONCLUSION: We confirmed the U-shaped distribution of death related to fibrinolysis system abnormalities. Both rTEG LY30 and EXTEM CLI60 can identify the spectrum of fibrinolytic phenotypes, have moderate agreement, and can be used to guide hemostatic resuscitation. LEVEL OF EVIDENCE: Diagnostic study, level III.