Abstract 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. Level III Prognostic
The Journal of Trauma and Acute Care Surgery – Wolters Kluwer Health
Published: Apr 1, 2017
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