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Published on: April 19, 2024
Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity
Hunter B Moore1, Ernest E Moore, Benjamin R Huebner
1From the Department of Surgery (H.B.M., E.E.M., B.R.H., M.D., G.R.S., G.R.N., P.J.L., A.B., C.S., A.S., K.C.H.), University of Colorado; Denver Health Medical Center (E.E.M., A.G., J.C.); and University of Colorado School of Public Health (A.S.), Denver, Colorado.
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 (t-PA) is a proposed mechanism for SD; however, patients with low PAI-1 levels present to the hospital with a rapid TEG (r-TEG) LY30 suggestive SD. We therefore hypothesized that two distinct phenotypes of SD exist, one, which is driven by t-PA inhibition, whereas another is due to an inadequate t-PA release in response to injury.
Methods:
Trauma activations from our Level I center between 2014 and 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 t-PA (t-TEG). Using the existing r-TEG 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 greater than 95th percentile of healthy volunteers (n = 140) was classified as t-PA hypersensitive and used to subdivide phenotypes. A nested cohort had t-PA and PAI-1 activity levels measured in addition to proteomic analysis of additional fibrinolytic regulators.
Results:
This study included 398 patients (median New Injury Severity Score, 18), t-PA-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-t-PA hypersensitive cohort, SD had a fivefold increase in mortality (15%) compared with non-SD patients (3%; p = 0.003) which remained significant after adjusting for Injury Severity Score and age (p = 0.033). Overall t-PA activity (p = 0.002), PAI-1 (p < 0.001), and t-PA/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 SD 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 Of Evidence:
Prognostic, level III.
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