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From the Department of Surgery (M.A.L., N.E.D., K.F.), University of Vermont, Burlington, Vermont; Department of Pathology and Laboratory Medicine and UNC Blood Research Center (L.A.H., A.S.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pharmacology (G.H.), University of Vermont, Burlington, Vermont; Synapse Research Institute (B.D.L.), Maastricht, the Netherlands; Department of Surgery (H.B.M., E.E.M., M.J.C.), University of Colorado School of Medicine (E.E.M.), Aurora; Ernest E Moore Shock Trauma Center at Denver Health (E.E.M.), Denver, Colorado; and Department of Biochemistry and Laboratory for Clinical Biochemistry Research (B.A.B.), University of Vermont, Burlington, Vermont.
Published: November 2022
AI Article Synopsis
Article Abstract
Background: Trauma patients with abnormal fibrinolysis have increased morbidity and mortality. Knowledge of mechanisms differentiating fibrinolytic phenotypes is important to optimize treatment. We hypothesized that subjects with abnormal fibrinolysis identified by whole blood viscoelastometry can also be distinguished by plasma thrombin generation, clot structure, fibrin formation, and plasmin generation measurements.
Methods: Platelet-poor plasma (PPP) from an observational cross-sectional trauma cohort with fibrinolysis shutdown (% lysis at 30 minutes [LY30] < 0.9, n = 11) or hyperfibrinolysis (LY30 > 3%, n = 9) defined by whole blood thromboelastography were studied. Noninjured control subjects provided comparative samples. Thrombin generation, fibrin structure and formation, and plasmin generation were measured by fluorescence, confocal microscopy, turbidity, and a fluorescence-calibrated plasmin assay, respectively, in the absence/presence of tissue factor or tissue plasminogen activator (tPA).
Results: Whereas spontaneous thrombin generation was not detected in PPP from control subjects, PPP from hyperfibrinolysis or shutdown patients demonstrated spontaneous thrombin generation, and the lag time was shorter in hyperfibrinolysis versus shutdown. Addition of tissue factor masked this difference but revealed increased thrombin generation in hyperfibrinolysis samples. Compared with shutdown, hyperfibrinolysis PPP formed denser fibrin networks. In the absence of tPA, the fibrin formation rate was faster in shutdown than hyperfibrinolysis, but hyperfibrinolysis clots lysed spontaneously; these differences were masked by addition of tPA. Tissue plasminogen activator-stimulated plasmin generation was similar in hyperfibrinolysis and shutdown samples. Differences in LY30, fibrin structure, and lysis correlated with pH.
Conclusion: This exploratory study using PPP-based assays identified differences in thrombin generation, fibrin formation and structure, and lysis in hyperfibrinolysis and shutdown subgroups. These groups did not differ in their ability to promote tPA-triggered plasmin generation. The ability to characterize these activities in PPP facilitates studies to identify mechanisms that promote adverse outcomes in trauma.
Level Of Evidence: Prognostic/Epidemiological; Level III.
