Fibrinolysis resistance in sepsis assessed by serial beside viscoelastometry is associated with plasma protein profiles and organ- failure severity: a prospective observational study

Background: Fibrinolysis resistance is associated with adverse outcomes in sepsis and can be quantified at the bedside by tissue plasminogen activator-enhanced viscoelastometric testing, using the fibrin-adjusted (FIBA10) clot lysis time (TPA-LT) expressed as the TPA-LT/FIBA10 ratio. In this study of adults admitted to intensive care with sepsis, plasma tissue plasminogen activator activity, plasminogen activator inhibitor-1 activity (PAI-1), plasminogen and a2-antiplasmin were measured serially alongside TPA-LT/FIBA10 and Sequential Organ Failure Assessment (SOFA-2) scores. Whether the bedside TPA-LT/FIBA10 measure of fibrinolysis resistance reflects the underlying plasma fibrinolytic protein environment, and whether it tracks organ-failure severity, has not been established. Results: This prospective observational study included 283 paired observations in 69 septic patients admitted with a median Acute Physiology and Chronic Health Evaluation III score 81, median SOFA-2 score 13 and a 38% ICU mortality. PAI-1 increased and plasminogen decreased with increasing fibrinolysis resistance (1.77 [1.50-2.09]-fold increase and 0.81 [0.76-0.87]-fold decrease, respectively, per e-fold increase in TPA-LT/FIBA10). Increasing organ-failure severity was also associated with increased PAI-1 and decreased plasminogen (1.23 [1.17-1.29]-fold increase and 0.95 [0.93-0.96]-fold decrease, respectively, per point increase in SOFA-2). In contrast, tissue plasminogen activator activity and absolute a2-antiplasmin did not relate to fibrinolysis resistance or organ failure. Principal component analysis of the fibrinolysis proteins, organ-failure severity and fibrinolysis resistance identified a dominant axis explaining 35% of the variance, on which PAI-1, SOFA-2 and TPA-LT/FIBA10 loaded together in opposition to plasminogen. Unsupervised clustering of the dataset, performed without reference to patient outcomes, separated a fibrinolysis inhibitor- high, substrate-depleted group with 61% mortality compared to 29% in the preserved- fibrinolysis group. During the ICU stay, PAI-1 decreased within 72 hours in survivors but remained unchanged in non-survivors (interaction p<0.001). A trend was observed for plasminogen levels increasing in survivors but remaining static in non-survivors. Conclusions: Changes in key fibrinolysis proteins, organ-failure severity and fibrinolysis resistance measured by viscoelastometry were coupled facets of the response to sepsis dominated by fibrinolysis inhibitor excess and substrate depletion rather than by reduced activator availability. These findings provide biological validation for bedside viscoelastometric quantification of fibrinolysis resistance and support prospective evaluation of substrate-directed profibrinolytic strategies.