Plasminogen supplementation reverses fibrinolytic insufficiency in sepsis-induced disseminated intravascular coagulation: a pilot study.

Abstract

PURPOSE: Sepsis-induced disseminated intravascular coagulation (DIC) is characterized by impaired fibrinolysis, partly due to neutrophil elastase-mediated plasminogen degradation. We aimed to evaluate whether plasminogen supplementation could restore fibrinolytic capacity in patients with sepsis-induced coagulopathy and in a murine model of septic DIC. METHODS: 60 patients with sepsis-induced coagulopathy were randomized to receive 12&#xa0;mL/kg of placebo (NaCl 0.9%) or OctaplasLG&#xae;, a pathogen-inactivated pooled human plasma containing 2&#xa0;&#xb5;M plasminogen. Pre- and post-infusion levels of functional plasminogen, plasmin generation, and fibrinolysis markers (plasmin-antiplasmin complexes, plasminogen activator inhibitor-1, and tissue-type plasminogen activator) were measured. In parallel, in a sepsis-induced DIC model, transgenic TMmice received either purified plasminogen or placebo. Functional plasminogen levels and plasmin generation were assessed via enzymatic assays. RESULTS: In patients, baseline plasminogen and plasmin generation were significantly lower than in healthy controls. OctaplasLG&#xae; significantly increased functional plasminogen (+&#x2009;46&#xa0;nM [-96; 118] vs. -84 [-180; 27] nM, p&#x2009;<&#x2009;0.05) and improved plasmin generation (0.12 [-0.25; 1.27] vs. -0.36 [-1.58; 0.12] fmol, p&#x2009;<&#x2009;0.05). No changes were observed in plasmin-antiplasmin, plasminogen activator inhibitor-1, or tissue-type plasminogen activator levels. A non-significant trend toward reduced mortality was noted in patients receiving OctaplasLG&#xae; (42.3% vs. 60.0%). Septic DIC-mice also exhibited reduced functional plasminogen (100 [66-126] vs. 295 [268-343] nM) and impaired plasmin generation (1.8 [1.4-2.1] vs. 3.0 [2.8-3.3] fmol, p&#x2009;<&#x2009;0.05), which were restored after plasminogen supplementation (plasminogen: 346 [287; 360] nM; plasmin generation: 4.1 [3.7; 5.5] fmol). CONCLUSION: Plasminogen supplementation restores fibrinolytic capacity, supporting its therapeutic potential in sepsis-induced DIC.