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Granulocyte Microvesicles with a High Plasmin Generation Capacity Promote Clot Lysis and Improve Outcome in Septic Shock

1Department of Hematology and Vascular Biology, CHU La Conception, AP-HM, Marseille, France, 2Aix-Marseille University, C2VN-UMR-INSERM 1263, INRA 1260, Faculty of Pharmacy, Marseille, France, 3Intensive Care Unit, CHU La Conception, APHM, Marseille, France, 4Department of Pathology and Neuropathology, CHU Timone, APHM, Aix-Marseille University, INSERM, MMGG, Marseille, France, 5R and T Department, BioCytex, Marseille, France, 6Aix Marseille University, APHM, INSERM, MMG, CHU Timone, APHM, Department of Cell Biology, Marseille, France, 7Intensive Care Unit, APHM, CHU Nord, Marseille, France CEReSS - Center for Studies and Research on Health Services and Quality of Life EA 3279, Aix-Marseille University, Marseille, France, 8Haematology Department, CHU La Timone, Marseille, France

Abstract Number: OC 02.1

Meeting: ISTH 2021 Congress

Theme: Fibrinogen, Fibrinolysis and Proteolysis » Fibrinolytic Factors and Inhibitors

Background: Septic shock (SS) is characterized by a systemic inflammation with coagulation activation and fibrinolysis imbalance. Microvesicles (MVs) are extracellular vesicles which play an ambivalent role in vascular hemostasis, both deleterious and favorable according to their cellular origin and their inducer. They have recently been shown to generate plasmin, a capacity which is increased in patients with SS with a favorable outcome.

Aims: We therefore hypothesized that the plasmin generation capacity (PGC) could confer to MVs a protective effect supported by their capacity to lyse a thrombus, and we investigated the mechanisms involved.

Methods: MVs were characterized using a MV-PGC kinetic assay, ELISA, fibrin zymography and flow cytometry. Their lytic effect was investigated using in vitro lysis tests a fluorescent clot lysis test and a lysis front retraction assay by fluorescent microscopy. A cecal ligation and puncture mice model of SS was used to test the effect of fibrinolytic MVs in vivo.

Results: We found that granulocyte MVs (Gran-MVs) from SS patients display a heterogeneous PGC profile driven by the uPA/uPAR system. In vitro, these MVs lyse a thrombus according to their MV-PGC levels in a uPA/uPAR-dependent manner. Fibrinolytic activators conveyed by MVs contribute to approximately 30% of the plasma plasminogenolytic activity of SS patients. In vivo, compared to the injection of low PGC Gran-MVs, the injection of high PGC Gran-MVs significantly improved mouse survival (92% vs. 50%, respectively, p=0.05) and reduced the number of thrombi in vital organs such as lungs or kidneys (3.7±0.9 vs. 7.7±1.9 thrombi/2.4 mm2, p=0.001).

Conclusions: In conclusion, we show for the first time that high PGC level confers to Gran-MVs a uPA/uPAR-dependent thrombolytic potential. In vivo these Gran-MVs reduce thrombus formation and improve survival conferring to Gran-MVs a protective role in a murine model of sepsis by counterbalancing the procoagulant state associated with SS.

To cite this abstract in AMA style:

Cointe S, Vallier L, Bonifay A, Harti K, Dacos M, Macagno N, Judicone C, Chareyre C, Frankel D, Robert s, Hraiech S, Alessi M-, Albanese J, Dignat-George f, Lacroix R. Granulocyte Microvesicles with a High Plasmin Generation Capacity Promote Clot Lysis and Improve Outcome in Septic Shock [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/granulocyte-microvesicles-with-a-high-plasmin-generation-capacity-promote-clot-lysis-and-improve-outcome-in-septic-shock-2/. Accessed October 1, 2023.

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