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Granulocyte microvesicles with a high plasmin generation capacity promote clot lysis and improve outcome in septic shock

Abstract : Abstract Microvesicles (MVs) have previously been shown to exert profibrinolytic capacity, which is increased in patients with septic shock (SS) with a favorable outcome. 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. Using an MV-PGC kinetic assay, ELISA, and flow cytometry, we found that granulocyte MVs (Gran-MVs) from SS patients display a heterogeneous PGC profile driven by the uPA (urokinase)/uPAR system. In vitro, these MVs lyse a thrombus according to their MV-PGC levels in a uPA/uPAR-dependent manner, as shown in a fluorescent clot lysis test and a lysis front retraction assay. Fibrinolytic activators conveyed by MVs contribute to approximately 30% of the plasma plasminogenolytic capacity of SS patients. In a murine model of SS, the injection of high PGC Gran-MVs significantly improved mouse survival and reduced the number of thrombi in vital organs. This was associated with a modification of the mouse coagulation and fibrinolysis properties toward a more fibrinolytic profile. Interestingly, mouse survival was not improved when soluble uPA was injected. Finally, using a multiplex array on plasma from SS patients, we found that neutrophil elastase correlates with the effect of high-PGC-capacity plasma and modulates the Gran-MV plasmin generation capacity by cleaving uPA-PAI-1 complexes. In conclusion, we show that the high PGC level displayed by Gran-MVs reduces thrombus formation and improves survival, conferring to Gran-MVs a protective role in a murine model of sepsis.
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https://hal-amu.archives-ouvertes.fr/hal-03666657
Contributor : GUILLAUME RANCHON Connect in order to contact the contributor
Submitted on : Thursday, May 12, 2022 - 4:30:28 PM
Last modification on : Friday, May 27, 2022 - 6:57:57 PM

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Sylvie Cointe, Loris Vallier, Pierre Esnault, Mathilde Dacos, Amandine Bonifay, et al.. Granulocyte microvesicles with a high plasmin generation capacity promote clot lysis and improve outcome in septic shock. Blood, 2022, 139 (15), pp.2377-2391. ⟨10.1182/blood.2021013328⟩. ⟨hal-03666657⟩

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