Improving the outcome of septic shock

Fanny Trifilieff: What is septic shock?

Sylvie Cointe: Septic shock (or severe sepsis) is an exaggerated inflammatory response in which circulatory, cellular and metabolic abnormalities are so intense as to result in high mortality. Septic shock is a frequent pathology, with an incidence of 19.3/100,000 people/year, accounting for 10-20% of admissions to intensive care. The excessive activation of coagulation that accompanies septic shock leads to a state of hypercoagulability associated with a failure of fibrinolysis*, resulting in reduced blood flow to tissues and, ultimately, organ failure and death. Despite recent advances, mortality is still very high: around 30 to 40% of patients suffering from septic shock, which represents 5 million deaths per year worldwide.

F.T: Why were you so interested in granulocyte microvesicles in particular?

S.C: The inflammatory cell activation characteristic of sepsis is closely associated with the generation of microvesicles. These are small vesicles (0.1 µm to 1 µm) resulting from the remodeling of membrane phospholipids in parent cells after activation or apoptosis. These microvesicles can have multiple biological effects. Initially described as pro-coagulant entities, these microvesicles have more recently been recognized as entities with fibrinolytic* activity, notably microvesicles of granulocytic origin. In a pilot clinical study involving patients in septic shock, our team showed that microvesicle-dependent fibrinolytic activity was greater in surviving patients than in non-surviving patients, suggesting a protective role for these microvesicles. However, the protective mechanism of this activity remains to be elucidated.

F.T: How did you go about your research?

S.C: To understand this mechanism, we developed a mouse model of septic shock. We hypothesized that fibrinolytic microvesicles could improve survival by dissolving clots blocking vessels. In this model, we showed that injection of granulocyte microvesicles with enhanced fibrinolytic activity was associated with 80% survival of mice at 5 days, compared with groups receiving microvesicles with little fibrinolytic activity, which had a survival of around 40-60%. Histological studies of vital organs such as the lung and kidney showed that this increase in survival was associated with a reduction in the number of clots in these mice. Furthermore, injection of a soluble fibrinolytic phase alone did not maintain the same survival in septic mice, demonstrating the added value of microvesicle vectorization at therapeutic level. Taken together, these results illustrate a new mechanism explaining the improved survival of mice injected with highly fibrinolytic microvesicles. They identify microvesicles as an original biomarker of mortality risk in septic shock, and represent an innovative therapeutic strategy based on the use of fibrinolytic vectors.