Proinflammatory potential of dysregulated platelets – platelet calcium signalling is influenced by sepsis and liver damage pathophysiology

Introduction: Sepsis and liver damage are associated with abnormalities in the coagulation system, including an increased incidence of disseminated thromboembolic events. The central role of platelets in these thromboinflammatory conditions is increasingly recognized. A number of platelet-related phenomena which could have a major impact on thromboembolic responses in inflammation and inflammatory processes themselves has recently come to light.

Method: In this project we investigate platelet canonical functions, procoagulant potential, interactions with other cell types, and involvement in inflammatory cascade. We use high-resolution platelet phenotyping and function monitoring to shed light on previously underinvestigated phenomena and underlying signalling events. We also perform a series of ex-vivo stimulations with patient-derived material to pinpoint the cause of platelet signalling dysregulation.

Results: We have observed that sepsis and liver damage patients both display a platelet phenotype of suppressed reactivity to stimuli, lower procoagulant potential and, correspondingly, suppressed ability to calcium flux. Sepsis and liver damage patients both display higher formation of platelet-leukocyte aggregates, composed of higher fraction of platelets displaying a procoagulant phenotype. Moreover, the stimulation of healthy platelets with sepsis and liver damage plasma conveys platelet pre-activation demonstrated by higher calcium flux without or with stimulation. Stimulation of healthy platelets with sepsis and liver damage isolated IgG antibody fraction also conveys platelet activation and priming and higher calcium flux.

Conclusion: Taken together this indicates a calcium-driven platelet phenotype possibly resembling a previously described exhausted platelets, but displaying a high proinflammatory potential. We also note a, previously unexplored in those diseases, antibody mediated component of platelet dysregulation. Further investigation of cell-cell interactions and complex signalling events may lead to the unlocking of potential molecular nexus allowing to interrupt the thromboinflammatory cascade.