To evaluate the role of the plasminogen activating system at promoting immunosuppression and worsening outcome in patients with Necrotising Fasciitis

Project overview: Plasminogen activation plays a key role in fibrinolysis, which is the process of blood clot removal. Plasminogen is an inactive zymogen and requires catalytic activity by tissue-type plasminogen activator on the clot surface, to produce its active enzymatic form plasmin, to break down the blood clot. However, plasminogen/plasmin has been described to have other functional roles, including modulating the immune response and promoting bacterial infectivity. Necrotising soft-tissue infection (NSTI) is a severe tissue infection commonly caused by group A Streptococci (GAS) bacteria. Current treatment approaches for NSTIs include surgical debridement, antimicrobial therapy and hyperbaric oxygen therapy. GAS bacterial strains secrete streptokinase, which activates host human plasminogen to plasmin to facilitate the breakdown of host barriers to allow bacteria to invade neighbouring tissue. In addition, plasmin formation is also able to promote an immunosuppressive state by binding to plasminogen receptors immune cells and altering immune cell function, weakening the immune system further favouring bacterial growth and promoting disease severity. Tranexamic acid (TXA) is a drug that binds to plasminogen and blocks its ability to bind to fibrin and to various plasminogen receptors, preventing plasmin formation. TXA has been shown to reverse the immunosuppressive effects of plasmin in other conditions. In this study, we will be exploring the use of TXA in the TRITON trial, where 60 patients who have been diagnosed with NSTIs are being randomised to TXA/placebo treatment, administered twice daily for 4 days. Our main technique will be flow cytometry of patients’ peripheral blood mononuclear cells (PBMCs) collected at pre-treatment and 72 hours after the first dosage. Our flow cytometry approach will be using novel antibody panels for 40 immune cell markers that will allow us to evaluate changes in immune profiles of these patients recruited to the trial. Plasma samples will also be obtained and will be tested for changes in key markers of fibrinolysis and inflammation. This study will be an important addition to the clinical read out of the TRITON trial and will provide novel information as to the effect of TXA in this debilitating condition.