Sepsis-triggered proteolysis of profibrinolytic annexin A2 associated with microvasculopathy-related organ dysfunction

• Sepsis-triggered proteolysis of annexin A2 (A2) reduces cell surface fibrinolytic activity. • A2 proteolysis is associated with microvasculopathic organ dysfunction in humans. Sepsis is a systemic inflammatory disorder marked by dysregulated inflammation and coagulopathy. Annexin A2 (A2), a profibrinolytic protein, assembles plasminogen and tissue plasminogen activator on cell surfaces, thereby maintaining vascular patency. However, its role in human sepsis has remained poorly defined. We investigated whether A2 undergoes qualitative or quantitative modification during human sepsis with associated end-organ dysfunction. Peripheral blood mononuclear cells (PBMCs) and plasma were collected from 65 sepsis patients and 27 healthy controls. A2 expression and integrity were evaluated with cell surface plasmin generation using immunoblot and fluorometric assays. Both A2 integrity and plasmin generation were significantly reduced in subjects with sepsis and with sepsis shock. A2 underwent sepsis-related membrane-associated proteolysis mediated by a serine protease. A2 reduction correlated with interleukin (IL)-18 levels, and was significantly associated with renal, pulmonary, cardiovascular, and neurologic dysfunction. A2 proteolysis may represent a novel biomarker and therapeutic target for sepsis-related microvasculopathy.