Procoagulant and Anti-Fibrinolytic Properties of Cell-free DNA and Histones in Sepsis

Abstract

Sepsis is a devastating clinical condition characterized by a systemic inflammatory response to infection, with concomitant dysregulated pathological thrombus formation. Although sepsis is triggered by the release of microorganisms and/or microbial toxins into the circulation, the presence of infection itself is rarely the cause of death in these patients. Rather, mortality in sepsis is attributed to irreversible organ damage resulting from prolonged, uncontrolled activation of inflammatory and coagulation pathways within the microcirculation. Despite recent advances in clinical management, treatment continues to be largely supportive in nature. As a result, sepsis remains the leading cause of morbidity and mortality in non-coronary intensive care units with mortality rates ranging from 18-30%. Sepsis-induced mortality is further increased following the development of disseminated intravascular coagulation, a thrombohemorrhagic state defined by a primary thrombotic and secondary hemorrhagic diathesis that may culminate in multi-organ failure. Clinical management of patients with sepsis is challenging and largely limited to supportive therapies, which is in part related to a limited understanding of the underlying pathophysiology. Recently, cell-free DNA (CFDNA) has emerged as an important link between innate immunity, coagulation, and inflammation. Furthermore, we have previously demonstrated that plasma levels of CFDNA have high discriminative power to predict ICU mortality in patients with severe sepsis. Patients with higher plasma concentrations of CFDNA are more likely to face severe complications such as organ dysfunction/failure, and death. The evidence presented in this thesis suggests that CFDNA may not simply be an innocuous marker of disease severity, but may itself exert pathological effects and contribute to the fatal coagulation abnormalities observed in sepsis patients.