Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps

Abstract

Disseminated intravascular coagulation (DIC) is an acquired condition that develops as a complication of systemic and sustained cell injury in conditions such as sepsis and trauma. It represents major dysregulation and increased thrombin generation in vivo. A poor understanding and recognition of the complex interactions in the coagulation, fibrinolytic, inflammatory, and innate immune pathways have resulted in continued poor management and high mortality rates in DIC. This review focuses attention on significant recent advances in our understanding of DIC pathophysiology. In particular, circulating histones and neutrophil extracellular traps fulfil established criteria in DIC pathogenesis. Both are damaging to the vasculature and highly relevant to the cross talk between coagulation and inflammation processes, which can culminate in adverse clinical outcomes. These molecules have a strong potential to be novel biomarkers and therapeutic targets in DIC, which is still considered synonymous with 'death is coming'.

Keywords: DIC; Thrombin; neutrophil extracellular.

Figure 1.. Bi-directional relationship between histones and neutrophil extracellular traps (NETs).

Cell damage releases histones which trigger NET formation and the formed NETs are a source for both localized and systemic histone release. The increased thrombin generation, which is the hallmark of disseminated intravascular coagulation, simultaneously affects coagulation, fibrinolysis, and inflammation processes to amplify the reciprocal relationship between histones and NETs.

Figure 2.. Functional consequences of circulating histones and neutrophil extracellular traps (NETs).

Summary of pro-coagulant, anti-fibrinolytic, pro-inflammatory, and cytotoxic effects of histones and NETs. IL, interleukin; NF-κB, nuclear factor-kappa B; TF, tissue factor; TNF-α, tumor necrosis factor-alpha.