Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice

Abstract

Neutrophil extracellular traps (NETs; webs of DNA coated in antimicrobial proteins) are released into the vasculature during sepsis where they contribute to host defense, but also cause tissue damage and organ dysfunction. Various components of NETs have also been implicated as activators of coagulation. Using multicolor confocal intravital microscopy in mouse models of sepsis, we observed profound platelet aggregation, thrombin activation, and fibrin clot formation within (and downstream of) NETs in vivo. NETs were critical for the development of sepsis-induced intravascular coagulation regardless of the inciting bacterial stimulus (gram-negative, gram-positive, or bacterial products). Removal of NETs via DNase infusion, or in peptidylarginine deiminase-4-deficient mice (which have impaired NET production), resulted in significantly lower quantities of intravascular thrombin activity, reduced platelet aggregation, and improved microvascular perfusion. NET-induced intravascular coagulation was dependent on a collaborative interaction between histone H4 in NETs, platelets, and the release of inorganic polyphosphate. Real-time perfusion imaging revealed markedly improved microvascular perfusion in response to the blockade of NET-induced coagulation, which correlated with reduced markers of systemic intravascular coagulation and end-organ damage in septic mice. Together, these data demonstrate, for the first time in an in vivo model of infection, a dynamic NET-platelet-thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis.

How I treat disseminated intravascular coagulation

“…In addition, recent studies point to a prominent role of intravascular webs ('neutrophil-extracellular traps') consisting of denatured DNA from damaged cells and entangling neutrophils, plateles, fibrin and kationic proteins, such as histones, in the development of thrombus deposition. 30 Thrombin generation in DIC is initiated through the tissue factor/factor VII(a) pathway that will activate downstream coagulation factors. 31 Tissue factor may be expressed by activated monocytes but also by vascular endothelial cells or cancer cells.…”

Mechanisms of erosion of atherosclerotic plaques

“…Extracellular nucleic acids in NETs bind circulating platelets, coagulation factors, and VWF, acting as a solid-state reactor for the coagulation cascade and providing a scaffold for developing thrombi. 434445 Neutrophil proteinases and extracellular histones activate platelets and accelerate thrombin formation. 4647 In addition, histones, elastase, and MPO-generated hypochlorous acid each induce endothelial TF production.…”

Therapeutic effects of curcumin on sepsis and mechanisms of action: A systematic review of preclinical studies

“…According to the global statistics, there are 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually worldwide (Yin, Tao, Wei, Zhang, & Ma, ). Innate immune system and hemostasis process (coagulation factors and platelets) are a major contributor of sepsis pathogenesis (McDonald et al, ). When the body is exposed to pathogen, the first line of defense is innate immune response (Jin, Batra, & Jeyaseelan, ; Taner et al, ).…”