Platelets and neutrophil extracellular traps collaborate to promote intravascular
coagulation during sepsis in mice
#MMPMID28073784
McDonald B
; Davis RP
; Kim SJ
; Tse M
; Esmon CT
; Kolaczkowska E
; Jenne CN
Blood
2017[Mar]; 129
(10
): 1357-1367
PMID28073784
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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.
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