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

Braedon McDonald, Rachelle P. Davis, Seok-Joo Kim, Mandy Tse, Charles T. Esmon, Elzbieta Kolaczkowska and Craig N. Jenne

Key points

  • In vivo imaging reveals a NETs-platelets-thrombin axis that promotes intravascular coagulation in sepsis.

  • Inhibition of NETs during sepsis reduces intravascular coagulation, improves microvascular perfusion, and reduces organ damage.

Abstract

Neutrophil extracellular traps (NETs; webs of DNA coated in anti-microbial 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 multi-color 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 (PAD4)-deficient mice (which have impaired NETs production), resulted in significantly lower quantities of intravascular thrombin activity, reduced platelet aggregation, and improved microvascular perfusion. NETs-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 blockade of NETs-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 NETs-platelets-thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis.

  • Submitted September 22, 2016.
  • Accepted December 30, 2016.