Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice

作者：Wang, Yongzhi; Luo, Lingtao; Braun, Oscar O.; Westman, Johannes; Madhi, Raed; Herwald, Heiko; Morgelin, Matthias; Thorlacius, Henrik^*

来源：Scientific Reports, 2018, 8(1): 4020.

DOI：10.1038/s41598-018-22156-5

• TISSUE FACTOR
• SEPTIC SHOCK
• M-PROTEIN
• BLOOD
• SEPSIS
• PHOSPHATIDYLSERINE
• MYELOPEROXIDASE
• RECRUITMENT
• INVOLVEMENT
• HEMOSTASIS

Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation ( TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps ( NETs) and/or microparticles ( MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture ( CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation.

• 出版日期2018-3-5
• 单位厦门大学