Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis

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Abstract

Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.

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Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Animals, Annexin A5/blood, Antithrombin III, Blood Coagulation, Blood Platelets/immunology, Cell-Derived Microparticles/immunology, Chemokines, CXC/metabolism, Disease Models, Animal, Inflammation/blood, Interleukin-6/metabolism, Lung/immunology, Male, Mice, Inbred C57BL, Neutrophil Infiltration, Peptide Hydrolases/blood, Phosphatidylserines/blood, Sepsis/blood, Signal Transduction, Thrombin/metabolism, Time Factors
Original languageEnglish
Pages (from-to)1051-1060
Number of pages10
JournalJournal of Cellular Physiology
Volume233
Issue number2
Publication statusPublished - 2018 Feb
Publication categoryResearch
Peer-reviewedYes

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