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

Wang, Yongzhi LU ; Zhang, Su LU ; Luo, Lingtao LU ; Norström, Eva LU ; Braun, Oscar Ö LU ; Mörgelin, Matthias LU and Thorlacius, Henrik LU (2018) In Journal of Cellular Physiology 233(2). p.1051-1060
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... (More)

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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Contribution to journal
publication status
published
subject
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
in
Journal of Cellular Physiology
volume
233
issue
2
pages
10 pages
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:85019117840
  • pmid:28409836
ISSN
1097-4652
DOI
10.1002/jcp.25959
language
English
LU publication?
yes
additional info
© 2017 Wiley Periodicals, Inc.
id
951bfc61-d004-41ff-a44c-77d428ff0730
date added to LUP
2019-06-18 22:31:12
date last changed
2020-07-08 04:56:26
@article{951bfc61-d004-41ff-a44c-77d428ff0730,
  abstract     = {<p>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.</p>},
  author       = {Wang, Yongzhi and Zhang, Su and Luo, Lingtao and Norström, Eva and Braun, Oscar Ö and Mörgelin, Matthias and Thorlacius, Henrik},
  issn         = {1097-4652},
  language     = {eng},
  number       = {2},
  pages        = {1051--1060},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Journal of Cellular Physiology},
  title        = {Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis},
  url          = {http://dx.doi.org/10.1002/jcp.25959},
  doi          = {10.1002/jcp.25959},
  volume       = {233},
  year         = {2018},
}