PMID- 27405066
OWN - NLM
STAT- MEDLINE
DCOM- 20180129
LR  - 20180302
IS  - 1540-0514 (Electronic)
IS  - 1073-2322 (Linking)
VI  - 46
IP  - 6
DP  - 2016 Dec
TI  - Extracellular Histones Increase Tissue Factor Activity and Enhance Thrombin 
      Generation by Human Blood Monocytes.
PG  - 655-662
AB  - OBJECTIVES: Sepsis is characterized by systemic activation of inflammatory and 
      coagulation pathways in response to infection. Recently, it was demonstrated that 
      histones released into the circulation by dying/activated cells may contribute to 
      sepsis pathology. Although the ability of extracellular histones to modulate the 
      procoagulant activities of several cell types has been investigated, the 
      influence of histones on the hemostatic functions of circulating monocytes is 
      unknown. To address this, we investigated the ability of histones to modulate the 
      procoagulant potential of THP-1 cells and peripheral blood monocytes, and 
      examined the effects of plasmas obtained from septic patients to induce a 
      procoagulant phenotype on monocytic cells. METHODS/RESULTS: Tissue factor (TF) 
      activity assays were performed on histone-treated THP-1 cells and blood 
      monocytes. Exposure of monocytic cells to histones resulted in increases in TF 
      activity, TF antigen, and phosphatidylserine exposure. Histones modulate the 
      procoagulant activity via engagement of Toll-like receptors 2 and 4, and this 
      effect was abrogated with inhibitory antibodies. Increased TF activity of 
      histone-treated cells corresponded to enhanced thrombin generation in plasma 
      determined by calibrated automated thrombography. Finally, TF activity was 
      increased on monocytes exposed to plasma from septic patients, an effect that was 
      attenuated in plasma from patients receiving unfractionated heparin (UFH). 
      CONCLUSIONS: Our studies suggest that increased levels of extracellular histones 
      found in sepsis contribute to dysregulated coagulation by increasing TF activity 
      of monocytes. These procoagulant effects can be partially ameliorated in sepsis 
      patients receiving UFH, thereby identifying extracellular histones as a potential 
      therapeutic target for sepsis treatment.
FAU - Gould, Travis J
AU  - Gould TJ
AD  - *Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada 
      daggerThrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada 
      double daggerDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, 
      Ontario, Canada  section signGeorge and Fay Yee Center for Healthcare Innovation, Internal 
      Medicine, University of Manitoba, Winnipeg, Manitoba, Canada ||Department of 
      Medicine, McMaster University, Hamilton, Ontario, Canada.
FAU - Lysov, Zakhar
AU  - Lysov Z
FAU - Swystun, Laura L
AU  - Swystun LL
FAU - Dwivedi, Dhruva J
AU  - Dwivedi DJ
FAU - Zarychanski, Ryan
AU  - Zarychanski R
FAU - Fox-Robichaud, Alison E
AU  - Fox-Robichaud AE
FAU - Liaw, Patricia C
AU  - Liaw PC
CN  - Canadian Critical Care Translational Biology Group
LA  - eng
GR  - MOP-136878/CIHR/Canada
GR  - MOP-123313/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Shock
JT  - Shock (Augusta, Ga.)
JID - 9421564
RN  - 0 (Histones)
RN  - 0 (Phosphatidylserines)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Adult
MH  - Blood Coagulation/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Histones/*pharmacology
MH  - Humans
MH  - Monocytes/*drug effects/*metabolism
MH  - Phosphatidylserines/pharmacology
MH  - Plasma/metabolism
MH  - Sepsis/immunology/metabolism
MH  - THP-1 Cells
MH  - Thrombin/*metabolism
MH  - Thromboplastin/*metabolism
EDAT- 2016/07/13 06:00
MHDA- 2018/01/30 06:00
CRDT- 2016/07/13 06:00
PHST- 2016/07/13 06:00 [pubmed]
PHST- 2018/01/30 06:00 [medline]
PHST- 2016/07/13 06:00 [entrez]
AID - 10.1097/SHK.0000000000000680 [doi]
PST - ppublish
SO  - Shock. 2016 Dec;46(6):655-662. doi: 10.1097/SHK.0000000000000680.