title: Procoagulant role of neutrophil extracellular traps in patients with gastric cancer.
abstract: BACKGROUND
  Patients with gastric cancer (GC) commonly exhibit a hypercoagulable state that results in significant morbidity and mortality. Recent studies have shown that neutrophil extracellular traps (NETs) trigger coagulation through an intrinsic pathway and contribute to thrombus initiation and progression. In this study, we aimed to determine the procoagulant activity (PCA) of NETs in patients with GC.
  
  
  METHODS
  NET formation and their PCAs were assessed in 48 patients with GC and 36 healthy controls using immunofluorescence microscopy of neutrophil markers and extracellular DNA as well as a modified capture ELISA technique, and thrombin-antithrombin complex and clot (fibrin) spectroscopic detection, respectively.
  
  
  RESULTS
  Here we showed that neutrophils isolated from patients with GC displayed significantly enhanced NET formation compared with those from healthy controls; furthermore, plasma or platelets obtained from patients with GC induced control neutrophils to release NETs. In addition, NETs released by GC neutrophils significantly increased the potency of control plasma to generate thrombin and fibrin. Notably, these procoagulant effects were dramatically attenuated by application of DNase I. We further found that spontaneous NET formation in patients with GC was significantly higher than that in controls, increased with tumor- node-metastasis stage elevation, and positively correlated with thrombin-antithrombin complex levels and D-dimers. Additionally, the effect of DNase I on cell-free plasma generation of fibrin was dependent on the concentration of NET formation.
  
  
  CONCLUSIONS
  These results suggest that GC creates a systemic environment that primes neutrophils to release procoagulant NETs. Thus, targeting NETs might improve the coagulopathy of patients with GC.
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory Services, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Research Center, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Xingku
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of General Surgery of The First Hospital of Harbin Harbin, China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Xuanye
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Changjian
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zou
mesh_terms: D000368:Aged; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation; D016022:Case-Control Studies; D003850:Deoxyribonuclease I / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009367:Neoplasm Staging; D009504:Neutrophils / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000097:blood / Q000150:complications* / Q000473:pathology; D013917:Thrombin / Q000378:metabolism; D019851:Thrombophilia / Q000097:blood / Q000209:etiology*; D015854:Up-Regulation
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D000990:Antithrombin III; D003850:Deoxyribonuclease I; D010447:Peptide Hydrolases; D013917:Thrombin
keywords: NETs; Stomach neoplasm; cell-free DNA; neutrophils; prothrombotic state
references.citation: J Clin Invest. 2012 Jul;122(7):2661-71
references.pmid: 22684106
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2123-9
references.pmid: 15699480
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):147-51
references.pmid: 23104849
references.citation: J Thromb Haemost. 2013 Apr 2;:null
references.pmid: 23551930
references.citation: Cancer Res. 2015 Jul 1;75(13):2653-62
references.pmid: 26071254
references.citation: Front Immunol. 2013 Mar 06;4:48
references.pmid: 23508552
references.citation: Blood. 2002 Nov 15;100(10):3484-8
references.pmid: 12393647
references.citation: Lancet Oncol. 2014 Oct;15(11):e493-503
references.pmid: 25281468
references.citation: Nat Med. 2010 Feb;16(2):219-23
references.pmid: 20081861
references.citation: Lancet Oncol. 2002 Jan;3(1):27-34
references.pmid: 11908507
references.citation: Cancer Cell. 2006 Nov;10(5):355-62
references.pmid: 17097558
references.citation: Blood. 2011 Oct 13;118(15):4015-23
references.pmid: 21860019
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2130-5
references.pmid: 15699479
references.citation: Lancet Oncol. 2005 Jun;6(6):401-10
references.pmid: 15925818
references.citation: Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):2032-40
references.pmid: 23818485
references.citation: Blood. 2013 Sep 5;122(10):1712-23
references.pmid: 23908465
references.citation: Nat Rev Clin Oncol. 2012 Aug;9(8):437-49
references.pmid: 22777060
references.citation: Blood. 2011 Mar 17;117(11):3172-80
references.pmid: 21248061
references.citation: Jpn J Clin Oncol. 2008 Jan;38(1):2-7
references.pmid: 18258711
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Arch Intern Med. 2006 Feb 27;166(4):458-64
references.pmid: 16505267
references.citation: Tumour Biol. 2012 Oct;33(5):1519-25
references.pmid: 22535370
references.citation: Blood. 2011 Aug 18;118(7):1952-61
references.pmid: 21673343
references.citation: J Clin Invest. 2013 Jul 1;:null
references.pmid: 23863628
references.citation: Nat Med. 2014 May;20(5):511-7
references.pmid: 24784231
references.citation: Carcinogenesis. 2005 Mar;26(3):631-6
references.pmid: 15579481
references.citation: Blood. 2012 Aug 9;120(6):1157-64
references.pmid: 22611154
references.citation: Science. 2004 Mar 5;303(5663):1532-5
references.pmid: 15001782
references.citation: J Thromb Haemost. 2011 Nov;9(11):2251-61
references.pmid: 21883880
references.citation: Sci Transl Med. 2013 Mar 27;5(178):178ra40
references.pmid: 23536012
references.citation: J Thromb Haemost. 2014 Oct;12(10):1697-702
references.pmid: 25069624
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13076-81
references.pmid: 22826226
references.citation: Eur Heart J. 2015 Jun 7;36(22):1405-14
references.pmid: 25660055
references.citation: Dig Liver Dis. 2001 Oct;33(7):546-50
references.pmid: 11816542
references.citation: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8674-9
references.pmid: 23650392
references.citation: Thromb Haemost. 2012 Jul;108(1):160-5
references.pmid: 22535219
references.citation: Biomarkers. 2006 Mar-Apr;11(2):184-93
references.pmid: 16766394
references.citation: Nat Med. 2015 Jul;21(7):815-9
references.pmid: 26076037
references.citation: J Thromb Haemost. 2010 Mar;8(3):540-7
references.pmid: 20040044
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15880-5
references.pmid: 20798043
references.citation: Nat Med. 2009 Jun;15(6):623-5
references.pmid: 19448636
references.citation: N Engl J Med. 2012 Feb 16;366(7):661-2
references.pmid: 22335745
references.citation: J Thromb Haemost. 2012 Mar;10(3):437-46
references.pmid: 22212198
references.citation: Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1977-84
references.pmid: 25012129