Thromb Haemost 2016; 115(04): 738-751
DOI: 10.1160/TH15-09-0710
Coagulation and Fibrinolysis
Schattauer GmbH

Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease

Zhangxiu He*
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
2   Department of Nephrology, First Hospital, Harbin Medical University, Harbin, China
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Yu Si*
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Tao Jiang*
3   Department of General Surgery, First Hospital, Harbin Medical University, Harbin, China
,
Ruishuang Ma
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Yan Zhang
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
,
Muhua Cao
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Tao Li
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
,
Zhipeng Yao
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
,
Lu Zhao
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
,
Shaohong Fang
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Bo Yu
5   Department of Cardiology of the Second Hospital, Harbin Medical University, Harbin, China
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Zengxiang Dong
4   Department of Cardiology, First Hospital, Harbin Medical University, Harbin, China
,
Hemant S. Thatte
7   Department of Surgery, Brigham and Women’s Hospital, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
,
Yayan Bi
4   Department of Cardiology, First Hospital, Harbin Medical University, Harbin, China
,
Junjie Kou
5   Department of Cardiology of the Second Hospital, Harbin Medical University, Harbin, China
,
Shufen Yang
6   The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
,
Daxun Piao
3   Department of General Surgery, First Hospital, Harbin Medical University, Harbin, China
,
Lirong Hao
2   Department of Nephrology, First Hospital, Harbin Medical University, Harbin, China
,
Jin Zhou
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
,
Jialan Shi
1   Department of Hematology, First Hospital, Harbin Medical University, Harbin, China
7   Department of Surgery, Brigham and Women’s Hospital, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
› Author Affiliations
Financial support: This work was in part supported by the National Natural Science Foundation of China (81270588, 81470301 and 81570638) and the Education Doctoral Foundation of Ministry (20122307110011).
Further Information

Publication History

Received: 08 September 2015

Accepted after major revision: 08 November 2015

Publication Date:
29 November 2017 (online)

Summary

Inflammatory bowel disease (IBD)-associated thromboembolic event often lacks precise aetiology. The aim of this study was to investigate the contribution of phosphatidylserine (PS) exposure and neutrophil extracellular traps (NETs) towards the hypercoagulable state in IBD. We demonstrated that the levels of PS exposed MPs and the sources of MP-origin, platelets, erythrocytes, leukocytes and cultured endothelial cells (ECs) were higher in IBD groups than in healthy controls using flow cytometry and confocal microscopy. Wright-Giemsa and immunofluorescence staining demonstrated that the elevated NETs were released by activated IBD neutrophils or by control neutrophils treated with IBD sera obtained from patients with the active disease. MPs and MP-origin cells in IBD groups, especially in active stage, markedly shortened coagulation time and had increased levels of fibrin, thrombin and FXa production as assessed by coagulation function assays. Importantly, we found that on stimulated ECs, PS rich membranes provided binding sites for FXa and FVa, promoting fibrin formation while TNF blockage or IgG depletion attenuated this effect. Treatment of control neutrophils with TNF and isolated IgG from PR3-ANCA-positive active IBD patients also resulted in the release of NETs. Blockade of PS with lactadherin prolonged coagulation time, decreased fibrin formation to control levels, and inhibited the procoagulant enzymes production in the MPs and MP-origin cells. NET cleavage by DNase I partly decreased PCA in IBD or stimulated neutrophils. Our study reveals a previously unrecognised link between hypercoagulable state and PS exposure or NETs, and may further explain the epidemiological association of thrombosis within IBD patients.

* Equal contribution.


 
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