Thromb Haemost 2018; 118(12): 2064-2073
DOI: 10.1055/s-0038-1675788
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia

Yae Hu*
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
2  Department of Pathophysiology, Medical School of Nantong University, Nantong University, Nantong, China
,
Hui Li*
3  Central Laboratory, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
,
Ruhong Yan
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
,
Can Wang
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
,
Yun Wang
4  Department of Obstetrics and Gynecology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
,
Ce Zhang
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
,
Meng Liu
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
,
Tiantian Zhou
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
,
Weipei Zhu
5  Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
,
Hong Zhang
5  Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
,
Ningzheng Dong
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
6  MOH Key Laboratory of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, Medical College, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
7  Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
,
Qingyu Wu
1  Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou, China
7  Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
8  Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States
› Author Affiliations
Funding This work was supported in part by grants from the National Science Foundation of China (81671485, 81503304, 81570457 and 91639116), the National Basic Research Program of China (2015CB943302), the Priority Academic Program Development of Jiangsu Higher Education Institutes and the NIH (HD093727 and HL126697).
Further Information

Publication History

04 June 2018

06 October 2018

Publication Date:
19 November 2018 (eFirst)

Abstract

Pre-eclampsia (PE) is a chronic inflammatory disease in pregnancy, which is associated with enhanced blood coagulation and high thrombotic risk. To date, the mechanisms underlying such an association are not fully understood. Previous studies reported high levels of plasma deoxyribonucleic acid (DNA) in PE women, but the cellular source of the circulation DNA remains unknown. In this study, we tested the hypothesis that activated neutrophils undergoing cell death, also called NETosis, may be responsible for the elevated plasma DNA levels in PE women. We analysed plasma samples from non-pregnant, normal pregnant and PE women and found high levels of double-stranded DNA, myeloperoxidase (an abundant neutrophil granular enzyme) and histones (the major nucleosome proteins) in PE-derived samples, indicating increased NETosis in the maternal circulation. The high plasma DNA levels positively correlated with enhanced blood coagulation in PE women. When isolated neutrophils from normal individuals were incubated with PE-derived plasma, an elevated NETosis-stimulating activity was detected. Further experiments showed that endothelial micro-particles, but not soluble proteins, in the plasma were primarily responsible for the NETosis-stimulating activity in PE women. These results indicate that circulating micro-particles from damaged maternal endothelium are a potent stimulator for neutrophil activation and NETosis in PE women. Given the pro-coagulant and pro-thrombotic nature of granular and nuclear contents from neutrophils, enhanced systemic NETosis may represent an important mechanism underlying the hyper-coagulability and increased thrombotic risk in PE.

* These authors contributed equally to this work.


Supplementary Material