Thromb Haemost 2018; 118(12): 2086-2097
DOI: 10.1055/s-0038-1675228
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Plasma Phospholipid Transfer Protein Promotes Platelet Aggregation

Xiao-Min Zhao*
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Yun Wang*
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Yang Yu*
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Hui Jiang
2  Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, United States
,
Anna Babinska
2  Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, United States
,
Xiu-Yu Chen
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Ke-Gui He
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Xiang-Dong Min
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Ji-Ju Han
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Chen-Xi Yang
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Kevin Deng
2  Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, United States
,
Jing Xue
3  Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, China
,
Xiangjian Zhang
3  Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, China
,
Guo-Hua Song
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Shu-Cun Qin
1  The Institute of Atherosclerosis, Taishan Medical University, Taian, China
,
Xian-Cheng Jiang
2  Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, United States
4  Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States
› Author Affiliations
Funding This work was supported by China Natural Science Funds (31371190, 91539114, 81173061), Taishan Scholar Foundation of Shandong Province of China (ts201511057) and Natural Science Foundation of Shandong Province of China (ZR2014HQ007, ZR2017MH048), Veterans Affairs Merit award 000900–01 and National Institutes of Health grant R56HL121409.
Further Information

Publication History

11 January 2018

12 September 2018

Publication Date:
12 November 2018 (eFirst)

Abstract

It remains unclear whether plasma phospholipid transfer protein (PLTP) is involved in hyper-coagulation or hypo-coagulation. This study investigated the direct effect of PLTP on platelet aggregation and the underlying mechanism. Washed platelets from humans or mice and mouse platelet-rich plasma and human recombinant PLTP were isolated. PLTP is present in human platelets. We assessed adenosine diphosphate (ADP)-, collagen- and thrombin-induced platelet aggregation, phosphatidylserine externalization and photothrombosis-induced cerebral infarction in mice. PLTP over-expression increased platelet aggregation, while PLTP deficiency had the opposing reaction. Human recombinant PLTP increased both mouse and human platelet aggregation in a dose-dependent manner. Phosphatidylserine externalization provides a water/lipid surface for the interaction of coagulation factors, which accelerates thrombosis. Compared with wild-type controls, platelets from PLTP transgenic mice had significantly more phosphatidylserine on the exterior surface of the plasma membrane, whereas platelets from PLTP-deficient mice had significantly less phosphatidylserine on the surface, thus PLTP influences fibrinogen binding on the plasma membrane. Moreover, recombinant PLTP together with ADP significantly increased phosphatidylserine exposure on the plasma membrane of PLTP-deficient platelets, thereby increasing fibrinogen binding. PLTP over-expression significantly accelerated the incidence of photothrombosis-induced infarction in mice, whereas PLTP deficiency significantly reduced the frequency of infarction. We concluded that PLTP promotes phosphatidylserine externalization at the plasma membrane of platelets and accelerates ADP- or collagen-induced platelet aggregation. This effect plays an important role in the initiation of thrombin generation and platelet aggregation under sheer stress conditions. Thus, PLTP is involved in hyper-coagulation. Therefore, PLTP inhibition could be a novel approach for countering thrombosis.

Authors' Contributions

X.M.Z., Y.W. and Y.Y designed the study and performed most of the experiments, and they contributed equally to this work. H.J., A.B., X.Y.C., K.G.H., X.D.M., J.J.H., C.X.Y., J.X., X.Z. and G.H.S. performed some experiments. S.C.Q. and X.C.J. designed the study and wrote the manuscript.


* These authors contributed equally to this work.


Supplementary Material