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The regulation of blood coagulation by high-density lipoprotein particles

Oslakovic, Cecilia LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:67.
Abstract
High-density lipoprotein (HDL) has anti-atherogenic properties and the plasma level of HDL cholesterol correlates inversely with the risk of coronary artery disease. The atheroprotective functions of HDL can be explained by its function in the reverse cholesterol transport. Blood coagulation is activated in response to tissue damage and involves a series of enzymatic protein complexes that assemble on the surface of anionic phospholipids, e.g. activated platelets. Lipoproteins contain a phospholipid surface, which may provide another phospholipid surface, other than platelets, that could stimulate the reactions of blood coagulation. Lipoproteins have been reported to have dual roles in the regulation of blood coagulation, therefore in this... (More)
High-density lipoprotein (HDL) has anti-atherogenic properties and the plasma level of HDL cholesterol correlates inversely with the risk of coronary artery disease. The atheroprotective functions of HDL can be explained by its function in the reverse cholesterol transport. Blood coagulation is activated in response to tissue damage and involves a series of enzymatic protein complexes that assemble on the surface of anionic phospholipids, e.g. activated platelets. Lipoproteins contain a phospholipid surface, which may provide another phospholipid surface, other than platelets, that could stimulate the reactions of blood coagulation. Lipoproteins have been reported to have dual roles in the regulation of blood coagulation, therefore in this thesis the role of HDL in blood coagulation was investigated.



HDL was studied in its ability to stimulate prothrombin activation. Anionic phospholipids lost their procoagulant function when incorporated into reconstituted HDL particles. The anionic phospholipids of these particles were unable to support binding to activated factor V (FVa). Serum was also shown to neutralize the procoagulant effect of anionic liposomes with transfer of phospholipids to both low-density lipoprotein (LDL) and HDL particles. The transfer of phospholipids was dependent on a catalytically active form of phospholipid transfer protein (PLTP). Total HDL, HDL3 and very high-density lipoprotein, all which contained endogenous PLTP, were all able to neutralize procoagulant liposomes. Addition of exogenous PLTP to either LDL or HDL2, which were both absent of endogenous PLTP, increased the neutralization of procoagulant liposomes.



HDL has been reported to function as a cofactor to anticoagulant activated protein C (APC) in the degradation of FVa in the presence of protein S. HDL isolated by ultracentrifugation was found to stimulate the APC-mediated degradation of FVa. However, further purification of HDL by size-exclusion chromatography revealed that the stimulating activity was not a property of HDL but instead caused by contaminating anionic phospholipid membranes. (Less)
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author
supervisor
opponent
  • Morrissey, James, College of Medicine, University of Illinois at Urbana-Campaign
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:67
pages
90 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
CRC aula, entrance 72, Skåne University Hospital
defense date
2010-06-18 09:00
ISSN
1652-8220
ISBN
978-91-86443-83-2
language
English
LU publication?
yes
id
4bdeb101-e169-47f0-a387-ba0520924f99 (old id 1608666)
date added to LUP
2010-05-31 12:44:22
date last changed
2018-05-29 11:11:35
@phdthesis{4bdeb101-e169-47f0-a387-ba0520924f99,
  abstract     = {High-density lipoprotein (HDL) has anti-atherogenic properties and the plasma level of HDL cholesterol correlates inversely with the risk of coronary artery disease. The atheroprotective functions of HDL can be explained by its function in the reverse cholesterol transport. Blood coagulation is activated in response to tissue damage and involves a series of enzymatic protein complexes that assemble on the surface of anionic phospholipids, e.g. activated platelets. Lipoproteins contain a phospholipid surface, which may provide another phospholipid surface, other than platelets, that could stimulate the reactions of blood coagulation. Lipoproteins have been reported to have dual roles in the regulation of blood coagulation, therefore in this thesis the role of HDL in blood coagulation was investigated.<br/><br>
<br/><br>
HDL was studied in its ability to stimulate prothrombin activation. Anionic phospholipids lost their procoagulant function when incorporated into reconstituted HDL particles. The anionic phospholipids of these particles were unable to support binding to activated factor V (FVa). Serum was also shown to neutralize the procoagulant effect of anionic liposomes with transfer of phospholipids to both low-density lipoprotein (LDL) and HDL particles. The transfer of phospholipids was dependent on a catalytically active form of phospholipid transfer protein (PLTP). Total HDL, HDL3 and very high-density lipoprotein, all which contained endogenous PLTP, were all able to neutralize procoagulant liposomes. Addition of exogenous PLTP to either LDL or HDL2, which were both absent of endogenous PLTP, increased the neutralization of procoagulant liposomes. <br/><br>
<br/><br>
HDL has been reported to function as a cofactor to anticoagulant activated protein C (APC) in the degradation of FVa in the presence of protein S. HDL isolated by ultracentrifugation was found to stimulate the APC-mediated degradation of FVa. However, further purification of HDL by size-exclusion chromatography revealed that the stimulating activity was not a property of HDL but instead caused by contaminating anionic phospholipid membranes.},
  author       = {Oslakovic, Cecilia},
  isbn         = {978-91-86443-83-2},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {90},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {The regulation of blood coagulation by high-density lipoprotein particles},
  volume       = {2010:67},
  year         = {2010},
}