title: High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.
abstract: The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in self-associated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders.
authors.affiliation: Bloodworks Research Institute, Seattle, WA; Department of Biochemistry.
authors.forename: Dominic W
authors.initials: DW
authors.lastname: Chung
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Junmei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Minhua
authors.initials: M
authors.lastname: Ling
authors.affiliation: Bloodworks Research Institute, Seattle, WA; Department of Medicine.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Fu
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Teri
authors.initials: T
authors.lastname: Blevins
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Scott
authors.initials: S
authors.lastname: Parsons
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Jennie
authors.initials: J
authors.lastname: Le
authors.affiliation: Bloodworks Research Institute, Seattle, WA;
authors.forename: Jeff
authors.initials: J
authors.lastname: Harris
authors.affiliation: Division of Pulmonary and Critical Care, and.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.affiliation: Bloodworks Research Institute, Seattle, WA; Department of Medicine.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Konkle
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Bloodworks Research Institute, Seattle, WA; Department of Biochemistry, Department of Medicine.
authors.forename: José A
authors.initials: JA
authors.lastname: López
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism* / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D010973:Platelet Adhesiveness; D055503:Protein Multimerization; D013921:Thrombocytopenia / Q000517:prevention & control; D013927:Thrombosis / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D014841:von Willebrand Factor