Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Poster Abstracts

8-POS Board 8 High Density Lipoprotein Modulates Thrombosis by Preventing Von Willebrand Factor Self-Association Dominic W. Chung 1,2 , Junmei Chen 1 , Minhua Ling 1 , Xiaoyun Fu 1,3 , Barbara A. Konkle 1,3 , Ying Zheng 4 , José A. López 1,2,3 . 1 BloodworksNW, Seattle, WA, USA, 3 University of Washington, Seattle, WA, USA, 4 University of Washington, Seattle, WA, USA. 2 University of Washington, Seattle, WA, USA, Von Willebrand factor (VWF) is a multimeric glycoprotein in plasma that plays an important role in hemostasis by mediating platelet binding to sites of vascular injury. In recent studies, VWF has also been implicated in microvascular thrombosis, in part because of its unique ability to self-associate in response to shear stress and form hyperadhesive strands of enormous sizes attached to the endothelial surface. These surface-bound VWF strands, if not removed by the metalloprotease ADAMTS13 in plasma, can bind platelets efficiently and form occlusive thrombi in the microvasculature. Using several experimental systems, we show that VWF self- association was responsible for (1) adsorption of purified VWF onto plastic or glass surface under static conditions, (2) adsorption of VWF in plasma onto surfaces under shear stress, (3) assembly of secreted VWF molecules into VWF strands on the endothelial surface in flow chambers, and (4) incorporation of fluid-phase VWF molecules onto endothelial VWF fibers in synthetic microvessels. Importantly, we also found that VWF self-association in each of these instances could be markedly attenuated by high density lipoprotein (HDL) particles or its major apolipoprotein, ApoA-I. Platelet adhesion to VWF strands or fibers was also reduced in proportion to the reduction in self-associated VWF. In a mouse model of thrombotic microangiopathy, HDL attenuated the thrombocytopenia induced by injection of high doses of VWF. Consistent with its antithrombotic properties, the level of ApoA-I in patients with hyperadhesive forms of VWF, such as thrombotic thrombocytopenic purpura and sepsis, was significantly reduced. These results suggest that regulation of VWF self-association may be another mechanism by which HDL protects against cardiovascular disease and interference with VWF self-association would be a new approach to treating thrombotic disorders.

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