68 / 89
64
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.