Document Detail

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.
MedLine Citation:
PMID:  23288905     Owner:  NLM     Status:  MEDLINE    
Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.
Erik Westein; Andries D van der Meer; Marijke J E Kuijpers; Jean-Philippe Frimat; Albert van den Berg; Johan W M Heemskerk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-23     Completed Date:  2013-03-21     Revised Date:  2013-07-24    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1357-62     Citation Subset:  IM    
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.
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MeSH Terms
Atherosclerosis / blood,  complications*,  pathology*,  physiopathology
Carotid Artery Thrombosis / blood,  etiology*,  pathology*,  physiopathology
Carotid Stenosis / blood,  complications*,  pathology*,  physiopathology
Disease Models, Animal
Endothelium, Vascular / physiopathology
Human Umbilical Vein Endothelial Cells
Mice, Inbred C57BL
Microfluidic Analytical Techniques
Microscopy, Fluorescence, Multiphoton
Models, Cardiovascular
Platelet Adhesiveness
Platelet Aggregation
von Willebrand Factor / physiology*
Reg. No./Substance:
0/von Willebrand Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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