title: Histological and biomechanical changes in a mouse model of venous thrombus remodeling.
abstract: BACKGROUND
  Deep vein thrombosis and the risk of pulmonary embolism are significant causes of morbidity and mortality. Much remains unclear, however, about the mechanisms by which a venous thrombus initiates, progresses, or resolves. In particular, there is a pressing need to characterize the evolving mechanical properties of a venous thrombus for its mechanical integrity is fundamental to many disease sequelae.
  
  
  OBJECTIVE
  The primary goal of the present study was to initiate a correlation between evolving histological changes and biomechanical properties of venous thrombus.
  
  
  METHODS
  We employed an inferior vena cava ligation model in mice to obtain cylindrical samples of thrombus that were well suited for mechanical testing and that could be explanted at multiple times following surgery. Using uniaxial micro-mechanical testing, we collected stress-stretch data that were then fit with a microstructurally-inspired material model before submitting the samples to immunohistological examination.
  
  
  RESULTS
  We found that venous thrombus underwent a radially inward directed replacement of fibrin with collagen between 2 weeks and 4 weeks of development, which was accompanied by the infiltration of inflammatory and mesenchymal cells. These histological changes correlated with a marked increase in material stiffness.
  
  
  CONCLUSIONS
  We demonstrated that 2 to 4 week old venous thrombus undergoes drastic remodeling from a fibrin-dominated mesh to a collagen-dominated microstructure and that these changes are accompanied by dramatic changes in biomechanical behavior.
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Y-U
authors.initials: YU
authors.lastname: Lee
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Humphrey
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Rausch
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D066253:Vascular Remodeling; D014682:Vena Cava, Inferior / Q000737:chemistry* / Q000378:metabolism / Q000503:physiopathology; D020246:Venous Thrombosis / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D005337:Fibrin; D003094:Collagen
keywords: Venous ligation; clot; intraluminal thrombosis; stiffness; stress