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von Willebrand factor is a major determinant of ADAMTS‐13 decrease during mouse sepsis induced by cecum ligation and puncture
Author(s) -
LEROLLE N.,
DUNOISLARDé C.,
BADIROU I.,
MOTTO D. G.,
HILL G.,
BRUNEVAL P.,
DIEHL J. L.,
DENIS C. V.,
BARUCH D.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03313.x
Subject(s) - adamts , sepsis , von willebrand factor , metalloproteinase , adamts13 , medicine , wild type , cecum , immunology , endocrinology , chemistry , platelet , matrix metalloproteinase , gene , mutant , thrombospondin , biochemistry
Summary. Background: During sepsis, von Willebrand factor (VWF) is abundantly secreted; the main mechanism regulating its size involves specific proteolysis by the metalloprotease ADAMTS‐13. Objectives: To determine whether ADAMTS‐13 consumption due to its binding to, and/or cleavage, of VWF contributes to its decrease during sepsis and whether abrogating or enhancing ADAMTS‐13 activity influences sepsis outcome. Methods: ADAMTS‐13 activity was evaluated in a model of sepsis induced by cecum ligature and puncture (CLP) in wild‐type and Vwf −/− mice. Sepsis outcome was studied in those mice and in Adamts‐13 −/− mice. Finally, survival was studied in wild‐type mice injected hydrodynamically with the human ADAMTS‐13 gene. Results: In wild‐type mice, CLP‐induced sepsis elicited a significant ADAMTS‐13 decrease, and a strong negative correlation existed between VWF and ADAMTS‐13. In Vwf −/− mice, CLP also induced severe sepsis, but ADAMTS‐13 was not significantly diminished. Notably, Vwf −/− mice lived significantly longer than wild‐type mice. In contrast, Adamts‐13 −/− mice and wild‐type mice were comparable with regard to thrombocytopenia, VWF concentrations, absence of thrombi, and survival. Hydrodynamic hADAMTS‐13 gene transfer with the pLIVE expression vector resulted in high and stable ADAMTS13 activity in CLP mice; however, no impact on survival was observed. Conclusions : VWF secretion is a major determinant of ADAMTS‐13 decrease in the CLP model, and plays an important role in sepsis‐induced mortality, but the complete absence of its regulating protease, ADAMTS‐13, had no detectable impact in this sepsis model. Furthermore, increasing ADAMTS‐13 activity had no impact on survival.