von Willebrand factor is a major determinant of ADAMTS-13 decrease during mouse sepsis induced by cecum ligation and puncture.
BACKGROUND
During sepsis, von Willebrand factor (VWF) is abundantly secreted; the main mechanism regulating its size involves specific proteolysis by the metalloprotease ADAMTS-13.


OBJECTIVE
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.
Lerolle
N
N
Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
Dunois-Lardé
C
C
Badirou
I
I
Motto
D G
DG
Hill
G
G
Bruneval
P
P
Diehl
J-L
JL
Denis
C V
CV
Baruch
D
D
D000071120:ADAMTS13 Protein; D000818:Animals; D002432:Cecum / Q000473:pathology*; D004195:Disease Models, Animal; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000378:metabolism*; D014841:von Willebrand Factor / Q000235:genetics / Q000502:physiology*
D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein