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Updated: Jun 26, 2026
Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation
Published on: August 14, 2017
von Willebrand factor is a major determinant of ADAMTS-13 decrease during mouse sepsis induced by cecum ligation and
N Lerolle1, C Dunois-Lardé, I Badirou
1Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
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.
Insights
Sepsis increases von Willebrand factor (VWF), leading to decreased ADAMTS-13 activity. While VWF impacts sepsis mortality, manipulating ADAMTS-13 levels did not alter survival outcomes in this study.
Area of Science:
- Hematology
- Critical Care Medicine
- Molecular Biology
Background:
- Sepsis involves abundant secretion of von Willebrand factor (VWF).
- ADAMTS-13, a metalloprotease, regulates VWF size through proteolysis.
- Understanding the interplay between VWF and ADAMTS-13 in sepsis is crucial.
Purpose of the Study:
- To investigate if ADAMTS-13 consumption, due to VWF binding and cleavage, causes its decrease during sepsis.
- To determine if altering ADAMTS-13 activity affects sepsis outcomes.
Main Methods:
- Cecum ligature and puncture (CLP) model of sepsis in wild-type, Vwf(-/-), and Adamts-13(-/-) mice.
- Evaluation of ADAMTS-13 activity and VWF levels.
- Assessment of sepsis outcomes, including survival and thrombocytopenia.
- Hydrodynamic gene transfer to enhance ADAMTS-13 activity in wild-type mice.
Main Results:
- Sepsis in wild-type mice significantly decreased ADAMTS-13 activity, correlating negatively with VWF levels.
- In Vwf(-/-) mice, sepsis severity was high, but ADAMTS-13 levels remained stable; these mice showed improved survival.
- Complete absence of ADAMTS-13 did not alter sepsis-induced thrombocytopenia, VWF concentrations, or survival compared to wild-type mice.
- Enhanced ADAMTS-13 activity via gene transfer did not improve survival in CLP-induced sepsis.
Conclusions:
- VWF secretion significantly contributes to ADAMTS-13 decrease in sepsis and influences mortality.
- Complete deficiency of ADAMTS-13 had no discernible impact on the sepsis model.
- Augmenting ADAMTS-13 activity did not improve survival rates in sepsis.
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