Cleavage of von Willebrand factor by granzyme M destroys its factor VIII binding capacity
Publication year
2011Source
PLoS One, 6, 9, (2011), article e24216ISSN
Publication type
Article / Letter to editor

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Organization
Internal Medicine
Journal title
PLoS One
Volume
vol. 6
Issue
iss. 9
Subject
N4i 3: Poverty-related infectious diseases NCEBP 13: Infectious diseases and international healthAbstract
Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet aggregation and stabilizes coagulation factor VIII (FVIII) in plasma. The metalloproteinase ADAMTS13 regulates the platelet aggregation function of VWF via proteolysis. Severe deficiency of ADAMTS13 is associated with thrombotic thrombocytopenic purpura, but does not always correlate with its clinical course. Therefore, other proteases could also be important in regulating VWF activity. In the present study, we demonstrate that VWF is cleaved by the cytotoxic lymphocyte granule component granzyme M (GrM). GrM cleaved both denaturated and soluble plasma-derived VWF after Leu at position 276 in the D3 domain. GrM is unique in that it did not affect the multimeric size and pro-hemostatic platelet aggregation ability of VWF, but instead destroyed the binding of VWF to FVIII in vitro. In meningococcal sepsis patients, we found increased plasma GrM levels that positively correlated with an increased plasma VWF/FVIII ratio in vivo. We conclude that, next to its intracellular role in triggering apoptosis, GrM also exists extracellularly in plasma where it could play a physiological role in controlling blood coagulation by determining plasma FVIII levels via proteolytic processing of its carrier VWF.
This item appears in the following Collection(s)
- Academic publications [205106]
- Electronic publications [103308]
- Faculty of Medical Sciences [81055]
- Open Access publications [71821]
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