Journal article
Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site
Blood, Vol.114(8), pp.1666-1674
Thrombosis and Hemostasis
08/20/2009
DOI: 10.1182/blood-2009-01-195461
PMCID: PMC2731642
PMID: 19541819
Abstract
The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF. We identified 4 leukocyte proteases that cleave the synthetic VWF substrate FRETS-VWF73 and multimeric VWF. Elastase and proteinase 3 (PR3) cleave multimeric VWF and FRETS-VWF73 at the V
1607
-T
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peptide bond; cathepsin G and matrix metalloprotease 9 cleave VWF substrates at the Y
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-M
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and M
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-V
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bonds, respectively. Isolated intact human neutrophils cleave FRETS-VWF73 at the V
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-T
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peptide bond, suggesting that elastase or PR3 expressed on leukocyte surfaces might cleave VWF. In the presence of normal or ADAMTS13-deficient plasma, cleavage of FRETS-VWF73 by resting neutrophils is abolished. However, activated neutrophils retain proteolytic activity toward FRETS-VWF73 in the presence of plasma. Although the in vivo relevance remains to be established, these studies suggest the existence of a “hot spot” of VWF proteolysis in the VWF A2 domain, and support the possibility that activated leukocytes may participate in the proteolytic regulation of VWF.
Details
- Title: Subtitle
- Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site
- Creators
- Thomas J Raife - Department of Pathology, University of Iowa Carver College of Medicine, Iowa CityWenjing Cao - Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Medical CenterBonnie S Atkinson - Blood Research Institute, Blood Center of Wisconsin, MilwaukeeBruce Bedell - Department of Pathology, University of Iowa Carver College of Medicine, Iowa CityRobert R Montgomery - Blood Research Institute, Blood Center of Wisconsin, MilwaukeeSteven R Lentz - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa CityGeorge F Johnson - Department of Pathology, University of Iowa Carver College of Medicine, Iowa CityX. Long Zheng - Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Medical Center
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.114(8), pp.1666-1674
- Publisher
- American Society of Hematology
- Series
- Thrombosis and Hemostasis
- DOI
- 10.1182/blood-2009-01-195461
- PMID
- 19541819
- PMCID
- PMC2731642
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- HL 55556; HL 44612; HL 81588; HL 33721; HL079027 / National Institutes of Health
- Language
- English
- Date published
- 08/20/2009
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Epidemiology; Pathology; Internal Medicine
- Record Identifier
- 9984094564802771
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