The Journal of Experimental Medicine
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Published online August 11, 2008
doi:10.1084/jem.20080130
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Chauhan et al.
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ARTICLE

 ADAMTS13: a new link between thrombosis and inflammation

Anil K. Chauhan1,2, Janka Kisucka1,2, Alexander Brill1,2, Meghan T. Walsh1, Friedrich Scheiflinger3, and Denisa D. Wagner1,2

1 Immune Disease Institute and 2 Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Baxter Bioscience, 1220 Vienna, Austria

CORRESPONDENCE Denisa D. Wagner: wagner{at}idi.harvard.edu

von Willebrand factor (VWF) levels are elevated and a disintegrin-like and metalloprotease with thrombospondin type I repeats–13 (ADAMTS13) activity is decreased in both acute and chronic inflammation. We hypothesized that by cleaving hyperactive ultralarge VWF (ULVWF) multimers, ADAMTS13 down-regulates both thrombosis and inflammation. Using intravital microscopy, we show that ADAMTS13 deficiency results in increased leukocyte rolling on unstimulated veins and increased leukocyte adhesion in inflamed veins. Both processes were dependent on the presence of VWF. Depletion of platelets in Adamts13–/– mice reduced leukocyte rolling, suggesting that platelet interaction with ULVWF contributes to this process. Increased levels of endothelial P-selectin and plasma VWF in Adamts13–/– compared with wild-type (WT) mice indicated an elevated release of Weibel-Palade bodies. ULVWF multimers released upon stimulation with histamine, a secretagogue of Weibel-Palade bodies, slowed down leukocyte rolling in Adamts13–/– but not in WT mice. Furthermore, in inflammatory models, ADAMTS13 deficiency resulted in enhanced extravasation of neutrophils, and this process was also dependent on VWF. Our findings reveal an important role for ADAMTS13 in preventing excessive spontaneous Weibel-Palade body secretion, and in the regulation of leukocyte adhesion and extravasation during inflammation.

Abbreviations used: ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin type I repeats–13; H&E, hematoxylin and eosin; MPO, myeloperoxidase; TTP, thrombotic thrombocytopenia purpura; ULVWF, ultralarge VWF; VWF, von Willebrand factor.

© 2008 Chauhan et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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