The Journal of Experimental Medicine
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Published online 13 March 2006 doi:10.1084/jem.20051732
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 767-776
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ARTICLE

 Systemic antithrombotic effects of ADAMTS13

Anil K. Chauhan1,2, David G. Motto3, Colin B. Lamb1, Wolfgang Bergmeier1,2, Michael Dockal5, Barbara Plaimauer5, Friedrich Scheiflinger5, David Ginsburg4, and Denisa D. Wagner1,2

1 CBR Institute for Biomedical Research and 2 Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Department of Pediatrics, University of Michigan, and 4 Department of Internal Medicine, University of Michigan and Howard Hughes Medical Institute, Ann Arbor, MI 48109
5 Baxter Bioscience, Vienna, A-1220 Austria

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

The metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) cleaves highly adhesive large von Willebrand factor (VWF) multimers after their release from the endothelium. ADAMTS13 deficiency is linked to a life-threatening disorder, thrombotic thrombocytopenic purpura (TTP), characterized by platelet-rich thrombi in the microvasculature. Here, we show spontaneous thrombus formation in activated microvenules of Adamts13–/– mice by intravital microscopy. Strikingly, we found that ADAMTS13 down-regulates both platelet adhesion to exposed subendothelium and thrombus formation in injured arterioles. An inhibitory antibody to ADAMTS13 infused in wild-type mice prolonged adhesion of platelets to endothelium and induced thrombi formation with embolization in the activated microvenules. Absence of ADAMTS13 did not promote thrombi formation in {alpha}IIbß3 integrin-inhibited blood. Recombinant ADAMTS13 reduced platelet adhesion and aggregation in histamine-activated venules and promoted thrombus dissolution in injured arterioles. Our findings reveal that ADAMTS13 has a powerful natural antithrombotic activity and recombinant ADAMTS13 could be used as an antithrombotic agent.

Abbreviations used: ADAMTS, a disintegrin-like and metalloprotease with thrombospondin type I repeats; r-hu, recombinant human; TTP, thrombotic thrombocytopenic purpura; UL-VWF, ultra-large VWF; VWF, von Willebrand factor.


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