title: Platelet-derived VWF-cleaving metalloprotease ADAMTS-13.
abstract: The adhesion ligand von Willebrand factor (VWF) is synthesized and stored in vascular endothelial cells and megakaryocytes/platelets. As in endothelial cells, platelet VWF also contains ultra-large (UL) multimers that are hyperactive in aggregating platelets. ULVWF in platelet lysates of thrombin-stimulated platelets was only detected in the presence of EDTA, suggesting that ULVWF is cleaved by a divalent cation-dependent protease. A recent study shows that platelets contain the VWF-cleaving metalloprotease ADAMTS-13, but its activity remains unknown. In this study, we show that platelet lysates cleave endothelial cell-derived ULVWF under static and flow conditions. This activity is inhibited by EDTA and by an ADAMTS-13 antibody from the plasma of a patient with acquired TTP. ADAMTS-13 was detected in platelet lysates and on the platelet surface by four antibodies that bind to different domains of the metalloprotease. Expression of ADAMTS-13 on the platelet surface increases significantly upon platelet activation by the thrombin receptor-activating peptide, but not by ADP. These results demonstrate that platelets contain functionally active ADAMTS-13. This intrinsic activity may be physiologically important to prevent the sudden release of hyperactive ULVWF from platelets and serves as the second pool of ADAMTS-13 to encounter the increase in ULVWF release from endothelial cells.
authors.affiliation: Department of Medicine, Thrombosis Research Section, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Choi
authors.forename: A
authors.initials: A
authors.lastname: Bernardo
authors.forename: A L
authors.initials: AL
authors.lastname: Bergeron
authors.forename: L
authors.initials: L
authors.lastname: Nolasco
authors.forename: C
authors.initials: C
authors.lastname: Ruan
authors.forename: J L
authors.initials: JL
authors.lastname: Moake
authors.forename: J-F
authors.initials: JF
authors.lastname: Dong
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D004492:Edetic Acid / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D018179:Receptors, Thrombin / Q000378:metabolism; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D018179:Receptors, Thrombin; D014841:von Willebrand Factor; D004492:Edetic Acid; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human