Platelet-derived VWF-cleaving metalloprotease ADAMTS-13.
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.
Liu
L
L
Department of Medicine, Thrombosis Research Section, Baylor College of Medicine, Houston, TX 77030, USA.
Choi
H
H
Bernardo
A
A
Bergeron
A L
AL
Nolasco
L
L
Ruan
C
C
Moake
J L
JL
Dong
J-F
JF
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*
D000925:Anticoagulants; D018179:Receptors, Thrombin; D014841:von Willebrand Factor; D004492:Edetic Acid; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human