Submitted July 25, 2008
Accepted February 7, 2009
C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates and protects against carotid artery occlusion and cerebral stroke
Zongdong Li, Michael A. Nardi, Yong-Sheng Li, Wei Zhang, Ruimin Pan, Suying Dang, Herman Yee, David Quartermain, Saran Jonas, and Simon Karpatkin*
Department of Medicine, New York University School of Medicine, New York, NY, United States
Department of Pediatrics, New York University School of Medicine, New York, NY, United States
Department of Neurology, New York University School of Medicine, New York, NY, United States
Department of Pathology, New York University School of Medicine, New York, NY, United States
* Corresponding author; email: simon.karpatkin{at}med.nyu.edu.
Anti-platelet integrin GPIIIa49-66 Ab induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385 amino acid fragment of ADAMTS-18 (A Disintegrin Metalloproteinase with Thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCl3 induced carotid artery thrombosis as well as cerebral infarction in a post-ischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18.
