Submitted September 5, 2007
Accepted October 3, 2007
Functional imaging of shear-dependent activity of ADAMTS13 in regulating mural thrombus growth under
whole blood flow conditions
Yasuaki Shida, Kenji Nishio, Mitsuhiko Sugimoto*, Tomohiro Mizuno, Masaaki Hamada, Seiji Kato, Masanori Matsumoto, Kazuo Okuchi, Yoshihiro Fujimura, and Akira Yoshioka
Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
Department of Emergency and Critical Care Medicine, Nara Medical University, Kashihara, Nara, Japan
Department of Blood Transfusion, Nara Medical University, Kashihara, Nara, Japan
* Corresponding author; email: sugi-ped{at}naramed-u.ac.jp.
The metalloprotease ADAMTS13 is assumed to regulate the functional levels of von Willebrand factor (VWF) appropriate for normal hemostasis in vivo by reducing VWF multimer size, which directly represents the thrombogenic activity of this factor. Using an in vitro perfusion chamber system, we studied the mechanisms of ADAMTS13 action during platelet thrombus formation on a collagen surface under whole blood flow conditions. Inhibition studies with a function-blocking anti-ADAMTS13 antibody, combined with immunostaining of thrombi with an anti-VWF monoclonal antibody that specifically reflects the VWF-cleaving activity of ADAMTS13, provided visual evidence for a shear rate-dependent action of ADAMTS13 that limits thrombus growth directly at the site of the on-going thrombus generation process. Our results identify an exquisitely specific regulatory mechanism that prevents arterial occlusion under high shear rate conditions during mural thrombogenesis.
