Calibrated ADAMTS13 inhibition prevents cardiovascular shear coagulopathy
Saito, K.; Isozumi, N.; Shiraishi, Y.; Hattori, Y.; Sakai, K.; Ueda, T.; Hamamura, A.; Imamura, R.; Kayashima, M.; Nakano, K.; Yambe, T.; Kumeta, H.; Shigehisa, R.; Mori, M.; Imamura, T.; Nakanishi, M.; Oda, M.; Kanemura, S.; Okumura, M.; Niwa, T.; Martel, A.; Porcar, L.; Morishima, K.; Okuda, A.; Sugiyama, M.; Takatsuka, M.; Tomimatsu, N.; Saio, T.; Hikoso, S.; Mori, E.; Matsumoto, M.
Show abstract
Mechanical circulatory support essential for managing severe heart failure frequently triggers bleeding complications, driven by shear stress-induced over-proteolysis of von Willebrand factor (VWF) by ADAMTS13. Inhibiting ADAMTS13 presents a rationale to treat this condition, known as acquired von Willebrand syndrome (AVWS). However, conventional therapeutic strategies remain limited due to the risk of triggering thrombotic thrombocytopenic purpura. Here we show that HA10, a humanized anti-ADAMTS13 antibody, preserves a residual level of ADAMTS13 activity above the thrombosis-associated threshold. Multimodal structural and biophysical analyses--including NMR, SAXS, and SANS--revealed that HA10 bound to the disintegrin-like domain of ADAMTS13, dynamically competing with VWF while leaving 10- 20% residual enzymatic activity. The therapeutic efficacy and safety of HA10 were verified in non-human primate models of AVWS. Our findings establish a novel paradigm of enzymatic calibration rather than complete blockade, offering a mechanistically targeted and safe therapeutic approach for cardiovascular bleeding.
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