Inhibition of ADAMTS13 Activity by Peptidylarginine Deiminase IV Exacerbates Pancreatic Necrosis in Acute Pancreatitis

BACKGROUND & AIMS: Dysregulation of the Von Willebrand factor (VWF) and its protease-ADAMTS13 has been implicated in the pathogenesis of pancreatic necrosis during acute pancreatitis (AP), but the underlying mechanisms remain incompletely understood. NETosis and their enzyme component, peptidylarginine deiminase type IV (PAD4), have been proposed to inhibit ADAMTS13. We aimed to determine whether PAD4-mediated inhibition of ADAMTS13 contributes to the progression of pancreatic injury in AP. METHODS: ). RESULTS: AP patients with >30% pancreatic necrosis exhibited significantly reduced ADAMTS13 activity, elevated PAD4 levels, and accumulation of large VWF multimers. In mouse AP models, ADAMTS13 deficiency worsened pancreatic necrosis and systemic injury, whereas rhADAMTS13 treatment conferred protection. Mechanistically, PAD4 suppressed ADAMTS13 activity both in vitro and in vivo; this inhibition was reversed by Cl-amidine. PAD4 inhibition attenuated AP severity, but this effect was abolished in Adamts13-/ mice, demonstrating that PAD4 aggravates AP primarily through ADAMTS13 suppression. CONCLUSIONS: An early imbalance in the VWF-ADAMTS13 axis and PAD4 activation is a hallmark of both clinical and experimental AP. By inhibiting ADAMTS13 activity, PAD4 promotes pancreatic necrosis and exacerbates disease severity. Targeting PAD4 or restoring ADAMTS13 activity may represent a promising therapeutic strategy to protect against pancreatic injury in AP.