von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury

• Published in: Blood 2018-09, Vol.132 (10), p.1075-1084
• Main Authors: Wu, Yingang, Liu, Wei, Zhou, Yuan, Hilton, Tristan, Zhao, Zilong, Wang, Min, Yeon, Jason, Houck, Katie, Thiagarajan, Perumal, Zhang, Fangyi, Shi, Fu-Dong, Wu, Xiaoping, Li, Min, Dong, Jing-fei, Zhang, Jianning
• Format: Article
• Language: English
• Subjects: Animals; Blood Coagulation Disorders - genetics; Blood Coagulation Disorders - metabolism; Blood Coagulation Disorders - pathology; Brain Injuries - genetics; Brain Injuries - metabolism; Brain Injuries - pathology; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; Male; Mice; Mice, Knockout; Microvessels - metabolism; Microvessels - pathology; Thrombosis and Hemostasis; von Willebrand Factor - genetics; von Willebrand Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-03-841932

von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute traumatic brain injury (TBI) was activated and became microvesicle-bound. The VWF-bound microvesicles promoted vascular leakage and systemic coagulation. Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion. rADAMTS-13 protected the integrity of endothelial cell barriers and prevented TBI-induced coagulopathy by enhancing VWF cleavage without impairing basal hemostasis. Promoting microvesicle clearance by lactadherin had efficacy similar to that of rADAMTS-13. This study uncovers a novel synergistic action between VWF and cellular microvesicles in TBI-induced vascular leakage and coagulopathy and demonstrates protective effects of rADAMTS-13. •Injured brain releases hyperadhesive and microvesicle-bound VWF that causes neurological dysfunction and a systemic hypercoagulable state.•ADAMTS-13 protected the blood-brain barrier to prevent TBI-induced neurological dysfunction and systemic coagulopathy. [Display omitted]