Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice

• Published in: Blood Vol. 137; no. 4; pp. 544 - 555
• Main Authors: Xu, Xin, Wang, Chenyu, Wu, Yingang, Houck, Katie, Hilton, Tristan, Zhou, Ashley, Wu, Xiaoping, Han, Cha, Yang, Mengchen, Yang, Wei, Shi, Fu-Dong, Stolla, Moritz, Cruz, Miguel A., Li, Min, Zhang, Jianning, Dong, Jing-fei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.01.2021; American Society of Hematology
• Subjects: Acute-Phase Reaction; Animals; Blood Platelets - metabolism; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - drug therapy; Capillary Leak Syndrome - etiology; Capillary Leak Syndrome - prevention & control; Case-Control Studies; Cerebral Hemorrhage - etiology; Cerebral Hemorrhage - prevention & control; Cerebrovascular Circulation; Disseminated Intravascular Coagulation - etiology; Disseminated Intravascular Coagulation - prevention & control; Endothelium, Vascular - drug effects; Extracellular Vesicles; Humans; Infusions, Intravenous; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Platelet Activation - drug effects; Protein Conformation; Protein Domains - drug effects; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Thrombosis and Hemostasis; von Willebrand Factor - antagonists & inhibitors; von Willebrand Factor - chemistry; von Willebrand Factor - physiology; von Willebrand Factor - therapeutic use
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020007364

Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI. •VWF released during acute TBI was hyperadhesive in mediating extracellular vesicles to active endothelial cells and platelets.•Recombinant VWF A2 domain prevented TBI-induced coagulopathy by selectively blocking the exposed A1 domain of the hyperadhesive VWF. [Display omitted]