Conformation-Dependent Blockage of Activated Vwf Improves Outcomes of Traumatic Brain Injury in Mice

Authors

Xin Xu
Chenyu Wang
Yingang Wu
Katie Houck
Tristan Hilton
Ashley Zhou
Xiaoping Wu
Cha Han
Mengchen Yang
Wei Yang
Fu-Dong Shi
Moritz Stolla
Miguel A Cruz
Min Li
Jianning Zhang
Jing-Fei Dong

Publication Date

1-28-2021

Journal

Blood

DOI

10.1182/blood.2020007364

PMID

33507292

PMCID

PMC7845006

PubMedCentral® Posted Date

8-5-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Acute-Phase Reaction, Animals, Blood Platelets, Brain Injuries, Traumatic, Capillary Leak Syndrome, Case-Control Studies, Cerebral Hemorrhage, Cerebrovascular Circulation, Disseminated Intravascular Coagulation, Endothelium, Vascular, Extracellular Vesicles, Humans, Infusions, Intravenous, Injections, Intraperitoneal, Male, Mice, Mice, Inbred C57BL, Peptide Fragments, Platelet Activation, Protein Conformation, Protein Domains, Recombinant Fusion Proteins, von Willebrand Factor

Abstract

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.

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