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

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.

• 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
• Journal: Blood (Blood) Vol. 137 Issue 4 Pg. 544-555 (01 28 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33507292 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptide Fragments
• Recombinant Fusion Proteins
• von Willebrand Factor

Topics

• Acute-Phase Reaction
• Animals
• Blood Platelets (metabolism)
• Brain Injuries, Traumatic (complications, drug therapy)
• Capillary Leak Syndrome (etiology, prevention & control)
• Case-Control Studies
• Cerebral Hemorrhage (etiology, prevention & control)
• Cerebrovascular Circulation
• Disseminated Intravascular Coagulation (etiology, prevention & control)
• Endothelium, Vascular (drug effects)
• Extracellular Vesicles
• Humans
• Infusions, Intravenous
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred C57BL
• Peptide Fragments (administration & dosage, pharmacology, therapeutic use)
• Platelet Activation (drug effects)
• Protein Conformation
• Protein Domains (drug effects)
• Recombinant Fusion Proteins (administration & dosage, pharmacology, therapeutic use)
• von Willebrand Factor (antagonists & inhibitors, chemistry, physiology, therapeutic use)