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

Blood. 2021 Jan 28;137(4):544-555. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • von Willebrand Factor / antagonists & inhibitors*
  • von Willebrand Factor / chemistry
  • von Willebrand Factor / physiology
  • von Willebrand Factor / therapeutic use


  • Peptide Fragments
  • Recombinant Fusion Proteins
  • von Willebrand Factor