Role of von Willebrand factor and ADAMTS‐13 in early brain injury after experimental subarachnoid hemorrhage |
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| Authors: | H. Wan Y. Wang J. Ai S. Brathwaite H. Ni R.L. Macdonald E.M. Hol J.C.M. Meijers M.D.I. Vergouwen |
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| Affiliation: | 1. Division of Neurosurgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;2. Labatt Family Centre of Excellence in Brain Injury and Trauma Research, University of Toronto, Toronto, Ontario, Canada;3. Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada;5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;6. Canadian Blood Services, Toronto, Ontario, Canada;7. Department of Physiology, University of Toronto, Toronto, Ontario, Canada;8. CCOA Therapeutics Inc, Toronto, Ontario, Canada;9. Department of Surgery, University of Toronto, Toronto, Ontario, Canada;10. Brain Center Rudolf Magnus, Department of Translational Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands;11. Netherlands Institute of Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands;12. Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands;13. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;14. Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands |
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| Abstract: | Essentials - von Willebrand Factor (VWF) and ADAMTS13 may affect early injury after subarachnoid hemorrhage (SAH).
- Early brain injury was assessed in VWF?/?, ADAMTS13?/? and recombinant (r) ADAMTS13 treated mice.
- VWF?/? and rADAMTS13 treated mice had less brain injury than ADAMTS13?/? and wild‐type mice.
- Early administration of rADAMTS13 may improve outcome after SAH by reducing early brain injury.
Summary Background Early brain injury is an important determinant of poor functional outcome and case fatality after aneurysmal subarachnoid hemorrhage (SAH), and is associated with early platelet aggregation. No treatment exists for early brain injury after SAH. We investigated whether von Willebrand factor (VWF) is involved in the pathogenesis of early brain injury, and whether ultra‐early treatment with recombinant ADAMTS‐13 (rADAMTS‐13) reduces early brain injury after experimental SAH. Methods Experimental SAH in mice was induced by prechiasmatic injection of non‐anticoagulated blood from a littermate. The following experimental SAH groups were investigated: C57BL/6J control (n = 21), VWF?/? (n = 25), ADAMTS‐13?/? (n = 23), and C57BL/6J treated with rADAMTS‐13 (n = 26). Mice were killed at 2 h after SAH. Primary outcome measures were microglial activation (IBA‐1 surface area) and neuronal injury (number of cleaved caspase‐3‐positive neurons). Results As compared with controls, microglial activation was decreased in VWF?/? mice (mean difference of ? 20.0%, 95% confidence interval [CI] ? 4.0% to ? 38.6%), increased in ADAMTS‐13?/? mice (mean difference of + 34.0%, 95% CI 16.2–51.7%), and decreased in rADAMTS‐13‐treated mice (mean difference of ? 22.1%, 95% CI ? 3.4% to ? 39.1%). As compared with controls (185 neurons, interquartile range [IQR] 133–353), neuronal injury in the cerebral cortex was decreased in VWF?/? mice (63 neurons, IQR 25–78), not changed in ADAMTS‐13?/? mice (53 neurons, IQR 26–221), and reduced in rADAMTS‐13‐treated mice (45 neurons, IQR 9–115). Conclusions Our findings suggest that VWF is involved in the pathogenesis of early brain injury, and support the further study of rADAMTS‐13 as a treatment option for early brain injury after SAH. |
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| Keywords: | brain diseases platelet aggregation subarachnoid hemorrhage thrombosis von Willebrand factor |
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