TY - JOUR
T1 - Role of von Willebrand factor and ADAMTS-13 in early brain injury after experimental subarachnoid hemorrhage
AU - Wan, H.
AU - Wang, Y.
AU - Ai, J.
AU - Brathwaite, S.
AU - Ni, H.
AU - Macdonald, R. L.
AU - Hol, E. M.
AU - Meijers, J. C.M.
AU - Vergouwen, M. D.I.
N1 - Funding Information:
M. D. I. Vergouwen received a research grant, partly for this study, from Baxalta US Inc., now part of Shire. Recombinant ADAMTS-13 was kindly provided by Baxalta under the same grant, and Baxalta US Inc., now part of Shire, had no further role in project planning, experiments, or data analysis. R. L. Macdonald reports receiving grants from the Brain Aneurysm Foundation, grants from the Canadian Institutes of Health Research, and grants from Ontario Genomics, and having stock, stock options and employment from Edge Therapeutics, all outside the submitted work. The other authors state that they have no conflict of interest.
Funding Information:
M. D. I. Vergouwen received a research grant, partly for this study, from Baxalta US Inc., now part of Shire. Recombinant ADAMTS-13 was kindly provided by Bax-alta under the same grant, and Baxalta US Inc., now part of Shire, had no further role in project planning, experiments, or data analysis. R. L. Macdonald reports receiving grants from the Brain Aneurysm Foundation, grants from the Canadian Institutes of Health Research, and grants from Ontario Genomics, and having stock, stock options and employment from Edge Therapeutics, all outside the submitted work. The other authors state that they have no conflict of interest.
Publisher Copyright:
© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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.
KW - ADAMTS13 Protein/administration & dosage
KW - Animals
KW - Apoptosis
KW - Brain/drug effects
KW - Brain Injuries/enzymology
KW - Calcium-Binding Proteins/metabolism
KW - Caspase 3/metabolism
KW - Disease Models, Animal
KW - Drug Administration Schedule
KW - Female
KW - Genetic Predisposition to Disease
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Microfilament Proteins/metabolism
KW - Microglia/drug effects
KW - Neurons/drug effects
KW - Neuroprotective Agents/administration & dosage
KW - Phenotype
KW - Recombinant Proteins/administration & dosage
KW - Subarachnoid Hemorrhage/complications
KW - Time Factors
KW - von Willebrand Factor/genetics
KW - platelet aggregation
KW - thrombosis
KW - von Willebrand factor
KW - brain diseases
KW - subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=85049525750&partnerID=8YFLogxK
U2 - 10.1111/jth.14136
DO - 10.1111/jth.14136
M3 - Article
C2 - 29729651
AN - SCOPUS:85049525750
SN - 1538-7933
VL - 16
SP - 1413
EP - 1422
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 7
ER -