title: FVIIa prevents the progressive hemorrhaging of a brain contusion by protecting microvessels via formation of the TF-FVIIa-FXa complex.
abstract: Factor VII (FVII) plays a key role in the initiation of the coagulation cascade and, in clinical situations, recombinant human activated FVII (rFVIIa) effectively prevents progressive hemorrhaging after a brain contusion. However, it remains unclear whether decreases in FVII activity directly lead to progressive hemorrhaging and, moreover, the precise mechanisms underlying this process are not yet known. The present study demonstrated that decreased FVII activity directly led to progressive hemorrhaging of the cerebral contusions. Administration of FVII prevented the progression of hemorrhaging from cerebral contusions by protecting microvessel endothelial cells in the penumbra of the contusion. The present study also showed that the ternary TF-FVIIa-FXa complex cleaved endogenous protease-activated receptor 2 (PAR2) on endothelial cells, activated the p44/42 mitogen-activated protein kinase (MAPK) signaling cascade, and inhibited p65 nuclear factor-κB (NF-κB) signaling. Furthermore, exposure to ternary TF-FVIIa-FXa protected endothelial cells from thrombin- or inflammatory cytokine-induced apoptosis. Although activation of the p44/42 MAPK signaling pathway is endothelial cell protein C receptor (EPCR)-dependent, inhibition of the p65 NF-κB signaling pathway is EPCR-independent; thus, the regulation mechanism underlying the effects of TF-FVIIa-FXa in vascular endothelial cells appears to be multiple signaling pathways. In summary, the present findings demonstrated that FVIIa prevented the progressive hemorrhaging of brain contusions by protecting microvessel endothelial cells via the formation of the ternary TF-FVIIa-FXa complex. These findings are novel and of great clinical significance because FVIIa is used to prevent the progressive hemorrhaging of brain contusions in humans.
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Soochow University, Suzhou, PR China.
authors.forename: Dalong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Soochow University, Suzhou, PR China.
authors.forename: Sirong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Biomedical Engineering and Technology, Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai 200062, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Yirui
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Zhuoying
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China. Electronic address: 277089712@qq.com.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China. Electronic address: yq123abc2011@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015942:Factor VIIa / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020300:Intracranial Hemorrhages / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D055806:Microvessels / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D044464:Receptor, PAR-2; D048049:Extracellular Signal-Regulated MAP Kinases; D015942:Factor VIIa
keywords: FVIIa; TF–FVIIa–FXa complex; brain contusion; endothelial cell; progressive hemorrhage