107 FVIIa Prevents the Progressive Hemorrhaging of a Brain Contusion by Protecting Microvessels Via Formation of the TF-FVIIa-FXa Complex

INTRODUCTION 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. METHODS Controlled cortical impact model of mouse brain contusion was used to examine whether decreased FVII activity would directly lead to the occurrence of progressive hemorrhaging in mice and whether administration of FVIIa would prevent the delayed catastrophic structural failure of microvessels and the progressive hemorrhaging of brain contusions by protecting vascular endothelial cells via formation of the ternary TF FVIIa FXa complex. Activations of p44/42 MAPK, p38 MAPK, and p65 NF-kB signaling pathways by ternary TF FVIIa FXa complex were tested by WB in HUVECs. RESULTS >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-kB (NF-kB) 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-kB 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. CONCLUSION 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.