Shibani Pati1, Daniel R Potter, Gyulnar Baimukanova, David H Farrel, John B Holcomb, Martin A Schreiber. 1. From the Blood Systems Research Institute (S.P., D.R.P., G.B.); and Department of Laboratory Medicine (S.P., D.R.B., G.B.), University of California San Francisco, San Francisco, California; Department of Surgery (J.B.H.), University of Texas-Houston Medical School, Houston, Texas; and Department of Surgery (D.H.F., M.A.S.), Oregon Health & Science University, Portland, Oregon.
Abstract
BACKGROUND: Transfusion of balanced ratios of plasma to platelets and red blood cells has been shown to reduce early death from exsanguination in trauma patients. Aside from hemostasis, recent work has shown that plasma reduces vascular endothelial permeability, inflammation, and organ edema after hemorrhagic shock (HS), all components of the endotheliopathy of trauma. We hypothesized that Kcentra could have protective effects on the endotheliopathy of trauma comparable with fresh frozen plasma (FFP). METHODS: In vitro, endothelial cell (EC) barrier function was assessed by measuring changes in transendothelial electrical resistance for Kcentra, FFP, and albumin. In vivo, a modified Miles assay was used on mice to study the effects of Kcentra, FFP, and albumin on vascular permeability induced by VEGF-A. The same groups were studied in a second in vivo model of pulmonary vascular leak induced by HS and laparotomy. The identification of proteins in Kcentra was assessed by liquid chromatography/mass spectrometry. RESULTS: We found that FFP and Kcentra inhibit EC permeability. We also found that Kcentra and FFP have equivalent capacity to restore EC adherens junction breakdown induced by VEGF-A. In vivo, we found that Kcentra and FFP, but not albumin, significantly inhibited vascular permeability induced by VEGF-A and HS-induced vascular permeability in mice. Investigation of the protein content of Kcentra by mass spectroscopy revealed that there are a number of proteins in Kcentra, derived from plasma that may have contributory roles in the noted effects of Kcentra on vascular leak. CONCLUSION: Taken together, we have demonstrated that FFP and Kcentra inhibit vascular permeability in vivo and in vitro. These beneficial effects of Kcentra may be due in part to the modulation of vascular function by soluble factors present in Kcentra aside from the known clotting factors II, VII, IX, and X. The clinical implications of these findings are unknown and warrant further investigation.
BACKGROUND: Transfusion of balanced ratios of plasma to platelets and red blood cells has been shown to reduce early death from exsanguination in traumapatients. Aside from hemostasis, recent work has shown that plasma reduces vascular endothelial permeability, inflammation, and organ edema after hemorrhagic shock (HS), all components of the endotheliopathy of trauma. We hypothesized that Kcentra could have protective effects on the endotheliopathy of trauma comparable with fresh frozen plasma (FFP). METHODS: In vitro, endothelial cell (EC) barrier function was assessed by measuring changes in transendothelial electrical resistance for Kcentra, FFP, and albumin. In vivo, a modified Miles assay was used on mice to study the effects of Kcentra, FFP, and albumin on vascular permeability induced by VEGF-A. The same groups were studied in a second in vivo model of pulmonary vascular leak induced by HS and laparotomy. The identification of proteins in Kcentra was assessed by liquid chromatography/mass spectrometry. RESULTS: We found that FFP and Kcentra inhibit EC permeability. We also found that Kcentra and FFP have equivalent capacity to restore EC adherens junction breakdown induced by VEGF-A. In vivo, we found that Kcentra and FFP, but not albumin, significantly inhibited vascular permeability induced by VEGF-A and HS-induced vascular permeability in mice. Investigation of the protein content of Kcentra by mass spectroscopy revealed that there are a number of proteins in Kcentra, derived from plasma that may have contributory roles in the noted effects of Kcentra on vascular leak. CONCLUSION: Taken together, we have demonstrated that FFP and Kcentra inhibit vascular permeability in vivo and in vitro. These beneficial effects of Kcentra may be due in part to the modulation of vascular function by soluble factors present in Kcentra aside from the known clotting factors II, VII, IX, and X. The clinical implications of these findings are unknown and warrant further investigation.
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