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Influence of endothelial cell protein C receptor on plasma clearance of factor VIIa

Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX Department of Medicine, Malmo University Hospital, University of Lund, Malmo, Sweden Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, OK.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 02/2012; 10(5):971-3. DOI: 10.1111/j.1538-7836.2012.04670.x
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Available from: Ulla Hedner, Oct 13, 2014
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    • "Recently, we have shown that rFVIIa administered to mice intravenously (i.v) associates with EPCR, and EPCR facilitates the entry of FVIIa from circulation into perivascular tissues [25]. Once entered into perivascular tissues, FVIIa was retained there in functionally active state for extended time periods (24 h to 7 days) [25], which sharply contrasts to the short circulating half-life (<30 min) of FVIIa [26]. Since EPCR is present primarily on the endothelium whereas TF is mainly localized in extravascular cells, it raises the possibility that TF may be involved in FVIIa retention in extravascular tissues. "
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    ABSTRACT: Recent studies have suggested that antithrombin (AT) could act as a significant physiologic regulator of FVIIa. However, in vitro studies showed that AT could inhibit FVIIa effectively only when it was bound to tissue factor (TF). Circulating blood is known to contain only traces of TF, at best. FVIIa also binds endothelial cell protein C receptor (EPCR), but the role of EPCR on FVIIa inactivation by AT is unknown. The present study was designed to investigate the role of TF and EPCR in inactivation of FVIIa by AT in vivo. Low human TF mice (low TF, ∼1% expression of the mouse TF level) and high human TF mice (HTF, ∼100% of the mouse TF level) were injected with human rFVIIa (120 µg kg-1 body weight) via the tail vein. At varying time intervals following rFVIIa administration, blood was collected to measure FVIIa-AT complex and rFVIIa antigen levels in the plasma. Despite the large difference in TF expression in the mice, HTF mice generated only 40-50% more of FVIIa-AT complex as compared to low TF mice. Increasing the concentration of TF in vivo in HTF mice by LPS injection increased the levels of FVIIa-AT complexes by about 25%. No significant differences were found in FVIIa-AT levels among wild-type, EPCR-deficient, and EPCR-overexpressing mice. The levels of FVIIa-AT complex formed in vitro and ex vivo were much lower than that was found in vivo. In summary, our results suggest that traces of TF that may be present in circulating blood or extravascular TF that is transiently exposed during normal vessel damage contributes to inactivation of FVIIa by AT in circulation. However, TF's role in AT inactivation of FVIIa appears to be minor and other factor(s) present in plasma, on blood cells or vascular endothelium may play a predominant role in this process.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Since we recently found that human FVIIa and not mouse FVIIa binds to EPCR effectively [19], we used human rFVIIa in the present study. In line with earlier pharmacokinetic studies [24,25], rFVIIa recovered in plasma was substantially lower than predicted soon after its administration in all genotypes. FVIIa activity levels in plasma at 30 min after the injection were about 10% of the injected concentration. "
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    ABSTRACT: Background: Recent studies show that activated factor VII (FVIIa) binds to the endothelial cell protein C receptor (EPCR) on the vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown. Objective: The aim of the present study was to investigate the role of the FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues. Methods: Wild-type, EPCR-deficient or ECPR-over-expressing mice were injected with human recombinant (r)FVIIa (120 μg kg−1 body weight) via the tail vein. At varying time intervals after rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR. Results: The data reveal that, after intravenous (i.v.) injection, rFVIIa rapidly disappears from the blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that the association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. The FVIIa association with the endothelium was undetectable at time points exceeding 24 h post-FVIIa administration. The levels of rFVIIa accumulated in tissue correlate with expression levels of EPCR in mice and FVIIa associated with tissues remained functionally active for periods of at least 7 days. Conclusions: The observation that an EPCR-dependent association of FVIIa with the endothelium is most pronounced soon after rFVIIa administration and subsequently declines temporally, combined with the retention of functionally active FVIIa in tissue homogenates for extended periods, indicates that FVIIa binding to EPCR on the endothelium facilitates the transport of FVIIa from circulation to extravascular tissues where TF resides.
    Full-text · Article · Sep 2012 · Journal of Thrombosis and Haemostasis