Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa.

• Background: Recent studies show that FVIIa binds to endothelial cell protein C receptor (EPCR) on vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown. Objective, The aim of the present study is to investigate the role of 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 rFVIIa (120 μg/kg b.w.) via tail vein. At varying time intervals following 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, following intravenous injection, rFVIIa rapidly disappears from blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. FVIIa association with the endothelium was undetectable at time points exceeding 24 h post FVIIa administration. The levels of rFVIIa accumulated in tissue correlates 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 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. © 2012 International Society on Thrombosis and Haemostasis.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

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