Factor VII activating protease (FSAP) in thrombosis and haemostasis in vivo

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SubramaniamSaravanan_2014_10_06.pdf (12.75 MB)

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2014

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http://dx.doi.org/10.22029/jlupub-14090

Abstract

Factor VII activating protease (FSAP), a serine protease produced in the liver (plasma conc.12 microgramm/mL) has been associated with cardiovascular diseases. In vitro studies revealed that FSAP has a dual function in the coagulation system via inhibition of tissue factor pathway inhibitor (TFPI) and activation of pro-urokinase (pro-uPA). Even though functional polymorphism in the FSAP gene is linked with cardiovascular diseases, due to contradictory clinical observations as well as its dual role in the coagulation system in vitro, the real function and mechanistic aspects of FSAP is ambiguous. To identify the actual function of FSAP in thrombosis and haemostasis, we characterized the FSAP deficient mice using various in vivo and ex-vivo mouse models. Our results showed that in pulmonary thromboembolism model FSAP-/- mice had a significantly higher survival than WT littermates (p smaller than 0.01). The carotid artery injury as well as mesenteric arteriole models revealed that the occlusion time was significantly increased in FSAP-/- mice (p smaller than 0.01). Partial venous thrombosis (PVT) showed a trend in the reduction of total thrombus content and thrombus weight in FSAP-/- mice. Western blotting analysis of plasma samples as well as immunohistochemical analysis of thrombotic carotid arteries and lung tissue extracts showed a slightly increased TFPI expression in FSAP-/- mice when compared to the WT littermates. In situ and gel-based casein zymography showed that FSAP-/- mice had more uPA than the WT littermates. Plasma samples from all these models did not show any influence of plasminogen levels. In vitro analysis of FSAP on platelet TFPI demonstrated that FSAP could inhibit not only the circulating beta form of TFPI but also the platelet derived alpha form of TFPI. Tail-bleeding assay revealed that more than 80% of FSAP-/-mice showed re-bleeding incidences compared to WT littermate controls. The clinical relevance of Marburg-I polymorphism is not well understood because of contradictory observations in various studies. Interestingly, our mice models revealed that the endogenous FSAP plays a key role in extrinsic coagulation cascade via inhibition of TFPI.

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