Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP)

Summary

Factor VII (FVII) activating protease (FSAP) is a circulating protease with a putative function in blood coagulation and fibrinolysis. Genetic epidemiological studies have implied a role for FSAP in carotid stenosis, stroke and thrombosis. To date, no in vivo evidence is available to support these claims. We have, for the first time, used FSAP^-/- mice to define its role in thrombosis and haemostasis in vivo and to characterise the molecular mechanisms involved. FeCl₃–induced arterial thrombosis in carotid and mesenteric artery revealed that the occlusion time was significantly increased in FSAP^-/- mice (p< 0.01) and that some FSAP^-/- mice did not occlude at all. FSAP^-/- mice were protected from lethal pulmonary thromboembolism induced by collagen/ epinephrine infusion (p< 0.01). Although no spontaneous bleeding was evident, in the tail bleeding assay a re-bleeding pattern was observed in FSAP^-/- mice. To explain these observations at a mechanistic level we then determined how haemostasis factors and putative FSAP substrates were altered in FSAP^-/- mice. Tissue factor pathway inhibitor (TFPI) levels were higher in FSAP^-/- mice compared to WT mice whereas FVIIa levels were unchanged. Other coagulation factors as well as markers of platelet activation and function revealed no significant differences between WT and FSAP^-/- mice. This phenotype of FSAP^-/- mice could be reversed by application of exogenous FSAP. In conclusion, a lack of endogenous FSAP impaired the formation of stable, occlusive thrombi in mice. The underlying in vivo effect of FSAP is more likely to be related to the modulation of TFPI rather than FVIIa.

Keywords

Coagulation - fibrinolysis - thrombosis - haemostasis - FSAP - HABP2

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