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

Area of Science:

• Biochemistry
• Hematology
• Molecular Biology

Background:

• Factor VII activating protease (FSAP) is a circulating enzyme implicated in blood coagulation and fibrinolysis.
• Genetic studies suggest FSAP's role in carotid stenosis, stroke, and thrombosis, but in vivo evidence is lacking.

Purpose of the Study:

• To investigate the in vivo role of FSAP in thrombosis and hemostasis using FSAP knockout mice.
• To elucidate the molecular mechanisms underlying FSAP's function in hemostasis.

Main Methods:

• Induction of arterial thrombosis using ferric chloride (FeCl3) in carotid and mesenteric arteries.
• Assessment of lethal pulmonary thromboembolism via collagen/epinephrine infusion.
• Tail bleeding assay to evaluate hemostasis.
• Measurement of coagulation factors (FVIIa, TFPI) and platelet activation markers in FSAP-/- mice.

Main Results:

• FSAP-/- mice exhibited significantly increased arterial occlusion times and protection from lethal pulmonary thromboembolism.
• A re-bleeding pattern was observed in FSAP-/- mice during tail bleeding assays.
• FSAP deficiency led to elevated tissue factor pathway inhibitor (TFPI) levels, while FVIIa levels remained unchanged.
• The observed phenotype was reversible upon administration of exogenous FSAP.

Conclusions:

• The absence of endogenous FSAP impairs the formation of stable, occlusive thrombi in vivo.
• FSAP's primary in vivo function in thrombosis appears to be through modulation of TFPI, rather than FVIIa.