Published Online
on February 3, 2003

A more recent version of this article appeared on February 11, 2003

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Submitted on October 24, 2002
Revised on December 13, 2002
Accepted on December 17, 2002

Marburg I Polymorphism of Factor VII-Activating Protease. A Prominent Risk Predictor of Carotid Stenosis

Johann Willeit MD^*, Stefan Kiechl MD, Thomas Weimer PhD, Artur Mair MD, Peter Santer MD, Christian J. Wiedermann MD, and Juergen Roemisch PhD

From the Departments of Neurology (J.M., S.K., A.M.) and Internal Medicine (C.J.W.), University Clinics, Innsbruck, Austria; Laboratory Medicine (P.S.), Bruneck Hospital, Bruneck, Italy; and Aventis Behring GmbH (T.W., J.R.), Research, Marburg, Germany.

^* To whom correspondence should be addressed. E-mail: johann.willeit{at}uibk.ac.at.

Background--Atherothrombosis is a main pathomechanism in the evolution of vessel stenosis and is counteracted by endogenous fibrinolysis. Recently, the plasmatic serine protease "factor seven-activating protease" (FSAP) was recognized as a potent activator of prourokinase in vitro. The Marburg I polymorphism of FSAP impairs this potential and may thus facilitate arterial thrombosis.

Methods and Results--This analysis of the Bruneck Study involved 810 men and women aged 40 to 79 years. The ultrasound-based atherosclerosis progression model (5-year follow-up) permits differentiation between early atherogenesis and the advanced stenotic stages of carotid artery disease. The FSAP Marburg I polymorphism was found in 37 subjects (carriage rate 4.4%). Individuals with this genetic variant showed a prominently reduced in vitro capacity to activate prourokinase. No relation was found to exist between the Marburg I polymorphism and early atherogenesis. In contrast, it emerged as a strong and independent risk predictor of incident/progressive carotid stenosis (multivariate odds ratio [95%CI], 6.6 [1.6 to 27.7]). This finding equally applied to subjects with and without co-segregation of the Marburg II polymorphism. The risk profile of advanced atherogenesis further includes cigarette smoking, high lipoprotein(a), the factor V Leiden mutation, low antithrombin III, high fibrinogen, and diabetes.

Conclusions--In concert with other genetic and acquired conditions known to interfere with coagulation or fibrinolysis, the Marburg I polymorphism of FSAP, which attenuates its capacity to activate prourokinase, is a significant risk predictor for the evolution and progression of carotid stenosis.

Key words: atherosclerosis • risk factors • thrombosis • thrombolysis

Related Article:

Factor VII-Activating Protease: Coagulation, Fibrinolysis, and Atherothrombosis?

Kenneth G. Mann
Circulation 2003 107: 654-655. [Extract] [Full Text]

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