Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2003;107:654-655
doi: 10.1161/01.CIR.0000057382.68508.3D
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mann, K. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mann, K. G.
Related Collections
Right arrow Risk Factors
Right arrow Thrombosis risk factors
Right arrow Coagulation and fibronolysis
Right arrow Genetics of cardiovascular disease
Right arrowRelated Article

(Circulation. 2003;107:654.)
© 2003 American Heart Association, Inc.

Editorial

Factor VII-Activating Protease

Coagulation, Fibrinolysis, and Atherothrombosis?

Kenneth G. Mann, PhD

From the University of Vermont, Departments of Biochemistry and Medicine, Burlington, Vt.

Correspondence to Kenneth G. Mann, PhD, University of Vermont, Departments of Biochemistry and Medicine, C-401 Given Building, 89 Beaumont Avenue, Burlington, VT 05405-0068. E-mail kenneth.mann{at}uvm.edu


Key Words: Editorials • factor VII-activating protease • coagulation • fibrinolysis • thrombosis

The mechanistic description of a biological process first involves the development of an inventory of constituents that are presumed essential for the expression of the function. Although initially based on pathology, more frequently this inventory is developed by in vitro tests on the biochemistry, cell biology, or molecular genetics of a process. Elaborate schemes describing physiological reaction systems are frequently developed on the basis of these in vitro-developed inventories; however, it is becoming commonplace knowledge that the ultimate test of biological relevance, ie, a clinical phenotype, does not exist. In the coagulation system, this is evident in descriptions of the "intrinsic pathway" of coagulation, which take the view that surface contact activation of factor XII is the initial process.1,2 However, defects in the contact pathway produce no hemorrhagic phenotype.3 More recently, the use of transgenic animal models has provided a powerful tool for pathological phenotype recognition.4,5

See p 667

In the present issue of Circulation, the article titled "Marburg I Polymorphism of Factor VII-Activating Protease: A Prominent Risk Predictor of Carotid Stenosis" by Willeit and colleagues6 provides important observations that appear to require the inclusion of a novel serine protease, the factor VII-activated protease (FSAP), into the inventory of molecules associated with the coagulation/fibrinolytic process. FSAP was identified by a number of investigators and isolated either because of its affinity for immobilized hyaluronic acid7 or its presence in commercial prothrombin complex concentrates.8 The protein contains domain structures frequently associated with coagulation and fibrinolytic enzymes, including three "EGF"- like domains, a "kringle," and a serine protease domain. Additional studies indicated that FSAP is a potent activator of the coagulation zymogen factor VII9 (hence its name) and was also an activator of single-chain pro-urokinase-type plasminogen activator.10

Genetic studies11 observed relatively common polymorphisms in this protein, one of which (Marburg 1) showed diminished activity in pro-urokinase activation. The present study by Willeit et al6 presents an epidemiological analysis of 810 subjects with regard to the association of the Marburg polymorphisms with progressive stages of stenotic vessel disease originating from atherothrombosis. These data demonstrate an association between the Marburg 1 polymorphism and the risk for the evolution and progression of carotid stenosis. The observation of a phenotype associated with this FSAP mutation appears to require its inclusion into the inventory of reactants in coagulation/fibrinolytic mechanisms.

Because the Marburg 1 polymorphism is associated with reduced activity in the fibrinolytic system, one might jump to the conclusion that the pathological phenotype is associated with a diminished capacity for clot dissolution; however, it is also appealing to consider that the function potential for this protein is coincident with its title. Plasma factor VIIa is an essential contributor to the initiation of a coagulation response. Approximately 1% of total plasma factor VII protein is present as the cleaved enzymatic form of the protein, factor VIIa.12 However, the activity of this erstwhile serine protease is virtually nonexistent until it binds to tissue factor.13 As a consequence, plasma factor VIIa is impervious to the numerous serpin inhibitors present in blood. Factor VII is feedback activated by many of the proteases produced during the blood coagulation response, but the extent of the thrombin production reaction is largely dependent on the preexistent concentration of factor VIIa in plasma and the concentration of tissue factor presented by the vascular lesion. At present, no adequate description exists for the mechanism by which resident plasma factor VIIa is produced and circulates. Studies linking plasma factor VII/VIIa activity with cardiovascular risk have been reported but remain controversial.14–18 It is difficult to say at this juncture whether the discrepancies in the various studies are a consequence of differences in study design or of the difficulty in measuring factor VII zymogen and factor VIIa activity with functional assays. The FSAP is a leading candidate for the maintenance of plasma factor VIIa, and its evaluation may prove useful. The FSAP also provides an additional linkage between the initiation of the coagulation system and fibrinolysis; thus, the association of the protein with an atherothrombotic phenotype is most intriguing.

Acknowledgments

Dr Mann is supported by grant No. HL-46703 from the National Institutes of Health.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964; 145: 1310–1312.[Abstract/Free Full Text]
  2. MacFarlane RG. An enzyme cascade in the blood clotting mechanism and its function as a biochemical amplifier. Nature. 2000; 202: 498–499.
  3. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003; 23: 17–25.[Abstract/Free Full Text]
  4. Gailani D, Lasky NM, Broze GJ, Jr. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis. 1997; 8: 134–144.[Medline] [Order article via Infotrieve]
  5. Ishiguro K, Kojima T, Kadomatsu K, et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 2002; 106: 873–878.
  6. Willeit J, Kiechl S, Weimer T, et al. Marburg I polymorphism of factor VII-activating protease: a prominent risk predictor of carotid stenosis. Circulation. 2003; 107: 667–670.[Abstract/Free Full Text]
  7. Choi-Miura NH, Tobe T, Sumiya J, et al. Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. J Biochem (Tokyo). 1996; 119: 1157–1165.[Abstract/Free Full Text]
  8. Hunfeld A, Eischeid MKH, Seitz R, et al. Identification of the thrombin-like activity of PCC’s. Ann Haematol. 1998; 76: A101. Abstract.
  9. Romisch J, Feussner A, Vermoehlen S, et al. A protease isolated from human plasma activating factor VII independent of tissue factor. Blood Coagul Fibrinolysis. 1999; 10: 471–479.[Medline] [Order article via Infotrieve]
  10. Roemisch J, Vermoehlen SFA, Stoehr HA. The FVII activating protease cleaves single-chain plasminogen activators. Haemostasis. 1999; 76: 292–299.
  11. Roemisch J, Feussner A, Nerlich C, et al. The frequent Marburg I polymorphism impairs the prourokinase activating potency of the factor VII-activating protease (FSAP). Blood Coagul Fibrinolysis. 2002; 13: 433–441.[CrossRef][Medline] [Order article via Infotrieve]
  12. Morrissey JH, Macik BG, Neuenschwander PF, et al. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood. 1993; 81: 734–744.[Abstract/Free Full Text]
  13. Butenas S, Mann KG. Kinetics of human factor VII activation. Biochemistry. 1996; 35: 1904–1910.[CrossRef][Medline] [Order article via Infotrieve]
  14. Miller GJ, Walter SJ, Stirling Y, et al. Assay of factor VII activity by two techniques: evidence for increased conversion of VII to alpha VIIa in hyperlipidaemia, with possible implications for ischaemic heart disease. Br J Haematol. 1985; 59: 249–258.[Medline] [Order article via Infotrieve]
  15. Noto D, Barbagallo CM, Cefalu’ AB, et al. Factor VII activity is an independent predictor of cardiovascular mortality in elderly women of a Sicilian population: results of an 11- year follow-up. Thromb Haemost. 2002; 87: 206–210.[Medline] [Order article via Infotrieve]
  16. Wu K. Epidemiologic studies of thrombosis and atherosclerosis. Thromb Haemost. 1989; 62: 9.
  17. Salomaa V, Rasi V, Kulathinal S, et al. Hemostatic factors as predictors of coronary events and total mortality: the FINRISK ’92 Hemostasis Study. Arterioscler Thromb Vasc Biol. 2002; 22: 353–358.[Abstract/Free Full Text]
  18. Folsom AR. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view. Thromb Haemost. 2001; 86: 366–373.[Medline] [Order article via Infotrieve]

Related Article:

Marburg I Polymorphism of Factor VII–Activating Protease: A Prominent Risk Predictor of Carotid Stenosis
Johann Willeit, Stefan Kiechl, Thomas Weimer, Artur Mair, Peter Santer, Christian J. Wiedermann, and Juergen Roemisch
Circulation 2003 107: 667-670. [Abstract] [Full Text]




This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mann, K. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mann, K. G.
Related Collections
Right arrow Risk Factors
Right arrow Thrombosis risk factors
Right arrow Coagulation and fibronolysis
Right arrow Genetics of cardiovascular disease
Right arrowRelated Article

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.