Pathophysiologic roles of the fibrinogen gamma chain.
OBJECTIVE
Fibrinogen binds through its gamma chains to cell surface receptors, growth factors, and coagulation factors to perform its key roles in fibrin clot formation, platelet aggregation, and wound healing. However, these binding interactions can also contribute to pathophysiologic processes, including inflammation and thrombosis. This review summarizes the latest findings on the role of the fibrinogen gamma chain in these processes, and illustrates the potential for therapeutic intervention.


RESULTS
Novel gamma chain epitopes that bind platelet integrin alpha IIbbeta3 and leukocyte integrin alphaMbeta2 have been characterized, leading to the revision of former dogma regarding the processes of platelet aggregation, clot retraction, inflammation, and thrombosis. A series of studies has shown that the gamma chain serves as a depot for fibroblast growth factor-2 (FGF-2), which is likely to play an important role in wound healing. Inhibition of gamma chain function with the monoclonal antibody 7E9 has been shown to interfere with multiple fibrinogen activities, including factor XIIIa crosslinking, platelet adhesion, and platelet-mediated clot retraction. The role of the enigmatic variant fibrinogen gamma chain has also become clearer. Studies have shown that gamma chain binding to thrombin and factor XIII results in clots that are mechanically stiffer and resistant to fibrinolysis, which may explain the association between gammaA/gamma' fibrinogen levels and cardiovascular disease.


CONCLUSIONS
The identification of new interactions with gamma chains has revealed novel targets for the treatment of inflammation and thrombosis. In addition, several exciting studies have shown new functions for the variant gamma chain that may contribute to cardiovascular disease.
Farrell
David H
DH
Department of Pathology, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA. farrelld@ohsu.edu
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology; D005337:Fibrin / Q000276:immunology / Q000378:metabolism*; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005342:Fibrinolysis / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
D016023:Integrins; D016222:Fibroblast Growth Factor 2; D005337:Fibrin; D005340:Fibrinogen