The Relationship Between the Fibrinogen D Domain Self-Association/Cross-Linking Site (gammaXL) and the Fibrinogen Dusart Abnormality (Aalpha R554C-albumin): Clues to Thrombophilia in the "Dusart Syndrome"

Authors

Michael W. Mosesson, University of Wisconsin Medical SchoolFollow
Kevin R. Siebenlist, Marquette UniversityFollow
James F. Hainfeld, University of Wisconsin Medical SchoolFollow
J. S. Wall, University of Wisconsin Medical SchoolFollow
C. Soria, University of Wisconsin Medical School
J. P. Caen, University of Wisconsin Medical SchoolFollow

Document Type

Article

Publication Date

5-1996

Publisher

American Society for Clinical Investigation

Source Publication

Journal of Clinical Investigation

Source ISSN

0021-9738

Original Item ID

DOI: 10.1172/JCI118677

Abstract

Cross-linking of fibrinogen at its COOH-terminal gamma chain cross-linking site occurs in the presence of factor XIIIa due to self-association at a constitutive D domain site ("gammaXL"). We investigated the contribution of COOH-terminal regions of fibrinogen Aalpha chains to the gammaXL site by comparing the gamma chain cross-linking rate of intact fibrinogen (fraction I-2) with that of plasma fraction I-9, plasmic fraction I-9D, and plasmic fragment D1, which lack COOH-terminal Aalpha chain regions comprising approximately 100, approximately 390, and 413 residues, respectively. The cross-linking rates were I-2 > I-9 > 1-9D = D1, and indicated that the terminal 100 or more Aalpha chain residues enhance gammaXL site association. Fibrinogen Dusart, whose structural abnormality is in the COOH-terminal "alphaC" region of its Aalpha chain (Aalpha R554C-albumin), is associated with thrombophilia ("Dusart Syndrome"), and is characterized functionally by defective fibrin polymerization and clot structure, and reduced plasminogen binding and tPA-induced fibrinolysis. In the presence of XIIIa, the Dusart fibrinogen gamma chain cross-linking rate was about twice that of normal, but was normalized in proteolytic fibrinogen derivatives lacking the Aalpha chain abnormality, as was reduced plasminogen binding. Electron microscopy showed that albumin-bound Dusart fibrinogen "alphaC" regions were located in the vicinity of D domains, rather than at their expected tethered location near the fibrinogen E domain. In addition, there was considerable fibrinogen aggregation that was attributable to increased intermolecular COOH-terminal Aalpha chain associations promoted by untethered Dusart fibrinogen aC domains. We conclude that enhanced Dusart fibrinogen self-assembly is mediated through its abnormal alphaC domains, leads to increased gammaXL self-association and gamma chain cross-linking potential, and contributes to the thrombophilia that characterizes the "Dusart Syndrome."

Comments

Published version. Journal of Clinical Investigation, Vol. 97, No. 10 (May 1996): 2342-2350. DOI. © 1996 American Society for Clinical Investigation. Used with permission.

Kevin R. Siebenlist was affiliated with University of Wisconsin Medical School at the time of publication.

Recommended Citation

Mosesson, Michael W.; Siebenlist, Kevin R.; Hainfeld, James F.; Wall, J. S.; Soria, C.; and Caen, J. P., "The Relationship Between the Fibrinogen D Domain Self-Association/Cross-Linking Site (gammaXL) and the Fibrinogen Dusart Abnormality (Aalpha R554C-albumin): Clues to Thrombophilia in the "Dusart Syndrome"" (1996). Biomedical Sciences Faculty Research and Publications. 246.
https://epublications.marquette.edu/biomedsci_fac/246