Document Type
Article
Publication Date
8-1-1995
Publisher
American Society for Clinical Investigation
Source Publication
Journal of Clinical Investigation
Source ISSN
0021-9738
Original Item ID
DOI: 10.1172/JCI118091
Abstract
Intermolecular end-to-middle domain pairing between a thrombin-exposed 'A' polymerization site in the central 'E' domain of fibrin, and a constitutive complementary 'a' site in each outer 'D' domain ('D:E'), is necessary but not alone sufficient for normal fibrin assembly, as judged from previous studies of a congenital dysfibrinogen, Tokyo II (gamma 275 arg-->cys), which showed defective fibrin clot assembly and a normal D:E interaction (Matsuda, M., M. Baba, K. Morimoto, and C. Nakamikawa, 1983. J. Clin. Invest. 72:1034-1041). In addition to the 'a' polymerization site, two other constitutive intermolecular association sites on fibrinogen D domains have been defined: between gamma chain regions containing the carboxy-terminal factor XIIIa crosslinking site ('gamma XL:gamma XL'); and between sites located at the outer ends of each molecule ('D:D') (Mosesson, M. W., K. R. Siebenlist, J. F. Hainfeld, and J. S. Wall, manuscript submitted for publication). We evaluated the function of these sites in Tokyo II fibrinogen, and confirmed that there was a normal fibrin D:E interaction, as determined from a normal fibrin crosslinking rate in the presence of factor XIIIa. We also found a normal gamma XL: gamma XL interaction, as assessed by a normal fibrinogen crosslinking rate. Judging from electron microscopic images, factor XIIIa-crosslinked Tokyo II fibrinogen failed to form elongated double-stranded fibrils like normal fibrinogen. Instead, it formed aggregated disordered collections of molecules, with occasional short fibrillar segments. In addition, Tokyo II fibrin formed an abnormal, extensively branched clot network containing many tapered terminating fibers. These findings indicate that the Tokyo II fibrinogen defect results in a functionally abnormal D:D self-association site, and that a normal D:D site interaction is required, in addition to D:E, for normal fibrin or fibrinogen assembly.
Recommended Citation
Mosesson, Michael W.; Siebenlist, Kevin R.; DiOrio, James P.; Matsuda, M.; Hainfeld, James F.; and Wall, J. S., "The Role of Fibrinogen D Domain Intermolecular Association Sites in the Polymerization of Fibrin and Fibrinogen Tokyo II (γ275 Arg→Cys)" (1995). Biomedical Sciences Faculty Research and Publications. 237.
https://epublications.marquette.edu/biomedsci_fac/237
Comments
Published version. Journal of Clinical Investigation, Vol. 96, No. 2 (August 1, 1995): 1053-1058. DOI. © 1995 American Society for Clinical Investigation. Used with permission.
Kevin R. Siebenlist was affiliated with University of Wisconsin Medical School, Sinai Samaritan Medical Center, Milwaukee, WI at the time of publication.