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".
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."
Mosesson
M W
MW
University of Wisconsin Medical School, Milwaukee Clinical Campus, Sinai Samaritan Medical Center 53233, USA.
Siebenlist
K R
KR
Hainfeld
J f
Jf
Wall
J S
JS
Soria
J
J
Soria
C
C
Caen
J P
JP
D003911:Dextrans / Q000494:pharmacology; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry* / Q000378:metabolism; D015241:Fibrinogens, Abnormal / Q000737:chemistry*; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D017348:Microscopy, Electron, Scanning Transmission; D010958:Plasminogen / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology*
D003911:Dextrans; D005338:Fibrin Fibrinogen Degradation Products; D015241:Fibrinogens, Abnormal; C015214:fibrinogen D fragment; D010958:Plasminogen; D005990:Glycerol