The alphaC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis.
The functions of the alphaC domains of fibrinogen in clotting and fibrinolysis, which have long been enigmatic, were determined using recombinant fibrinogen truncated at Aalpha chain residue 251. Scanning electron microscopy and confocal microscopy revealed that the fibers of alpha251 clots were thinner and denser, with more branch points than fibers of control clots. Consistent with these results, the permeability of alpha251 clots was nearly half that of control clots. Together, these results suggest that in normal clot formation, the alphaC domains enhance lateral aggregation to produce thicker fibers. The viscoelastic properties of alpha251 fibrin clots differed markedly from control clots; alpha251 clots were much less stiff and showed more plastic deformation, indicating that interactions between the alphaC domains in normal clots play a major role in determining the clot's mechanical properties. Comparing factor XIIIa cross-linked alpha251 and control clots showed that gamma chain cross-linking had a significant effect on clot stiffness. Plasmin-catalyzed lysis of alpha251 clots, monitored with both macroscopic and microscopic methods, was faster than lysis of control clots. In conclusion, these studies provide the first definitive evidence that the alphaC domains play an important role in determining the structure and biophysical properties of clots and their susceptibility to fibrinolysis.
Collet
Jean-Philippe
JP
Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, France.
Moen
Jennifer L
JL
Veklich
Yuri I
YI
Gorkun
Oleg V
OV
Lord
Susan T
ST
Montalescot
Gilles
G
Weisel
John W
JW
D004591:Electrophoresis, Polyacrylamide Gel; D005337:Fibrin / Q000737:chemistry / Q000648:ultrastructure; D005340:Fibrinogen / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure*; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure*; D011994:Recombinant Proteins / Q000737:chemistry / Q000648:ultrastructure; D013927:Thrombosis / Q000378:metabolism*
D010446:Peptide Fragments; D011994:Recombinant Proteins; C098000:fibrinogen alphaC; D005337:Fibrin; D005340:Fibrinogen