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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3680. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Galanakis, D. K. Search for Related Content PubMed Articles by Galanakis, D. K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Collet et al, page 3824 Another fibrin C scene unmasked Dennis K. Galanakis STATE UNIVERSITY OF NEW YORK AT STONY BROOK In this issue, Collet and colleagues identified C as the major determinant of viscoelastic clot properties and unambiguously highlighted its polymerization and fibrinolysis roles. Fibrinogen1 consists of 3 pairs of disulfide-linked polypeptide chains, A,B, and , and possesses globular regions at each end and in its N terminal center. The carboxyl terminal A-chain region, commencing with residue 220, is termed C and is required for certain fibrin functions (see figure). Following release by thrombin of amino terminal fibrinopeptides, fibrin monomers formed polymerize in a half-staggered manner, the central domain of one binding the outer domain of another. When 600 to 800 nm long, the 2-stranded, twisting protofibrils assemble laterally forming fibrils. Lateral contact pairs include B knobs–b holes; C–C; and possibly2 (350-360)–(370-380). Viscoelastic properties of thrombus are regarded essential to its physiologic functions.3 The markedly decreased storage modulus (stiffness) by 251 clots implies that interactions among juxtaposed molecules via their C domains largely determine the normal level of clot stiffness. Additionally, C domains play a significant role in minimizing the irreversible deformation (plasticity) of clots. Also, - bonds confer appreciable stiffness even before clots are cross-linked. Thus, C-C compared with - bonds constitute the major determinant of stiffness. View larger version (42K): [in this window] [in a new window]   Fibrin functions mediated in part or entirely by C.   Other likely minor determinants are - and A knob–a hole bonds.4 Not surprisingly, stiffness from the first 2 sets of determinants is maximized by factor XIIIa–catalyzed cross-links. Decreased porosity in 251 clots, relative to that of normal clots, underscores the role of C. Under certain in vivo conditions (eg, variable thrombin concentrations), a thrombus is likely to contain both increased and decreased porosity domains. The latter may be enhanced by the high-fibrinogen excess at blood-thrombus interface(s). Decreased porosity domains, by limiting intrathrombus circulatory flow, may shield intrathrombus microenvironments and by extension enhance hemostatic/tissue repair effectiveness and limit fibrinolysis. Along with decreased porosity, the distinctly fine 251 networks are consistent with long-held views on the network of fibrin lack C, while emphasizing the C role in lateral polymerization. The latter process is poorly understood, in contrast to protofibril formation and branching. The C pair, self-associated at their ends and tethered to the central region, become untethered following fibrinopeptide B release. Whether they participate in lateral polymerization in tethered, untethered, or both forms remains unclear. Reptilase clots display ample lateral polymerization, suggesting that either tethered C participates by an unknown mechanism or other parts of the molecule are involved. Be that as it may, participation in lateral polymerization, while significant, may not be a major function of C domains. Decreased plasmin resistance by fibrin 251 clots appears inconsistent with reports of increased plasmin resistance by normal fine network clots. However, fibrin 251 results imply that interactions among C domains are more important for plasmin resistance than other clot network structure(s). Additionally, C regulates fibrinolysis, evident from its binding of an impressive array of plasminogen activation and inhibitory proteins.5 These new results, moreover, support the view that the C domains contribute directly to fibrinolysis resistance. The impressive C repertoire tempts speculation that more scenes remain undiscovered. References Weisel JW. Fibrinogen and fibrin. Adv Protein Chem. 2004;70: 247-299. Yang Z, Mochalkin I, Doolittle RF. A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides. Proc Natl Acad Sci U S A. 2000;97: 14156-14161.[Abstract/Free Full Text] Weisel JW. The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem. 2004;112: 267-276.[CrossRef][Medline] [Order article via Infotrieve] Litvinov RI, Gorkun OV, Owen SF, Shuman H, Weisel JW. Polymerization of fibrin: specificity, strength, and stability of knob:hole interactions studied at the single molecule level. Blood. Prepublished on July 5, 2005, as DOI 10.1182/blood-2005-05-2039.[Abstract/Free Full Text] Mossesson MW. Fibrinogen and fibrin structure and function. J Thromb Haemost. 2005;3: 1894-1904.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The C domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis Jean-Philippe Collet, Jennifer L. Moen, Yuri I. Veklich, Oleg V. Gorkun, Susan T. Lord, Gilles Montalescot, and John W. Weisel Blood 2005 106: 3824-3830. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Galanakis, D. K. Search for Related Content PubMed Articles by Galanakis, D. K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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