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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2933. 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 Litvinov et al, page 2944 Fibrin A-knob caught in the act Dennis K. Galanakis SUNY, STONY BROOK, SCHOOL OF MEDICINE The long-known key bond between 2 fibrin molecules that is critical to formation of a physiologic clot was captured in the act and quantified by Litvinov and colleagues in this issue of Blood. It is long known that release of fibrinopeptide A (FpA) is more rapid than that of fibrinopeptide B (FpB), and that FpA release is essential for polymerization under physiologic conditions. FpA and FpB release exposes polymerization epitopes on the central fibrin region, termed A- and B-knobs,1 respectively. These bind to complementary and always exposed outer region counterparts, termed "a-hole" and "b-hole." The fibrin monomers resulting from FpA and FpB release are known as -fibrin and -fibrin, respectively. Under physiologic conditions, -fibrin cannot initiate but participates in polymerization. Apart from Shainoff and Dardik's estimate2 that -fibrin binding to other fibrin molecules is approximately 6-fold tighter than that of -fibrin, there has been little information on the characteristics of these physiologically important bonds. In this issue, Litvinov and colleagues used laser tweezers to examine these fibrin-fibrin interactions. The technique involved focusing a laser beam with a microscope objective to a spot in the specimen plane. Rather than using light for the more usual purposes of illumination or heating, the energy of the laser beam is converted to mechanical energy to trap small particles with a higher refractive index than that of the surrounding medium. The particles in this case were a latex beads covalently coated with fibrinogen or a fragment D, containing its outer domain, and during the experiment they were flowed into a chamber. One bead was grasped by the tweezers and moved in an oscillating manner to contact an immobile pedestal in the chamber. To enable binding to the fibrinogen or its fragment D-holes, the pedestal contained on its surface a covalently immobilized fibrin fragment, N-terminal disulphide knot (N-DSK), containing the central fibrin region, with either its A- or A- and B-knobs exposed. The bead-pedestal contact was measured by a quadrant force detector in the microscope that detects the displacement of the bead to an accuracy of a few nanometers. The voltage signal, expressed in piconewtons (10–12N, about the weight of a red blood cell), is proportional to the displacement of the bead center from the focal point of the microscope. Underscoring the usefulness of this technique is compelling evidence that a single deflection represents the discrete rupture force produced by a surface-bound single molecular pair.3 This study enabled for the first time a quantitative definition of a single A-knob–a-hole bond. It turns out that this bond is very strong and brittle, properties that underpin its pivotal role in the polymerization process. Moreover, this technique makes it possible to sort out the complex interactions, yet to be understood, that occur during polymerization. By extension, this study significantly enhances our understanding of the role of this important A-knob–a-hole bond in thrombogenesis. References Doolittle RF. Fibrinogen and fibrin. In: Bloom AL, Thomas DP, eds. Haemostasis and Thrombosis. New York, NY: Churcill Livingstone; 1981: 163-191. Shainoff J, Dardik B. Fibrinopeptide B in fibrin assembly and metabolism: physiologic significance in delayed release of the peptide. Ann N Y Acad Sci. 1983;408: 254-268.[Medline] [Order article via Infotrieve] Litvinov RI, Shuman H, Bennett JS, Weisel JW. Binding strength and activation state of single fibrinogen-integrin pairs on living cells. Proc Natl Acad Sci U S A. 2002;99: 7426-7431.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Polymerization of fibrin: specificity, strength, and stability of knob-hole interactions studied at the single-molecule level Rustem I. Litvinov, Oleg V. Gorkun, Scott F. Owen, Henry Shuman, and John W. Weisel Blood 2005 106: 2944-2951. [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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