8/1/2023 0 Comments 3d model of fibrin jmol![]() During fibrinolysis, plasmin initially cleaves the αC regions, and then cleaves the three polypeptide chains connecting the central (E) and end (D) regions ( Fig. ![]() In particular, the αC regions contain lysine-dependent tPA- and plasminogen-binding sites (K d = 16–33 nM) within residues Aα392–610. Cryptic plasminogen and plasmin binding sites in fibrinogen and fibrin monomers are exposed by fibrin monomer polymerization. Following thrombin-mediated cleavage of fibrinopeptides A and B from the N-termini of the Aα- and Bβ-chains, respectively, fibrin monomers polymerize into half-staggered, double-stranded protofibrils that bundle into fibers via interactions of the αC regions. The fibrinogen molecule is comprised of three pairs of distinct peptide chains: two Aα-chains, two Bβ-chains, and two γ-chains, which are interlinked by disulfide bridges ( Fig. Plasmin is the activated form of plasminogen and is produced either in the blood stream by urokinase-type plasminogen activator (uPA), or on the fibrin surface, where bound plasmin and tissue-type plasminogen activator (tPA) are protected from their respective inhibitors, α 2-antiplasmin and plasminogen-activator-inhibitor 1. The primary enzyme mediating fibrinolysis is the serine protease plasmin, which cleaves the fibrin molecule at specific sites. When the hemostatic role of the clot is fulfilled, it is removed via the fibrinolytic system. Blood clots contain an interconnected web of fibrin and blood cells, including platelets, that mediate clot retraction. Inappropriate clot formation within blood vessels (thrombosis) leads to ischemia and tissue loss. Blood clots must be strong enough to limit extravascular blood flow following injury, yet dissolve appropriately during wound healing. The hemostatic system must strike a balance between hemorrhage and vessel occlusion. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was supported by National Institutes of Health grant P41-EB002025 and by National Science Foundation grant CMMI-1030640. Received: JAccepted: DecemPublished: February 25, 2015Ĭopyright: © 2015 Bucay et al. University Hospital Medical Centre, GERMANY (2015) Physical Determinants of Fibrinolysis in Single Fibrin Fibers. These results highlight how subtle differences in the diameter and prestrain of fibers could lead to dramatically different lytic susceptibilities.Ĭitation: Bucay I, O’Brien ET III, Wulfe SD, Superfine R, Wolberg AS, Falvo MR, et al. Using polymer physics- and continuum mechanics-based mathematical models, we show that fibers polymerize in a strained state and that thicker fibers lose their prestrain more rapidly than thinner fibers during lysis, which may explain why thick fibers elongate and thin fibers lyse. Because lysis rates were greatly reduced in elongated fibers, we hypothesize that plasmin activity depends on fiber strain. Thinner fibers were more likely to lyse, while fibers greater than 200 ± 30 nm in diameter were more likely to elongate. Thrombin and plasmin dose-response experiments showed that the elongation behavior was independent of plasmin concentration, but was instead dependent on the concentration of thrombin used during fiber polymerization, which correlated inversely with fiber diameter. ![]() We found that during lysis 64 ± 6% of fibers were transected at one point, but 29 ± 3% of fibers increase in length rather than dissolving or being transected. Using an inverted optical microscope and fluorescently-labeled fibers suspended between micropatterned ridges, we have directly measured the lysis of individual fibrin fibers. To understand blood clot dissolution, the influence of clot structure and fiber properties must be separated from the effects of enzyme kinetics and perfusion rates into clots. Fibrin fibers form the structural backbone of blood clots fibrinolysis is the process in which plasmin digests fibrin fibers, effectively regulating the size and duration of a clot. ![]()
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