The sequence A??-(154 ??? 159) of fibrinogen is capable of accelerating the t-PA catalysed activation of plasminogen

Schielen, W.J.G.; Adams, Hans P.H.M.; Voskuilen, Marijke; Tesser, G. I.; Nieuwenhuizen, W.

doi:10.1097/00001721-199106000-00010

Cited by 20 publications

(14 citation statements)

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“…The interaction of tPA with fibrin involves interactions with D domain epitopes a(148-160) and y(311-379) some of which are hidden in fibrinogen (23)(24)(25). However, KI of tPA may also contribute to some extent toward fibrin binding (26).…”

Section: Discussionmentioning

confidence: 99%

Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

Diamond²

1995

J. Clin. Invest.

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Thrombolysis is dramatically slower when high concentrations of lytic agent are used. This paradoxical observation, first described as "plasminogen steal," was originally believed to be due to depletion of extrinsic plasminogen and consequent leaching of clot-bound plasminogen. We report that administration of increasing concentrations of recombinant human tissue plasminogen activator (tPA) to fibrin gels resulted in Iysis rates that displayed a maximum, with significantly slower rates found at higher tPA, regardless of whether plasminogen was supplied extrinsically or intrinsically. A similar maximum in lysis rates was observed in a system lacking an extrinsic phase when plasminogen was added to fibrin suspensions preincubated with increasing tPA. Thus, intrinsic plasminogen leakage and a2-antiplasmin were not required for the decreased lysis at high tPA. No maximum was observed for increasing concentrations of urokinase. Using fibrin suspensions or gels preincubated with tPA before addition of plasmin, we report that tPA, but not urokinase, caused a dose-dependent inhibition of the fibrinolytic action of plasmin. With respect to optimal dosage schemes and the design of novel lytic agents, these findings indicate that (a) there exists a biochemical mechanism against minimizing reperfusion time with increasing tPA dosages and (b) the fibrin affinity of tPA may cause reduced fibrinolysis by plasmin. (J. Clin. Invest. 1995. 95:2483-2490

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Section: Discussionmentioning

confidence: 99%

Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

Diamond²

1995

J. Clin. Invest.

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“…81 Two sites in fibrin are involved in enhancement of plasminogen activation by tPA, Aα148-160 and γ312-324. 84,85 These sites are cryptic in fibrinogen a M.W.M. became interested in this problem as a member of the Scientific Review Committee for Professor Gert Müller-Berghaus' research group in Giessen, Germany, during which he had the opportunity of reviewing and discussing Eberhard Selmayr's experiments.…”

Section: Fibrinogen and Fibrinolysismentioning

confidence: 99%

The Structure and Biological Features of Fibrinogen and Fibrin

Mosesson

Siebenlist

Meh

2001

Annals of the New York Academy of Sciences

561

349

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Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia. These events are regulated to a large extent by fibrin formation itself and by complementary interactions between specific binding sites on fibrin(ogen) and extrinsic molecules including proenzymes, clotting factors, enzyme inhibitors, and cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed Aα, Bβ, and γ, that are joined by disulfide bridging within the N‐terminal E domain. The molecules are elongated 45‐nm structures consisting of two outer D domains, each connected to a central E domain by a coiled‐coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, crosslinking, and platelet interactions (e.g., thrombin substrate, Da, Db, γXL, D:D, αC, γA chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non‐substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA‐dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non‐substrate thrombin binding site are located on variant γ′ chains that comprise a minor proportion of the γ chain population. Initiation of fibrin assembly by thrombin‐mediated cleavage of fibrinopeptide A from Aα chains exposes two EA polymerization sites, and subsequent fibrinopeptide B cleavage exposes two EB polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end‐to‐middle intermolecular Da to EA associations, resulting in linear double‐stranded fibrils and equilaterally branched trimolecular fibril junctions. Side‐to‐side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin‐activated factor XIIIa introduce intermolecular covalent ε‐(γ glutamyl)lysine bonds into these polymers, first creating γ dimers between properly aligned C‐terminal γXL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on γ chains (forming γ‐polymers), and even more slowly among γ dimers to create higher order crosslinked γ trimers and tetramers, to complete the mature network structure.

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“…Maybe localizations of six non conserved tyrosines might be crucial in this case, however two conserved tyrosines probably are important for fibrinogen function. From these 2 conserved tyrosines only Tyr178 is conserved in all vertebrates [47], might be nitrated in human fibrinogen [48] and is located near the place of t-Pa plasminogen activation [49][50][51][52]. There are also suggestions that this location may be important for fibrinogen polymerization and fibrin lysis.…”

Section: Discussionmentioning

confidence: 99%

The comparison of peroxynitrite action on bovine, porcine and human fibrinogens

et al. 2013

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Subjects of bovine and porcine flocks are sometimes susceptible to death before time of slaughter, and some of those deaths may be due to cardiovascular problems connected with stress. The role of oxidative stress in farm animals is yet unexplored. Human fibrinogen seems to be highly susceptible to nitration. Peroxynitrite produced from superoxide and nitric oxide initiates noticeable changes in the structure of human fibrinogen molecule. The objective of this work is to compare the in vitro interactions of peroxynitrite with human fibrinogen and with fibrinogen from mammals of great economic importance, namely cows and pigs. Using western blots and ELISA we show that porcine fibrinogen is susceptible to tyrosine nitration induced by peroxynitrite whereas, bovine fibrinogen is more resistant. Moreover, porcine fibrinogen polymerization is susceptible to peroxynitrite action, whereas bovine fibrinogen is the least susceptible to inhibition of polymerization caused by peroxynitrite. These observed differences may result from differences in amino acid sequence of fibrinogen chains, mostly including tyrosine content and location in the Aα chain. Protection against toxic effects of peroxynitrite activity in the circulatory system seems to be important in avoiding cardiovascular diseases and may prevent production loss in pig breeding herds.

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The sequence A??-(154 ??? 159) of fibrinogen is capable of accelerating the t-PA catalysed activation of plasminogen

Cited by 20 publications

References 0 publications

Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

The Structure and Biological Features of Fibrinogen and Fibrin

The comparison of peroxynitrite action on bovine, porcine and human fibrinogens

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