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Thromb Haemost 2001; 85(03): 502-508
DOI: 10.1055/s-0037-1615612
Review Article
Schattauer GmbH

Like Fibrin, (DD)E, the Major Degradation Product of Crosslinked Fibrin, Protects Plasmin from Inhibition by α2-antiplasmin[*]

Agnes Y. Y. Lee
1   Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
,
James C. Fredenburgh
1   Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
,
Ronald J. Stewart
,
Janice A. Rischke
1   Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
,
Jeffrey I. Weitz
› Author Affiliations
Further Information

Publication History

Received 04 July 2000

Accepted after resubmission 28 September 2000

Publication Date:
27 December 2017 (online)

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Summary

Plasmin generation is localized to the fibrin surface because tissue-type plasminogen activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to fibrin is protected from inhibition by α2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting systemic activation of plasminogen. In this study we investigated whether (DD)E also protects plasmin from inhibition by α2-antiplasmin, facilitating degradation of this soluble t-PA effector. (DD)E and fibrin reduce the rate of plasmin inhibition by α2-antiplasmin by 5- and 10-fold, respectively. Kringle-dependent binding of plasmin to (DD)E and fibrin, with Kd values of 52 and 410 nM, respectively, contributes to the protective effect. When (DD)E is extensively degraded by plasmin, yielding uncomplexed fragment E and (DD), protection of plasmin from inhibition by α2-antiplasmin is attenuated. These studies indicate that (DD)E-bound plasmin, whose generation reflects the ability of (DD)E to stimulate plasminogen activation by t-PA, has the capacity to degrade (DD)E by virtue of its resistance to inhibition. This provides a mechanism to limit the concentration of (DD)E and maintain the fibrin-specificity of t-PA.

Keywords

Plasmin - α2-antiplasmin - fibrin - tissue-type plasminogen activator - (DD)E

* This work was supported by operating grants from the Heart and Stroke Foundation of Ontario (T-3768) and the Ontario Research and Development Challenge Fund. 1Recipient of a Research Fellowship from the Heart and Stroke Foundation of Canada. 2Recipient of a Traineeship from the Heart and Stroke Foundation of Canada. 3A Career Investigator of the Heart and Stroke Foundation of Ontario and recipient of the Heart and Stroke Foundation of Ontario/ J. Fraser Mustard Endowed Chair in Cardiovascular Research


 

  • References

  • 1 Lijnen HR, Collen D. Molecular and cellular basis of fibrinolysis. In: Hematology. Basic Principles and Practice. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE. eds. New York: Churchill Livingstone.; 1995: 1588-96.
    Google Scholar
  • 2 Bachmann F. The plasminogen-plasmin enzyme system. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J. B. Lipincott Company.; 1994: 1592-622.
    Google Scholar
  • 3 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257: 2912-9.
    PubMedGoogle Scholar
  • 4 Lijnen HR, Collen D. Molecular interactions between tissue-type plasminogen activator and plasminogen. Methods Enzymol 1993; 223: 197-206.
    PubMedGoogle Scholar
  • 5 Horrevoets AJ, Pannekoek H, Nesheim ME. A steady-state template model that describes the kinetics of fibrin-stimulated [Glu1]- and [Lys78] plasminogen activation by native tissue-type plasminogen activator and variants that lack either the finger or kringle-2 domain. J Biol Chem 1997; 272: 2183-91.
    CrossrefPubMedGoogle Scholar
  • 6 Norrman B, Wallen P, Ranby M. Fibrinolysis mediated by tissue plasminogen activator. Disclosure of kinetic transition. Eur J. Biochem 1985; 149: 193-200.
    CrossrefPubMedGoogle Scholar
  • 7 Suenson E, Lutzen O, Thorsen S. Initial plasmin-degradation of fibrin as the basis of a positive feed-back mechanism in fibrinolysis. Eur J. Biochem 1984; 140: 513-22.
    CrossrefPubMedGoogle Scholar
  • 8 Suenson E, Bjerrum P, Holm A, Lind B, Meldal M, Selmer J, Petersen LC. The role of fragment X polymers in the fibrin enhancement of tissue plasminogen activator-catalyzed plasmin formation. J Biol Chem 1990; 265: 22228-37.
    PubMedGoogle Scholar
  • 9 de Vries C, Veerman H, Pannekoek H. Identification of the domains of tissue-type plasminogen activator involved in the augmented binding to fibrin after limited digestion with plasmin. J Biol Chem 1989; 264: 12604-10.
    PubMedGoogle Scholar
  • 10 Thorsen S, Mullertz S, Suenson E, Kok P. Sequence of formation of molecular forms of plasminogen and plasmin inhibitor complexes in plasma activated by urokinase or tissue-type plasminogen activator. Biochem J 1984; 223: 179-87.
    CrossrefPubMedGoogle Scholar
  • 11 Weitz JI, Leslie B, Ginsberg J. Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis. J Clin Invest 1991; 87: 1082-90.
    CrossrefPubMedGoogle Scholar
  • 12 Weitz JI, Leslie B, Hirsh J, Klement P. Alpha-2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis. J Clin Invest 1993; 91: 1343-50.
    CrossrefPubMedGoogle Scholar
  • 13 Walker JB, Boffa MB, Nesheim ME. Molecular mass dependence and the effect of TAFIa on the t-PA and DSPA cofactor activities of soluble fibrin degradation products. Fibrinolysis and Proteolysis 1999; 12 (Suppl. 01) 11 (Abstr).
    PubMedGoogle Scholar
  • 14 Gaffney PJ, Joe F. The lysis of crosslinked human fibrin by plasmin yields initially a single molecular complex, D dimer-E. Thromb Res 1979; 15: 673-87.
    CrossrefPubMedGoogle Scholar
  • 15 Olexa SA, Budzynski AZ. Primary soluble plasmic degradation product of human cross-linked fibrin. Isolation and stoichiometry of the (DD)E complex. Biochemistry 1979; 18: 991-5.
    CrossrefPubMedGoogle Scholar
  • 16 Olexa SA, Budzynski AZ, Doolittle RF, Cottrell BA, Greene TC. Structure of fragment E species from human cross-linked fibrin. Biochemistry 1981; 20: 6139-6145.
    CrossrefPubMedGoogle Scholar
  • 17 Olexa SA, Budzynski AZ. Binding phenomena of isolated unique plasmic degradation products of human cross-linked fibrin. J Biol Chem 1979; 254: 4925-32.
    Google Scholar
  • 18 Moskowitz KA, Budzynski AZ. The (DD)E complex is maintained by a composite fibrin polymerization site. Biochemistry 1994; 33: 12937-44.
    CrossrefPubMedGoogle Scholar
  • 19 Stewart RJ, Fredenburgh JC, Weitz JI. Characterization of the interactions of plasminogen and tissue and vampire bat plasminogen activators with fibrinogen, fibrin, and the complex of D-dimer noncovalently linked to fragment E. J Biol Chem 1998; 273: 18292-9.
    CrossrefPubMedGoogle Scholar
  • 20 Lijnen HR, Collen D. Alpha 2-Antiplasmin. In: Proteinase Inhibitors. arrett A. J., and Salvesen G.. eds. New York: Elsevier Science Publishers BV; 1986: 457-76.
    Google Scholar
  • 21 Lijnen HR, Van Hoef B, Matsuo O, Collen D. On the molecular interactions between plasminogen-staphylokinase, alpha-2-antiplasmin and fibrin. Biochim Biophys Acta 1992; 1118: 144-8.
    CrossrefPubMedGoogle Scholar
  • 22 Wiman B, Lijnen HR, Collen D. On the specific interaction between the lysine-binding sites in plasmin and complementary sites in alpha-2-antiplasmin and in fibrinogen. Biochim Biophys Acta 1979; 579: 142-54.
    CrossrefPubMedGoogle Scholar
  • 23 Christensen U, Bangert K, Thorsen S. Reaction of human alpha-2-anti-plasmin and plasmin stopped-flow fluorescence kinetics. FEBS Lett. 1996; 387: 58-62.
    CrossrefPubMedGoogle Scholar
  • 24 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-5.
    CrossrefPubMedGoogle Scholar
  • 25 Castellino FJ.. Recent advances in the chemistry of the fibrinolytic system. Chem Rev 1981; 81: 431-46.
    CrossrefPubMedGoogle Scholar
  • 26 Horrevoets AJG, Tans G, Smilde AE, van Zonneveld AJ, Pannekoek H. Thrombin-variable region 1 (VR1). Evidence for the dominant contribution of VR1 of serine proteases to their interaction with plasminogen activator inhibitor 1. J. Biol. Chem. 1993; 268: 779-82.
    PubMedGoogle Scholar
  • 27 De Cristofaro R, Di Cera E. Phenomenological analysis of the clotting curve. J Protein Chem 1991; 10: 455-68.
    CrossrefPubMedGoogle Scholar
  • 28 Ye J, Rezaie AR, Esmon CT. Glycosaminoglycan contributions to both protein C activation and thrombin inhibition involve a common arginine-rich site in thrombin that includes residues arginine 93, 97, and 101. J Biol Chem 1994; 269: 17965-70.
    PubMedGoogle Scholar
  • 29 Olson ST, Björk I, Shore JD. Kinetic characterization of heparin-catalyzed and uncatalyzed inhibition of blood coagulation proteinases by antithrombin. Methods Enzymol. 1993; 222: 525-60.
    PubMedGoogle Scholar
  • 30 Nesheim ME, Fredenburgh JC, Larsen GR. The dissociation constants and stoichiometries of the interactions of Lys-plasminogen and chloromethyl ketone derivatives of tissue plasminogen activator and the variant ΔFEIX with intact fibrin. J Biol Chem 1990; 265: 21541-8.
    PubMedGoogle Scholar
  • 31 Fredenburgh JC, Stafford AR, Weitz JI. Evidence for allosteric linkage between exosites 1 and 2 of thrombin. J Biol Chem 1997; 272: 25493-9.
    CrossrefPubMedGoogle Scholar
  • 32 Kolev K, Lerant I, Tenekejiev K, Machovich R. Regulation of fibrinolytic activity of neutrophil leukocyte elastase, plasmin, and miniplasmin by plasma protease inhibitors. J Biol Chem 1994; 269: 17030-4.
    PubMedGoogle Scholar
  • 33 Collen D, Lijnen HR, De Cock F, Durieux JP, Loffet A. Kinetic properties of tripeptide lysyl chloromethyl ketone and lysyl p-nitroanilide derivatives towards trypsin-like serine proteinases. Biochim Biophys Acta 1980; 165: 158-66.
    PubMedGoogle Scholar
  • 34 Suenson E, Thorsen S. Secondary-site binding of Glu-plasmin, Lys-plasmin and miniplasmin to fibrin. Biochem J 1981; 197: 619-28.
    CrossrefPubMedGoogle Scholar
  • 35 Gils A, Declerck PJ. Proteinase specificity and functional diversity in point mutants of plasminogen activator inhibitor 1. J Biol Chem 1997; 272: 12662-6.
    CrossrefPubMedGoogle Scholar
  • 36 Anonick PK, Gonias SL. Soluble fibrin preparations inhibit the reaction of plasmin with alpha-2-macroglobulin. Biochem J 1991; 275: 53-9.
    CrossrefPubMedGoogle Scholar
  • 37 Edelberg JM, Pizzo SV. Lipoprotein (a) promotes plasmin inhibition by alpha-2-antiplasmin. Biochem. J. 1992; 286 Pt 1 79-84.
    CrossrefPubMedGoogle Scholar
  • 38 Ugarova T. P., Budzynski A. Z., Shattil S. J., Ruggeri Z. M., Ginsberg M. H., Plow E. F.. Conformational changes in fibrinogen elicited by its interaction with platelet membrane glycoprotein GPIIb-IIIa. J Biol Chem 1993; 268: 21080-7.
    PubMedGoogle Scholar
  • 39 Wiman B, Collen D. On the kinetics of the reaction between human antiplasmin and plasmin. Eur J. Biochem 1978; 84: 573-8.
    CrossrefPubMedGoogle Scholar
  • 40 Wiman B, Boman L, Collen D. On the kinetics of the reaction between human antiplasmin and a low-molecular-weight form of plasmin. Eur J. Biochem 1978; 87: 143-6.
    CrossrefPubMedGoogle Scholar
  • 41 Olexa SA, Budzynski AZ, Marder VJ. Modification of high molecular weight plasmic degradation products of human crosslinked fibrin. Biochem Biophys Acta 1979; 576: 39-50.
    CrossrefPubMedGoogle Scholar
  • 42 Masson C, Angles-Cano E. Kinetic analysis of the interaction between plasminogen activator inhibitor-1 and tissue-type plasminogen activator. Biochem J 1988; 256: 237-44.
    CrossrefPubMedGoogle Scholar
  • 43 Chmielewska J, Ranby M, Wiman B. Kinetics of the inhibition of plasmingen activators by the plasminogen activator inhibitor. Biochem J 1988; 251: 327-32.
    CrossrefPubMedGoogle Scholar
  • 44 DeSerrano VS, Castellino FJ. Structural determinants of the noncatalytic chain of tissue-type plasminogen activator that modulate its association rate with plasminogen activator inhibitor-1. J Biol Chem. 1990; 265: 10473-8.
    PubMedGoogle Scholar
  • 45 Wilhelm OG, Jaskunas SR, Vlahos CJ, Bang NU. Functional properties of the recombinant kringle 2 domain of tissue plasminogen activator produced in E. coli. J Biol Chem 1990; 265: 14606-11.
    PubMedGoogle Scholar
  • 46 Kaneko M, Sakata Y, Matsuda M, Mimuro J. Interactions between the finger and kringle-2 domains of tissue-type plasminogen activator and plasminogen activator inhibitor-1. J Biochem 1992; 111: 244-8.
    CrossrefPubMedGoogle Scholar
  • 47 Stringer HAR, Van Swieten P, Horrevoets AJG, Smilde A, Pannekoek H. The role of the finger domain of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) in initiation and progression of thrombolysis. Thromb Haemost 1994; 72: 900-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Madison EL. Probing structure-function relationships of tissue-type plasminogen activator by site-specific mutagenesis. Fibrinolysis 1994; 8 (Suppl. 01) 221-36.
    PubMedGoogle Scholar
  • 49 Bennett WF, Paoni NF, Keyt BA, Botstein D, Jones AJS, Presta L, Wurm FM, Zoller MJ. High resolution analysis of functional determinants on human tissue-type plasminogen activator. J Biol Chem 1991; 266: 5191-201.
    PubMedGoogle Scholar
  • 50 Krishnamurti C, Alving BM. Plasminogen activator inhibitor type 1: Biochemistry and evidence for modulation of fibrinolysis in vivo. Semin Thromb Haemost 1992; 18: 67-79.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Robbie LA, Bennett B, Croll AM, Brown PA, Booth NA. Proteins of the fibrinolytic system in human thrombi. Thromb Haemost 1996; 75: 127-33.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Marder VJ, Hirsh J, Bell WR. Rationale and practical basis of thrombolytic therapy. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J B Lipincott Company; 1994: 1514-40.
    Google Scholar
  • 53 Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR, Knatterud G, Robertson TL, Terrin ML. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11: 1-11.
    CrossrefPubMedGoogle Scholar
  • 54 Goldhaber SZ, Vaughan DE, Markis JE, Selwyn AP, Meyerovitz MF, Loscalzo J, Kim DS, Kessler CM, Dawley DL, Sharma GV. Acute pulmonary embolism treated with tissue plasminogen activator. Lancet 1986; 2: 886-9.
    PubMedGoogle Scholar