PDF herunterladen
Thromb Haemost 2007; 98(02): 359-367
DOI: 10.1160/TH07-02-0098
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Down-regulation of activated factor XIII by polymorphonuclear granulocyte proteases within fibrin clot

Zsuzsa Bagoly
1   University of Debrecen, Medical and Health Science Center, Clinical Research Center and Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary
,
Gizella Haramura
1   University of Debrecen, Medical and Health Science Center, Clinical Research Center and Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary
,
László Muszbek
1   University of Debrecen, Medical and Health Science Center, Clinical Research Center and Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary
› InstitutsangabenFinancial support: This work was supported by grants from the Hungarian National Research Fund (OTKA-NKTH NI 69238), from the Hungarian Academy of Sciences (MTA 11003, 2006TKI227), from the Hungarian Ministry of Health and Social Affairs (ETT 406/2006) and from the National Office of Research and Technology (NKTH-OTKA, RET-06/2004).
Weitere Informationen

Publikationsverlauf

Received 08. Februar 2007

Accepted after revision 04. Mai 2007

Publikationsdatum:
28. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Activated clotting factors are down-regulated by two major mechanisms which involve protease inhibitors or proteolytic degradation. To date, no down-regulating mechanism for activated factor XIII (FXIIIa) has been demonstrated. As the hemostatic plug contains polymorphonuclear granulocytes (PMNs) rich in proteolytic enzymes, we tested if these proteases are released in fibrin clots, and become involved in the down-regulation of FXIIIa.The supernatant of stimulated granulocytes proteolytically degraded and inactivated FXIIIa. In the fibrin clot formed from fibrinogen solution elastase, cathepsin G and matrix metalloprotease-9 (MMP-9) were released from granulocytes without any external stimulus. PMN proteases released in fibrin clot exerted a fibrinolytic effect and almost completely de-graded both FXIII subunits.The elastase inhibitor, ONO 5046, partially inhibited the proteolytic degradation of FXIII in PMNsupplemented fibrin clots. Cathepsin G and MMP-9 inhibitors provided less protection; in these cases intermediate split products accumulated.The proteolytic degradation of FXIII by PMNs was also significant when the clot was made from whole plasma. The main plasma protease inhibitor, α1-antitrypsin, provided only partial protection. In the fibrin clot which contained α1-antitrypsin FXIIIa was degraded by PMN proteases significantly faster than cross-linked fibrin.The results suggest that the degradation of FXIII subunits by the concerted action of PMN proteases released within the clot represents a novel mechanism for the down-regulation of FXIIIa.

Keywords

Elastase - factor XIII - fibrinogen - fibrin - polymorphonuclear granulocytes
 

  • References

  • 1 Muszbek L, Ádány R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation and function. Crit Rev Lab Sci 1996; 33: 357-421.
    PubMedGoogle Scholar
  • 2 Greenberg CS, Sane DC, Lai T. Factor XIII and fibrin stabilization. In: Hemostasis and Thrombosis. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2006: 317-334.
    Google Scholar
  • 3 Muszbek L, Ariens RA, Ichinose A. Factor XIII: recommended terms and abbreviations. J Thromb Haemost 2007; 5: 181-183.
    CrossrefPubMedGoogle Scholar
  • 4 Francis CW, Marder VJ. Increased resistance to plasmic degradation of fibrin with highly crosslinked α-polymer chains formed at high factor XIII concentrations. Blood 1988; 71: 1361-1365.
    PubMedGoogle Scholar
  • 5 Francis CW, Marder VJ. Rapid formation of large molecular weight α-polymers in cross-linked fibrin induced by high factor XIII concentrations. Role of platelet factor XIII. J Clin Invest 1987; 80: 1459-1465.
    CrossrefPubMedGoogle Scholar
  • 6 Colman RW, Cloves AW, George JN. et al. Overview of hemostasis. In: Hemostasis and Thrombosis. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2006: 3-20.
    Google Scholar
  • 7 Rider DM, McDonagh J. Resistance of factor XIII to degradation or activation by plasmin. Biochim Biophys Acta 1981; 675: 171-177.
    CrossrefPubMedGoogle Scholar
  • 8 Plow EF. Leukocyte elastase release during blood coagulation. A potential mechanism for activation of the alternative fibrinolytic pathway. J Clin Invest 1982; 69: 564-572.
    CrossrefPubMedGoogle Scholar
  • 9 Nakajima K, Powers JC. Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. J Biol Chem 1979; 254: 4027-4032.
    PubMedGoogle Scholar
  • 10 Katona É, Haramura G, Kárpáti L. et al. A simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2). Thromb Haemost 2000; 83: 268-273.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 11 Castillo MJ, Nakajima K, Zimmerman M. et al. Sensitive substrates for human leukocyte and porcine pancreatic elastase: A study of the merits of various chromophoric and fluorogenic leaving group in assays of serine proteases. Anal Biochem 1979; 99: 53-64.
    CrossrefPubMedGoogle Scholar
  • 12 Beekman B, Drijfhout JW, Bloemhoff W. et al. Convenient fluorometric assay for matrix metalloproteinase activity and its application in biological media. FEBS Letts 1996; 390: 221-225.
    CrossrefPubMedGoogle Scholar
  • 13 Kawabata K, Suzuki M, Sugitani M. et al. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 1991; 177: 814-820.
    CrossrefPubMedGoogle Scholar
  • 14 Greco MN, Hawkins MJ, Powell ET. et al. Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design. J Am Chem Soc 2002; 124: 3810-3811.
    CrossrefPubMedGoogle Scholar
  • 15 Levin JI, Chen J, Du M. et al. The discovery of anthranilic acid based MMP inhibitors. Part 2: SAR of the 5-position and P1(1) groups. Bioorg Med Chem Lett 2001; 11: 2189-2192.
    CrossrefPubMedGoogle Scholar
  • 16 Lorand L, Credo RB, Janus TG. Factor XIII (fibrin stabilizing factor). Methods Enzymol 1981; 80: 333-341.
    PubMedGoogle Scholar
  • 17 Kárpáti L, Penke B, Katona É. et al. A modified optimized kinetic photometric assay for the determination of blood coagulation factor XIII activity in plasma. Clin Chem 2000; 46: 1946-1955.
    PubMedGoogle Scholar
  • 18 Shemirani AH, Haramura G, Bagoly Z. et al. The combined effect of fibrin formation and factor XIII A subunit Val34Leu polymorphism on the activation of factor XIII in whole plasma. Biochim Biophys Acta 2006; 1764: 1420-1423.
    CrossrefPubMedGoogle Scholar
  • 19 Parks WC, Mecham RP. Matrix Metalloproteases. San Diego (CA): Academic Press; 1998
    Google Scholar
  • 20 Opdenakker G, Van den Steen PE, Dubois B. et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001; 69: 851-859.
    PubMedGoogle Scholar
  • 21 Wiedow O, Mayer-Hoffert U. Neutrophil serine proteases: potential key regulators of cell signalling during inflammation. J Int Med 2005; 257: 319-328.
    CrossrefPubMedGoogle Scholar
  • 22 Korkmaz B, Poutrain P, Hazouard E. et al. Competition between elastase and related proteases from human neutrophil for binding to alpha1-protease inhibitor. Am J Respir Cell Mol Biol 2005; 32: 553-559.
    CrossrefPubMedGoogle Scholar
  • 23 Fontaine V, Jacob M, Houard X. et al. Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 2002; 161: 1701-1710.
    CrossrefPubMedGoogle Scholar
  • 24 Adeyemi EO, Hodgson HJF. Augmented release of human leukocyte lactoferrin (and elastase) during coagulation. J Clin Lab Immunol 1988; 27: 1-4.
    PubMedGoogle Scholar
  • 25 Moir E, Booth NA, Bennett B. et al. Polymorhonuclear leucocytes mediate endogenous thrombus lysis via a u-PA-dependent mechanism. Brit J Haematol 2001; 113: 72-80.
    CrossrefPubMedGoogle Scholar
  • 26 Owen CA, Campbell MA, Sannes PL. et al. Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteases. J Cell Biol 1995; 131: 775-789.
    CrossrefPubMedGoogle Scholar
  • 27 Makowski GS, Ramsby ML. Binding of latent matrix metalloprotease 9 to fibrin. Activation via a plasmin- dependent pathway. Inflammation 1998; 22: 287-305.
    CrossrefPubMedGoogle Scholar
  • 28 Owen CA, Hu Z, Barrick B. et al. Inducible expression of tissue inhibitor of metalloproteinases-resistant matrix metalloproteinase-9 on the cell surface of neutrophils. Am J Respir Cell Mol Biol 2003; 29: 283-294.
    CrossrefPubMedGoogle Scholar
  • 29 Palabrica T, Lobb R, Furie BC. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-851.
    CrossrefPubMedGoogle Scholar
  • 30 Kirchhofer D, Riederer MA, Baumgartner HR. Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model. Blood 1997; 89: 1270-1278.
    PubMedGoogle Scholar
  • 31 Gross PL, Furie BC, Merrill-Skoloff G. et al. Leukocyte- versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J Leukoc Biol 2005; 78: 1318-1326.
    CrossrefPubMedGoogle Scholar
  • 32 Kuijper PH, Gallardo Torres HI, Lammers JW. et al. Platelet and fibrin deposition at the damaged vessel wall: cooperative substrates for neutrophil adhesion under flow conditions. Blood 1997; 89: 166-175.
    PubMedGoogle Scholar
  • 33 Clark RA, Stone PJ, El Hag A. et al. Myeloperoxidase- catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils. J Biol Chem 1981; 256: 3348-3353.
    PubMedGoogle Scholar
  • 34 Liu Z, Zhou X, Shapiro SD. et al. The serpin α1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 2000; 102: 647-655.
    CrossrefPubMedGoogle Scholar
  • 35 Schmidt W, Egbring R, Havemann K. Effect of elastase-like and chymotrypsin-like neutral proteases from human granulocytes on isolated clotting factors. Thromb Res 1975; 6: 315-326.
    CrossrefPubMedGoogle Scholar
  • 36 Klingemann HG, Egbring R, Holst F. et al. Degradation of human plasma fibrin stabilizing factor XIII subunits by human granulocytic proteinases. Thromb Res 1982; 28: 793-801.
    CrossrefPubMedGoogle Scholar