PDF herunterladen
Thromb Haemost 1999; 82(06): 1703-1708
DOI: 10.1055/s-0037-1614902
Rapid Communication
Schattauer GmbH

Factor XI Dependent and Independent Activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) in Plasma Associated with Clot Formation

Bonno N. Bouma
1   From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
2   Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht and University of Utrecht, The Netherlands
3   Institute of Biomembranes, University of Utrecht, The Netherlands
,
Laurent O. Mosnier
2   Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht and University of Utrecht, The Netherlands
3   Institute of Biomembranes, University of Utrecht, The Netherlands
,
Joost C. M. Meijers   *
2   Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht and University of Utrecht, The Netherlands
3   Institute of Biomembranes, University of Utrecht, The Netherlands
,
John H. Griffin
1   From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 29. April 1999

Accepted after revision 08. Juli 1999

Publikationsdatum:
10. Dezember 2017 (online)

    Lizenzen und Reprints

Summary

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) also known as plasma procarboxypeptidase B is activated by relatively high concentrations of thrombin in a reaction stimulated by thrombomodulin. In plasma an intact factor XI-dependent feed back loop via the intrinsic pathway is necessary to generate sufficient thrombin for TAFI activation. This thrombin generation takes place after clot formation with consequent down-regulation of fibrinolysis. We developed a specific and sensitive assay for activated TAFI (TAFIa) and studied its factor XI-dependent generation during clot formation. In the absence of thrombomodulin, addition of 20 nM thrombin to normal plasma generated 5-10% of the amount of TAFIa generated by 20 nM thrombin in the presence of 8 nM thrombomodulin. Minimal activation of TAFI was detected in factor II deficient plasma when clotting was initiated by 20 nM thrombin. Addition of 320-640 nM of thrombin to factor II deficient plasma resulted in the same amount of TAFIa as in normal plasma, suggesting that ~50% of factor II has to be converted to thrombin for extensive activation of TAFI. A Mab that neutralizes activated factor XII had no effect on TAFI activation indicating that an intact contact system is not necessary for the activation of TAFI. The dependency of TAFI activation of factor XI was tested using a Mab that neutralizes activated factor XI. When plasmas from 13 healthy individuals were tested, this Mab reduced TAFI activation by 65% (range 35-89%). Our results indicate that activation of TAFI in serum after clot formation can be quantitated and that it takes place in both factor XI-dependent and factor XI-independent mechanisms.

Keywords

Factor XI - TAFI - fibrinolysis

* JCMM is an Established Investigator of the Netherlands Heart Foundation (Grant D96.021). Supported in part by NIH grant HL 21544 and grant 96.088 from the Netherlands Heart Foundation.


 

  • References

  • 1 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin activable fibrinolysis inhibitor. J Biol Chem 1995; 270: 14477-84.
    CrossrefPubMedGoogle Scholar
  • 2 Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 1981; 68: 1221-8.
    CrossrefPubMedGoogle Scholar
  • 3 Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 86: 1218-23.
    PubMedGoogle Scholar
  • 4 Sakata Y, Curriden S, Lawrence D, Griffin JH, Loskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci USA 1985; 82: 1121-5.
    CrossrefPubMedGoogle Scholar
  • 5 van Hinsbergh VW, Bertina RM, van Wijngaarden A, van Tilburg NH, Emeis JJ, Haverkate F. Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium. Blood 1985; 65: 444-51.
    PubMedGoogle Scholar
  • 6 de Fouw NJ, Haverkate F, Bertina RM. Protein C and fibrinolysis: a link between coagulation and fibrinolysis. Adv Exp Med Biol. 1990; 281: 235-43.
    PubMedGoogle Scholar
  • 7 Bajzar L, Fredenburgh JC, Nesheim ME. The activated protein C-mediated enhancement of tissue-type plasminogen activator-induced fibrinolysis in a cell-free system. J Biol Chem 1990; 265: 16948-54.
    PubMedGoogle Scholar
  • 8 Bajzar L, Nesheim ME. The effect of activated protein C on fibrinolysis in cell free plasma can be attributed specifically to attenuation of prothrombin activation. J Biol Chem 1993; 268: 8608-16.
    PubMedGoogle Scholar
  • 9 Eaton DL, Malloy BE, Tsai SP, Henzel W, Drayna D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem 1991; 266: 21833-8.
    PubMedGoogle Scholar
  • 10 Wang W, Hendriks DF, Scharpé SS. Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J Biol Chem 1994; 269: 15937-44.
    PubMedGoogle Scholar
  • 11 Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-91.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Bajzar L, Morser J, Nesheim ME. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271: 16603-8.
    CrossrefPubMedGoogle Scholar
  • 13 Tan AK, Eaton DL. Activation and characterization of procarboxypeptidase B from human plasma. Biochemistry 1995; 34: 5811-6.
    CrossrefPubMedGoogle Scholar
  • 14 Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96: 2534-8.
    CrossrefPubMedGoogle Scholar
  • 15 Hendriks D, Wang W, Scharpe S, Lommaert MP, van Sande M. Purification and characterization of a new arginine carboxypeptidase in human serum. Biochim Biophys Acta 1990; 1034: 86-92.
    CrossrefPubMedGoogle Scholar
  • 16 Hendriks D, Scharpe S, van Sande M, Lommaert MP. Characterization of a carboxypeptidase in human serum distinct from carboxypeptidase N. J Clin Chem Clin Biochem 1989; 27: 277-85.
    PubMedGoogle Scholar
  • 17 Von dem Borne PAKr, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-42.
    PubMedGoogle Scholar
  • 18 Von dem Borne PAKr, Bajzar L, Meijers JCM, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibition of fibrinolysis. J Clin Invest 1997; 99: 2323-7.
    CrossrefPubMedGoogle Scholar
  • 19 Minnema MC, Friederich PW, Levi M, von dem Borne PAKr, Mosnier LO, Meijers JCM, Biemond BJ, Hack CE, Bouma BN, ten Cate H. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor. J Clin Invest 1998; 101: 10-4.
    CrossrefPubMedGoogle Scholar
  • 20 Gresele P, Momi S, Berrettini M, Nenci GG, Schwarz HP, Semeraro N, Colucci M. Activated protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein C reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. J Clin Invest 1998; 101: 667-76.
    CrossrefPubMedGoogle Scholar
  • 21 Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991; 266: 7353-8.
    PubMedGoogle Scholar
  • 22 Gailani D, Broze GJ. Factor XI activation in a revised model of coagulation. Science 1991; 253: 909-12.
    CrossrefPubMedGoogle Scholar
  • 23 Von dem Borne PAKr, Koppelman SJ, Bouma BN, Meijers JCM. Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. Thromb Haemost 1994; 72: 397-402.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 24 Minnema MC, Pajkrt D, Wuillemin WA, Roem D, Bleeker WK, Levi M, van Deventer SJH, Hack CE, ten Cate H. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood 1998; 92: 3294-3301.
    PubMedGoogle Scholar
  • 25 Von dem Borne PAKr, Mosnier LO, Tans G, Meijers JCM, Bouma BN. Factor XI activation by meizothrombin: stimulation by phospholipids vesicles containing both phosphatidylserine and phosphatidylethanolamine. Thromb Haemost 1997; 78: 834-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 26 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999; 19: 170-7.
    CrossrefPubMedGoogle Scholar
  • 27 Gailani D, Broze GJ. Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood 1993; 82: 813-9.
    PubMedGoogle Scholar
  • 28 Lawson JH, Kalafatis M, Stram S, Mann KG. A model for the tissue factor pathway to thrombin. An empirical study. J Biol Chem 1994; 269: 23357-66.
    PubMedGoogle Scholar
  • 29 Mosnier LO, von dem Borne PAKr, Meijers JCM, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost 1998; 80: 829-35.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 30 Sakharov DV, Plow EF, Rijken DC. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem 1997; 272: 14477-82.
    CrossrefPubMedGoogle Scholar
  • 31 Boffa MB, Wang W, Bajzar L, Nesheim ME. Plasma and recombinant thrombin-activable fibrinolysis inhibitor (TAFI) and activated TAFI compared to glycosylation, thrombin/thrombomodulin-dependent activation, thermal stability, and enzymatic properties. J Biol Chem 1998; 273: 2127-35.
    CrossrefPubMedGoogle Scholar
  • 32 Nesheim ME, Boffa MB, Wang W. The effects of temperature, GEMSA and EACA on the stability of activated TAFI. Fibrinolysis 1996; 10: 126 (Abstract).
    PubMedGoogle Scholar
  • 33 Wang W, Boffa MB, Walker J, Nesheim ME. Reciprocal inactivation of TAFIa and plasmin. Fibrinolysis 1996; 10: 124 (Abstract).
    PubMedGoogle Scholar
  • 34 Meijers JCM. Regulation of the blood coagulation mechanism by plasma proteinase inhibitors. Ph D Thesis State University of Utrecht; 1988: 93-108.
    PubMedGoogle Scholar
  • 35 Hurst PL, Lovell Smith CJ. An optimized assay for serum angiotensin-converting enzyme. Clin Chem 1981; 27: 2048-52.
    PubMedGoogle Scholar
  • 36 Hayakari M, Kondo Y, Izumi H. A rapid and simple spectrophotometric assay of angiotensin-converting enzyme. Anal Biochem 1970; 84: 361-9.
    PubMedGoogle Scholar
  • 37 Suzuki S, Hachimori Y, Yaoeda U. Spectrophotometric determination of glycine with 2,4,6-trichloro-s-triazine. Anal Chem 1970; 42: 101-3.
    CrossrefPubMedGoogle Scholar
  • 38 Hendriks D, van Sande M, Scharpé S. Colorimetric assay for carboxypeptidase N in serum. Clin Chim Acta 1986; 157: 103-8.
    CrossrefPubMedGoogle Scholar
  • 39 Kessels H, Beguin S, Andree H, Hemker HC. Measurement of thrombin generation in whole blood – the effect of heparin and aspirin. Thromb Haemost 1994; 72: 78-83.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 40 Weitz JI, Hudoba D, Massel J, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 386-91.
    PubMedGoogle Scholar
  • 41 Kumar R, Beguin S, Hemker HC. The influence of fibrinogen on thrombin generation: evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost 1994; 72: 713-21.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 42 Von dem Borne PAKr, Meijers JCM, Bouma BN. Effect of heparin on the activation of factor XI by fibrin bound thrombin. Thromb Haemost 1996; 76: 347-53.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 43 Biemond BJ, Friederich PW, Levi M, Vlasuk GP, Büller HR, ten Cate JW. Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. Circulation 1996; 93: 153-60.
    CrossrefPubMedGoogle Scholar
  • 44 Braat EAM, Los P, Rijken DC. The inactivation of single-chain urokinase-type plasminogen activator by thrombin in a plasma milieu: the effect of thrombomodulin. Blood Coag Fibrinol 1998; 9: 419-27.
    CrossrefPubMedGoogle Scholar
  • 45 Braat EAM, Rijken DC. The inactivation of single-chain urokinase type-plasminogen activator by thrombin may provide an additional explanation for the antifibrinolytic effect of factor XI. Thromb Haemost 1999; 81: 657.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 46 Bouma BN, von dem Borne PAKr, Meijers JCM. Factor XI and protection of the fibrin clot against lysis - a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost 1998; 80: 24-7.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 47 Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. New Engl J Med 1991; 325: 153-8.
    CrossrefPubMedGoogle Scholar
  • 48 Berliner S, Horowitz I, Martinowitz U, Brenner B, Seligsohn U. Dental surgery in patients with severe factor XI deficiency without plasma replacement. Blood Coagul Fibrinol 1991; 3: 465-8.
    PubMedGoogle Scholar
  • 49 Hsu TC, Shore SK, Seshsmma T, Bagasra O, Walsh PN. Molecular cloning of platelet factor XI, an alternative splice product of the plasma factor XI gene. J Biol Chem 1998; 273: 13787-93.
    CrossrefPubMedGoogle Scholar
  • 50 Hu CJ, Baglia FA, Mills DC, Konkle BA, Walsh PN. Tissue-specific expression of functional platelet factor XI is independent of plasma factor XI expression. Blood 1998; 91: 3800-7.
    PubMedGoogle Scholar