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. 1997 May 15;99(10):2323–2327. doi: 10.1172/JCI119412

Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.

P A Von dem Borne 1, L Bajzar 1, J C Meijers 1, M E Nesheim 1, B N Bouma 1
PMCID: PMC508069  PMID: 9153272

Abstract

Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased twofold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.

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Selected References

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  1. Asakai R., Chung D. W., Davie E. W., Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med. 1991 Jul 18;325(3):153–158. doi: 10.1056/NEJM199107183250303. [DOI] [PubMed] [Google Scholar]
  2. Bajzar L., Manuel R., Nesheim M. E. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1995 Jun 16;270(24):14477–14484. doi: 10.1074/jbc.270.24.14477. [DOI] [PubMed] [Google Scholar]
  3. Bajzar L., Morser J., Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem. 1996 Jul 12;271(28):16603–16608. doi: 10.1074/jbc.271.28.16603. [DOI] [PubMed] [Google Scholar]
  4. Bajzar L., Nesheim M. E., Tracy P. B. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. 1996 Sep 15;88(6):2093–2100. [PubMed] [Google Scholar]
  5. Bajzar L., Nesheim M. 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 Apr 25;268(12):8608–8616. [PubMed] [Google Scholar]
  6. Bajzár L., Fredenburgh J. C., Nesheim M. The activated protein C-mediated enhancement of tissue-type plasminogen activator-induced fibrinolysis in a cell-free system. J Biol Chem. 1990 Oct 5;265(28):16948–16954. [PubMed] [Google Scholar]
  7. Broze G. J., Jr, Higuchi D. A. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. 1996 Nov 15;88(10):3815–3823. [PubMed] [Google Scholar]
  8. Comp P. C., Esmon C. T. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest. 1981 Nov;68(5):1221–1228. doi: 10.1172/JCI110368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eaton D. L., Malloy B. E., Tsai S. P., Henzel W., Drayna D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem. 1991 Nov 15;266(32):21833–21838. [PubMed] [Google Scholar]
  10. FOLK J. E., PIEZ K. A., CARROLL W. R., GLADNER J. A. Carboxy-peptidase B. 4. Purification and characterization of the porcine enzyme. J Biol Chem. 1960 Aug;235:2272–2277. [PubMed] [Google Scholar]
  11. Gailani D., Broze G. J., Jr Factor XI activation in a revised model of blood coagulation. Science. 1991 Aug 23;253(5022):909–912. doi: 10.1126/science.1652157. [DOI] [PubMed] [Google Scholar]
  12. Gailani D., Broze G. J., Jr Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood. 1993 Aug 1;82(3):813–819. [PubMed] [Google Scholar]
  13. Hendriks D., Wang W., Scharpé S., Lommaert M. P., van Sande M. Purification and characterization of a new arginine carboxypeptidase in human serum. Biochim Biophys Acta. 1990 Apr 23;1034(1):86–92. doi: 10.1016/0304-4165(90)90157-r. [DOI] [PubMed] [Google Scholar]
  14. Kessels H., Béguin S., Andree H., Hemker H. C. Measurement of thrombin generation in whole blood--the effect of heparin and aspirin. Thromb Haemost. 1994 Jul;72(1):78–83. [PubMed] [Google Scholar]
  15. Kisiel W., Smith K. J., McMullen B. A. Proteolytic inactivation of blood coagulation factor IX by thrombin. Blood. 1985 Dec;66(6):1302–1308. [PubMed] [Google Scholar]
  16. Miles L. A., Dahlberg C. M., Plescia J., Felez J., Kato K., Plow E. F. Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry. 1991 Feb 12;30(6):1682–1691. doi: 10.1021/bi00220a034. [DOI] [PubMed] [Google Scholar]
  17. 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 Apr 25;266(12):7353–7358. [PubMed] [Google Scholar]
  18. Pannell R., Black J., Gurewich V. Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained. J Clin Invest. 1988 Mar;81(3):853–859. doi: 10.1172/JCI113394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Redlitz A., Tan A. K., Eaton D. L., Plow E. F. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. 1995 Nov;96(5):2534–2538. doi: 10.1172/JCI118315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sakata Y., Loskutoff D. J., Gladson C. L., Hekman C. M., Griffin J. H. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood. 1986 Dec;68(6):1218–1223. [PubMed] [Google Scholar]
  21. Wang W., Hendriks D. F., Scharpé S. S. Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J Biol Chem. 1994 Jun 3;269(22):15937–15944. [PubMed] [Google Scholar]
  22. de Fouw N. J., Haverkate F., Bertina R. M. Protein C and fibrinolysis: a link between coagulation and fibrinolysis. Adv Exp Med Biol. 1990;281:235–243. doi: 10.1007/978-1-4615-3806-6_23. [DOI] [PubMed] [Google Scholar]
  23. van der Graaf F., Greengard J. S., Bouma B. N., Kerbiriou D. M., Griffin J. H. Isolation and functional characterization of the active light chain of activated human blood coagulation factor XI. J Biol Chem. 1983 Aug 25;258(16):9669–9675. [PubMed] [Google Scholar]
  24. von dem Borne P. A., Koppelman S. J., Bouma B. N., Meijers J. C. Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. Thromb Haemost. 1994 Sep;72(3):397–402. [PubMed] [Google Scholar]
  25. von dem Borne P. A., Meijers J. C., Bouma B. N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood. 1995 Oct 15;86(8):3035–3042. [PubMed] [Google Scholar]

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