Ambivalent roles of carboxypeptidase B in the lytic susceptibility of fibrin

András Kovács, László Szabó, Colin Longstaff, Kiril Tenekedjiev, Raymund Machovich, Krasimir Kolev

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background Removal of C-terminal lysine residues that are continuously exposed in lysing fibrin is an established anti-fibrinolytic mechanism dependent on the plasma carboxypeptidase TAFIa, which also removes arginines that are exposed at the time of fibrinogen clotting by thrombin. Objective To evaluate the impact of alterations in fibrin structure mediated by constitutive carboxypeptidase activity on the function of fibrin as a template for tissue plasminogen activator-(tPA) induced plasminogen activation and its susceptibility to digestion by plasmin. Methods and results We used the stable carboxypeptidase B (CPB), which shows the same substrate specificity as TAFIa. If 1.5 - 6 μM fibrinogen was clotted in the presence of 8 U/mL CPB, a denser fibrin network was formed with thinner fibers (the median fiber diameter decreased from 138 - 144 nm to 89 - 109 nm as established with scanning electron microscopy). If clotting was initiated in the presence of 5 - 10 μM arginine, a similar decrease in fiber diameter (82 -95 nm) was measured. The fine structure of arginine-treated fibrin enhanced plasminogen activation by tPA, but slowed down lysis monitored using fluorescent tPA and confocal laser microscopy. However, if lysis was initiated with plasmin in CPB-treated fibrin, the rate of dissolution increased to a degree corresponding to doubling of the plasmin concentration. Conclusion The present data evidence that CPB activity generates fine-mesh fibrin which is more difficult to lyse by tPA, but conversely, CPB and plasmin together can stimulate fibrinolysis, possibly by enhancing plasmin diffusion.

Original languageEnglish
Pages (from-to)80-87
Number of pages8
JournalThrombosis research
Volume133
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • Carboxypeptidase
  • Fibrin
  • Fibrinolysis
  • Plasmin
  • tPA

ASJC Scopus subject areas

  • Hematology

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