Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis

N.J. Mutch, J.S. Koikkalainen, S.R. Fraser, K.M. Duthie, Martin Griffin, J. Mitchell, H.G. Watson, N.A. Booth

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Activated factor XIII (FXIIIa), a transglutaminase, introduces fibrin-fibrin and fibrin-inhibitor cross-links, resulting in more mechanically stable clots. The impact of cross-linking on resistance to fibrinolysis has proved challenging to evaluate quantitatively. Methods: We used a whole blood model thrombus system to characterize the role of cross-linking in resistance to fibrinolytic degradation. Model thrombi, which mimic arterial thrombi formed in vivo, were prepared with incorporated fluorescently labeled fibrinogen, in order to allow quantification of fibrinolysis as released fluorescence units per minute. Results: A site-specific inhibitor of transglutaminases, added to blood from normal donors, yielded model thrombi that lysed more easily, either spontaneously or by plasminogen activators. This was observed both in the cell/platelet-rich head and fibrin-rich tail. Model thrombi from an FXIII-deficient patient lysed more quickly than normal thrombi; replacement therapy with FXIII concentrate normalized lysis. In vitro addition of purified FXIII to the patient's preprophylaxis blood, but not to normal control blood, resulted in more stable thrombi, indicating no further efficacy of supraphysiologic FXIII. However, addition of tissue transglutaminase, which is synthesized by endothelial cells, generated thrombi that were more resistant to fibrinolysis; this may stabilize mural thrombi in vivo. Conclusions: Model thrombi formed under flow, even those prepared as plasma 'thrombi', reveal the effect of FXIII on fibrinolysis. Although very low levels of FXIII are known to produce mechanical clot stability, and to achieve ?-dimerization, they appear to be suboptimal in conferring full resistance to fibrinolysis.
Original languageEnglish
Pages (from-to)2017-2024
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number9
Early online date24 Jun 2010
DOIs
Publication statusPublished - Sept 2010

Bibliographical note

For non-commercial and non-promotional purposes individual users may access, download, copy, display and redistribute to colleagues OnlineOpen articles, as well as adapt, translate, text- and data-mine the content subject to the following conditions:
•The authors' moral rights are not compromised. These rights include the right of "paternity" (also known as "attribution" - the right for the author to be identified as such) and "integrity" (the right for the author not to have the work altered in such a way that the author's reputation or integrity may be impugned).
•Where content in the article is identified as belonging to a third party, it is the obligation of the user to ensure that any reuse complies with the copyright policies of the owner of that content.
•If article content is copied, downloaded or otherwise reused for non-commercial research and education purposes, a link to the appropriate bibliographic citation (authors, journal, article title, volume, issue, page numbers, DOI and the link to the definitive published version on Wiley Online Library) should be maintained. Copyright notices and disclaimers must not be deleted.
•Any translations, for which a prior translation agreement with Wiley has not been agreed, must prominently display the statement: "This is an unofficial translation of an article that appeared in a Wiley publication. The publisher has not endorsed this translation.

Keywords

  • factor XIII
  • thrombi
  • stability
  • flow
  • fibrinolysis

Fingerprint

Dive into the research topics of 'Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis'. Together they form a unique fingerprint.

Cite this