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 journalArticle

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 - Sep 2010

Fingerprint

Factor XIII
Fibrinolysis
Thrombosis
Fibrin
Transglutaminases
Factor XIIIa
Plasminogen Activators
Dimerization
Blood Donors
Fibrinogen
Blood Platelets
Endothelial Cells
Fluorescence
Head

Bibliographical note

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•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

Cite this

Mutch, N.J. ; Koikkalainen, J.S. ; Fraser, S.R. ; Duthie, K.M. ; Griffin, Martin ; Mitchell, J. ; Watson, H.G. ; Booth, N.A. / Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis. In: Journal of Thrombosis and Haemostasis. 2010 ; Vol. 8, No. 9. pp. 2017-2024.
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Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis. / Mutch, N.J.; Koikkalainen, J.S.; Fraser, S.R.; Duthie, K.M.; Griffin, Martin; Mitchell, J.; Watson, H.G.; Booth, N.A.

In: Journal of Thrombosis and Haemostasis, Vol. 8, No. 9, 09.2010, p. 2017-2024.

Research output: Contribution to journalArticle

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AU - Koikkalainen, J.S.

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AU - Duthie, K.M.

AU - Griffin, Martin

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AU - Watson, H.G.

AU - Booth, N.A.

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