Kovacs, A and Szabo, L and Longstaff, C and Tenekedjiev, K and Machovich, R and Kolev, K, Ambivalent roles of carboxypeptidase B in the lytic susceptibility of fibrin, Thrombosis Research, 133, (1) pp. 80-87. ISSN 0049-3848 (2014) [Refereed Article]
Copyright 2013 The Authors. Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0) https://creativecommons.org/licenses/by/3.0/
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.
|Item Type:||Refereed Article|
|Keywords:||lytic susceptibility, fibrin, mathematical modelling, carboxypeptidase, fibrin, fibrinolysis, plasmin, tPA|
|Research Division:||Mathematical Sciences|
|Research Field:||Applied statistics|
|Objective Division:||Expanding Knowledge|
|Objective Group:||Expanding knowledge|
|Objective Field:||Expanding knowledge in the information and computing sciences|
|UTAS Author:||Tenekedjiev, K (Professor Kiril Tenekedjiev)|
|Web of Science® Times Cited:||14|
|Deposited By:||NC Maritime Engineering and Hydrodynamics|
|Downloads:||135 View Download Statistics|
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