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Carboxypeptidase U (CPU, carboxypeptidase B2, activated thrombin‐activatable fibrinolysis inhibitor) inhibition stimulates the fibrinolytic rate in different in vitro models
Author(s): ,
D. Leenaerts
Affiliations:
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium
,
S. Loyau
Affiliations:
Laboratory for Vascular Translational Sciences, U1148, Paris Diderot University, Paris, France
,
J. C. Mertens
Affiliations:
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium
,
W. Boisseau
Affiliations:
Laboratory for Vascular Translational Sciences, U1148, Paris Diderot University, Paris, France
,
J. B. Michel
Affiliations:
Laboratory for Vascular Translational Sciences, U1148, Paris Diderot University, Paris, France
,
A. M. Lambeir
Affiliations:
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium
,
M. Jandrot‐Perrus
Affiliations:
Laboratory for Vascular Translational Sciences, U1148, Paris Diderot University, Paris, France
D. Hendriks
Affiliations:
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium
Correspondence: D. Hendriks, Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, B‐2610 Wilrijk, Belgium|Tel.: +32 3265 2727|E‐mail: dirk.hendriks@uantwerpen.be
ISTH Academy. Hendriks D. Oct 4, 2018; 234177
D. Hendriks
D.  Hendriks

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Background
Carboxypeptidase U (CPU, carboxypeptidase B2, activated thrombin‐activatable fibrinolysis inhibitor) is a basic carboxypeptidase that attenuates fibrinolysis. This characteristic has raised interest in the scientific community and pharmaceutical industry for the development of inhibitors as profibrinolytic agents.
Objectives
Little is known about the contribution of CPU to clot resistance in more advanced hemostatic models, which include blood cells and shear stress. The aim of this study was to evaluate the effects of the CPU system in in vitro systems for fibrinolysis with different grades of complexity.
Methods
The contribution of the CPU system was evaluated in the following systems: (i) plasma clot lysis; (ii) rotational thromboelastometry (ROTEM) in whole blood; (iii) front lysis with confocal microscopy in platelet‐free and platelet‐rich plasma; and (iv) a microfluidic system with whole blood under arterial shear stress. Experiments were carried out in the presence or absence of AZD9684, a specific CPU inhibitor.
Results
During plasma clot lysis, addition of AZD9684 resulted in 33% faster lysis. In ROTEM, the lysis onset time was decreased by 38%. For both clot lysis and ROTEM, an AZD9684 dose‐dependent response was observed. CPU inhibition in front lysis experiments resulted in 47% and 50% faster lysis for platelet‐free plasma and platelet‐rich plasma, respectively. Finally, a tendency for faster lysis was observed only in the microfluidic system when AZD9684 was added.
Conclusions
Overall, these experiments provide novel evidence that the CPU system can also modulate fibrinolysis in more advanced hemostatic systems. The extent of the effects appears to be dependent upon the exact experimental conditions.
Keyword(s)
carboxypeptidase B2, carboxypeptidase U, fibrinolysis, in vitro techniques, thrombin‐activatable fibrinolysis inhibitor
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