Carboxypeptidase U (CPU, carboxypeptidase B2, activated thrombin-activatable fibrinolysis inhibitor) inhibition stimulates the fibrinolytic rate in different in vitro models
Autor: | Jean-Baptiste Michel, Dirk Hendriks, Martine Jandrot-Perrus, Anne-Marie Lambeir, Stéphane Loyau, Dorien Leenaerts, William Boisseau, Joachim C. Mertens |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Carboxypeptidase B2 Lysis Carboxypeptidase U Pyridines medicine.medical_treatment 030204 cardiovascular system & hematology Pharmacology 03 medical and health sciences 0302 clinical medicine Fibrinolytic Agents Fibrinolysis medicine Humans Protease Inhibitors Whole blood biology Chemistry Hematology Carboxypeptidase In vitro Thromboelastometry Butyrates Kinetics 030104 developmental biology biology.protein Human medicine Blood Coagulation Tests |
Zdroj: | Journal of thrombosis and haemostasis |
ISSN: | 1538-7836 1538-7933 |
Popis: | Essentials AZD9684 is a potent inhibitor of carboxypeptidase U (CPU, TAFIa, CPB2). The effect of AZD9684 on fibrinolysis was investigated in four in vitro systems. The CPU system also attenuates fibrinolysis in more advanced hemostatic systems. The size of the observed effect on fibrinolysis is dependent on the exact experimental conditions. SUMMARY 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. |
Databáze: | OpenAIRE |
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