Vascular protease‐activated receptor 4 upregulation, increased platelet aggregation, and coronary lipid deposits induced by long‐term dabigatran administration – results from a diabetes animal model
Author(s): ,
Alina Scridon
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Center for Advanced Medical and Pharmaceutical Research, Tîrgu Mureș, Romania
,
Alina Mărginean
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Emergency Military Hospital ‘Dr Constantin Papilian’, Cluj‐Napoca, Romania
,
Adina Huțanu
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Center for Advanced Medical and Pharmaceutical Research, Tîrgu Mureș, Romania
,
Laura Chinezu
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Histopathological Department, Forensic Medicine Institute of Tîrgu Mureș, Tîrgu Mureș, Romania
,
Dan Gheban
Affiliations:
Pathology Department, ‘Iuliu Hațieganu’ University of Medicine and Pharmacy, Cluj‐Napoca, Romania
,
Marcel Perian
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania
,
Adriana Vântu
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania
,
Doina Gherțescu
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Emergency Institute for Cardiovascular Diseases and Transplantation, Tîrgu Mureș, Romania
,
Paul C. Fișcă
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Emergency Institute for Cardiovascular Diseases and Transplantation, Tîrgu Mureș, Romania
,
Rǎzvan C. Șerban
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Emergency Institute for Cardiovascular Diseases and Transplantation, Tîrgu Mureș, Romania
Correspondence: Răzvan C. Șerban, University of Medicine and Pharmacy of Tîrgu Mureș, 38, Gheorghe Marinescu Street, 540139 Tîrgu Mureș, Romania|Tel: +40 26 521 5551 (223)|E‐mail: serbanrazvan1@gmail.com
,
Philippe Chevalier
Affiliations:
Service de Rythmologie, Hôpital Louis Pradel, Bron, France
Dan Dobreanu
Affiliations:
University of Medicine and Pharmacy of Tîrgu Mureș, Tîrgu Mureș, Romania. Emergency Institute for Cardiovascular Diseases and Transplantation, Tîrgu Mureș, Romania
ISTH Academy. C. Șerban R. Mar 1, 2019; 273399
Răzvan C. Șerban
Răzvan  C. Șerban
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Journal Abstract
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Background
Besides its role in the coagulation cascade, thrombin contributes to platelet aggregation and to a plethora of non‐hemostatic functions.
Objectives
To assess the impact of long‐term thrombin inhibition with dabigatran etexilate (DE) on platelet aggregation and on extrahemostatic thrombin‐related functions in diabetic and control rats.
Methods
Markers of inflammation, endothelial dysfunction, oxidative stress, angiogenesis and cell adhesion molecules were quantified in control rats (Control; n = 6), DE‐treated control rats (Control‐Dabi; n = 8), diabetic rats (Diabetes; n = 5), and DE‐treated diabetic rats (Diabetes‐Dabi; n = 8). Agonist‐induced platelet aggregation, aortic and coronary lipid deposits and aortic protease‐activated receptor 4 (PAR4) expression were also assessed.
Results
Control‐Dabi rats showed significantly higher high‐sensitivity C‐reactive protein, von Willebrand factor (VWF), vascular endothelial growth factor (VEGF) and fibronectin levels, and significantly lower PAR4 agonist‐induced aggregation, than Control rats. Control‐Dabi rats also showed mild aortic lipid deposits, whereas no such changes were observed in Control rats. Diabetes‐Dabi rats showed significantly higher VWF, VEGF and fibronectin levels than Diabetes rats, and similar PAR4 agonist‐induced aggregation as Diabetes rats, and significantly higher ADP‐induced aggregation than Diabetes rats. Coronary lipid deposits were observed in 75% of Diabetes‐Dabi rats and in none of the Diabetes rats. PAR4 expression was 20.4% higher in Control‐Dabi rats and 27.4% higher in Diabetes‐Dabi rats than in their non‐treated peers.
Conclusions
This study indicates that long‐term thrombin inhibition increases vascular PAR4 expression, promotes atherosclerosis‐related mechanisms, and, in diabetic rats, increases platelet aggregation and favors the occurrence of coronary lipid deposits. These experimental data suggest that long‐term thrombin inhibition may increase atherosclerotic and atherothrombotic risk, particularly in the presence of diabetes.
Keyword(s)
atherosclerosis, dabigatran, platelet aggregation, thrombin, thrombin inhibition
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