RESUMEN
Essentials The impact of long-term thrombin inhibition outside the coagulation cascade is far from clear. We aimed to assess the impact of dabigatran etexilate (DE) in diabetic and control rats. In diabetic rats, DE increased platelet aggregation and lead to coronary lipid deposits. Long-term thrombin inhibition may increase atherosclerotic and atherothrombotic risk. SUMMARY: 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.
Asunto(s)
Antitrombinas/toxicidad , Aorta/efectos de los fármacos , Aterosclerosis/inducido químicamente , Vasos Coronarios/efectos de los fármacos , Dabigatrán/toxicidad , Diabetes Mellitus Experimental/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Receptores de Trombina/metabolismo , Animales , Antitrombinas/administración & dosificación , Aorta/metabolismo , Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/patología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Dabigatrán/administración & dosificación , Diabetes Mellitus Experimental/patología , Esquema de Medicación , Masculino , Placa Aterosclerótica , Ratas Wistar , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: Dabigatran etexilate (DE) has similar stroke prevention efficacy in patients with and without diabetes mellitus (DM). However, the benefit of reducing major bleeding was not seen in diabetics. Thus, this study investigated anticoagulant responses to DE and the biological predictors of this response in a DM model. METHODS: Experiments were performed in six control (C), eight DE-treated control (CD), five diabetic (D), and eight DE-treated diabetic (DD) rats. Dabigatran etexilate (50 mg/kg/day) was administered in chow for 12 weeks. At the end of the study, plasma glucose, triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and plasma creatinine were measured. Correlations were ascertained with the diluted thrombin time (dTT). RESULTS: When corrected for similar DE intake, dTT was significantly higher in DD than CD rats (P < 0.001). There was a significant negative correlation between creatinine clearance (CCr) and dTT (r = -0.91, P < 0.01) in DD rats. In addition, dTT was positively correlated with TC (r = 0.96, P < 0.01), LDL-C (r = 0.75, P = 0.04), and glucose (r = 0.83, P = 0.02). In multiple regression analysis, CCr (r = -0.81, P = 0.01), TC (r = 0.93, P < 0.001), and LDL-C (r = 0.74, P < 0.01) remained the only independent predictors of dTT. CONCLUSIONS: The results show a significantly more intense DE-induced anticoagulation in diabetic rats that does not seem to be solely related to altered kidney function, and demonstrate that plasma cholesterol can significantly affect DE anticoagulation in this setting.