Revacept significantly improved endothelial dysfunction and reduced vascular wall thickness in atherosclerotic rabbits without prolonging bleeding time, even when combined with other anti-platelet drugs.
Does Revacept improve vascular dysfunction and reduce thrombus formation without impacting bleeding time in animal models of atherosclerosis?
In an animal model of atherosclerosis, Revacept improved endothelial dysfunction and vascular morphology without increasing bleeding time, suggesting a safe anti-platelet profile.
p-value: p=<0.05
AIMS: Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications. METHODS AND RESULTS: We investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times. CONCLUSION: Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.
Ungerer et al. (2013) studied Atherosclerosis and Atherothrombosis (n=85). Revacept vs. Vehicle control (PBS, 4% mannitol, 1% sucrose) was evaluated on Endothelial dysfunction (acetylcholine-induced vasoreactivity) and vessel wall thickening (p=<0.05). Revacept significantly improved endothelial dysfunction and reduced vascular wall thickness in atherosclerotic rabbits without prolonging bleeding time, even when combined with other anti-platelet drugs.