Abstract 170: Differential Effects of Atorvastatin and Digeranyl Bisphosphonate on Hemostasis and Thrombosis in Hypercholesterolemic Mice

Background and Hypothesis Statins inhibit HMG-CoA reductase, leading to decreased production of cholesterol and other isoprenoids. There is growing evidence that statins have protective effects on arterial thrombosis through pleiotropic mechanisms that may be independent of their cholesterol lowering effects. The antithrombotic effects of statins have been proposed to be related in part to diminished synthesis of geranyl-geranyl pyrophosphate (GGPP). To test this hypothesis, we determined the hemostatic and thrombotic effects of atorvastatin and digeranyl bisphosphonate (DGBP), a specific inhibitor of geranyl-geranyl pyrophosphate synthase, in apolipoprotein E-deficient (ApoE-/-) mice. Methods Tissue levels of GGPP and its precursor farnesyl pyrophosphate (FPP) were measured by HPLC. ApoE-/- mice were treated with either vehicle, atorvastatin (50 mg/kg/d), or DGBP (0.4 mg/kg/d) subcutaneously for 7 days. Susceptibility to thrombotic occlusion of the carotid artery was measured in response to injury with FeCl 3 . Tail-transection bleeding time and platelet clot retraction were also assessed. Results Compared with vehicle- or atorvastatin-treated mice, DGBP- treated mice had elevated levels of FPP in heart (P<0.001) and lung (P<0.001) and decreased levels of GGPP in heart (P<0.01) and liver (P<0.01). The time to stable occlusion of the carotid artery was prolonged in atorvastatin-treated mice compared with vehicle-treated mice (8.6±2.4 vs. 5.3±0.3 minutes; P<0.05). In contrast, DGBP-treated mice were not protected from carotid artery thrombosis (6.8±0.9 minutes). Bleeding times were markedly prolonged in DGBP-treated mice (388±88 seconds) compared with atorvastatin- (98±11 seconds) or vehicle-treated (150±91 seconds) mice (P<0.05). Platelet clot retraction also was delayed in DGBP-treated mice compared with atorvastatin or vehicle-treated mice (P<0.05). Conclusions Inhibition of GGPP production causes impairment of hemostasis but does not prevent arterial thrombosis in hypercholesterolemic mice. The differential effects of DGBP and atorvastatin suggest that the antithrombotic effects of statins are independent of geranyl-geranyl-mediated processes.