Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia

Szczeklik, Andrzej; Musiał, Jacek; Undas, Anetta; Gajewski, Piotr; Góra, Paweł; Swadźba, Jakub; Jankowski, Miłosz

doi:10.1016/s0735-1097(99)00023-6

Cited by 128 publications

(104 citation statements)

References 24 publications

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“…Several studies have shown that statins reduce circulating levels of F1 ϩ 2 (15,16) and F1 ϩ 2 in samples from bleeding time wounds in patients with hypercholesterolemia (17,18). Aoki et al (19) showed that increased platelet-dependent thrombin generation in hypercholesterolemic patients normalizes after pravastatin treatment, whereas Szczeklik et al (17) found that simvastatin inhibits thrombin formation in bleeding time blood. Aspirin had no further effect on thrombin formation.…”

Section: -The Reduction Of Vwfag Was ϫ53% After Pravastatin Treatmenmentioning

confidence: 99%

Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes

et al. 2004

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OBJECTIVE -Type 2 diabetes is associated with increased plasma concentrations of coagulation and inflammation markers. Different studies have shown that treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) is associated with antithrombotic and antiinflammatory effects in addition to a cholesterol-lowering effect. Our objective was to evaluate the effect of pravastatin (40 mg/day) on coagulation and inflammation markers in type 2 diabetic patients. RESEARCH DESIGN AND METHODS -This was an open, randomized, crossover study designed with an 8-week intervention period. The study group was comprised of 50 patients with type 2 diabetes (median HbA 1c 7.1%) and serum total cholesterol of 5-10 mmol/l. We evaluated plasma levels of fibrinogen, F1 ϩ 2, D-dimer, soluble tissue factor (sTF), von Willebrand Factor antigen (vWFag), and C-reactive protein (CRP) in blood samples drawn after fasting on day 1 and after 8 and 16 weeks.RESULTS -Significant reductions of total cholesterol (Ϫ22%; P Ͻ 0.001), LDL cholesterol (Ϫ32%; P Ͻ 0.001), and triglycerides (Ϫ10%; P Ͻ 0.05) were achieved after 8 weeks of treatment with pravastatin. In addition, significant reductions of plasma levels of F1 ϩ 2 (Ϫ4.4%; P Ͻ 0.05), vWFag (Ϫ5.3%; P Ͻ 0.05), and sTF (Ϫ3.4%; P Ͻ 0.05) were observed after treatment with pravastatin. Furthermore, plasma levels of CRP were also significantly reduced (Ϫ13%; P Ͻ 0.05). Levels of fibrinogen and D-dimer did not decrease after treatment with pravastatin.CONCLUSIONS -The results indicated that pravastatin reduces levels of coagulation and inflammation markers in type 2 diabetic patients. These antithrombotic and anti-inflammatory effects of treatment with statins could play a role in reducing cardiovascular complications in type 2 diabetic patients. Diabetes Care 27:468 -473, 2004T ype 2 diabetes is a leading cause of vascular morbidity and death. It is often complicated by other cardiovascular risk factors such as hypercholesterolemia, hypertension, obesity, and increased markers of coagulation (1) and inflammation (2). It has therefore been recommended that therapeutic prevention of cardiovascular disease in type 2 diabetes focus not only on optimal regulation of hyperglycemia but also on treatment of other cardiovascular risk factors (3,4).A subgroup analysis of several large randomized clinical trials (5,6) shows that the relative risk for cardiovascular complications in type 2 diabetic patients can be reduced by 25% using aggressive treatment of dyslipidemia with hydroxymethylglutaryl-CoA reductase inhibitors, also known as statins. Treatment with statins may be beneficial not only because of these agents' lipid-lowering action, but also because of their effect on inflammation, endothelial function, adhesion of leukocytes to endothelium, and thrombus formation (7). Although statins have proven to be effective in the prevention of cardiovascular disease in type 2 diabetes, little is known about these socalled pleiotropic effects in patients with type 2 diabetes.Our objective was to determi...

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Section: -The Reduction Of Vwfag Was ϫ53% After Pravastatin Treatmenmentioning

confidence: 99%

Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes

et al. 2004

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“…Although the underlying mechanism remains undetermined, statins inhibit fibrinogen expression and thrombin formation in vitro and reduce platelet aggregation and deposition in diseased vessels in vivo. [83][84][85][86][87][88][89] Reduced expression of cyclooxygenase 2 (COX-2), thromboxane A 2 (TxA 2 ), or TxB 2 and enhanced synthesis of prostacyclin caused by statin treatment may contribute to diminished platelet activation. 90 -92 Statins may also regulate other aspects of the inflammatory response underlying atherogenesis, including endothelial vasodilatation via enhanced expression of endothelial nitric oxide synthase (eNOS), reduced blood viscosity, and diminished oxidative modification of LDL via their potential antioxidant properties.…”

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confidence: 99%

Inflammation, Immunity, and HMG-CoA Reductase Inhibitors

Schönbeck

Libby²

2004

Circulation

419

335

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Abstract-According to traditional thinking, atherosclerosis results from passive lipid deposition in the vascular wall.Thus, therapies predominantly targeted lipid metabolism. The contemporary view of atherosclerosis, however, has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system. This recognition prompted the question of whether antiinflammatory interventions might provide a novel avenue for the treatment of atherosclerosis. Uncertainties about the type of antiinflammatory regimen and appropriate patient selection currently hamper clinical investigation. Yet cardiovascular scientists have begun to address these questions at the bench, in experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising tools with dual functions. Originally designed to target elevated lipids, the "traditional" cause of atherosclerosis, statins might also confer cardiovascular benefit by directly or indirectly modulating the inflammatory component of this prevalent disease. Yet controversy persists regarding the (clinical) relevance of these potential non-LDL-lowering "pleiotropic" functions of statins. This overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents. Cardiovascular Benefits of Statins Beyond Lipid Lowering: Hints From Clinical TrialsIn 1994, the landmark Scandinavian Simvastatin Survival Study (4S) established the benefits of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) on mortality in patients with atherosclerosis. 1 In accord with traditional acceptance of atherosclerosis as a consequence of lipid disorders, post-hoc analysis of the 4S trial suggested that the benefit provided by simvastatin in individual patients indeed related to the magnitude of change in low-density-lipoprotein cholesterol (LDL-C). 2 Subsequent studies, however, differed with this conclusion even as they affirmed the clinical benefits of statins as a class on cardiovascular (CV) morbidity and mortality in patients with or without established atherosclerotic disease. In one post-hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) population, the Framingham coronary heart disease model accurately predicted the risk in placebo-treated subjects but underestimated the CV benefit to the statintreated group predicted by the degree of LDL lowering. 3 In the Cholesterol and Recurrent Events (CARE) study, pravastatin-mediated lowering of cholesterol and triglycerides appeared to account for most but not all of the benefits, lending further support to the hypothesis that statins provide CV benefit beyond lipid lowering. 4 Indeed, analysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, 5 the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, 6 and the Heart Protection Study (HPS) 7 suggested that treatment effects...

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“…4 There is evidence for antithrombotic effects of statins. 5,6 Proposed mechanisms of antithrombotic actions are inhibition of thrombin signaling, 7 prevention of LDL oxidation, 8 upregulation of endothelial NO synthase, 9,10 downregulation of platelet-induced upregulation of monocyte tissue factor expression, 11 and induction of CD39/ATPdase in thrombinactivated endothelial cells. 12 Agents that are released from activated platelets and injured cardiovascular cells have been recognized as major factors in the development of thrombosis.…”

mentioning

confidence: 99%

“…21 Simvastatin (SVN) treatment resulted in normalization of altered platelet aggregation and reduced the thromboxane-metabolite excretion. 6,7 As clinical benefits of statins are evident even in patients receiving aspirin, 6 reduction in thromboxane per se is unlikely to be the explanation for antithrombotic effects. Indirectly, modification of endothelial function may alter platelet activity, 12,14 even though some antiplatelet effects of statins are thought to be lipid dependent.…”

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confidence: 99%

Rho-GTPase–Dependent Platelet-Neutrophil Interaction Affected by HMG-CoA Reductase Inhibition With Altered Adenosine Nucleotide Release and Function

Kaneider

Egger

Dunzendorfer

et al. 2002

ATVB

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Abstract-Platelet activation and aggregation is considered a crucial step in the initiation and aggravation of arterial thrombosis. ADP from activated platelets is recognized as major factor in thrombus formation and is a potent stimulator of oxygen-free radical release from neutrophils. The aim of the present investigation was to determine in vitro the direct effects of statins on ATP and ADP secretion by platelets and its impact on subsequent oxidative burst activity in neutrophils. Human neutrophils and platelets were isolated from peripheral blood. Levels of platelet-derived ATP and ADP were measured by high-performance liquid chromatography, oxygen-free radical release of neutrophils was measured fluorometrically, and chemotaxis experiments were performed. Rho-GTPases were studied by Western blot analysis. Thrombin-activated platelets primed neutrophils for enhanced oxygen-free radical release on triggering with formyl-Met-Leu-Phe, reduced by cerivastatin and simvastatin treatment of platelets. The two statins decreased the amount of adenosine-derivative release in these cells. Rho-GTPases, required for the thrombin signaling in platelets and neutrophils, were decreased after coincubation with statins. Data demonstrate that inhibition of Rho-GTPases by statins inhibit platelet ADP and ATP release and the consecutive augmentation of neutrophil oxygen-free radical release. Statins affect platelet-neutrophil interactions by altering Rho-GTPase-dependent adenosine nucleotide function.

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Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia

Cited by 128 publications

References 24 publications

Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes

Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes

Inflammation, Immunity, and HMG-CoA Reductase Inhibitors

Rho-GTPase–Dependent Platelet-Neutrophil Interaction Affected by HMG-CoA Reductase Inhibition With Altered Adenosine Nucleotide Release and Function

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