Platelet-Dependent Thrombin Generation in Patients With Hyperlipidemia

Aoki, I; Aoki, Nobuo; Kawano, Koichi; Maki, Akira; Hòmori, Masashi; Yanagisawa, Atsuo; Yamamoto, Masakazu; Kawai, Yohko; Ishikawa, Kinya

doi:10.1016/s0735-1097(97)00129-0

Cited by 87 publications

(54 citation statements)

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“…10,11 A body of evidence accumulating throughout the past decade, derived from a variety of in vitro and in vivo studies, indicates that statin therapy results in decreased thrombin formation. [5][6][7][8][9] Methodological approaches to the evaluation of the effect of HMG-CoA reductase inhibitors on thrombin formation encompass: (1) measurements of thrombin markers in venous blood drawn from treated subjects; (2) ex vivo perfusion systems that evaluate thrombotic potential of the blood obtained from these patients and exposed to thrombogenic substrate at various flow velocities; 27,29,30 (3) in vitro models of thrombin formation in recalcified plasma; 31 and (4) analysis of prothrombin activation, performed in consecutive blood samples collected from standardized bleeding-time wounds (the Simplate model). 32,33 Significant reductions in thrombin generation, reflected by lower levels of prothrombin fragment F1.2 (residues 1 to 156) cleaved from the prothrombin molecule by thrombin, were observed in hypercholesterolemic subjects.…”

Section: Thrombin Formation and Thrombin-mediated Coagulant Reactionsmentioning

confidence: 99%

“…29 Also in recalcified plasma, pravastatin 15 mg/d has been effective in reducing plateletdependent thrombin generation in hypercholesterolemic subjects. 31 Using a model of microvascular injury, which reflects TF-initiated blood coagulation, 32,33 we have demonstrated [37][38][39] that simvastatin 20 to 40 mg/d depresses thrombin generation in subjects with hypercholesterolemia. We found that at the site of hemostatic plug formation, depletion of prothrombin was reduced by 16%, whereas the rate of formation of prothrombin activation products, such as F1.2, prethrombin 2 (residues 274 to 579), and thrombin B-chain, was decreased by 27% and the time of their appearance was delayed by Ϸ60 seconds in hypercholesterolemic subjects receiving simvastatin.…”

Section: Thrombin Formation and Thrombin-mediated Coagulant Reactionsmentioning

confidence: 99%

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Statins and Blood Coagulation

Undas

Brummel‐Ziedins²,

Mann³

2005

ATVB

240

192

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Abstract-The 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) have been shown to exhibit several vascular protective effects, including antithrombotic properties, that are not related to changes in lipid profile. There is growing evidence that treatment with statins can lead to a significant downregulation of the blood coagulation cascade, most probably as a result of decreased tissue factor expression, which leads to reduced thrombin generation. Accordingly, statin use has been associated with impairment of several coagulant reactions catalyzed by this enzyme. Moreover, evidence indicates that statins, via increased thrombomodulin expression on endothelial cells, may enhance the activity of the protein C anticoagulant pathway. Most of the antithrombotic effects of statins are attributed to the inhibition of isoprenylation of signaling proteins. These novel properties of statins, suggesting that these drugs might act as mild anticoagulants, may explain, at least in part, the therapeutic benefits observed in a wide spectrum of patients with varying cholesterol levels, including subjects with acute coronary events. Key Words: statins Ⅲ blood coagulation Ⅲ thrombin Ⅲ protein C T he 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors, the so-called statins, have been proven to be highly effective in the management of hyperlipidemia and the prevention of atherosclerotic vascular disease, especially coronary artery disease (CAD). 1,2 The therapeutic benefits from statin therapy, however, are only poorly correlated with cholesterol lowering, suggesting other mechanisms are at play. Mevalonate, the product of HMGCoA reductase, is the precursor of not only cholesterol but also isoprenoid compounds that permit the attachment of signaling proteins to the cell membrane. 3,4 Abundant experimental and clinical evidence in this rapidly expanding field has resulted in the widely accepted concept of cholesterol-independent pleiotropic effects produced by statins that include alteration of endothelial dysfunction, leading to increased nitric oxide (NO) bioavailability, atherosclerotic plaque stabilization, regulation of angiogenesis, reduction of the inflammatory response, and antithrombotic properties. [5][6][7] Apart from profibrinolytic and antiplatelet effects, reported in several studies, 5,7-9 increasing evidence indicates that the HMG-CoA reductase inhibitors also modulate the blood coagulation cascade at multiple levels, leading to reduced thrombogenicity.The activation of the extrinsic coagulation pathway initiated by an exposure or expression of tissue factor (TF) plays a key role in hemostasis (Figure). The localized process involves multiple components, including blood coagulation factors, platelets, blood cells, the endothelium, and sublayers of a damaged vessel. Platelets provide the catalytic surface for the formation of the procoagulant complexes; the intrinsic factor Xase (FIXa-FVIIIa) and prothrombinase (prothrombin, FXa-FVa). These complexes accelerate thrombin ge...

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Section: Thrombin Formation and Thrombin-mediated Coagulant Reactionsmentioning

confidence: 99%

Section: Thrombin Formation and Thrombin-mediated Coagulant Reactionsmentioning

confidence: 99%

Statins and Blood Coagulation

Undas

Brummel‐Ziedins²,

Mann³

2005

ATVB

240

192

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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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“…One of the most important factors in these processes is thrombin generation (Wielders et al, 1997;Aoki et al, 1997). Our studies revealed increased thrombin generation during mastitis and metritis, especially in the first acute phase of the disease.…”

Section: Discussionmentioning

confidence: 60%

“…The more intense response in the metritis group in the first acute phase would be explained by the greater hypercoagulatory tendency in these animals. There is a lack of reports about thrombin generation in cows, although this parameter was previously used in humans for the estimation of prothrombotic state in atherosclerosis (Aoki et al, 1997). Moreover, increased thrombin generation may signal a thrombotic tendency in women using oral contraceptives, and in patients with coronary artery disease and deep vein thrombosis (Wielders et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between coagulation and inflammation in mastitis and metritis in dairy cows

Bobowiec

Wessely-Szponder

Hola³

2009

Acta Veterinaria Hungarica

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Coagulation and inflammation are closely related as part of the mechanisms of host defence during a severe infection. The aim of this study was to investigate the relation between thrombin as a factor in both the coagulative and inflammatory processes and neutrophil secretory function on the basis of lactoferrin (LF), elastase and myeloperoxidase release in the course of mastitis and metritis in cows. Thrombin generation was measured on the basis of hydrolysis of SAR-PRO-ARG-pNA and lactoferrin concentration was estimated by an ELISA method. The greatest thrombin generation was observed in the metritis group (1.18 ± 0.62 IU). The level of LF was the highest in the group of cows with mastitis (0.74 ± 0.55 mg/ml) in the first phase of the disease. In the second phase of the diseases the level of serum LF in cows with mastitis diminished to the value of 0.41 ± 0.16 mg/ml, whereas in cows with metritis the level of LF increased to 0.51 ± 0.17 mg/ml. This study reveals that the excessive production of thrombin not only causes hypercoagulatory disorders but also exaggerates neutrophil function by the release of some enzymes which may play a destructive role during disseminated intravascular coagulation (DIC). These enzymes also inhibit anticoagulative systems, thus potentially worsening the course of the disease.

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Platelet-Dependent Thrombin Generation in Patients With Hyperlipidemia

Abstract: Hypercholesterolemia, but not hypertriglyceridemia, was associated with increased platelet-dependent thrombin generation. Pravastatin normalized the generation of thrombin.

Cited by 87 publications

References 32 publications

Statins and Blood Coagulation

Statins and Blood Coagulation

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

Crosstalk between coagulation and inflammation in mastitis and metritis in dairy cows

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