Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin

Dangas, George; Smith, Donald A.; Badimon, Juan J.; Unger, Allen H.; Shao, John; Meraj, Perwaiz; Cohen, Adam Max; Levine, Daniel M.; Fallon, John T.; Ambrose, John A.

doi:10.1016/s0002-9149(99)00408-7

Cited by 32 publications

(17 citation statements)

References 18 publications

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“…45 Moreover, several recent studies have demonstrated beneficial effects of statin therapy on platelet function and fibrinolysis in hypercholesterolemic individuals. [45][46][47][48][49][50][51] Our findings, by contrast, demonstrate that statins inhibit platelet activation independent of serum cholesterol levels by upregulation of type III NOS. Therefore, our data may have direct clinical implications: eNOS upregulation may be the mechanism of protection in patients with average cholesterol levels, as observed in large statin trials.…”

Section: Discussionmentioning

confidence: 65%

Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice

Laufs

Gertz

Huang

et al. 2000

Stroke

354

216

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Background and Purpose-Thrombosis superimposed on atherosclerosis causes approximately two thirds of all brain infarctions. We previously demonstrated that statins protect from cerebral ischemia by upregulation of endothelial type III nitric oxide synthase (eNOS), but the downstream mechanisms have not been determined. Therefore, we investigated whether antithrombotic effects contribute to stroke protection by statins. Methods-129/SV wild-type and eNOS knockout mice were treated with atorvastatin for 14 days (0.5, 1, and 10 mg/kg).eNOS mRNA from aortas and platelets was measured by reverse-transcriptase polymerase chain reaction. Platelet factor 4 (PF 4) and ␤-thromboglobulin (␤-TG) in the plasma were quantified by ELISA. Transient cerebral ischemia was induced by filamentous occlusion of the middle cerebral artery followed by reperfusion. Results-Stroke volume after 1-hour middle cerebral artery occlusion/23-hour reperfusion was significantly reduced by 38% in atorvastatin-treated animals (10 mg/kg) compared with controls. Serum cholesterol levels were not affected by the treatment. eNOS mRNA was significantly upregulated in a dose-dependent manner in aortas and in thrombocytes of statin-treated mice compared with controls. Moreover, indices of platelet activation in vivo, ie, plasma levels of PF 4 and ␤-TG, were dose-dependently downregulated in the treatment group. Surprisingly, atorvastatin-treatment did not influence PF 4 and ␤-TG levels in eNOS knockout mice. Conclusions-The synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin upregulates eNOS in thrombocytes, decreases platelet activation in vivo, and protects from cerebral ischemia in normocholesterolemic mice. Antithrombotic and stroke-protective effects of statins are mediated in part by eNOS upregulation. Our results suggest that statins may provide a novel prophylactic treatment strategy independent of serum cholesterol levels.

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Section: Discussionmentioning

confidence: 65%

Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice

Laufs

Gertz

Huang

et al. 2000

Stroke

354

216

View full text Add to dashboard Cite

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“…26,27) In another study, although PAI-1 levels were significantly decreased in both men and women at 3 and 6 months of follow-up, the percent change in PAI-1 was more predominant in men than in women: by 18.8% and 23.5%, respectively, in men, and 12.6% and 18.7%, respectively, in women. 28) In the study, t-PA was significantly decreased at 6 months compared with baseline and D-dimer did not change with therapy between the genders.…”

Section: )mentioning

confidence: 69%

The Effects of Atorvastatin Treatment on the Fibrinolytic System in Dyslipidemic Patients

et al. 2004

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SUMMARYStatins have pleiotrophic effects related to the pathogenesis of atherosclerosis and thrombogenicity of the vessel wall beyond lipid lowering. The aim of the present study was to examine the effect of atorvastatin treatment on the fibrinolytic system in patients with dyslipidemia.The investigation was carried out on 41 dyslipidemic patients (21 males and 20 females) with a mean age of 53.8 years (range, 30-76). The patients were divided into subgroups according to their cholesterol and triglyceride levels as hypercholesterolemic (n = 26) and mixed-type hyperlipidemic (n = 15) and their risk factors for coronary heart disease including age, sex, hypertension, obesity, smoking, and family history. The patients were started on atorvastatin 10 mg/day, and evaluated within 6-12 weeks to assess the changes in fibrinolytic parameters including global fibrinolytic capacity, plasminogen activator inhibitor type-1 and tissue plasminogen activator, and lipids.After successful lipid-lowering therapy, global fibrinolytic capacity (P = 0.003) and tissue plasminogen activator levels (P = 0.04) were found to be increased and plasminogen activator inhibitor type-1 levels (P = 0.02) decreased in dyslipidemic patients. Global fibrinolytic capacity levels increased (P < 0.001) and plasminogen activator inhibitor type-1 levels decreased (P = 0.01) in patients with hypercholesterolemia (n = 26). However, no significant changes were observed in fibrinolytic parameters in patients with mixed-type hyperlipidemia (n = 15). When the patients were separately evaluated according to risk factors, significant beneficial effects on the fibrinolytic system were observed, especially in patients without obesity and hypertension as well as in older patients and males.These findings suggest that atorvastatin treatment has a beneficial effect on the fibrinolytic system in patients with hypercholesterolemia, but not in patients with mixed-type hyperlipidemia. Further studies are needed to show whether higher doses and longer periods of lipid lowering treatment have beneficial effects in patients with mixed type hyperlipidemia and some risk factors. (Jpn Heart J 2004; 45: 977-987)

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“…Indeed, patients with metabolic syndrome had higher values of F 1+2 than subjects without metabolic syndrome, but, again, women had higher values then men. A gender difference in blood thrombogenicity has also been observed in patients with hypercholesterolaemia, in whom the prothrombin fragment F 1+2 was higher in women than men [34]. Multiple regression analysis revealed that among the five components of metabolic syndrome sCD40L was only significantly associated with abdominal obesity.…”

Section: Discussionmentioning

confidence: 85%

Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation

et al. 2006

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Aims/hypothesis: The metabolic syndrome is associated with proinflammatory and prothrombotic states. This study was designed to assess the behaviour of soluble CD40 ligand (sCD40L) and prothrombin fragment F 1+2 , a marker of thrombin generation, in patients with the metabolic syndrome. Methods: We investigated 106 patients with the metabolic syndrome, diagnosed according to the ATPIII report, and 104 subjects without the metabolic syndrome. Results: Plasma values of sCD40L and F 1+2 were higher in patients with the metabolic syndrome (4.11±1.64 vs 2.61±0.89 ng/ml and 1.54±0.49 vs 0.87±0.21 nmol/l, respectively; p<0.001) and were significantly correlated (r=0.925, p<0.001). Stepwise multiple linear regression analysis showed that sCD40L was significantly associated with F 1+2 , female sex and waist circumference.Conclusions/interpretation: Patients with the metabolic syndrome have enhanced values of plasma sCD40L and F 1+2 . The study provides further insight into the relationship between metabolic syndrome, inflammation and thrombosis.

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Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin

Cited by 32 publications

References 18 publications

Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice

Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice

The Effects of Atorvastatin Treatment on the Fibrinolytic System in Dyslipidemic Patients

Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation

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