Residual vein thrombosis and onset of post-thrombotic syndrome: Influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. PATIENTS/METHODS: In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity. Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n=85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n=83). All patients were treated according to current protocols and re-examined after 3, 12 and 36months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. RESULTS: We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment. CONCLUSIONS: These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis

Older age and markers of inflammation are strong predictors of clinical events in women with asymptomatic carotid lesions

OBJECTIVE: Limited information exists regarding the association between markers of inflammation, such as high-sensitivity C-reactive protein (hs-CRP) and fibrinogen, and adverse events in postmenopausal women with subclinical atherosclerosis. Therefore, we investigated the prognostic impact of traditional risk factors and inflammation on adverse cardiac events in women with asymptomatic carotid lesions. DESIGN: We studied 250 postmenopausal women who were free of cardiovascular disease. Traditional cardiovascular risk factors were investigated, and laboratory analysis included measurement of plasma lipids, fibrinogen, and hs-CRP. The early phases of carotid atherosclerosis were assessed by B-mode ultrasonography. Women were asked about symptoms or a previous history of coronary artery disease and were followed for a period of 5 years. RESULTS: We found that the increment in age (in quintiles) was significantly associated with higher incidence of current smokers (P = 0.0286), hypertension (P = 0.0230), family history of coronary artery disease (P = 0.0216), dyslipidemia (P = 0.0330), and higher levels of fibrinogen (P = 0.0158). Moreover, older women had a higher prevalence of carotid lesions (P < 0.0001). After the follow-up, cardio- and cerebrovascular events were registered in 22% of the women. Using multivariate analysis, we observed that older age (odds ratio [OR], 1.7; 95% CI, 1.3-2.2; P < 0.0001), fibrinogen (OR, 1.6; 95% CI, 1.2-2.0; P < 0.0001), the presence of carotid lesions (OR, 2.0; 95% CI, 1.4-3.0; P = 0.0002), and hs-CRP (OR, 1.3; 95% CI, 1.2-2.0; P = 0.0175) were predictors of adverse events during the follow-up. CONCLUSIONS: Adverse events occurred more frequently in women with higher levels of fibrinogen and hs-CRP. The significance of these results requires confirmation in other studies, but they may have important implications for screening subjects at risk for cardiovascular disease and identifying candidates for anti-inflammatory therapy

Markers of inflammation are strong predictors of subclinical and clinical atherosclerosis in women with hypertension.

Cardiovascular diseases in women still rises and remains their leading cause of death in most developed countries; yet we have less sex-specific data in women than in men as a result of lower enrollment in clinical trials and low rates of sex-specific reporting. The aim of our study was to evaluate in hypertensive postmenopausal women the potential predictive role of markers of inflammation, for example, fibrinogen and C-reactive protein (CRP), on subclinical and clinical atherosclerosis, beyond that of the other established cardiovascular risk factors. We studied 127 asymptomatic hypertensive postmenopausal women with different degrees of carotid intima–media thickness, as examined by the eco-color-doppler ultrasonography, evaluating in a 5 years follow-up cerebrovascular and cardiovascular morbidity and mortality. We preliminarily found that both fibrinogen and CRP levels were associated with the extension of carotid atherosclerosis (P < 0.0001 and P= 0.0445, respectively). We also found that among all established traditional cardiovascular risk factors (including obesity, diabetes, smoking habit, family history of coronary artery disease, dyslipidemia) only older age (P = 0.0162), elevated fibrinogen (P = 0.0298), and CRP (P = 0.0345) were independent predictors of subclinical atherosclerosis. At the end of follow-up patients clinical events were registered in the 24% of patients and multivariate analysis revealed the following predictors of events: elevated CRP levels [odds ratio (OR): 12.6], the presence of family history of coronary artery disease(OR: 8.8) and older age (OR: 1.1). Beyond the utility of CRP and fibrinogen levels in the prediction of subclinical and clinical atherosclerosis, the therapeutic implications of these results remain to be evaluated by further studie

Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24-month follow-up study

BACKGROUND: The purpose of this study was to investigate whether the vasodilator response to brachial artery and the presence of carotid lesions may have a prognostic significance in patients with early stages of atherosclerosis. METHODS AND RESULTS: Vascular echography was performed to analyze flow-mediated vasodilatation (FMD) at the brachial artery and intima-media thickness (IMT) of carotid arteries in 84 asymptomatic patients. At baseline, we evaluated all the established traditional cardiovascular risk factors. Transient ischemic attack, stroke, effort or unstable angina, acute myocardial infarction, peripheral arterial disease and cerebrovascular and cardiovascular death served as outcome variables over a follow-up period of 24 months. Brachial FMD was correlated inversely with carotid IMT (P=0.003), systolic blood pressure (P=0.0001) and age (P=0.0001). IMT was positively correlated with systolic blood pressure (P=0.0001), waist circumference (P=0.004) and age (P=0.01). At the end of the follow-up cardiovascular and cerebrovascular events were registered in 29% of the patients and in a multivariate analysis, including all the variables evaluated at baseline, male sex [odds ratio (OR) 1.6, P=0.005], the presence of baseline carotid lesions (OR 3.5, P=0.02) and FMD below the median (OR 3.2, P=0.03) were the only variables predictive of clinical events. CONCLUSION: In this study, endothelial dysfunction and carotid lesions significantly increased the risk of vascular events in asymptomatic patients with early stages of atherosclerosis. Assessment of systemic vasoreactivity and carotid IMT evaluation may provide, in this category of patients, important prognostic information in addition to that derived from traditional established cardiovascular risk factors

Prediction of cardio- and cerebro-vascular events in patients with subclinical carotid atherosclerosis and low HDL-cholesterol

Low HDL-cholesterol concentrations are associated with increased cardiovascular risk and recent evidences suggest that HDL may aggravate the atherosclerotic process promoting inflammation: HDL are anti-inflammatory in the absence of inflammation but can become proinflammatory in the presence of atherosclerosis. Yet, no data is available on the cardiovascular outcome in subjects with low HDL-cholesterol and early stages of atherosclerosis. Therefore, we included in a prospective 5-year follow-up study 150 subjects with low HDL-cholesterol concentrations and subclinical carotid atherosclerosis, as assessed by carotid colour doppler, evaluating at baseline all the established traditional cardiovascular risk factors (e.g. male gender, older age, obesity, hypertension, diabetes, smoking, family history of coronary artery disease, hypercholesterolemia), as well as levels of two markers of inflammation (C-reactive protein and fibrinogen). At the end of the follow-up we registered vascular events in the 21% of patients and we found that lower HDL-cholesterol concentrations were associated with ischemic stroke (p=.0164), peripheral arterial disease (p=.0248) and the presence of any clinical event (p=.0105). By multivariate analysis we searched, among all baseline parameters, for independent variables associated with the events and we found a predictive role for elevated fibrinogen concentrations (OR 6.3, 95% CI 2.0-19.6, p=.0016), family history of coronary artery disease (OR 4.5, 95% CI 1.7-12.8, p=.0045) and lower HDL-cholesterol levels (OR 1.4, 95% CI 1.1-1.9, p=.0278). These findings further suggest a synergistic role of low-HDL and inflammation on the atherosclerotic disease progression from subclinical lesions to clinical events. Yet, their therapeutical implications remain to be established in future studies