Determinants of fibrinogen in an Italian population suffering from claudication. Lower fibrinogen in the south compared to middle and north of Italy. The ADEP Group.

Prospective studies have shown that high plasma levels of fibrinogen are independently associated with the risk of cardiovascular complications. In patients suffering from peripheral vascular disease (PVD) fibrinogen has been shown to be an independent predictor of cardiovascular disease but its determinants have never been examined in this clinical setting. DESIGN AND METHODS: Fibrinogen levels were related to clinical and laboratory variables in 2,111 patients suffering from PVD. We also analyzed whether there was a regional distribution of risk factors. RESULTS: The median values of fibrinogen was 312 mg/dL. The clinical variables examined did not differentiate patients with elevated or normal fibrinogen levels. In particular, patients with ankle/arm pressure ratio < 0.8 did not show a higher prevalence of fibrinogen > 312 mg/dL. Conversely, white blood cell (WBC) count and serum cholesterol levels were significantly associated with high fibrinogen levels (p < 0.0001). Multiple logistic regression analysis demonstrated that areas of Italy were differently associated with high plasma fibrinogen levels (p < 0.03): subjects in the north and middle of Italy having significantly higher values of fibrinogen than subjects in the south of Italy (p < 0.01). A similar regional distribution was observed for WBC count and serum cholesterol levels. INTERPRETATION AND CONCLUSIONS: The regional distribution of risk factors raises the question as to whether the already reported large variability of cardiovascular events so in PVD may be attributed to a non homogeneous distribution of risk factors

Crotalus atrox venom preconditioning increases plasma fibrinogen and reduces perioperative hemorrhage in a rat model of surgical brain injury.

Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries

Evidence that the degree of band 3 phosphorylation modulates human erythrocytes nitric oxide efflux – in vitro model of hyperfibrinogenemia

© 2011 – IOS Press and the authors. All rights reservedRecent evidence has shown that plasma fibrinogen, a major cardiovascular risk factor, interacts with the erythrocyte membrane and acts to influence blood flow via erythrocyte nitric oxide (NO) modulation. In the present pioneer in-vitro study, whole blood samples were harvested from healthy subjects and aliquots were incubated in the absence (control aliquots) and presence of fibrinogen at different degrees of band 3 phosphorylation, and the levels of NO, nitrite, nitrate and S-nitroglutathione (GSNO) were determined. Hyperfibrinogenemia interferes with erythrocyte NO mobilization without changing its efflux in a way that seems to be dependent of the degree of band 3 phosphorylation. In presence of higher fibrinogen concentrations the NO efflux is reinforced when band 3 is phosphorylated (p < 0.001). Higher levels of nitrite, nitrate and GSNO were documented (p < 0.05). However, the mechanisms by which fibrinogen signalling modulates erythrocyte function remain to be clarified and are currently under study. These conditions may be considered an approach to be followed in blood storage for transfusions.This study was supported by grants from the FCT - Fundação para a Ciência e a Tecnologia (project reference PTDC/SAU-OSM/73449/2006

Relationship between plasma sialic acid and fibinogen concentration and incident micro-and macrovascular complications in type 1 diabetes

AIMS/HYPOTHESIS: Type 1 diabetes is associated with an increased risk of vascular complications. This increased risk could be explained by sialic acid and/or fibrinogen. It is also not clear what explains the abolition of sex-related differences affecting risk of CHD in the presence of type 1 diabetes. Therefore, we examined whether fibrinogen and sialic acid are related to incident micro- and macrovascular complications in patients with type 1 diabetes. METHODS: A subset (n=2329) of the EURODIAB Prospective Complications Study was analysed. Sialic acid and fibrinogen concentrations were measured at baseline. The main outcomes after 7 years were development of albuminuria, retinopathy, neuropathy and CHD. RESULTS: Univariable and multivariable models using Cox proportional survival analyses showed that an SD unit increase in sialic acid and fibrinogen levels was significantly associated with CHD in men only. Adjusted standardised hazard ratios (sHRs) were 1.50 (95% CI 1.05-2.15) and 1.40 (95% CI 1.06-1.86) for sialic acid and fibrinogen, respectively. Initial associations between (1) sialic acid and incident retinopathy [standardised odds ratio (sOR) men 1.68, 95% CI 1.10-2.57], (2) fibrinogen and retinopathy (sOR women 1.37, 95% CI 1.06-1.78) and (3) sialic acid and neuropathy (sOR men 1.37, 95% CI 1.06-1.77) were shown, but became non-significant in multivariable models. CONCLUSIONS/INTERPRETATION: Sialic acid and fibrinogen are strong predictors of CHD in men with type 1 diabetes, beyond the effect of established risk factors. The associations found with microvascular complications were not independent of other risk factors

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial.

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (PC substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci

Association of increased fibrinogen concentration with impaired activation of anticoagulant protein C

BACKGROUND: Low levels of activated protein C (APC) are a risk factor for venous thrombosis. The mechanisms leading to interindividual differences in APC are not totally elucidated. Protein C is activated by the thrombin-thrombomodulin complex. As thrombin binds to fibrinogen and thrombomodulin through a common region, it is conceivable that fibrinogen influences the activation of protein C. This would help to explain the association between high levels of fibrinogen and an increased thrombotic risk. METHODS: We analyzed the association between circulating APC levels and fibrinogen concentration in 382 healthy subjects. Subsequently, we studied the effect of increasing fibrinogen concentrations on the APC generation on cultured endothelial cells. RESULTS: An independent inverse association between circulating APC levels and fibrinogen was found [betacoefficient, -0.16; 95% confidence interval (95% CI) -0.26, -0.06; P = 0.001]. For each 100 mg dL(-1) increase in fibrinogen, the independent risk of having low APC levels (<0.7 ng mL(-1)) was almost three times higher (OR 2.8; 95% CI 1.1, 7.2; P = 0.04). Accordingly, a notable association between increasing fibrinogen concentrations and the reduction in the thrombin-thrombomodulin dependent activation of protein C on endothelial cells was found (r = -0.57; P = 0.002). CONCLUSIONS: We present evidence of an inverse association between circulating APC and fibrinogen levels. According to this finding together with the results of our in vitro experiments, we propose that the impairment in the generation of APC on endothelial cells constitutes a new prothrombotic mechanism of fibrinogen

Blood rheology, cardiovascular risk factors, and cardiovascular disease: The West of Scotland Coronary Prevention Study

The West of Scotland Coronary Prevention Study (WOSCOPS) showed that pravastatin reduced the risk of coronary heart disease (CHD) events in 6,595 middle-aged hypercholesterolaemic men aged 45-64 years without prior myocardial infarction followed for an average of 4.9 years. We hypothesised prospectively (a) that baseline levels of haemorheological variables were related to baseline and incident CHD and to mortality; and (b) that reduction in lipoproteins by pravastatin would lower plasma and blood viscosity, a potential contributory mechanism to CHD events. We therefore studied plasma and blood viscosity, fibrinogen, haematocrit, and blood cell counts at baseline and 1 year. At baseline, plasma and blood viscosity were related to risk factors, CHD measures, and claudication. On univariate analysis, baseline levels of all rheological variables (except platelet count) were related to incident CHD; CHD mortality; and total mortality. On multivariate analysis including baseline CHD and risk factors, plasma and blood viscosity, haematocrit and white cell count each remained significantly associated with incident CHD; while fibrinogen remained an independent predictor of mortality (all p&lt;0.03). After one year, lipoprotein reduction by pravastatin was associated with significant reductions (about one quarter of a standard deviation) in plasma viscosity (mean difference 0.02 mPa.s, p&lt;0.001) and in blood viscosity (mean difference 0.06 mPa.s, p&lt;0.001), but was not associated with significant changes in other rheological variables. We therefore suggest that pravastatin therapy, which reduces elevated lipoproteins in hypercholesterolaemic men, may lower risks of CHD and mortality partly by lowering plasma and blood viscosity. Further studies are required to test this hypothesis

Hemostasis biomarkers and incident cognitive impairment: the REGARDS study

Essentials Cognitive disorders are increasing and vascular risk factors play a role in this. We performed a nested case control study of hemostasis biomarkers and cognitive impairment (CI). Higher baseline fibrinogen, factor VIII and D-dimer were related to incident CI over 3.5 years. Adjusted for other risk factors, 2+ abnormal markers (but not single ones) led to higher risk. SUMMARY: Background Vascular risk factors are associated with cognitive impairment, a condition that imposes a substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with the risk of incident cognitive impairment. Methods We performed a nested case-control study including 1082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30 239 black and white Americans aged ≥ 45 years. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII and protein C levels were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on two or more of three cognitive tests) and 587 controls. Results Unadjusted odds ratios (ORs) for incident cognitive impairment were 1.32 (95% confidence interval [CI] 1.02-1.70) for D-dimer > 0.50 μg mL-1 , 1.83 (95% CI 1.24-2.71) for fibrinogen > 90th percentile, 1.63 (95% CI 1.11-2.38) for FVIII > 90th percentile, and 1.10 (95% CI 0.73-1.65) for protein C < 10th percentile. There were no differences in associations by race or region. Adjustment for demographic, vascular and health behavior risk factors attenuated these associations. However, having at least two elevated biomarkers was associated with incident cognitive impairment, with an adjusted OR of 1.73 (95% CI 1.10-2.69). Conclusion Elevated D-dimer, fibrinogen and FVIII levels were not associated with the occurrence of cognitive impairment after multivariable adjustment; however, having at least two abnormal biomarkers was associated with the occurrence of cognitive impairment, suggesting that the burden of these biomarkers is relevant

Guidelines on fibrinogen assays

No abstract available