Circulating Levels Of Fibrinogen Research Articles

In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke

The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 μM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 μM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis

AbstractElevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga−/−) mice showed no evidence of occlusion, even with high-concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK, and FgaEK/EK mice, consistent with preserved fibrinogen–platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga−/− mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.

DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood

BackgroundFibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. ObjectivesTo perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. MethodsWe performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. ResultsWe identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. ConclusionWe identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform

BackgroundFibrinogen has an established, essential role in both coagulation and inflammatory pathways, and these processes are deeply intertwined in the development of thrombotic and atherosclerotic diseases. Previous studies aimed to better understand the (patho) physiological actions of fibrinogen by characterizing the genomic contribution to circulating fibrinogen levels. ObjectivesEstablish an in vitro approach to define functional roles between genes within these loci and fibrinogen synthesis. MethodsCandidate genes were selected on the basis of their proximity to genetic variants associated with fibrinogen levels and expression in hepatocytes and HepG2 cells. HepG2 cells were transfected with small interfering RNAs targeting candidate genes and cultured in the absence or presence of the proinflammatory cytokine interleukin-6. Effects on fibrinogen protein production, gene expression, and cell growth were assessed by immunoblotting, real-time polymerase chain reaction, and cell counts, respectively. ResultsHepG2 cells secreted fibrinogen, and stimulation with interleukin-6 increased fibrinogen production by 3.4 ± 1.2 fold. In the absence of interleukin-6, small interfering RNA knockdown of FGA, IL6R, or EEPD1 decreased fibrinogen production, and knockdown of LEPR, PDIA5, PLEC, SHANK3, or CPS1 increased production. In the presence of interleukin-6, knockdown of FGA, IL6R, or ATXN2L decreased fibrinogen production. Knockdown of FGA, IL6R, EEPD1, LEPR, PDIA5, PLEC, or CPS1 altered transcription of one or more fibrinogen genes. Knocking down ATXN2L suppressed inducible but not basal fibrinogen production via a post-transcriptional mechanism. ConclusionsWe established an in vitro platform to define the impact of select gene products on fibrinogen production. Genes identified in our screen may reveal cellular mechanisms that drive fibrinogen production as well as fibrin(ogen)-mediated (patho)physiological mechanisms.

The influence of circulating fibrinogen level on postoperative blood loss and blood transfusion in pediatric cardiac surgery: a retrospective observational study.

Pediatric patients are at high risk of massive bleeding after cardiac surgery under cardiopulmonary bypass (CPB). Fibrinogen is essential for coagulation; however, pediatric patients with congenital heart disease (CHD) present abnormal fibrinogen function. The pre- and post-operative fibrinogen level may affect the bleeding and transfusion amount in patients undergoing cardiac surgery. However, the relationship between plasma fibrinogen levels and the bleeding and transfusion amount in pediatric cardiac surgery remains unclear. This study aimed to assess the association of pre-CPB fibrinogen levels (PreFib) and post-CPB fibrinogen levels (PostFib) with postoperative bleeding and transfusion volume in pediatric cardiac surgery. We reviewed the medical records of 375 newborns and infants who underwent cardiac surgery under CPB for CHD. The primary endpoint was the correlation of the PreFib and PostFib values, as well as their difference (FibGap), with the bleeding and transfusion amount within 24 postoperative hours. There was no correlation of the PreFib, PostFib, and FibGap values with the bleeding and transfusion amounts at postoperative 24 hours. However, patients with PreFib and PostFib values of <150 and <100 mg/dL, respectively, showed a significantly higher frequency of postoperative platelet (PLT) transfusion. In patients with complex CHD, PreFib showed a weak negative correlation with the bleeding amount at postoperative 24 hours and the number of PLT-transfused patients. Our findings suggest that in pediatric patients with CHD who cannot undergo point-of-care (POC) tests, those presenting PreFib and PostFib values of <150 and <100 mg/dL, respectively, have a significantly higher frequency of postoperative PLT transfusion.

Association between Circulating Fibrinogen Level and Severity of Coronary Artery Disease in Type 2 Diabetic Patients with Chronic Stable Angina

Background: Prevalence of coronary artery disease (CAD) among Bangladeshi population is higher in urban than rural population. Among the conventional risk factors diabetes mellitus is a major concern for Bangladeshi population. Fibrinogen (Fg) in plasma is associated with severity of CAD in some populations with acute coronary syndrome.&#x0D; Objective: The aim of the study was to find out the correlation between circulating fibrinogen level and severity of coronary artery disease in patients with type 2 diabetes mellitus with chronic stable angina (CSA).&#x0D; Methods: The study was carried out in the Department of Cardiology, National Institute of Cardiovascular Diseases (NICVD), Dhaka from October 2015 to March 2016.Total 132 patients with chronic stable angina (CSA) and type 2 diabetes mellitus who got admitted for coronary angiogram were included in the study and they were divided into 2 groups according to the on admission level of fibrinogen. Coronary angiogram (CAG) was performed in all patients. The severity of the CAD was assessed by angiographic vessel score and Gensini score.&#x0D; Results: Mean Gensini score was 27.0±22.3 vs 22.2±16.4 and mean vessel score 1.6±0.9 vs 1.2±1.0 in group I and group II respectively (p=0.03 and 0.04, respectively). There was positive correlation between Fg and CAD severity in term of vessel score (r=0.19) and Gensini score (r=0.15). Univariate and multivariate analysis revealed that dyslipidemia, smoking and elevated fibrinogen were the independently significant predictors of severe CAD in type 2 diabetic patients with CSA.&#x0D; Conclusion: Elevated plasma fibrinogen positively correlates with the severity of CAD in patients with diabetes mellitus having chronic stable angina.&#x0D; Bangladesh Heart Journal 2020; 35(2) : 106-113

Circulating fibrinogen levels are elevated in patients with obstructive sleep apnea: a systemic review and meta-analysis

ObjectiveFibrinogen is believed to play a role in the pathophysiology of obstructive sleep apnea (OSA) and many studies have assessed circulating fibrinogen concentrations in OSA patients. However, the results from these studies were not consistent. To assess the association of circulating fibrinogen levels and OSA, a meta-analysis was performed. MethodsPubMed, Embase and Web of Science databases were searched for eligible studies. Data were extracted, and then weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. ResultsA total of 25 studies involving 1480 cases and 2312 controls were included in this meta-analysis. Combined data indicated that the circulating fibrinogen levels were higher in OSA patients than in controls (WMD: 0.38 g/L, 95% CI [0.29–0.47 g/L], p < 0.001; I2 = 80.3%, p < 0.001). In the subgroup analyses by disease severity, there were similar results in mild-moderate OSA patients (WMD: 0.27 g/L, 95% CI [0.14–0.41 g/L], p < 0.001; I2 = 29.3%, p = 0.185) and severe OSA patients (WMD: 0.54 g/L, 95% CI [0.28–0.79 g/L], p < 0.001; I2 = 65.9%, p = 0.012). Furthermore, in another subgroup analysis, the circulating fibrinogen levels were higher in OSA patients than those in controls who were matched for important potential confounders (WMD: 0.41 g/L, 95% CI [0.21–0.60 g/L], p < 0.001; I2 = 62.0%, p = 0.003). ConclusionsThis systematic review and meta-analysis reveals that circulating fibrinogen levels are elevated in patients with OSA.

Феномен влечения к алкоголю и фибриноген

Введение. Фибриноген, как и многие белки системы гемостаза и фибринолиза, участвует во многих физиологических процессах, при этом его содержание может увеличиваться или уменьшаться при различных патологических состояниях, и эти модуляции часто служат диагностическим признаком заболевания. Цель исследования: определить уровень фибриногена и время лизиса эуглобулиновой фракции плазмы крови в зависимости от степени влечения к этанолу у крыс. Материалы и методы. Работа выполнена на 300 крысах-самцах линии Вистар весом 250–350 г, у которых после двух-недельного периода акклиматизации ежедневно в течение 7 дней проводили тестирование потребления 10% раствора этанола и воды в индивидуальных боксах. Эти жидкости были доступны в течение 23 часов без доступа к пище. Позиции 2 питьевых пипеток объемом 50 мл случайным образом менялись местами через каждые 24 часа. Результаты. Установлено, что чем выраженнее была исходная степень влечения к этанолу, тем выше оказывалось содержание фибриногена и ниже фибринолитическая активность. Заключение. Случаи повышенного содержания фибриногена у исходно отвергающих, не имевших контакта с этанолом крыс указывает на возможность генетически обусловленной гиперфибриногенемии, которая может стать источником предтромбозных состояний в случае предрасположенности к потреблению алкоголя в качестве энергетической самокоррекции. Introduction. Fibrinogen, like many proteins of hemostasis and fi brinolysis system, participates in many physiological processes, and its content may increase or decrease under various pathological conditions, and these modulations often serve as a diagnostic sign of the disease. Aim: to determine fi brinogen level and euglobulin lysis time as function of attraction degree to ethanol in rats. Materials and methods. The work was performed on male Wistar rats (n = 300) weighing 250–350 g. After 2 weeks of acclimatization the consumption of 10% ethanol and water in individual boxes was daily tested for 7 days. These fl uids were available for 23 hours without access to food. Positions of 2 drinking pipettes of 50 ml volume randomly changed every 24 hours. Results. It was found that fi brinogen content was higher but fi brinolytic activity was lower in rats with more expressed initial degree of attraction to ethanol. Conclusion. The cases of increased fi brinogen content in initially refused rats that did not contact with ethanol indicate the possibility of genetically determined hyperfi brinogenemia that can become a source of prethrombotic conditions in case of predisposition to alcohol consumption as an energy self-correction.

Olive oil consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study.

Olive oil, being rich in mono-unsaturated fatty acids and anti-inflammatory compounds, may have protective effects against cardiovascular disease (CVD). The aim of the present work was to examine the association of olive oil consumption with the 10-year CVD incidence in adults without pre-existing CVD. The ATTICA Study is a prospective, population-based study conducted in the greater metropolitan area of Athens (Attica, Greece). During 2001-2002, 3042 CVD-free adults (1514 men and 1528 women) were voluntarily recruited to the ATTICA study. Among various dietary habits, consumption of olive oil and other fats/oils was assessed at baseline; participants were classified into three groups (no use; mixed use; and exclusive use of olive oil). In 2011-2012, the 10-year study follow-up was performed, recording the fatal/non-fatal CVD incidence in 2020 participants (mean follow-up duration: 8.41years). After controlling for various covariates, an inverse association between exclusive olive oil use and the risk of developing CVD was observed (relative risk 0.07, 95% CI: 0.01-0.66) compared to those not consuming olive oil. Further adjustment for fibrinogen plasma levels (among various inflammatory markers) showed a significant mediation effect on the previous association. These findings support exclusive olive oil consumption, a key component of the Mediterranean diet, for the primary CVD prevention, in adults without pre-existing disease. Circulating fibrinogen levels appear to play a mediating role in this relationship.

Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease.

The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P=0.017 under a recessive model), but not with PT, APTT or TT (P>0.05). Using a large case-control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P=0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.

Fibrin Accumulation Secondary to Loss of Plasmin‐Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice

Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis-related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis. Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen-deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the αM β2 binding motif. Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)-mediated activation of osteoclasts via activation of the leukocyte integrin receptor αM β2 on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the αM β2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels. Taken together, these data reveal for the first time that fibrin promotes inflammation-driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology.

A novel regulatory element between the human FGA and FGG genes

High circulating fibrinogen levels correlate with cardiovascular disease (CVD) risk. Fibrinogen levels vary between people and also change in response to physiological and environmental stimuli. A modest proportion of the variation in fibrinogen levels can be explained by genotype, inferring that variation in genomic sequences that regulate the fibrinogen genes ( FGA , FGB and FGG ) may affect hepatic fibrinogen production and perhaps CVD risk. We previously identified a conserved liver enhancer in the fibrinogen gene cluster (CNC12), between FGB and FGA . Genome-wide Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that transcription factors which bind fibrinogen gene promoters also interact with CNC12, as well as two potential fibrinogen enhancers (PFE), between FGA and FGG . Here we show that one of the PFE sequences has potent hepatocyte enhancer activity. Using a luciferase reporter gene system, we found that PFE2 enhances minimal promoter- and FGA promoter-driven gene expression in hepatoma cells, regardless of its orientation with respect to the promoters. A region within PFE2 bears a short series of conserved nucleotides which maintain enhancer activity without flanking sequence. We also demonstrate that PFE2 is a liver enhancer in vivo, driving enhanced green fluorescent protein expression in transgenic zebrafish larval livers. Our study shows that combining public domain ChIP-seq data with in vitro and in vivo functional tests can identify novel fibrinogen gene cluster regulatory sequences. Variation in such elements could affect fibrinogen production and influence CVD risk.

Levels of plasma fibrinogen are elevated in well-controlled rheumatoid arthritis

Patients with RA have systemic inflammation and increased risk of cardiovascular (CV) events, including thrombosis. Levels of fibrinogen, a pro-thrombotic protein with predictive value for CV disease (CVD), are elevated during systemic inflammation. We compared circulating fibrinogen levels in patients with RA with healthy controls and evaluated the relationship with measures of disease activity. Patients with RA and controls were recruited at the University of California, San Francisco (UCSF). Disease activity was evaluated using standard composite indices. Fibrinogen, ESR, serum CRP, acute-phase serum amyloid A and levels of selected cytokines were quantified. A total of 105 RA patients and 62 controls were studied. Among patients with RA, disease activity ranged from quiescent to highly active disease. Circulating fibrinogen levels were significantly higher in RA than in controls [median (interquartile range) 466 (391-575) vs 367 (309-419) mg/dl, respectively, P < 0.0001]. This difference remained highly statistically significant after adjustment for demographic variables and BMI. Although fibrinogen correlated significantly with clinical measures of disease activity, significantly elevated levels were observed at low levels of activity, even in RA patients with no detectable swollen or tender joints. In multivariable models, ~ 80% of the increased fibrinogen in RA was accounted for by increases in CRP and ESR. Circulating levels of fibrinogen are elevated in RA and correlated with markers of inflammation, but only modestly correlate with clinical assessments of disease activity. Even RA patients with excellent clinical disease control exhibit elevated levels compared with controls.

Regulation of fibrinogen production by microRNAs

AbstractElevated levels of fibrinogen are associated with increased risk of cardiovascular disease, whereas low fibrinogen can lead to a bleeding disorder. We investigated whether microRNAs (miRNAs), known to act as post-transcriptional regulators of gene expression, regulate fibrinogen production. Using transfection of a library of 470 annotated human miRNA precursor molecules in HuH7 hepatoma cells and quantitative measurements of fibrinogen production, we identified 23 miRNAs with down-regulating (up to 64% decrease) and 4 with up-regulating effects (up to 129% increase) on fibrinogen production. Among the down-regulating miRNAs, we investigated the mechanism of action of 3 hsa-miR-29 family members and hsa-miR-409-3p. Overexpression of hsa-miR-29 members led to decreased steady-state levels of all fibrinogen gene (FGA, FGB, and FGG) transcripts in HuH7 cells. Luciferase reporter gene assays demonstrated that this was independent of miRNA-fibrinogen 3′-untranslated region interactions. In contrast, overexpression of hsa-miR-409-3p specifically lowered fibrinogen Bβ mRNA levels, and this effect was dependent on a target site in the fibrinogen Bβ mRNA 3′-untranslated region. This study adds to the known mechanisms that control fibrinogen production, points toward a potential cause of variable circulating fibrinogen levels, and demonstrates that a screening approach can identify miRNAs that regulate clinically important proteins.

Association of Novel Genetic Loci With Circulating Fibrinogen Levels

Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance ( P &lt;5.0�10 −8 ). These included a single-nucleotide polymorphism located in the fibrinogen β chain ( FGB ) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB ( P =1.8�10 −30 ), rs2522056 downstream from the interferon regulatory factor 1 ( IRF1 ) gene ( P =1.3�10 −15 ), rs511154 within intron 1 of the propionyl coenzyme A carboxylase ( PCCB ) gene ( P =5.9�10 −10 ), and rs1539019 on the NLR family pyrin domain containing 3 isoforms ( NLRP3 ) gene ( P =1.04�10 −8 ). Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking

To study the blood clotting tests and endothelial function of polycystic ovary syndrome (PCOS) patients and non-hyperandrogenic women, and their changes during PCOS treatment, as a function of the presence of obesity and smoking. Case-control study followed by a randomized clinical trial. Blood clotting and endothelial function were analyzed in 40 PCOS patients and 20 non-hyperandrogenic women. Thirty-four PCOS women were randomized to an oral contraceptive containing 35 microg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane(35)Diario) or metformin (850 mg twice daily), monitoring the changes on these parameters during 24 weeks of treatment. The influence of obesity and smoking was also analyzed. Blood clotting and endothelial function tests were similar among PCOS patients and controls with the exception of a higher platelet count in the former. Obesity increased circulating fibrinogen levels, prothrombin activity and platelet counts, and reduced prothrombin and activated partial thromboplastin times. Smoking increased fibrinogen levels, platelet counts, and prothrombin activity, and reduced prothrombin time, in relation to the larger waist circumference of smokers. Irrespective of the treatment received, PCOS patients showed a decrease in prothrombin time and an increase in prothrombin activity, with a parallel increase in homocysteine levels in metformin users. The activated partial thromboplastin time decreased markedly in the patients treated with Diane(35)Diario. Finally, flow-mediated dilation improved in non-smokers irrespective of the drug received, but worsened in smokers. Oral contraceptives and metformin may exert deleterious effects on blood clotting tests of PCOS women, yet the effects of metformin appear to be milder. Because smoking potentiates some of these effects and deteriorates endothelial function, smoking cessation should be promoted in PCOS patients.

Insulin Resistance Is Associated With Circulating Fibrinogen Levels in Nondiabetic Patients Receiving Peritoneal Dialysis

Insulin resistance (IR) and inflammation are associated with increased risk of cardiovascular disease in the general population. Continuous glucose absorption in peritoneal dialysis (PD) may induce hyperglycemia and hyperinsulinemia. We evaluated IR in nondiabetic patients receiving PD, and analyzed the association between IR and systemic inflammation biomarkers by performing a cross-sectional study on ambulatory dialysis. A total of 25 nondiabetic patients receiving PD and 25 healthy individuals, matched for gender, age, and body mass index (BMI), were included. The PD group was composed of 11 men and 14 women, with a mean age of 47 +/- 14 years and mean BMI of 25.5 +/- 4.7 kg/m(2). The control group was composed of 10 men and 15 women, with a mean age of 45 +/- 12 years and BMI of 24.0 +/- 2.8 kg/m(2). IR was evaluated by the homeostasis model assessment method (HOMA-IR). Inflammation was assessed through high-sensitivity C-reactive protein (CRP) and fibrinogen. Body composition and truncal fat were evaluated by dual energy x-ray absorptiometry. HOMA-IR was significantly higher (P < .0001) in subjects receiving PD (4.9, range: 2.3-9.3 mmol/L x muU/mL) compared with healthy subjects (1.2, range: 0.4-4.8 mmol/L x muU/mL). As expected, compared with controls, patients receiving PD had significantly higher levels of insulin (26.5 +/- 7.5 muU/mL vs 6.3 +/- 3.4 muU/mL; P < .0001), CRP (6.3, range: 0.3-61.1 mg/L vs 2.4, range: 0.6-5.9 mg/L; P = .001), and fibrinogen (379 +/- 101 mg/dL vs 268 +/- 66 mg/dL; P < .0001). However, there were no significant differences in body and truncal fat mass between the groups. A significant correlation between HOMA-IR and fibrinogen (Rho = 0.48; P = .01) was observed. However, no correlation was found between HOMA-IR and CRP. Also, no significant correlations were found between HOMA-IR and body fat mass (Rho = 0.11), and between HOMA-IR and truncal fat mass (Rho = 0.19). Patients receiving PD demonstrate a state of IR that is associated with high circulating levels of fibrinogen. This suggests that hyperfibrinogenemia may be involved in the pathogenesis of IR in this setting.

Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort.

We examined whether plasma fibrinogen levels and the beta-fibrinogen gene G(-455)-->A polymorphism were related to microvascular or macrovascular disease in patients (n = 909) with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC). Univariate regression showed that fibrinogen levels were correlated with BMI (r = 0.15; P < 0.0001), HbA(1c) (r = 0.11; P = 0.0014), total cholesterol (r = 0.17; P < 0.0001), and LDL cholesterol (r = 0.16; P < 0.0001) in all patients. In men, but not women, waist-to-hip ratio (r = 0.20; P < 0.0001) and triglycerides (r = 0.13; P = 0.0047) also became powerful predictors of fibrinogen level; in women, but not men, fibrinogen was correlated with both diastolic (r = 0.16; P = 0.0011) and systolic (r = 0.11; P = 0.0241) blood pressure. Fibrinogen was correlated with urinary albumin excretion rates in men (r = 0.13; P = 0.0033), but not in women. In both sexes, however, the development of proteinuria (albumin excretion >300 mg/24 h) was accompanied by 1.5-fold increment in plasma fibrinogen compared with patients with normal excretion or microalbuminuria. In addition, high fibrinogen levels were associated with a lower average ankle-brachial index in women (r = -0.13; P = 0.0075), but not men. Multiple regression analyses demonstrated that plasma fibrinogen was independently correlated with high albumin excretion rate in men, and with low average ankle-brachial index in women. Fibrinogen was not correlated with the severity of retinopathy. Carotid artery intima-medial thickness was not correlated with fibrinogen, and the G(-455)-->A polymorphism in the 5' promoter region of the beta-fibrinogen gene did not influence circulating fibrinogen levels. However, the presence of the more common G(-455) allele was associated with greater intima-medial thickness in the internal carotid artery (ANCOVA P = 0.045). Last, hyperfibrinogenemia in type 1 diabetes is associated with components of the insulin resistance syndrome trait cluster, and the association is influenced by sex.

A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study

Introduction: Circulating levels of fibrinogen are associated with atherosclerosis and predict future coronary heart disease and stroke. Levels of fibrinogen are correlated among family members, suggesting a heritable component. Variants of the β-fibrinogen gene subunit on 4q28 are associated with fibrinogen levels but explain only a small proportion of the total genetic variability. It remains unknown what role, if any, is played by other genetic variants in the inter-individual variability in levels of fibrinogen in the general population. Materials and methods: We conducted a 10-cM spaced genome-wide scan using 402 original cohort subjects and 1193 offspring subjects from 330 extended families of the Framingham Heart Study. Heritability and linkage analyses were carried out using variance component methods. Regression analyses were performed to adjust for traditional risk factors and HindIII β-148 genotypes. Results and Discussions: The total heritability was estimated as 0.24. The highest and second highest LOD scores of linkage were found on chromosomes 2 (LOD=1.5 at 243 cM) and 10 (LOD=2.4 at 87 cM) using only offspring subjects in the analysis, and on chromosomes 2 (LOD=2.1 at 242 cM) and 10(LOD=1.4 at 86 cM), 17 (LOD=1.4 at 96 cM) and 20 (LOD=1.4 at 80 cM) using both original cohort and offspring. These results suggest that there may be influential genetic regions on these chromosomes. While no linkage with genome-wide significance was detected, further research to confirm our findings is warranted.

Fibrinogen Polymorphisms and Atherothrombotic Disease

Common polymorphisms of the fibrinogen gene cluster are associated with circulating fibrinogen level and with susceptibility to and/or severity of atherothrombotic disease. The frequencies of the polymorphisms vary among different ethnic groups but there is strong linkage disequilibrium at the beta-fibrinogen gene locus so that, in caucasian populations, there are only four common beta-fibrinogen haplotypes. One of these haplotypes, defined by the beta-fibrinogen -455A allele, is associated with elevated fibrinogen level and increased risk of atherothrombotic disease. The molecular mechanism of these associations is currently under investigation.