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1.
Fibrinogen is associated with glucose metabolism and cardiovascular outcomes in patients with coronary artery disease.
Liu, SL, Wu, NQ, Shi, HW, Dong, Q, Dong, QT, Gao, Y, Guo, YL, Li, JJ
Cardiovascular diabetology. 2020;(1):36
Abstract
BACKGROUND The present cohort study aims to examine the relationship between fibrinogen (Fib) levels and glucose metabolism [fasting blood glucose (FBG) and hemoglobin A1c (HbA1c)] and investigate the impact of high Fib on cardiovascular outcomes in patients with stable CAD and pre-diabetes mellitus (pre-DM) or diabetes mellitus (DM). METHODS This study included 5237 patients from March 2011 to December 2015. Patients were distributed into three groups according to Fib levels (low Fib, median Fib, high Fib) and further categorized by glucose metabolism status [normal glucose regulation (NGR), Pre-DM, DM]. All patients were followed up for the occurrences of major adverse cardiovascular events (MACEs), including cardiovascular mortality, nonfatal MI, stroke, and unplanned coronary revascularization. RESULTS Linear regression analyses showed that FBG and HbA1c levels were positively associated with Fib in overall CAD participants, either with or without DM (all P < 0.001). During an average of 18,820 patient-years of follow-up, 476 MACEs occurred. High Fib was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.57, 95% confidence interval (CI) 1.26-1.97, P < 0.001]. Furthermore, DM but not pre-DM was a significant predictor of MACEs (P < 0.001 and P > 0.05, respectively). When patients were stratified by both glucose metabolism status and Fib levels, high Fib was associated with a higher risk of MACEs in pre-DM (HR 1.66, 95% CI 1.02-2.71, P < 0.05). Medium and high Fib levels were associated with an even higher risk of MACEs in DM (HR 1.86, 95% CI 1.14-3.05 and HR 2.28, 95% CI 1.42-3.66, all P < 0.05). After adding the combination of Fib and glucose status to the Cox model, the C-statistic was increased by 0.015 (0.001-0.026). CONCLUSIONS The present study suggested that Fib levels were associated with FBG and HbA1c in stable CAD patients. Moreover, elevated Fib was independently associated with MACEs in CAD patients, especially among those with pre-DM and DM, suggesting that Fib may provide incremental value in the cardiovascular risk stratification of pre-DM and DM patients.
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2.
Reductions in plasmin inhibitor and fibrinogen predict the improved fibrin clot lysis 6 months after obesity surgery.
Pedersen, NB, Stolberg, CR, Mundbjerg, LH, Juhl, CB, Gram, B, Funch-Jensen, P, de Maat, MPM, Münster, AB, Bladbjerg, EM
Clinical obesity. 2020;(6):e12397
Abstract
Prothrombotic and metabolic variables are decreased after obesity surgery, and fibrin clot lysis is increased. It is unknown how fibrinolytic variables are affected, and whether fibrinolytic and metabolic changes predict the enhanced clot lysis. Study aims were to determine fibrinolytic biomarkers before and 6 months after Roux-en-Y gastric bypass (RYGB) and to identify predictors of the RYGB-induced increase in clot lysis. Women (n = 42) and men (n = 18) with obesity underwent RYGB, and factor XIII (FXIII), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen and plasmin inhibitor (PI) were measured before and 6 months after surgery. Regression analyses identified determinants of the RYGB-induced increase in clot lysis among changes in fibrinogen and in fibrinolytic and metabolic variables. Results showed that after RYGB, FXIII, TAFI, plasminogen and PI were reduced (P < .0005). Reductions in PI (β = -0.59) and fibrinogen (β = -0.35), together with age (β = -0.22) and male sex (β = 0.22), predicted the enhanced clot lysis with the model explaining 56% (P < .0005). Predictors of the reduction in PI were reductions in cholesterol (β = 0.37) and glucose (β = 0.29), together with male sex (β = -0.28), whereas reductions in fibrinogen were predicted by lowering of interleukin-6 (IL-6) (β = 0.32). In conclusion, fibrinolytic variables were reduced 6 months after RYGB. Targeting PI and fibrinogen, by reducing metabolic variables such as glucose, cholesterol and IL-6, has a profibrinolytic effect in obesity.
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3.
Relation of Fibrinogen-to-Albumin Ratio to Severity of Coronary Artery Disease and Long-Term Prognosis in Patients with Non-ST Elevation Acute Coronary Syndrome.
Li, M, Tang, C, Luo, E, Qin, Y, Wang, D, Yan, G
BioMed research international. 2020;:1860268
Abstract
Previous studies showed that fibrinogen-to-albumin ratio (FAR) regarded as a novel inflammatory and thrombotic biomarker was the risk factor for coronary artery disease (CAD). In this study, we sought to evaluate the relationship between FAR and severity of CAD, long-term prognosis in non-ST elevation acute coronary syndrome (NSTE-ACS) patients firstly implanted with drug-eluting stent (DES). A total of 1138 consecutive NSTE-ACS patients firstly implanted with DES from January 2017 to December 2018 were recruited in this study. Patients were divided into tertiles according to FAR levels (Group 1: ≤8.715%; Group 2: 8.715%~10.481%; and Group 3: >10.481%). The severity of CAD was evaluated using the Gensini Score (GS). The endpoints were major adverse cardiovascular events (MACE), including all-cause mortality, myocardial reinfarction, and target vessel revascularization (TVR). Positive correlation was detected by Spearman's rank correlation coefficient analysis between FAR and GS (r = 0.170, P < 0.001). On multivariate logistic analysis, FAR was an independent predictor of severe CAD (OR: 1.060; 95% CI: 1.005~1.118; P < 0.05). Multivariate Cox regression analysis indicated that FAR was an independent prognostic factor for MACE at 30 days, 6 months, and 1 year after DES implantation (HR: 1.095; 95% CI: 1.011~1.186; P = 0.025. HR: 1.076; 95% CI: 1.009~1.147; P = 0.026. HR: 1.080; 95% CI: 1.022~1.141; P = 0.006). Furthermore, adding FAR to the model of established risk factors, the C-statistic increased from 0.706 to 0.720, 0.650 to 0.668, and 0.611 to 0.632, respectively. And the models had incremental prognostic value for MACE, especially for 1-year MACE (NRI: 13.6% improvement, P = 0.044; IDI: 0.6% improvement, P = 0.042). In conclusion, FAR was associated independently with the severity of CAD and prognosis, helping to improve risk stratification in NSTE-ACS patients firstly implanted with DES.
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4.
The importance of measurement of plasma fibrinogen level among patients with type- 2 diabetes mellitus.
Abdul Razak, MK, Sultan, AA
Diabetes & metabolic syndrome. 2019;(2):1151-1158
Abstract
BACKGROUND & AIM: Fibrinogen has been implicated as a cause of atherosclerosis and its complications in patients with type 2 DM. We aimed to measure the plasma fibrinogen level in type 2 diabetics and to correlate it with the duration, type of treatment, HbA1c, smoking, lipid profile, diabetic retinopathy, hypertension and ischemic heart disease in comparison to control. METHODS A case control single center study included 50 patients with type 2 DM between the ages of 35-85 y who were randomly selected from the medical units of Baghdad Teaching Hospital compared to 30 non-diabetics as a control. After taking verbal consents; plasma fibrinogen levels were estimated and correlated with aimed variables. Odds ratios with 95% CI were calculated and regression analysis was performed for correlations. P ≤ 0.05 was considered statistically significant. RESULTS There were statistically significant differences regarding total cholesterol, TG, and LDL between cases and control. Mean HbA1c of diabetics was 8.31 ± 1.75% (P < 0.001). Cases showed plasma fibrinogen of (4.01 ± 1.89 g/dL) compared to (2.79 ± 0.55 g/dL) of control (P < 0.001). ROC curve revealed that the AUC was (0.679 ± 0.06, 95%CI = 0.561-0.797, P < 0.008). The sensitivity and specificity of the test at cut off value of 3.05 g/dL were 0.62 and 0.567 respectively. There was a significant correlation between fibrinogen level and each of HbA1c (r = 0.497, P < 0.001) and TG (r = 0.359, P = 0.01). CONCLUSIONS HbA1c has a significant positive effect on plasma fibrinogen and it is important to measure plasma fibrinogen level in patients with type 2 DM.
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5.
Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.
Ward-Caviness, CK, de Vries, PS, Wiggins, KL, Huffman, JE, Yanek, LR, Bielak, LF, Giulianini, F, Guo, X, Kleber, ME, Kacprowski, T, et al
PloS one. 2019;(5):e0216222
Abstract
BACKGROUND Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
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6.
Effect of soy milk consumption on glycemic status, blood pressure, fibrinogen and malondialdehyde in patients with non-alcoholic fatty liver disease: a randomized controlled trial.
Maleki, Z, Jazayeri, S, Eslami, O, Shidfar, F, Hosseini, AF, Agah, S, Norouzi, H
Complementary therapies in medicine. 2019;:44-50
Abstract
OBJECTIVE Diet plays a critical role in the management of non-alcoholic fatty liver disease (NAFLD). Studies on the NAFLD's experimental models have reported that soy had positive effects on the improvement of metabolic parameters. However, there is a lack of clinical trials regarding the efficacy of whole soy foods. Therefore, this study was conducted to determine the effect of soy milk on some of the metabolic characteristics in patients with NAFLD. METHODS Sixty-sex patients diagnosed with NAFLD were included in this randomized, parallel, controlled trial and were randomly assigned to either the soy milk or control group. Both groups received a 500-deficit calorie diet plan. Also, patients in the soy milk group consumed 240 ml/day soy milk for 8 weeks. Fasting blood sugar (FBS), serum insulin, HOMA-IR, HOMA-β%, and QUICKI as well as serum malondialdehyde (MDA), plasma fibrinogen, and blood pressure (BP) were measured at the beginning and end of the study. RESULTS After 8-weeks of intervention, soy milk group had a greater significant reduction in serum insulin(-3.44 ± 5.02 vs. -1.09 ± 3.77 μIU/ml, P = 0.04), HOMA-IR (-0.45±0.64 vs -0.14 ± 0.47, P = 0.03), systolic (-3.81±4.15 vs -1.48±2.93 mmHg, P = 0.01) and diastolic (-2.39±2.80 vs. -0.94±2.76 mmHg, P = 0.04) BP, and also, a significant increase in QUICKI (0.02± 0.032 vs. 0.008±0.018, P = 0.04) compared to the control group. While, changes in the FBS, HOMA-β%, fibrinogen, and MDA were not significantly different between the study groups. CONCLUSION A low-calorie diet containing soy milk had beneficial effects on serum insulin, HOMA-IR, QUICKI, and BP in patients with NAFLD.
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7.
Binding of Coagulation Factor XIII Zymogen to Activated Platelet Subpopulations: Roles of Integrin αIIbβ3 and Fibrinogen.
Kotova, YN, Podoplelova, NA, Obydennyy, SI, Kostanova, EA, Ryabykh, AA, Demyanova, AS, Biriukova, MI, Rosenfeld, MA, Sokolov, AV, Chambost, H, et al
Thrombosis and haemostasis. 2019;(6):906-915
Abstract
Factor XIIIa (fXIIIa) is a transglutaminase that plays a crucial role in fibrin clot stabilization and regulation of fibrinolysis. It is known to bind to procoagulant platelets. In contrast, the zymogen fXIII interaction with platelets is not well characterized. We investigated the interaction of zymogen fXIII with activated platelet subpopulations. Confocal microscopy and flow cytometry using fluorescently labelled factors and antibodies. Phosphatidylserine (PS)-positive activated platelets bound 700 to 800 molecules/cell of fXIII at 100 nM, while both PS-negative activated platelets and resting platelets bound 200 to 400 molecules/cell. The binding was reversible, calcium-independent and linear within the fXIII concentration range of up to 1,000 nM. fXIII predominantly bound to the caps of procoagulant platelets and co-localized with fibrinogen. Exogenous fibrinogen promoted fXIII binding by activated PS-negative platelets; this effect was abolished by the integrin αIIbβ3 antagonist monafram. The fXIII binding was 1.5- to 3-fold decreased for platelets from four patients with grey platelet syndrome, and was variable for platelets from six patients with Glanzmann's thrombasthenia. Strong platelet stimulation, fibrinogen and αIIbβ3 play essential roles in fXIII binding, without any of them fXIII does not bind to platelets. The preferential binding in the cap-like structures might be important for increasing local fXIII concentration in platelet thrombi.
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8.
Insight into the biological pathways underlying fibromyalgia by a proteomic approach.
Ramírez-Tejero, JA, Martínez-Lara, E, Rus, A, Camacho, MV, Del Moral, ML, Siles, E
Journal of proteomics. 2018;:47-55
Abstract
UNLABELLED Fibromyalgia (FM) is a form of non-articular rheumatism difficult to diagnose and treat because its etiology remains still elusive. Proteomics makes possible the systematic analysis of hundreds of proteins in clinical samples. Consequently, it has become a key tool for finding altered molecular pathways in different diseases. In this context, the present study analyzes changes in the plasma proteome of patients with FM by nanoscale liquid chromatography coupled to tandem mass spectrometry. Deregulated proteins were studied using Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes. Conventional analytical methods were used to validate selected proteins. We found a total of 33 proteins differentially expressed in patients with FM. Haptoglobin and fibrinogen showed the highest FM/control ratio. IPA analysis revealed that the top enriched canonical pathways were acute-phase response signaling, Liver-X Receptor/Retinoid-X Receptor activation, Farnesoid-X Receptor/Retinoid-X Receptor activation, and coagulation and complement systems. The importance of inflammation in FM was corroborated by the increase in erythrocyte sedimentation rate. In conclusion, our results support the existence of a plasma protein signature of FM that involves different biological pathways all of them related to inflammation, and point to haptoglobin and fibrinogen as plausible biomarker-candidates for future studies. SIGNIFICANCE The etiology of fibromyalgia (FM) remains elusive making its diagnosis and treatment difficult. The characterization of the proteome signature of this syndrome will improve its understanding. However, to date proteomic analyses in FM are scarce. The goal of the present work is to analyse, for the first time, changes in plasma protein profiles of patients with FM in comparison to control subjects, using label free relative protein quantification by nanoscale liquid chromatography coupled to tandem mass spectrometry. Our data demonstrate the existence of a common protein signature in the plasma of patients with FM that could explain some of the symptoms associated to this syndrome. The analysis of the 33 proteins differentially expressed corroborates the crucial role of inflammation in the pathogenesis of this syndrome. The interplay of the complement and coagulation cascades contributes to the inflammatory process, while the activation of Liver-X Receptor/Retinoid-X Receptor and Farnesoid-X Receptor/Retinoid-X Receptor could attempt to alleviate it. Finally, we have identified two proteins, haptoglobin and fibrinogen, as potential biomarker-candidates of FM for future studies.
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9.
Abnormal fibrinogen with an Aα 16Arg → Cys substitution is associated with multiple cerebral infarctions.
Luo, M, Wei, A, Xiang, L, Yan, J, Liao, L, Deng, X, Deng, D, Cheng, P, Lin, F
Journal of thrombosis and thrombolysis. 2018;(3):409-419
Abstract
We found a heterozygous dysfibrinogenemia caused by a substitution of AαArg16Cys. The proband suffered multiple cerebral infarctions. Routine coagulation tests revealed a prolonged thrombin time. The fibrinogen levels in the functional assays were considerably lower than the levels in the immunological assays. The polymerization of the purified fibrinogen was strongly impaired in the presence of calcium. As previously observed in other heterozygous Aα R16C variants, the release rate and amount of fibrinopeptide A (FPA) were lower in the proband than those in normal controls. Additionally, the release of fibrinopeptide B (FpB) was delayed. The immunoblotting analysis using antibodies against human serum albumin indicated that albumin is bound to Aα R16C. The mass spectrometry analysis showed that the Aα R16C fibrinogen chains appeared in the patient's circulation. The clot structure analysis using scanning electron microscopy (SEM) revealed that the fibrin network was dense and consisted of thin and highly branched fibres. Using overlaid fibrinolytic enzymes in a clot lysis experiment, clot degradation was observed to be delayed. These results indicated that the thrombotic tendency may be ascribed to a fibrinolytic resistance caused by an abnormal clot structure with thin fibres and fibrinogen-albumin complexes.
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10.
Oxidation of proteins: is it a programmed process?
Rosenfeld, MA, Vasilyeva, AD, Yurina, LV, Bychkova, AV
Free radical research. 2018;(1):14-38
Abstract
Proteins represent extremely susceptible targets for oxidants. Oxidative modifications of proteins may bring about violation of their structure and functionality. It implies that the structures of proteins are not infallible in terms of their antioxidant defence. The protection mechanisms in preventing oxidative damages for proteins within cells are mainly related to a large variety of antioxidant enzymatic systems. In contrast, plasma proteins are scarcely protected by these systems, so the mechanism that provides their functioning in the conditions of generating reactive oxygen species (ROS) seems to be much more complicated. Oxidation of many proteins was long considered as a random process. However, the highly site-specific oxidation processes was convincingly demonstrated for some proteins, indicating that protein structure could be adapted to oxidation. According to our hypothesis, some of the structural elements present in proteins are capable of scavenging ROS to protect other protein structures against ROS toxicity. Various antioxidant elements (distinct subdomains, domains, regions, and polypeptide chains) may act as ROS interceptors, thus mitigating the ROS action on functionally crucial amino acid residues of proteins. In the review, the oxidative modifications of certain plasma proteins, such as α2-macroglobulin, serum human albumin, fibrinogen, and fibrin-stabilising factor, which differ drastically in their spatial structures and functions, are analysed. The arguments that demonstrate the possibility of existing hypothetical antioxidant structures are presented. For the first time, the emphasis is being placed on the programmed mechanism of protein oxidation.