The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation

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

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

The use of fibrinogen concentrate for the management of trauma-related bleeding. A systematic review and meta-analysis

Haemorrhage following injury is associated with significant morbidity and mortality. The role of fibrinogen concentrate in trauma-induced coagulopathy has been the object of intense research in the last 10 years and has been systematically analysed in this review. A systematic search of the literature identified six retrospective studies and one prospective one, involving 1,650 trauma patients. There were no randomised trials. Meta-analysis showed that fibrinogen concentrate has no effect on overall mortality (risk ratio: 1.07, 95% confidence interval: 0.83-1.38). Although the metaanalytic pooling of the current literature evidence suggests no beneficial effect of fibrinogen concentrate in the setting of severe trauma, the quality of data retrieved was poor and the final results of ongoing randomised trials will help to further elucidate the role of fibrinogen concentrate in traumatic bleeding

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

Canine reference intervals for coagulation markers using the STA Satellite and the STA-R Evolution analyzers

The aim of the current study was to determine canine reference intervals for prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, and antithrombin (AT) according to international recommendations. The STA Satellite coefficients of variation of within-laboratory imprecision were 3.9%, 1.3%, 6.9%, and 5.1% for PT, APTT, fibrinogen, and AT, respectively. At 4uC, citrated specimens were stable up to 8 hr for whole blood and 36 hr for plasma, except for APTT, which increased slightly (<1 sec). Nonparametric reference intervals determined in citrated plasma from 139 healthy fasting purebred dogs were 6.9–8.8 sec, 13.1–17.2 sec, 1.24–4.30 g/l, and 104–188% for PT, APTT, fibrinogen, and AT, respectively. Based on Passing–Bablok comparison between STA Satellite and STA-R Evolution using 60 frozen specimens from a canine plasma bank, the corresponding reference intervals were transferred to the STA-R Evolution: 7.1–9.2 sec, 12.9–17.3 sec, 1.20–4.43 g/l, and 94–159% for PT, APTT, fibrinogen, and AT, respectively

Does sticky blood predict a sticky end? Associations of blood viscosity, haematocrit and fibrinogen with mortality in the West of Scotland

There is increasing evidence that blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen) are associated with an increased risk of incident cardiovascular events; however, their associations with mortality are not established. We therefore studied the associations of these variables with cardiovascular events and total mortality in 1238 men and women aged 25-64 years, followed for 13 years in the first North Glasgow MONICA (MONItoring CArdiovascular disease) survey and West of Scotland centres in the Scottish Heart Health Study. After adjustment for age and sex, increasing whole blood viscosity, plasma viscosity, haematocrit and fibrinogen (analysed by both von Clauss and heat precipitation assays) were significantly associated with mortality. Only the association for fibrinogen (von Clauss assay) remained significant after adjustment for major cardiovascular risk factors. We conclude that clottable fibrinogen may be independently associated with mortality. However, the significance of this association, and the extent to which viscosity is associated with mortality, remain to be established in larger studies and meta-analyses

A performance evaluation of commercial fibrinogen reference preparations and assays for Clauss and PT-derived fibrinogen

The wide availability of fibrinogen estimations based on the prothrombin time (PT-Fg) has caused concern about the variability and clinical utility of fibrinogen assays. In a multi-centre study, we investigated fibrinogen assays using various reagents and analysers, Clauss assays generally gave good agreement, although one reagent gave 15-30% higher values in DIC and thrombolysis. Two commercial reference preparations had much lower potencies than the manufacturers declared, and plasma turbidity influenced parallelism in some Clauss assays, PT-Fg assays gave higher values than Clauss and showed calibrant dependent effects, the degree of disparity correlating with calibrant and test sample turbidity. Analyser and thromboplastin dependent differences were noted. The relationship between Clauss and PT-Fg assays was sigmoid, and the plateau of maximal PT-Fg differed by about 2 g/l between reagents. ELISA and immunonephelometric assays correlated well, but with a high degree of scatter. Antigen levels were higher than Clauss, but slightly lower than PT-Fg assays, which appeared to be influenced by degraded fibrinogen. Clauss assays are generally reproducible between centres, analysers and reagents, but PT-Fg assays are not reliable in clinical settings