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PubMed1992

Endogenous platelet fibrinogen: its modulation after surface expression is related to size-selective access to and conformational changes in the bound fibrinogen.

Platelet stimulation results in the release of endogenous platelet fibrinogen which binds to the platelet surface. Previous studies have demonstrated that plasma fibrinogen bound to activated platelets becomes inaccessible to a variety of probes. We have studied endogenous platelet fibrinogen binding to activated platelets by employing an immunopurified polyclonal anti-fibrinogen antibody and F26, a monoclonal anti-fibrinogen antibody, which recognizes fibrinogen only when it is bound to a surface. Employing the Ig or F(ab')2 of the poly- or monoclonal antibody we found a marked decrease of fibrinogen accessibility 30-60 min after platelet activation. In contrast, platelet-bound fibrinogen remains accessible to the Fab fragment of F26 at a constant level for 30 min and increases at 60 min. The reduction of the polyclonal Fab fragment binding at 30 and 60 min is similar to the F26 Ig. These results indicate that the decreased accessibility of bound fibrinogen is related to two mechanisms; (1) that the access route to fibrinogen in size selective for the antibody probes and only small antibody probes, e.g. Fab fragments, can gain access to fibrinogen and (2) fibrinogen undergoes a conformational change(s) after binding which exposes at least one neo-epitope in the D domain of fibrinogen and which may decrease or mask the reactivity of other fibrinogen domains. Only the F26 Fab probe has full access to and identifies fibrinogen present on the platelet surface 60 min after stimulation.

Antibodies, Monoclonal↗
PubMed2006

Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.

Adolescent↗
PubMed1977

Fibrinogen synthesis in rabbits: effects of altered levels of circulating fibrinogen.

The effects of altered fibrinogen concentrations on fibrinogen synthesis in rabbits were evaluated by determining the rate of appearance of [75Se]selenomethionine (75SeM) in circulating fibrinogen. Fibrinogen levels were maintained at twice normal by infusion of homologous fibrinogen for either 1 or 6 days before the intravenous injection of 20 micronCi of 75SeM, and the rate of appearance of labeled fibrinogen was measured during the subsequent 24 h. In both groups, synthesis was unchanged. Five hours after induction of partial defibrinogenation by the infusion of bovine thrombin, fibrinogen synthesis was increased threefold. Stimulation was not attributable to decreased fibrinogen concentrations; synthesis was increased equally when levels were maintained above normal by infusion of fibrinogen before administration of thrombin. Heat-inactivated thrombin and diisopropylfluorophosphate-inactivated thrombin did not stimulate fibrinogen synthesis. Thrombin produced elevated titers of fibrinogen-fibrin degradation products (FDP-fdp). However, fibrinogen synthesis was not increased in rabbits that had received FDP-fdp from thrombin-treated donors. These data suggest that neither the fibrinogen concentration nor FDP-fdp influenced fibrinogen synthesis.

Animals↗
PubMed2003

Combined segregation and linkage analysis of fibrinogen variability in Israeli families: evidence for two quantitative-trait loci, one of which is linked to a functional variant (-58G > A) in the promoter of the alpha-fibrinogen gene.

The association of alpha- and beta-fibrinogen polymorphisms with plasma fibrinogen levels was examined in a sample of 452 family members from 80 Israeli kindreds. The measured genotype analysis indicated that the beta-fibrinogen -455G > A polymorphism was not associated with fibrinogen levels, while the alpha-fibrinogen -58G > A locus showed a significant association with fibrinogen levels (chi2= 17.7; df = 3; p < 0.001), with the -58A allele being associated with higher levels. Segregation analysis in this sample suggested a recessive quantitative-trait locus (QTL) with a major effect that controlled the sex- and age-adjusted fibrinogen levels. Results from a combined segregation/linkage analysis indicated that a single QTL influencing plasma fibrinogen is in gametic equilibrium with the beta-fibrinogen -455G > A and alpha-fibrinogen -58G > A polymorphisms. An extended analysis with a two-QTL model significantly improved the fit of the model (p < or = 0.001), and gave support for linkage between the fibrinogen QTL and the alpha-fibrinogen polymorphism. In vitro analysis with a DNA fragment containing this variant, linked to a reporter gene, showed 2-fold higher expression of the A allele compared to the G allele in the liver cell line HepG2, both under basal conditions and after stimulation with interleukin 6. These results demonstrate that two QTLs are jointly involved in determining plasma fibrinogen levels in this sample of families, one of which is located close to a functional variant in the alpha-fibrinogen locus.

Cell Line↗
PubMed1987

Fibrinogen-induced erythrocyte aggregation: erythrocyte-binding site in the fibrinogen molecule.

The effect of fibrinogen and fibrinogen-derived products on the velocity of rouleau formation of human erythrocytes was quantitatively examined with a rheoscope combined with a video-camera, an image analyzer and a computer. (i) The velocity of rouleau formation by naturally occurring low-molecular-weight fibrinogen of 305 kDa and by desialylated fibrinogen was the same as that by native fibrinogen of 340 kDa. (ii) Concerning fibrinogen degradation products by plasmin, the velocity of rouleau formation decreased upon going from fibrinogen greater than fragment X greater than fragment Y (the ratio of molar concentration of fibrinogen, fragment X and fragment Y for giving a certain velocity of rouleau formation was approx. 1:2:5). The effect of fragments X and Y on the fibrinogen-induced rouleau formation was additive. (iii) Fragments D and E could not induce rouleau formation and did not affect the fibrinogen-, fragment X- and fragment Y-induced rouleau formation. (iv) Fibrinopeptides A and B and artificial tetrapeptides (Gly-Pro-Arg-Pro and Gly-His-Arg-Pro) did not affect the fibrinogen-induced rouleau formation. (v) The possible erythrocyte-binding site in fibrinogen molecule for leading to rouleaux was proposed to be in A alpha-chain (probably, around residues No. 207-303) near the terminal domain of the trinodular structure of fibrinogen.

Binding Sites↗
PubMed1985

Stimulation of fibrinogen synthesis in cultured rat hepatocytes by fibrinogen fragment E.

Because of the inherent difficulties of experimentation in intact animals, we used primary monolayer cultures of non-proliferating adult rat hepatocytes to study the effects of fibrinogen degradation products on fibrinogen biosynthesis. The freshly isolated hepatocytes obtained by collagenase perfusion of the liver in situ were cultured in a chemically defined serum-free medium. The rate of fibrinogen synthesis in control cultures was 40-50 pmol/2.5 X 10(6) cells per 24 h. Additions of 20, 60 or 100 micrograms of homologous stage I fibrinogen degradation products had no effect on fibrinogen synthesis. In contrast, addition of the same amounts of homologous or heterologous (human) stage III fibrinogen degradation products resulted in a concentration-dependent increase in fibrinogen biosynthesis without affecting the rate of synthesis of albumin. When purified stage III fibrinogen degradation products D and E (human) were tested in 10, 30 or 50 micrograms/3 ml medium only fragment E showed a significant increase in fibrinogen biosynthesis (1.9-, 2.8- and 5.6-fold, respectively, over the control cultures). The presence of excess fibrinogen had no effect. These results suggest that fibrinogen fragment E may be a specific stimulator of fibrinogen biosynthesis which may play an important role in maintaining normal levels of plasma fibrinogen.

Albumins↗
PubMed1979

The effect of homologous thrombin and fibrinogen degradation products on fibrinogen synthesis in rabbits.

The effect of intravenous infusions of purified homologous FDP and thrombin on fibrinogen synthesis was evaluated in rabbits. De novo fibrinogen production was measured by the rate of incorporation of 75SeM into circulating fibrinogen. After receiving either 100 or 200 NIH U/kg purified homologous thrombin over 1 hr, rabbits demonstrated threefold and fivefold increases in fibrinogen synthesis, respectively. A correlation between the titers of FDP-fdp and the degree of fibrinogen synthesis was evident. Prior administration of epsilon-ACA prevented the accelerated synthesis of fibrinogen induced by thrombin and inhibited the appearance of FDP-fdp in serum. epsilon-ACA did not interfere with normal fibrinogen production. Fibrinogen synthesis was assessed following infusions of FDP prepared by vitro by digestion of rabbit fibrinogen with plasmin and subsequently identified on SDS-polyacrylamide gels. Preparations which contained predominantly stage 2 intermediate (X, Y, D, and E) or stage 3 final (D and E) fragments accelerated fibrinogen synthesis, whereas those containing predominantly stage 1 fragment X did not. Prior treatment with epsilon-ACA did not alter these results. Infusion of the supernatants derived from immunoprecipitation of the FDP by either anti-rabbit fibrinogen antibody or specific anti-human D and E antibodies significantly diminished the enhanced fibrinogen synthesis induced by the unadsorbed materials. These experiments suggest that the accelerated fibrinogen synthesis induced by thrombin is mediated by FDP, with fragments D and E appearing to be the most potent.

Aminocaproic Acid↗
PubMed2004

Fibrinogen and high molecular weight fibrinogen during and after normal pregnancy.

INTRODUCTION: Pregnancy has recently been described as a generalized intravascular inflammatory response to the conceptus. Total fibrinogen concentrations increase during pregnancy. The percentage high molecular weight fibrinogen (HMW-Fg) of the concentration total fibrinogen is known to increase during acute-phase conditions like inflammation. Therefore, we investigated whether the percentage high molecular weight fibrinogen increases during normal pregnancy. MATERIALS AND METHODS: Eighteen healthy nulliparous women with uncomplicated pregnancies with normal course and outcome participated in this study. Five blood samples were drawn from every woman in the gestational age periods 9 to 16, 17 to 24, 25 to 33 and 34 to 42 weeks and at 12 to 20 weeks after delivery. Total fibrinogen concentrations were determined according to Clauss and the percentage high molecular weight fibrinogen was assessed by SDS-electrophoresis and densitometry after isolation of fibrinogen by precipitation. One-way analysis of variance (ANOVA) was used to evaluate differences between gestational age periods and correlation coefficients were calculated by Pearson's method. RESULTS: Total fibrinogen concentrations increased with advancing gestational age and decreased after delivery. The percentage high molecular weight fibrinogen of the total fibrinogen remained unaltered during and after pregnancy. CONCLUSIONS: During normal pregnancy, there is an increase of total fibrinogen concentrations with advancing gestational age, without a rise in percentage high molecular weight fibrinogen. After delivery, the total fibrinogen returns to baseline concentrations.

Adult↗
PubMed2003

Association of increased levels of fibrinogen and the -455G/A fibrinogen gene polymorphism with chronic periodontitis.

BACKGROUND: Fibrinogen is one of the acute-phase proteins whose levels are elevated during periodontal disease. Recent studies suggest that excessive fibrinogen production might play a role in upregulating host immune responses. In addition, there is a relationship between the -455G/A polymorphism (HaeIII) in the 5' flanking region of the beta-fibrinogen gene promoter and increased fibrinogen levels. In this study, we investigated the distribution of the -455G/A polymorphism and the relationship of this specific genotype to fibrinogen levels in periodontitis patients. METHODS: In order to assess the -455G/A polymorphism, restriction fragment length polymorphism (RFLP) analysis with HaeIII enzyme was performed in the promoter region of the beta-fibrinogen gene. This was carried out on 79 chronic periodontitis patients as compared to 75 periodontally healthy subjects, matched to age, gender, and race. Fibrinogen levels were determined by the radial immunodiffusion assay (RID). RESULTS: The frequency of homozygocity for the rare allele of the beta-fibrinogen gene (H2H2) was 13% for the periodontitis patients and 3% for the control group (P = 0.01). The distributions of H1H1 and H1H2 genotypes were 48% and 39% in the patient group and 70% and 27% in the control group, respectively. Chi-square analysis indicated that the distribution of these genotypes between the 2 groups was significantly different (P = 0.01). Fibrinogen levels were significantly higher in the patient group (2,496.5 mg/l +/- 105) compared to the control group (2,250.0 mg/l +/- 118.3) after adjusting for age, gender, and smoking status (P = 0.04). Consistent with previous reports, in our study population, those subjects with the H2H2 genotype had significantly higher fibrinogen levels (3,005.7 mg/l +/- 182.5) compared to subjects with the H1H1 genotype (2,325.0 mg/l +/- 91.6) or H1H2 genotype (2,438.0 mg/l +/- 117.4) (P = 0.001). Furthermore, the H1H2 and H2H2 genotypes were found at a higher frequency among periodontitis patients than controls. The odds ratios (OR) for these genotypes were 3.26 (95% confidence interval [CI]: 1.25 to 8.53) for the H1H2 genotype and 6.41 (95% CI: 1.15 to 35.83) for the H2H2 genotype as compared to individuals with the H1H1 genotype, after adjusting for age, gender, and smoking status. CONCLUSIONS: The results indicate that a higher percentage of chronic periodontitis patients exhibit genotypes associated with higher plasma fibrinogen levels than healthy individuals. Furthermore, periodontitis patients have significantly higher fibrinogen levels compared to healthy individuals. The presence of H1H2 or H2H2 genotypes as well as elevated fibrinogen levels, in conjunction with other factors, may put individuals at higher risk of having periodontal disease, or may result from periodontal infection-genetic interactions.

5' Flanking Region↗
PubMed1989

Human fibrinogen heterogeneity. A study of limited fibrinogen degradation.

Different fibrinogen species were examined in normal plasma following urokinase treatment, in isolated high molecular weight fibrinogen treated with plasmin and in plasma samples from patients with acute myocardial infarction receiving thrombolytic therapy. In normal plasmas two main fibrinogen species (Mr = 340,000 and Mr = 320,000) and an intermediate fragment (Mr = 330,000) were observed. The 340,000 fibrinogen was the most sensitive to degradation; it gave rise to 330,000 and 320,000 species. Degradation of isolated 340,000 fibrinogen was similar to plasma fibrinogen degradation. After thrombolytic therapy in acute myocardial infarction patients, when the plasma fibrinogen decreased near to zero, the new synthesized fibrinogen was 340,000 form. 'In vivo' conversion of 340,000 to 320,000 fibrinogen, associated with the transitory 330,000 form, was observed. The coagulation study of plasma fibrinogen showed that when Mr 340,000 fibrinogen decreased (40%), the gelation rate decreased and lag time increased drastically. The high 340,000 fibrinogen content found in acute myocardial infarction patients gave rise to the hypercoagulable state.

Blood Coagulation↗
PubMed1995

Measuring plasma fibrinogen levels in patients with liver cirrhosis. The occurrence of proteolytic fibrin(ogen) degradation products and their influence on several fibrinogen assays.

In patients with liver cirrhosis the fibrinogen molecule is under constant attack of various proteolytic enzymes, which might affect results of the different assay systems for fibrinogen. We therefore studied the measurement of fibrinogen in the plasma of patients with mild, moderate and severe cirrhosis of the liver. Fibrinogen levels were measured with the Clauss method (functional fibrinogen); an enzyme immuno assay (EIA) for HMW + L MW fibrinogen; and an assay that measures the total clottable fibrinogen. With all three methods we found normal or slightly increased fibrinogen levels in patients with mild or moderate cirrhosis, whereas patients with severe cirrhosis had decreased levels. No evidence was found for increased partial fibrinogen proteolysis, resulting in increases of LMW'-fibrinogen in cirrhotic patients. We further observed that fibrinogen degradation products levels increased slightly with the severity of the disease, but were still in the normal range in patients with severe cirrhosis. This indicates a very low level of primary fibrinolysis. Fibrin degradation products levels increased much stronger, which points to intravascular coagulation. The levels of the fibrin degradation products remained below the level where they are expected to influence the Clauss assay. In patients with liver cirrhosis the measurement of plasma fibrinogen levels with the three studied methods give comparable results. We suggest to apply the Clauss assay in cirrhotic patients because of this and because it has good reproducibility and because the test is cheap, quick and easy to perform.

Child↗
PubMed2001

Relationship between fibrinogen protein and fibrinogen function in postmyocardial infarction patients.

The present study investigates the association between increases in the concentration and function of plasma fibrinogen in two groups of patients with chronic ischemic heart disease (11 with recurrent ischemic events and 19 free of these episodes) and in 34 healthy controls. The fibrinogen function index (fibrinogen function per unit of fibrinogen protein) (FgFI) was used as a measure of the fibrinogen clotting potential. The prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) were used as procoagulant markers. Plasma sialic acid (SA) was also evaluated as an inflammatory marker. No differences were found between FgFI (1.06+/-0.13 vs. 1.02+/-0.13), F1+2 (1.2+/-0.5 vs. 1.1+/-0.4 nmol/l) and TAT (2.5+/-1.3 vs. 2.5+/-0.7 microg/ml) in postinfarction patients without recurrent coronary ischemic events and the control group. However, postinfarction patients who suffered recurrent coronary ischemic events had significantly higher FgFI than patients without these symptoms (1.19+/-0.09 vs. 1.06+/-0.13), P<.01) and than the control group (1.19+/-0.09 vs. 1.02+/-0.13, P<.001). Moreover, the F1+2 (1.4+/-0.5 vs. 1.1+/-0.4 nmol/l, P<.05) and TAT (3.6+/-3.3 vs. 2.5+/-0.7 microg/ml, P<.05) were significantly higher in patients who suffered recurrent coronary ischemic events than in the control group. However, F1+2 and TAT were not different between patients with and without these symptoms. The fibrinogen protein (Fg-protein) concentration and high molecular weight fibrinogen (HMW-Fg) levels were significantly higher in both postinfarction patient groups than in the control group and in postinfarction patients with recurrent coronary ischemic events than in postinfarction patients without these symptoms. The plasma SA levels were significantly increased in postinfarction patients with and without recurrent coronary ischemia as compared with the control group. A positive correlation was found between fibrinogen and SA levels (r=.5, P<.01). In conclusion, our study indicates that the procoagulant factors, among which we include fibrinogen, F1+2 and TAT play a very active role in recurrent ischemic events in postmyocardial infarction patients. High plasma concentrations of both fibrinogen and SA suggests that fibrinogen becomes elevated as a consequence of inflammatory processes. The FgFI as an indicator of clotting potential of fibrinogen appears to be associated with ischemic events in chronic coronary artery disease.

Adult↗
PubMed1992

Studies on the functionality of fibrinogen during rt-PA therapy: results of three different methods of fibrinogen determination.

The conversion of soluble fibrinogen to insoluble fibrin is a crucial event in the process of haemostasis. In the present study three different methods were used for the determination of plasma fibrinogen levels in 12 patients with acute myocardial infarction during rt-PA therapy. Two methods were based on fibrin formation and thus measured 'functional' fibrinogen: a clotting rate assay according to the Clauss method and a photometric polymerization rate assay. Thirdly, fibrinogen antigen was measured with a new enzyme immunoassay (EIA) for immunologically intact fibrinogen. The levels of functional and intact fibrinogen were strikingly different: 4.1 g/l (Clauss) and 3.6 g/l (photometric) vs 2.6 g/l (EIA) at baseline, 2.2 g/l (54% of preinfusion value) and 2.1 g/l (59%) vs 2.1 g/l (81%) at 90 min, 5.7 g/l (146%) and 4.5 g/l (130%) vs 2.7 g/l (106%) at 72 h. The rebound phenomenon exhibited by functional fibrinogen (130-150%) was not observed for levels of intact fibrinogen. A ratio was calculated of functional (Clauss method) to intact fibrinogen (EIA) for each individual patient and each time point. The mean ratio (n = 12 patients) was 1.6 at baseline, 1.0 at 90 min, and increased markedly between 8 and 24 h to a maximum of 2.1 (P less than 0.01). Our data indicate that the 'functionality', i.e. the clotting rate per unit concentration of circulating fibrinogen, changed during acute myocardial infarction and subsequent thrombolytic therapy. This is in keeping with data from literature that the relative amount of fast clotting high molecular weight (HMW) fibrinogen of total fibrinogen was increased in the initial phase of acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1996

Physical activity, fitness, and plasma fibrinogen with reference to fibrinogen genotypes.

The relation of daily energy expenditure (EE) and maximal oxygen uptake (VO2max) to plasma fibrinogen with reference to DNA polymorphism was analyzed in a random sample of men (N = 189), age 50-60. Fibrinogen polymorphism was detected using polymerase chain reaction (PCR) and digestion with HindIII and BclI (beta-fibrinogen), and TaqI (alpha-fibrinogen) restriction enzymes. Mean VO2max was 29.4 ml.kg-1.min-1 (95%CI 28.5; 30.2) and mean daily EE was 179 kJ.kg-1.d-1 (173; 186) and were similar in all fibrinogen genotypes. Plasma fibrinogen was 3.26 g.1-1 (3.18; 3.34) and did not associate with fibrinogen polymorphisms. Both EE and VO2max related inversely to fibrinogen level (r = -0.24, P < 0.001). Strongest predictors of plasma fibrinogen were VO2max in TaqI 800 bp homozygotes, and EE together with smoking in TaqI 900 bp homozygotes. The predictive role of VO2max was marginal in the common beta-fibrinogen genotypes, whereas physical activity level explained up to 9% of the variance in the less frequent genotypes. These data suggest that the association of VO2max and EE with plasma fibrinogen varies across the fibrinogen genotypes.

Cross-Sectional Studies↗
PubMed1996

Plasma fibrinogen inhibits platelets adhesion in flowing blood to immobilized fibrinogen.

The influence of variations in plasma fibrinogen concentration on platelet adhesion to immobilized fibrinogen was investigated in a parallel-plate perfusion chamber. At a shear rate of 1600 s-1 platelet adhesion decreased when increasing concentrations of purified fibrinogen were added to the plasma (IC50 = 1.5 +/- 0.2 g/L fibrinogen, n = 24). Washed platelets reconstituted in a human albumin solution with red blood cells were more sensitive for soluble fibrinogen (IC50 = 0.4 +/- 0.1 g/L, n = 5, P < .05). When platelet activation during circulation of the blood was minimized by using a single-passage perfusion system, an IC50 of 2.0 +/- 0.2 g/L was found (n = 9). To exclude the possibility that the inhibition of fibrinogen was caused by irreversible changes in the fibrinogen molecule during the purification procedure, normal plasma was mixed in different ratios with plasma from a patient with congenital afibrinogenemia. Under these conditions, the plasma fibrinogen IC50 was 1.5 +/- 1.1 g/L. Absence of endogenous fibrinogen in the platelets of the patient resulted in an IC50 of 1.2 +/- 0.5 g/L for plasma fibrinogen. These results demonstrate that increased plasma fibrinogen concentrations inhibit platelet adhesion to fibrinogen under flow.

Afibrinogenemia↗
PubMed1996

Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde.

BACKGROUND: Polymorphisms of the beta fibrinogen gene have been shown to affect plasma fibrinogen levels and the risk of peripheral arterial disease. We now present the results of a detailed analysis of the beta fibrinogen gene in relation to plasma fibrinogen and to the severity of coronary artery disease (CAD) in patients with myocardial infarction (MI) in the ECTIM Study. METHODS AND RESULTS: Ten polymorphisms of the beta fibrinogen gene, including five new polymorphisms identified by single-strand conformation polymorphism analysis, and one polymorphism in the 3' flanking region of the alpha fibrinogen gene were investigated in 565 patients with MI and 668 control subjects. The polymorphisms were in tight linkage disequilibrium and the genotype frequencies were similar in patients with MI and control subjects. In the multivariate analysis, only two polymorphisms, beta Hae III (P < .0003) and beta-854 (P < .01), were independently associated with plasma fibrinogen. The significant association between beta fibrinogen polymorphisms and plasma fibrinogen was present in smokers but not in nonsmokers. In French MI patients, the number of coronary arteries with > 50% stenosis was estimated by angiography and used as a criterion for severity of CAD. Presence of the less frequent allele of the beta Bcl I (P < .0003) and of other polymorphisms was positively associated with the severity of CAD. CONCLUSIONS: Genetic variants of the beta fibrinogen gene are associated with an increased plasma level of fibrinogen, especially in smokers. The association with CAD appears to be the consequence of an increased risk of MI in subjects with severe CAD who carry the predisposing beta fibrinogen genotypes.

Adult↗
PubMed2005

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels.

We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen gamma' (gammaA/gamma' plus gamma'/gamma') levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen gamma' levels and reduced ratios of fibrinogen gamma' to total fibrinogen. Multivariate analysis showed that reduced fibrinogen gamma' levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen gamma' to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of gammaA chain above that of gamma' chain. Fibrinogen gamma' contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1).

Adolescent↗