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PubMed1999

Beta-fibrinogen gene G/A-455 polymorphism in relation to fibrinogen concentrations and ischaemic heart disease in Chinese patients with type II diabetes.

AIMS/HYPOTHESIS: We investigated the relation between the G/A-455 (Hae III) beta-fibrinogen gene polymorphism and plasma fibrinogen concentration and its role in ischaemic heart disease in 264 Chinese patients with Type II (non-insulin-dependent) diabetes mellitus and 182 non-diabetic control subjects. METHODS: The G/A-455 polymorphism was determined in genomic DNA using polymerase chain reaction and Hae III restriction enzyme digestion. Fibrinogen was measured with the Claus method. RESULTS: Fibrinogen concentrations were higher in diabetic patients (3.3 +/- 0.5 vs 2.5 +/- 0.9 g/l in controls, p < 0. 0001) and in women (p < 0.03 vs men). Allele frequency of the variant A allele was 27 % in both diabetic patients and control subjects' similar to findings in Caucasians. In control subjects, the AA genotype was associated with higher fibrinogen concentrations (2.8 +/- 0.38 g/l vs 2.5 +/- 0.5 in GG or GA, p < 0.03), contributing to 4 % of the variance in plasma fibrinogen. The genotype effect was smaller and not significant among non-smokers, women and diabetic patients. Higher fibrinogen concentrations and AA genotype frequency were found in diabetic patients with ischaemic heart disease (p < 0.05 and p < 0.005, respectively vs unaffected patients). In a multiple logistic regression model, AA genotype, age and mean arterial pressure were associated with ischaemic heart disease, with odds ratios of 4.19 (p < 0.01), 1.05 (p < 0.0001) and 1.03 (p < 0.03), respectively. CONCLUSION/INTERPRETATION: The G/A-455 polymorphism is a genetic determinant of fibrinogen concentrations and ischaemic heart disease in this Chinese cohort. It also interacts with environmental influences associated with smoking, the female sex and Type II diabetes in determining plasma fibrinogen concentrations. [Diabetologia (1999) 42: 1250-1253]

Age Factors↗
PubMed1995

Impact of polymorphisms in the alpha- and beta-fibrinogen gene on plasma fibrinogen concentrations of coronary heart disease patients.

Despite many investigations in a variety of experimental settings, uncertainty remains concerning the size of the genetic contribution to plasma fibrinogen levels. We used the polymerase chain reaction to amplify the polymorphic sites for the restriction enzymes TaqI in the alpha-fibrinogen gene and HaeIII, HindIII and BclI in the beta-fibrinogen gene. Three hundred and eighty-four male coronary heart disease patients were investigated. Two alleles for each enzyme (+ or - designating, respectively, the presence or absence of the cutting site) were detected. The HaeIII and HindIII cutting sites were in complete linkage disequilibrium. A small but significant increase in fibrinogen level was associated with the rare cutting sites of HaeIII/HindIII, BclI and TaqI. At all polymorphic sites homozygosity for the frequent alleles was associated with about 0.20 g/l lower plasma fibrinogen concentrations than heterozygosity at the respective sites (p < 0.05). The frequencies and natures of the rare alleles were as follows: TaqI (+) 0.28, HaeIII/HindIII (-) 0.22 and BclI (+) 0.17. Mean fibrinogen levels in patients heterozygous for each of the four polymorphisms were 0.47 g/l greater than in subjects homozygous for the frequent allele at each cutting site (HaeIII/HindIII + -, TaqI + -, BclI + -: fibrinogen level 3.58 g/l (n = 32); HaeIII/HindIII + +, TaqI - -, BclI - -: fibrinogen level 3.11 g/l (n = 99), p = 0.003). Each polymorphism accounted for between 0.5 and 1.4% of the overall variance in fibrinogen concentration. Together, the polymorphisms in HaeIII, HindIII and TaqI explained 5.8% of overall variance, a proportion equivalent to that explained by age, smoking and body mass index (5.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2005

Efficacy and tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency.

The efficacy and tolerability of a pasteurised human fibrinogen concentrate were assessed in an open, multi-centre, non-controlled retrospective study in patients with congenital fibrinogen deficiency. Haemostatic efficacy was assessed by laboratory investigation and clinical observation. The study included 12 patients (afibrinogenaemia, n = 8; hypofibrinogenaemia, n = 3; dysfibrinogenaemia combined with hypofibrinogenaemia, n = 1). Fibrinogen substitution was indicated: to stop an ongoing bleed; as prophylaxis before surgery; or for routine prophylaxis to prevent spontaneous bleeding. In total, 151 fibrinogen infusions were recorded. The median single dosage was 63.5mg/kg body weight for bleeding events or surgery and 76.9 mg/kg for prophylaxis. The median total dose per event for bleeding events or surgery was 105.6 mg/kg. Fibrinogen was administered in 26 bleeding episodes; 11 surgical operations; and 89 prophylactic infusions, of which 86 were received by one patient. The median response (n = 8) was 1.5 mg/dl per substituted mg of fibrinogen per kg body weight (0.8-2.3). The median in vivo recovery (n = 8) was 59.8% (32.5-93.9). Clinical efficacy was very good in all events with the exception of one surgical procedure, where it was moderate. No intercurrent bleeding occurred during prophylaxis. All but one infusion was well tolerated; the patient, who was administered 86 prophylactic infusions, experienced an anaphylactic reaction after the 56th infusion. In addition, one patient developed deep vein thrombosis and non-fatal pulmonary embolism with treatment for osteosynthesis after collum femoris fracture. Fibrinogen substitution could not be excluded as a contributing factor in this high-risk patient. Substitution with pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiencies is efficient and generally well tolerated.

Afibrinogenemia↗
PubMed1998

Association between polymorphisms in the fibrinogen alpha- and beta-genes on the post-trauma fibrinogen increase.

Fibrinogen is an acute phase reactant, and therefore its plasma levels increase after severe injury. Polymorphisms in the fibrinogen alpha and beta genes have been found to be associated with plasma levels of fibrinogen, and it has also been suggested that they are associated with the fibrinogen increase in acute phase situations. In forty-five consecutive patients admitted to the Intensive Care Unit after acute cranial or thoracic trauma, we investigated the influence of four polymorphisms at the fibrinogen loci (-455G/A and BclI (beta gene), TaqI and T/A312 (alpha gene)) on the post-trauma increase of the fibrinogen levels. At admission, fibrinogen levels were comparable in the patients with the different genotypes for the four polymorphisms studied. However, patients carrying the -455A allele of the -455G/A polymorphism had a significantly wider variation and higher peak levels of fibrinogen, during their stay at the intensive care unit, than did the -455GA homozygotes (5.1 g/l (SD 1.3) and 5.9 g/l (SD 1.0), respectively, p<0.05). Such difference was not found for the other studied polymorphisms. The present study suggests that the increase of fibrinogen level in acute phase situations like severe trauma is associated with the beta-gene -455G/A polymorphism.

Adult↗
PubMed1981

Interaction of streptococcal cell wall components with fibrinogen. I. adsorption of fibrinogen by immobilized T-proteins of streptococcus pyogenes.

Immobilized streptococcal T1-, T3- and T4-proteins to AH-Sepharose 4B were tested for their ability to absorb human fibrinogen. Purified fibrinogen and plasma samples were used for affinity chromatography. T1-protein was able to retain specifically fibrinogen from plasma. T4-protein bound fibrinogen in a similar manner, but it was not as specific as T1-protein. T3-protein failed to bind purified fibrinogen as well as fibrinogen from plasma. Adsorption of fibrinogen was accomplished using a 0.05 M phosphate/0.2 M NaCl/0.02% NaN3/pH 7.0 buffer system followed by elution with 0.05 M PO4/1 M NaCl/0.02% NaN3 to remove non specifically bound components. Retained components were eluted with 8 M Urea/0.025 M NaOAc, pH 5 and the fractions analyzed for fibrinogen content by SDS polyacrylamide gel electrophoresis. The presence of fibrinogen was determined by observations of the characteristic A alpha, B beta and gamma chain bands.

Adsorption↗
PubMed1995

Staphylococcus aureus induces platelet aggregation via a fibrinogen-dependent mechanism which is independent of principal platelet glycoprotein IIb/IIIa fibrinogen-binding domains.

Platelet aggregation by bacteria is felt to play an important role in the pathogenesis of infective endocarditis. However, the mechanisms involved in bacterium-induced platelet aggregation are not well-defined. In the present study, we examined the mechanisms by which Staphylococcus aureus causes rabbit platelet aggregation in vitro. In normal plasma, the kinetics of S. aureus-induced platelet aggregation were rapid and biphasic. The onset and magnitude of aggregation phase 1 varied with the bacterium-platelet ratio, with maximal aggregation observed at a ratio of 5:1. The onset of aggregation phase 2 was delayed in the presence of apyrase (an ADP hydrolase), suggesting that this later aggregation phase may be triggered by secreted ADP. The onset of aggregation phase 2 was delayed in the presence of prostaglandin I2-treated platelets, and this phase was absent when paraformaldehyde-fixed platelets were used, implicating platelet activation in this process. Platelet aggregation phase 2 was dependent on S. aureus viability and an intact bacterial cell wall, and it was mitigated by antibody directed against staphylococcal clumping factor (a fibrinogen-binding protein) and by the cyclooxygenase inhibitor indomethacin. Similarly, aggregation phase 2 was either delayed or absent in three distinct transposon-induced S. aureus mutants with reduced capacities to bind fibrinogen in vitro. In addition, a synthetic pentadecapeptide, corresponding to the staphylococcal binding domain in the C terminus of the fibrinogen delta-chain, blocked aggregation phase 2. However, phase 2 of aggregation was not inhibited by two synthetic peptides (alone or in combination) analogous to the two principal fibrinogen-binding domains on the platelet glycoprotein (GP) IIb/IIIa integrin receptor: (i) a recognition site on the IIIa molecule for the Arg-Gly-Asp (RGD) sequence of the fibrinogen alpha-chain and (ii) a recognition site on the IIb molecule for a dodecapeptide sequence of the fibrinogen delta-chain. This differs from ADP-induced platelet aggregation, which relies on an intact platelet GP IIb/IIIa receptor with an accessible RGD sequence and dodecapeptide recognition site for fibrinogen. Furthermore, a monoclonal antibody directed against the RGD recognition site on rabbit platelet GP IIb/IIIa receptors failed to inhibit rabbit platelet aggregation by S. aureus. Collectively, these data suggest that S. aureus-induced platelet aggregation requires bacterial binding to fibrinogen but is not principally dependent upon the two major fibrinogen-binding domains on the platelet GP IIb/IIIa integrin receptor, the RGD and dodecapeptide recognition sites.

Adenosine Triphosphate↗
PubMed1996

The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453-A polymorphism of the beta-fibrinogen gene.

We have investigated the effects of chronic physical training and acute intensive exercise on plasma fibrinogen levels and the relationship of these responses to beta-fibrinogen G-453-A polymorphism genotype. One hundred fifty-six male British Army recruits were studied at the start of their 10-week basic training, which emphasizes physical fitness. Cohorts were restudied between 0.5 and 5 days after a major 2-day strenuous military exercise (ME) undertaken in their final week of training. Changes in fibrinogen concentration were adjusted for the effects of age, body mass index, and smoking history. Compared with baseline values, fibrinogen concentrations were significantly lower (11.9%, P=.04) at day 5 after ME, consistent with the beneficial effect of training. However, they were higher on days 1 through 3 after ME (suggesting an "acute-phase" response to strenuous exercise) and were maximal on days 1 and 2 (27.2%, P<.001 and 37.1%, P<.001 respectively). Fibrinogen genotype was available in 149 individuals. As expected from previous studies, men with one or more fibrinogen gene A-453 alleles had plasma fibrinogen concentration slightly but significantly higher at baseline (4.5%, P=.11). During the acute-phase response (days 2 and 3), however, the degree of rise was strongly related to the presence of the A allele, being 26.7+/-5.4% (mean+/-SE), 36.5+/-11.0%, and 89.2+/-30.7 for the GG, GA, and AA genotypes, respectively (P=.01). These results confirm that chronic exercise training lowers plasma fibrinogen levels, that intensive exercise generates an acute-phase rise in levels, and that this acute response is strongly influenced by the G/A polymorphism of the beta-fibrinogen gene.

Adolescent↗
PubMed1971

Functional evaluation of an inherited abnormal fibrinogen: fibrinogen "Baltimore".

The rate of clotting and the rate of development and degree of turbidity after addition of thrombin to plasma or purified fibrinogen from a patient with fibrinogen Baltimore was delayed when compared with normal, especially in the presence of low concentrations of thrombin. Optimal coagulation and development of translucent, rather than opaque, clots occurred at a lower pH with the abnormal fibrinogen than with normal. Development of turbidity during clotting of the abnormal plasma or fibrinogen was less than normal at each pH tested, but was maximal in both at approximately pH 6.4. The physical quality of clots formed from fibrinogen Baltimore was abnormal, as demonstrated by a decreased amplitude on thromboelastography. The morphologic appearance of fibrin strands formed from fibrinogen Baltimore by thrombin at pH 7.4 was abnormal when examined by phase contrast or electron microscopy, but those formed by thrombin at pH 6.4 or by thrombin and calcium chloride were similar to, though less compact, than normal fibrin. The periodicity of fibrin formed from fibrinogen Baltimore was similar to normal and was 231-233 A.A study of the release of the fibrinopeptides from the patient's fibrinogen and its chromatographic subfractions verified the existence of both a normally behaving and a defective form of fibrinogen in the patient's plasma. The defective form differed from normal in three functionally different ways: (a) the rate of release of fibrinopeptides A and AP was slower than normal; (b) no visible clot formation accompanied either partial or complete release of the fibrinopeptides from the defective form in 0.3 M NaCl at pH 7.4; and (c) the defective component possessed a high proportion of phosphorylated, relative to nonphosphorylated, fibrinopeptide A, while the coagulable component contained very little of the phosphorylated peptide (AP). The high phosphate content of the defective component did not appear to be the cause of the abnormality, but may be the result of an associated metabolic or genetic phenomenon.

Blood Coagulation↗
PubMedDate not supplied

Plasma fibrinogen levels and fibrinogen genotype in non-insulin dependent diabetics.

The association between plasma fibrinogen levels, fibrinogen genotype, and the development of macrovascular disease was studied in 100 patients with non-insulin dependent diabetes mellitus (NIDDM). The mean plasma fibrinogen levels in patients with macrovascular disease was higher than those without, although the difference was not statistically significant (3.67 g l-1, and 3.43 g l-1, respectively). The frequency of the rare allele of the fibrinogen gene DNA polymorphism detected with the restriction enzyme Bc1I was slightly higher in the group of patients with disease, but the difference was not statistically significant (0.20 vs 0.16). The frequency of the TaqI polymorphism rare allele was the same in both groups (0.30 vs 0.31). However, the Bc1I polymorphism was strongly associated with plasma fibrinogen levels, with those patients heterozygous for the rare allele having mean levels 16 per cent higher than those lacking the allele (3.81 g l-1 vs 3.28 g l-1, p < 0.05). This data demonstrates that variation at the fibrinogen locus is involved in determining fibrinogen levels in patients with NIDDM, and suggests the possibility that fibrinogen genotype and plasma fibrinogen levels could be one of the factors making a small contribution to the development of macrovascular disease in diabetic patients.

Aged↗
PubMed2003

Myocardial infarction in patients aged less than 40 years. Frequency of BclI polymorphism in the fibrinogen beta-chain gene and plasma fibrinogen.

BACKGROUND: Several polymorphisms in the genes encoding for three separate chains of fibrinogen have been described. Some of them (Hae III and B854) are associated with elevated fibrinogen plasma level. AIM: To determine the frequency of BclI polymorphism in the fibrinogen beta-chain gene (BclI betaFb) in young survivors of myocardial infraction (MI) and to assess the relationship between allele status, plasma fibrinogen concentration and the number of affected coronary arteries. METHODS: The study group consisted of 99 male patients (mean age 43.5, range 29-49 years) with premature coronary artery disease (CAD) diagnosed by coronary angiography who had MI in the mean age of 37.4+/-3.2 years. The control group involved 78 age- and gender-matched healthy volunteers. DNA was extracted from peripheral blood leukocytes using standard methods. Fibrinogen blood concentration was determined using biuretic method. The BclI polymorphism in the fibrinogen beta-chain gene was investigated using polymerase chain reaction (PCR). RESULTS: Obesity was found in 15%, smoking - in 89%, hypertension - in 21%, diabetes - in 14% and hyperlipidemia - in 86% of MI patients. A family history of MI was present in 50% of patients. Coronary angiography revealed single-vessel disease in 34%, two-vessel disease in 36%, and three-vessel disease in 16% of patients. In two patients coronary angiography was normal. The frequency of BclI polymorphism of the beta-fibrinogen gene was significantly higher in MI patients than in controls (40.4% vs 29.5%, p<0.01). Moreover, in MI patients carrying the mutant allele a higher concentration of blood fibrinogen was found in comparison to patients without this anomaly (3.87 vs 3.55 g/L, p=0.05). There was no evidence of an association between the number of affected coronary arteries and polymorphism of BclI betaFbg gene status. However, all patients carrying BclI polymorphism of betaFbg gene had abnormal coronary angiography, contrary to patients without any defect. CONCLUSIONS: 1. Polymorphism of BclI betaFbg gene is associated with an increased fibrinogen plasma level. 2. There is no association between BclI polymorphism of betaFbg gene and the number of affected coronary arteries. This may confirm the hypothesis of multi-factorial aetiology of CAD in young patients suffering MI.

Adult↗
PubMed2005

[Nine polymorphisms of fibrinogen gene and their association with plasma fibrinogen levels in Hainan Han population].

OBJECTIVE: To investigate the allelic frequencies of polymorphisms of alpha Taq I and beta Bcl I, Hinf I A/C, 448 G/A, beta BsmA I G/C, +1689T/G, -148C/T, -249C/T, -455G/A in Hainan Han population and their association with plasma fibrinogen level. METHODS: Turbidmetric assay was used to measure plasma fibrinogen level of two hundred and thirty-eight healthy individuals. The genotypes were characterized by PCR-RFLP and sequence analysis. The relationships between the genotypes and plasma fibrinogen levels were analyzed by t test and ANOVA. RESULTS: The frequencies of the rare alleles of alpha Taq I and beta Bcl I, Hinf I A/C, 448 G/A, beta BsmA I G/C, +1689T/G, -148C/T, -249C/T, -455G/A polymorphisms were 0.445, 0.239, 0.134, 0.235, 0.273, 0.241, 0.265, 0.441, 0.254 respectively. In the general population, the plasma fibrinogen level is significantly higher in the groups of genotypes -455GA and AA, -148CT and TT, alpha Taq I T1T1 than in the group of wild types(P=0.004, 0.015 and 0.043 respectively). In the men, plasma fibrinogen level is significantly higher in the groups of genotypes -455GA and AA, -148CT and TT, alpha Taq I T1T1, alpha Taq I T1T2 than in the group of wild types(P=0.001, 0.023, 0.003 and 0.032 respectively). In the women, no significant genotype association with plasma fibrinogen level was detected. CONCLUSION: There was linkage disequilibrium between the fibrinogen gene loci. The beta -455G/A beta 448G/A, alpha Fg Taq I polymorphisms were associated with the difference in plasma fibrinogen in men. A(-455), T(-148) and alpha Taq I T1 alleles were associated with higher fibrinogen levels.

Adult↗
PubMed1998

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.

BACKGROUND AND OBJECTIVE: 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.

Diabetes Mellitus↗