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PubMed2002

Association of beta-fibrinogen and factor VII polymorphism with plasma fibrinogen and factor VII levels, and no association of PAI-1 polymorphism with plasma PAI-1 levels in hemodialysis patients.

AIMS: Recent studies have stressed the roles of genetic factors on the plasma levels of hemostatic markers and on cardiovascular complications. We investigated the association of DNA polymorphisms for beta-fibrinogen, factor VII, and PAI-1 with plasma levels of these factors and with ischemic heart disease (IHD) and cerebral infarction (CI) in patients undergoing hemodialysis (HD). METHODS: beta-fibrinogen G/A-455, factor VII R353Q and PAI-1 4G/5G polymorphisms were determined by PCR-RFLP in 149 HD patients and in 100 controls. The plasma levels of fibrinogen, factor VII and PAI-1 were also measured. RESULTS: The allele frequencies and the genotype frequencies of these 3 polymorphisms were not different between HD patients and controls. In HD patients, plasma fibrinogen levels were significantly lower in the GG genotype than in the GA genotype, and plasma factor VII activity was significantly higher in the RR genotype than in the RQ genotype. Multiple regression analysis disclosed that CRP and beta-fibrinogen polymorphism were the significant determinants of fibrinogen levels. Plasma PAI-1 levels were not different among the 3 genotypes. The frequency of the A-455 allele was significantly higher in HD patients with CI than in those without CI, and the genotype distribution for beta-fibrinogen differed significantly between the 2 groups. Between the same 2 groups, however, significant differences were found neither in the frequency of the 353Q or 4G allele nor in the genotype distribution for factor VII and PAI-1. No significant differences in the frequency of the G-455, 353Q or 4G alleles, or in the genotype distribution for beta-fibrinogen, factor VII and PAI-1 were observed between patients with IHD and those without IHD. Multiple logistic regression analysis demonstrated that neither polymorphism was associated with CI or IHD. CONCLUSIONS: In HD patients, beta-fibrinogen and factor VII polymorphisms affected plasma levels of fibrinogen and factor VII, respectively. Beta-fibrinogen polymorphism was not an independent but a possible risk factor for CI in HD patients. Further study will be needed to confirm the precise role of 5-fibrinogen polymorphisms in the pathogenesis of CI in HD patients.

Adult↗
PubMed2001

Increased hepatic fibrinogen Bbeta-gene transcription is not enough to increase plasma fibrinogen levels. A transgenic mouse study.

The fibrinogen Aalpha, Bbeta, and gamma polypeptides are encoded by three separate genes, which are arranged in the order gamma-alpha-beta. In order to study the biosynthesis of fibrinogen in vivo we generated a line of transgenic mice carrying extra copies of the fibrinogen beta-gene. To clone the mouse fibrinogen Bbeta-chain gene, a mouse 129 Sv/Ev genomic cosmid library was screened, using the mouse fibrinogen Aalpha-, Bbeta-chain cDNA. A clone containing the complete fibrinogen Bbeta-chain gene including approximately 11-kb of the natural promoter region was identified and subsequently microinjected into mice. Southern blot analysis identified a founder that carried additional copies of the fibrinogen Bbeta-chain gene. Transgenic offspring of this founder were interbred and heterozygous and homozygous transgenic mice were obtained. Northern blot analysis demonstrated approximately a 3-fold increase in fibrinogen Bbeta mRNA in heterozygous mice as compared to wild-type, whereas homozygous transgenic mice showed approximately a 9-fold increase. The levels of the Aalpha and gamma mRNAs in transgenic homozygous mice were not changed as compared to those in wild-type mice. Fibrinogen levels in plasma were not significantly increased in transgenic mice as compared to wild-type mice. These results indicate that: additional copies of the fibrinogen Bbeta-chain gene lead to increased levels of the Bbeta-chain mRNA in the liver; the increased levels of Bbeta-chain mRNA in homozygous overexpression mice do not change the transcription levels of the two other fibrinogen mRNAs in vivo; the absence of an increased plasma fibrinogen level in the transgenic mice indicates that this level is not regulated solely by transcription of the Bbeta-chain gene.

Animals↗
PubMed1998

Microvesicles bind soluble fibrinogen, adhere to immobilized fibrinogen and coaggregate with platelets.

In the present study we have investigated whether platelet derived microvesicles can bind soluble fibrinogen, bind to immobilized fibrinogen, and coaggregate with platelets. Flow cytometry was used for studies on binding of soluble fibrinogen and coaggregation, whereas ELISA wells were used to study binding of microvesicles to immobilized fibrinogen. Biotinylated microvesicles produced by stimulation with A23187, thrombin or SFLLRN of platelets which had been surface-labelled with biotin, were used both for the coaggregation experiments and for the binding studies with immobilized fibrinogen. Unlabelled microvesicles and biotinylated fibrinogen were employed when studying binding of soluble fibrinogen to the microvesicles. For the flow cytometry, the biotinylated proteins were reacted with avidin or streptavidin which was PE-conjugated, whereas the same substances were conjugated with alkaline phosphatase for the ELISA studies. The microvesicles formed after stimulation of platelets by SFLLRN or A23187 clearly bound the soluble, biotinylated fibrinogen. Moreover, isolated biotinylated microvesicles added to washed platelets prior to activation, were associated to the microaggregates that formed after stimulation. A significant binding of biotinylated microvesicles to immobilized fibrinogen could also be detected. The binding of microvesicles to soluble and immobilized fibrinogen and association to platelets was clearly specific and at least partly dependent on the GPIIb-IIIa complex, as all of these phenomena could be prevented or reduced by addition of the c7E3 Fab which blocks the activated form of this receptor complex. From these in vitro results it is clear that microvesicles can bind to immobilized fibrinogen, bind soluble fibrinogen and are able to coaggregate with platelets. It may be speculated that these results also reflect a haemostatic role of microvesicles in vivo.

Blood Platelets↗
PubMed1982

Fibrinogen Bondy: a new case of dysfibrinogenemia. Isolation of the abnormal fibrinogen molecules.

In a 81 year old health woman, gross abnormalities of fibrin formation led to the discovery of an abnormal fibrinogen named fibrinogen Bondy. Clottability of purified fibrinogen Bondy was only 53% compared to 95-98% for normal fibrinogen. Functional studies revealed (i) delayed coagulation by thrombin and batroxobin (Reptilase), (ii) incomplete release of fibrino-peptides A and B, (iii) poor fibrin monomer aggregation, (iv) delayed fibrin proteolysis by plasmin. Electrophoretic mobility of fibrinogen Bondy, its three chains and the products of fibrin cross-linking, was normal. Fibrinogen NH2-terminal residues of fibrinogen Bondy were found to be normal. The presence of Ala, in addition to Gly and Tyr in the fibrin clot and its supernatant, showed that a part of fibrinogen molecules was not clotted, i.e. either copolymerised with fibrin or remaining in solutions. Gel filtration of the supernatant allowed the separation of both soluble complexes and fibrinogen. This fibrinogen population was shown to be unclottable by thrombin and to inhibit clotting of normal fibrinogen.

Aged↗
PubMed1985

Precipitation of fibrinogen, fibrinogen degradation products and fibrin monomer by histone H3.

Incubation of histone H3 with normal citrated plasma resulted in the formation of insoluble aggregates, as determined by turbidity measurements. The precipitate was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, confirming that fibrinogen was a major component. Purified fibrinogen precipitated rapidly as determined with turbidity experiments and experiments with radioiodinated protein. The amount of fibrinogen precipitation was strongly dependent on H3 concentration. Variation of ionic strength (0.2-0.84) and pH (5.3-7.4), however, had little or no effect on the reaction. Fibrinogen subjected to gelatin-Sepharose chromatography or dialysis against 3.3M urea reacted equivalently with H3. Precipitation of 125I-fibrinogen by H3 was strongly favored by increasing temperature (4 degrees-45 degrees C). Precipitation of fibrinogen by protamine was maximized by decreasing the temperature. In addition, formation of insoluble fibrinogen-protamine aggregates was highly dependent on ionic strength and pH, suggesting that different types of protein-interaction are involved in the two studied precipitation reactions. Of the fibrinogen degradation products, only fragment X precipitated significantly when incubated with H3. Radioiodinated fibrin monomer also precipitated when incubated with H3 in solutions of sufficient ionic strength to prevent spontaneous polymerization. The extent of precipitation was equivalent for fibrin monomer and fibrinogen. Fragment D inhibited the precipitation of fibrinogen by H3 or protamine. These studies indicate that the proteins termed "paracoagulants" are not all equivalent and that the hydrophobic domain of H3 plays a critical role in fibrinogen precipitation.

Chemical Precipitation↗
PubMed1996

The relationship between the fibrinogen D domain self-association/cross-linking site (gammaXL) and the fibrinogen Dusart abnormality (Aalpha R554C-albumin): clues to thrombophilia in the "Dusart syndrome".

Cross-linking of fibrinogen at its COOH-terminal gamma chain cross-linking site occurs in the presence of factor XIIIa due to self-association at a constitutive D domain site ("gammaXL"). We investigated the contribution of COOH-terminal regions of fibrinogen Aalpha chains to the gammaXL site by comparing the gamma chain cross-linking rate of intact fibrinogen (fraction I-2) with that of plasma fraction I-9, plasmic fraction I-9D, and plasmic fragment D1, which lack COOH-terminal Aalpha chain regions comprising approximately 100, approximately 390, and 413 residues, respectively. The cross-linking rates were I-2 > I-9 > 1-9D = D1, and indicated that the terminal 100 or more Aalpha chain residues enhance gammaXL site association. Fibrinogen Dusart, whose structural abnormality is in the COOH-terminal "alphaC" region of its Aalpha chain (Aalpha R554C-albumin), is associated with thrombophilia ("Dusart Syndrome"), and is characterized functionally by defective fibrin polymerization and clot structure, and reduced plasminogen binding and tPA-induced fibrinolysis. In the presence of XIIIa, the Dusart fibrinogen gamma chain cross-linking rate was about twice that of normal, but was normalized in proteolytic fibrinogen derivatives lacking the Aalpha chain abnormality, as was reduced plasminogen binding. Electron microscopy showed that albumin-bound Dusart fibrinogen "alphaC" regions were located in the vicinity of D domains, rather than at their expected tethered location near the fibrinogen E domain. In addition, there was considerable fibrinogen aggregation that was attributable to increased intermolecular COOH-terminal Aalpha chain associations promoted by untethered Dusart fibrinogen aC domains. We conclude that enhanced Dusart fibrinogen self-assembly is mediated through its abnormal alphaC domains, leads to increased gammaXL self-association and gamma chain cross-linking potential, and contributes to the thrombophilia that characterizes the "Dusart Syndrome."

Dextrans↗
PubMed1985

Characterization of fibrinogen New York 1. A dysfunctional fibrinogen with a deletion of B beta(9-72) corresponding exactly to exon 2 of the gene.

Fibrinogen New York 1 (NY-1) was identified in a family with a thrombotic tendency. Studies on fibrinogen NY-1 and the fibrinogen from her brother, designated NY-1a, showed that both have abnormal thrombin-nonclottable fibrinogen (50% of the total fibrinogen in NY-1 and 35-40% in NY-1a) and that the trait is heterozygous and autosomal codominant. The abnormal fibrinogen polymerizes in the presence of calcium and can be further cross-linked by Factor XIIIa. The release rates of fibrinopeptides A and B by thrombin from both (NY-1 and NY-1a) were slower than those from normal fibrinogen. Two mol of fibrinopeptide A but only 0.6-1.0 (NY-1) or 1.0-1.3 (NY-1a) mol of fibrinopeptide B were released per mol of fibrinogen. Additionally, only 1.0 (NY-1) or 1.3 (NY-1a) mol of the B beta(1-42) peptide were released by plasmin/mol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the reduced fibrinogen revealed two protein bands in the B beta-chain region (Mr = 54,000 as compared with 57,300 for the normal). When NY-1a fibrinogen was treated with CNBr, two sizes of the NH2-terminal disulfide knot were obtained (Mr = 59,000 and 49,000). The Mr = 49,000 component is consistent with an abnormal NH2-terminal disulfide knot with two defective NH2-terminal B beta-chains. Amino acid sequence analyses demonstrated that the abnormal B beta-chain is the result of a deletion in the sequence from residues 9 to 72. This deletion corresponds exactly to exon 2 of the gene. Since this family has a thrombotic tendency, the defect in the fibrinogen may be important in the pathogenesis of thrombosis in this family.

Amino Acid Sequence↗
PubMed1981

Immunochemical mapping of the conformation of human fibrinogen. The gamma 95-264 segment in inaccessible to antibody in native fibrinogen but progressively exposed by plasmic cleavage.

The accessibility of the gamma 95-264 sequence to specific antibody probes in the native fibrinogen molecule and its plasmic cleavage fragments have been investigated. The gamma 95-264 segment was generated by cyanogen bromide cleavage of the gamma chain and isolated by gel filtration and ion exchange chromatography. Rabbit antisera to this peptide and to gamma chain recognized at least five antigenic loci uniformly distributed throughout this segment. In primary binding assays, antibodies to gamma 95-264 bound gamma 95-264, free gamma chain, and fibrinogen fragment D, but not native fibrinogen. Also, gamma 95-264 was bound by antibodies to gamma chain and fibrinogen fragment D, but not by antibodies generated to native fibrinogen. Thus, the gamma 95-264 sequence was not accessible to antibody in the native structure. In competitive equilibrium radioimmunoassays, neither native fibrinogen nor highly soluble fibrinogen fraction I-9 inhibited the binding of gamma 95-264 by its antiserum or anti-gamma chain. With plasmic cleavage, however, the gamma 95-264 sequence became accessible to antibody and the series of fragments D greater than Y greater than D:E = X describes the relative reactivity of the gamma chain sequence in fibrinogen degradation products. Differential expression of gamma 95-264 antigenic loci was also observed with D fragments differing in molecular weight. Plasmic cleavage of cross-linked and noncross-linked fibrin generated D fragments which did not express gamma 95-264 as well as fibrinogen D derivatives, indicating that the D domains of fibrinogen and fibrin are immunochemically distinguishable. These findings indicate that the central segment of the gamma chain is inaccessible to antibody in native fibrinogen, but that proper surface orientation is achieved upon plasmic degradation.

Antibodies↗
PubMed1994

Fluorescein derivatization of fibrinogen for flow cytometric analysis of fibrinogen binding to platelets.

Dog and human fibrinogen were derivatized with N-hydroxysuccinimido-fluorescein and utilized for flow cytometric estimation of fibrinogen binding to activated platelets. Fluorescein-fibrinogen binding fulfilled the criteria for specific binding to platelets; the binding was saturable, dependent on agonist activation, and inhibited by unlabeled fibrinogen. In addition, EDTA and barbourin, a KGD-containing peptide, were found to inhibit the binding of fluorescein-fibrinogen. Fluorescein-fibrinogen bound to dog platelets with an apparent affinity of 0.31 microM after stimulation with either adenosine-5'-diphosphate (ADP) or plateletactivating factor. The labeled fibrinogen was also used to study the fibrinogen binding capacity of aged, biotinylated platelets. Aged platelets were indistinguishable from young platelets with regard to fibrinogen binding in response to ADP. These studies document that direct derivatization of fibrinogen with fluorescein generates a useful probe for analyzing fibrinogen binding to platelets with flow cytometry.

Adenosine Diphosphate↗
PubMed2006

Glycation of fibrinogen in uncontrolled diabetic patients and the effects of glycaemic control on fibrinogen glycation.

INTRODUCTION: Evidence exists for a relationship between glycaemic control and macrovascular disease. Non-enzymatic glycation of proteins may explain this relationship in part. We investigated the effect of blood glucose control, under out-patient conditions, on fibrinogen glycation as well as the relationship between glycated fibrinogen and glycaemic control using a new sensitive method for the measurement of glycated fibrinogen. MATERIALS AND METHODS: Blood samples were taken from twenty subjects with uncontrolled Type 2 diabetes (HbA1c>7%) to determine the levels of glycation. The subjects were then treated with insulin in order to control blood glucose. Twenty age and BMI matched non-diabetic subjects were included as a reference group. RESULTS: The subjects with diabetes had significantly higher mean fibrinogen glycation at baseline than the non-diabetic subjects (7.84 vs 3.89 mol glucose/mol fibrinogen; p<0.001). After control of blood glucose, fibrinogen glycation was reduced significantly in the subjects with diabetes (7.84 to 5.24 mol glucose/mol fibrinogen; p<0.0002). The change in glycation during the intervention correlated significantly with the change in capillary glucose in the diabetic group (r=0.6, p=0.005). Fibrinogen glycation was comparable to HbA1c in predicting glycaemic control (p=0.54). Fibrinogen glycation correlated best with the average fasting capillary glucose of the preceding 5-8 days (r=0.54, p=0.014). CONCLUSION: We conclude that glucose control under out-patient conditions decreases fibrinogen glycation in subjects with Type 2 diabetes and that glycated fibrinogen compares well with HbA1c in its relation to glycaemic control.

Adult↗
PubMed2000

Contribution of fibrinogen and lipoproteins to plasma viscosity in hypercholesterolemia and hypertriglyceridemia: evaluation by selective depletion of low-density lipoproteins or fibrinogen.

Epidemiological studies suggest that the plasma fibrinogen concentration is the main determinant of plasma viscosity (PV), but the concentration of other macromolecules (eg, immunoglobulins) and low-density lipoprotein (LDL) cholesterol and triglycerides are also correlated with PV. However, only a few data exist concerning the in vitro effects of these plasma constituents on PV. Therefore, we investigated PV before and after the specific elimination of fibrinogen and LDL in hypercholesterolemic and hypertriglyceridemic plasma. First, hypercholesterolemic samples (n = 7) were pumped simultaneously through 2 columns: a fibrinogen-depleting column containing the pentapeptide Gly-Pro-Arg-Pro-Lys (GPRPK) and a LDL-depleting column containing specific antibodies against apolipoprotein B-100. In the plasma and in each fraction from the column, the cholesterol level was measured enzymatically, fibrinogen was determined by immunonephelometry, and PV was analyzed using a low-shear rotation viscosimeter. After the fibrinogen-depleting column, the fibrinogen concentration decreased from 3.21 +/- 0.20 to 0.94 +/- 0.16 g/L (P < .005), inducing a decrease in PV from 1.27 +/- 0.02 to 1.17 +/- 0.01 mPas (milliPascal seconds) (P < .005). Despite a marked reduction of the LDL cholesterol after the LDL-depleting column (from 6.40 +/- 0.23 to 4.08 +/- 0.32 mmol/L, P < .005), PV remained unchanged. Second, hypertriglyceridemic samples (n = 7) were pumped through the fibrinogen-depleting column, which reduced the fibrinogen concentration from 4.29 +/- 0.79 to 1.62 +/- 0.69 g/L (P < .001) and PV from 1.42 +/- 0.06 to 1.03 +/- 0.05 mPas (P < .01) while the triglyceride concentration remained unchanged. Our results confirm the epidemiological correlation between the fibrinogen concentration and PV in patients with hypercholesterolemia and hypertriglyceridemia. The influence of fibrinogen on PV seems much more pronounced than the direct effect of lipoprotein concentrations. Therefore, the elevated PV in patients with hypercholesterolemia and especially with hypertriglyceridemia seems mainly due to elevated fibrinogen levels.

Antibodies↗
PubMed1993

Anti-fibrinogen antibody mediates fibrinogen binding to platelet membrane glycoprotein IIb-IIIa.

The binding of fibrinogen to platelets requires the agonist activation of platelet membrane glycoprotein IIb/IIIa. We have now found an anti-fibrinogen polyclonal antibody (YCU-R3) that increases the fibrinogen affinity of GPIIb/IIIa-binding function (activation) and subsequent platelet aggregation. The addition of intact IgG, F(ab)2 fragments or Fab fragments induced platelet aggregation. The antibody-mediated fibrinogen binding was specific and saturable. This binding was inhibited by native fibrinogen, the RGDS peptide, the peptide of the C-terminus gamma chain of fibrinogen (gamma 397-411), and the anti-GPIIb/IIIa monoclonal antibody (LJ-CP8). The antibody-dependent fibrinogen binding was similar to that induced by ADP. Moreover, after pretreatment with the anti-fibrinogen antibody and fibrinogen, formalin-fixed platelets bound to fibrinogen saturably. These results suggest that this anti-fibrinogen antibody may function as partial agonist.

Antibodies↗
PubMed1993

Genetic variation at the beta-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM Study.

Increased plasma fibrinogen concentration is a major cardiovascular risk factor. Conflicting results on genetic variations in plasma fibrinogen levels have been reported. Furthermore, whether fibrinogen genotype is associated with the risk of ischemic heart disease has not been studied so far. An HaeIII restriction fragment length polymorphism of the beta-fibrinogen gene was used in a case-control study to investigate the genetic variation at this locus in relation to plasma fibrinogen concentrations and the risk of myocardial infarction (MI). Five hundred thirty-three male patients aged 27-66 years and 648 control subjects were recruited from four World Health Organization MONICA centers in Northern Ireland and in France. The absence of the HaeIII cutting site (H2 allele) was associated with a significant rise in fibrinogen concentrations in both patients and control subjects. The effect of the HaeIII polymorphism on plasma fibrinogen levels did not significantly differ between centers. Fibrinogen levels were higher in smokers than in nonsmokers. The difference between the two groups was larger in subjects with the genotype H2H2 than in those with either genotype H1H1 or H1H2, regardless of the case-control status. However, there was no significant interaction between smoking status and genotype in their effects on variance in fibrinogen levels, whereas fibrinogen levels. HaeIII genotype accounted for approximately 1% of the total variance in fibrinogen levels, whereas smoking and age together explained 7% and 5% in control subjects and patients, respectively. The frequency of the H2 allele was 0.21 in control subjects and 0.19 in patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Gender-specific associations of the fibrinogen B beta 448 polymorphism, fibrinogen levels, and acute cerebrovascular disease.

Fibrinogen is an independent risk factor for the development of stroke. Factors influencing circulating levels of fibrinogen include age, smoking, gender, and genetic factors. The aim of this study was to determine the relationship between a polymorphism at position 448 of the B beta fibrinogen gene, fibrinogen levels, gender, and the risk of stroke. Fibrinogen levels were determined in 305 patients with stroke, taken within 10 days of the acute event and 3 months later, and in 197 control subjects. Initial fibrinogen levels in patients (4.49 g/L) were significantly higher than at 3 months (3.85 g/L, P < .0001), consistent with resolution of the acute-phase response. At 3 months, levels were only significantly higher than for control subjects in the male patients (3.86 g/L versus 3.31 g/L, P < .0001). Fibrinogen levels were associated with B beta 448 genotype in male patients at 3 months (1/1 = 3.62 g/L, 1/2 + 2/2 = 4.27 g/L, P = .01). There was a significant difference in the genotype distribution in female patients and control subjects (patients: 1/1 = 95, 1/2 = 34, 2/2 = 6; control subjects: 1/1 = 61, 1/2 = 50, 2/2 = 3, P = .008). These data suggest that the mechanisms linking fibrinogen and the development of cerebrovascular disease are different in males and females. In male patients, the increase in fibrinogen levels may be influenced by environmental factors, while in females there may be a functional difference in the fibrinogen molecule unrelated to fibrinogen levels.

Acute Disease↗
PubMed1974

Fibrinogen Cleveland II. An abnormal fibrinogen with defective release of fibrinopeptide A.

An abnormal fibrinogen (fibrinogen Cleveland II) was detected in the plasma of a 23-yr-old white man with a mild bleeding diathesis. The one-stage prothrombin time, thrombin time, and Reptilase time were all prolonged. 16 of 24 tested relatives had the defect, which appeared to be transmitted as an autosomal dominant characteristic. The thrombin time of normal plasma was slightly inhibited by the proband's plasma. The abnormally long thrombin time of fibrinogen Cleveland II was partially corrected by addition of calcium ions. Fibrinogen Cleveland II was indistinguishable from normal fibrinogen by immunoelectrophoresis, DEAE-cellulose column chromatography, or polyacrylamide gel electrophoresis of reduced fibrinogen in sodium dodecyl sulfate. The major defect detected appeared to be impaired release of fibrinopeptide A when fibrinogen Cleveland II was incubated with thrombin. This defect was localized to the NH(2)-terminal disulfide knot portion of the molecule. An abnormality of polymerization of fibrin monomers was also present, but the abnormal fibrin demonstrated relatively normal crosslinking. Despite these defects, fibrinogen Cleveland II achieved a degree of coagulability similar to normal fibrinogen and appeared to incorporate some molecules of fibrin with intact fibrinopeptide A into the clot. The fibrin clot that was formed appeared to be abnormal by electron microscopy. These functional defects and other descriptive characteristics appear to distinguish fibrinogen Cleveland II from other inherited abnormal fibrinogens.

Adult↗
PubMed1997

A common mutation (G-455--> A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study.

A common mutation (G-455--> A) in the promoter region of the beta-fibrinogen gene has been associated with elevated plasma fibrinogen levels. Whether fibrinogen genotype affects plasma fibrinogen levels and risk of ischemic heart disease in the general population has not been studied. We investigated the association between fibrinogen genotype, plasma fibrinogen levels, and ischemic heart disease in a general population sample (n = 9,127). The A-allele (relative frequency, 0.20) was associated with elevated plasma fibrinogen levels in both genders (P < 0.001). While the effect of the A-allele on fibrinogen level was additive in men, the effect was dominant in postmenopausal women. The A-allele raising effect appeared to be two- to threefold greater in individuals with ischemic heart disease than in those without. An increase of 1 SD in plasma fibrinogen increased the odds ratio for ischemic heart disease by approximately 20% (P < 0.01 for women and < 0.005 for men). However, the frequency of the A-allele was similar in those with and without ischemic heart disease, and genotype was not a predictor of disease. These results demonstrate that the (G-455--> A) mutation in the promoter region of the beta-fibrinogen gene is associated with an increase in plasma fibrinogen in both genders in the general population. This increase does not appear to cause ischemic heart disease.

Adult↗
PubMed2000

Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Although several mutations in the fibrinogen genes associated with dysfibrinogenemia and hypofibrinogenemia have been described, the genetic defects of congenital afibrinogenemia are largely unknown, except for a recently reported 11-kb deletion of the fibrinogen Aalpha-chain gene. Nevertheless, mutation mechanisms other than the deletion of a fibrinogen gene are likely to exist because patients with afibrinogenemia showing no gross alteration within the fibrinogen cluster have been reported. We tested this hypothesis by studying the affected members of two families, one Italian and one Iranian, who had no evidence of large deletions in the fibrinogen genes. Sequencing of the fibrinogen genes in the 2 probands detected 2 different homozygous missense mutations in exons 7 and 8 of the Bbeta-chain gene, leading to amino acid substitutions Leu353Arg and Gly400Asp, respectively. Transient transfection experiments with plasmids expressing wild-type and mutant fibrinogens demonstrated that the presence of either mutation was sufficient to abolish fibrinogen secretion. These findings demonstrated that missense mutations in the Bbeta fibrinogen gene could cause congenital afibrinogenemia by impairing fibrinogen secretion. (Blood. 2000;95:1336-1341)

Adolescent↗
PubMed1975

Fibrinogen ""New York"--an abnormal fibrinogen associated with thromboembolism: functional evaluation.

A 54-yr-old woman presented with a 23-yr history of repeated life-threatening thromboembolism. The presence of a qualitatively abnormal fibrinogen was suggested by the demonstration of delayed and incomplete coagulation of plasma or partially purified fibrinogen by thrombin or Reptilase. Two brothers showed a similar in vitro defect but were clinically not affected. The plasma fibrinogen concentration was 0.50-1.64 mg/ml when estimated by heat turbidity, clottability, or immunologic techniques. The serum contained 80-820 mug/ml of unclottable fibrinogen-related materials even after 24 hr exposure to thrombin. The fibrinogen-related material in the serum showed faster anodal mobility an immunoelectrophoresis than that of normal plasma. Immunodiffusion studies with rabbit antihuman fibrinogen antiserum showed lines of identity between control plasma and the patient's plasma and serum. Studies of the kinetics of thrombin action on fibrinogen demonstrated impaired release of fibrinopeptide A and B and defective polymerization of preformed fibrin monomers. The maximum amount of fibrinopeptide A released by exhaustive treatment with thrombin was similar (per milligram protein) for both the patient's and control fibrinogen. This abnormal fibrinogen varient is tentatively designated fibrinogen "New York"; its possible identity with one of the previously described abnormal fibrinogens has not been excluded.

Aprotinin↗