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PubMed1986

Plasmodium coatneyi: alterations of transcapillary escape rate and capillary permeability to fibrinogen in rhesus monkeys.

The transcapillary escape rate and plasma clearance of fibrinogen were studied in six rhesus monkeys infected with Plasmodium coatneyi as well as in six control monkeys using 131I-fibrinogen as a tracer. The mean transcapillary escape rate of fibrinogen in the infected group was significantly higher than that of the control group. Both plasma volume and plasma fibrinogen concentration were also elevated in the infected group, these resulting in a significantly higher intravascular fibrinogen mass, plasma clearance rate, and outflux of fibrinogen from the intravascular to the extravascular compartments. Both effective capillary pore area/unit path length available for restricted diffusion and the specific permeability coefficient of plasma fibrinogen in the infected monkeys were also found to be significantly higher than those of the control group. These findings indicated that there was an increased leakage of plasma fibrinogen from the circulation into the extravascular space which was due either to increased capillary surface area and/or to an increased capillary permeability in rhesus monkeys infected with P. coatneyi.

Animals↗
PubMed1993

Inverse relationship between physical activity and plasma fibrinogen in postmenopausal women.

The relationship between habitual physical activity and plasma level of fibrinogen was investigated in a cohort of 180 postmenopausal women, aged 60-69 years. Plasma fibrinogen was determined from prediluted plasma by adding an appropriate amount of thrombin to the sample. The time until fibrin formation occurred was measured. Physical activity during the month and year preceding the examination was assessed using self-administered questionnaires. There was a statistically significant inverse relationship between physical activity and fibrinogen (beta = -0.20; P = 0.005). For further analyses of the association between physical activity and fibrinogen the subjects were classified into three categories according to their weekly physical activity frequency: 0 to 1, 2 to 3, and 4 or more during the preceding month. The mean (S.D. [95% CI]) levels of fibrinogen from lowest to highest categories were: 3.49 (1.10 [2.99, 3.99]), 3.31 (1.52 [2.82, 3.81]), and 3.20 (2.26 [2.73, 3.67]) g/l, respectively, when age, body mass index (BMI), smoking, alcohol intake, LDL-cholesterol and estrogen use were allowed for (P = 0.021). BMI was directly associated with fibrinogen (beta = 0.30; P < 0.001), especially in the physically least active women. Smoking was directly (beta = 0.19; P = 0.006) and estrogen use inversely (beta = -0.15; P = 0.037) related to plasma fibrinogen level. The present data suggest that in postmenopausal women a low level of physical activity is associated with a high level of plasma fibrinogen.

Aged↗
PubMed1985

Factor XIII catalyzed formation of fibrinogen-fibronectin oligomers--a thiol enhanced process.

Fibrinogen and plasma fibronectin were shown to interact in the presence of factor XIIIa. The reaction was enhanced by dithiothreitol and was accompanied by an increase in the turbidity of the solution and the formation of particulate matter and gel structures. At a constant concentration of fibrinogen the turbidity increase was dependent on the fibronectin concentration and at a constant concentration of fibronectin, on the fibrinogen concentration. Kinetic experiments showed that an initial step in the reaction between fibrinogen and fibronectin was the formation of a transient intermediate containing 1 mole of fibrinogen and 1 mole of fibronectin. Transient intermediates of larger molecular weight and containing both fibrinogen and fibronectin were also formed. These heterooligomers eventually reached huge molecular sizes and at early times formed particulate matter that sedimented on centrifugation. The predominant molecular species formed in an equimolar mixture of fibrinogen and fibronectin were heteropolymers. Small amounts of homopolymers composed of fibrinogen and possibly also homopolymers of fibronectin were detected. The results are discussed in terms of reaction mechanism and potential importance of this novel oligomerization pathway in haemostasis, thrombosis and tissue repair.

Dithiothreitol↗
PubMed1986

Half life and incorporation into venous thrombi of the normally occurring plasma fibrinogen fractions HMW and LMW.

The main plasma fibrinogen species, high molecular weight fibrinogen (HMW, mw. 340,000) and LMW (mw. 305,000), displaying different in vitro properties, were examined as to half-life and incorporation into venous thrombi (DVT). Total plasma fibrinogen and relative amounts of HMW were measured pre- and postoperatively in eighteen patients undergoing total hip arthroplasty, and related to the occurrence of deep vein thrombosis, as determined by the fibrinogen uptake test (FUT). Total fibrinogen and HMW did not disclose significant differences between scan-negative and scan-positive groups. HMW and LMW, prepared from purified fibrinogen, were labelled with I125 and I131, injected simultaneously and the incorporation into thrombi registered by leg-scanning. In 5 patients demonstrating a positive FUT, HMW as well as LMW were incorporated approximately to the same extent. This result implies that neither of these fibrinogen fractions offer any advantage as compared to ordinary fibrinogen when used for FUT. The half-lives of HMW and LMW were calculated from the elimination curves of the plasma clot-radioactivity. In all the surgical patients (n = 10) as well as in the two medical DVT-patients and in two healthy volunteers the half-life of LMW was approximately 10% longer than that of HMW.

Fibrinogen↗
PubMed1987

Endogenous forms of fibrinogen in Hep G2 cells.

The three polypeptide chains of fibrinogen, A alpha, B beta and gamma chain, are synthesized on separate polysomes. Fully formed fibrinogen is a six chain, disulfide-linked, dimeric molecule with a molecular weight of 340kDa. Previous pulse-chase studies with L-35 S methionine using the human hepatocellular carcinoma cell line, Hep-G2, showed that the three chains are not immediately disulfide-linked and that there exist intermediate precursors as well as pools of A alpha and gamma chains (J. Biol. Chem. 259, 10574-10581, 1984). In this study the endogenous levels of fibrinogen and its precursors are measured by two different methods; pulse and steady-state labelling with L-35 S-methionine and immunoblotting. In Hep-G2 cells intracellular fibrinogen-related antigen is primarily (30-53%) composed of an A alpha-gamma complex and, to a smaller degree, of fully-formed fibrinogen (13-33%). Furthermore, the Hep G2 cell also contains endogenous pools of free gamma chain (11-26%). Other fibrinogen precursors (namely, the B beta-A alpha, B beta-gamma complexes as well as the fibrinogen half-molecule) do not appear to accumulate intracellularly. Most, if not all, of these precursors occur as isoforms but this heterogeneity is not due to varying degrees of glycosylation. In all the intracellular fibrinogen forms identified thus far, free sulfhydryl groups, detected by 14C-iodoacetamide incorporation, occur only in the A alpha-gamma complex and the free gamma chains.

Carcinoma, Hepatocellular↗
PubMed1987

Glycosylation of human fibrinogen and fibrin in vitro. Its consequences on the properties of fibrin(ogen).

As observed for many proteins, glucose has been shown to bind non enzymatically to fibrinogen and to fibrin. The in vitro degree of glycosylation depends upon the concentration of glucose added to fibrinogen and also on the incubation period. This glycosylation induces a decrease in fibrin lysis by plasmin. On the contrary, it does not influence either fibrinogen activity as cofactor in ADP-induced platelet aggregation or the binding of thrombin onto a clot. Despite the 4 day half life of fibrinogen, since clearance of fibrinogen is exponential, it is assumed that very small quantities of fibrinogen may remain for a long time in the circulation leading to the presence of a low level of a highly glycosylated form of fibrinogen. Consequently, poorly degradable fibrin might be derived from this highly glycosylated fibrinogen and thus be responsible for capillary occlusion and also for atherosclerotic complications in the diabetic patient.

Adenosine Diphosphate↗
PubMed1988

The influence of the fibrinolytic system on the affinity of fibrinogen for the endothelial-plasma interface.

We use intravital fluorescence microscopy to study the endo-endothelial lining of microcirculatory vessels in vivo and in situ (exposed rat mesentery). In earlier experiments we found that fibrinogen had an affinity for the inner lining of microvessels, particularly venules. This affinity was specific to fibrinogen (and fibronectin); most other plasma proteins (albumin, antithrombin III, gamma-globulin) did not accumulate on the inner surface of microcirculatory blood vessels. We postulated the existence of receptors for fibrinogen and/or fibronectin on the endo-endothelial surface, whose turnover rate differed in arterioles and venules. Blockade of the intravascular coagulation process by heparin did not alter the interaction between fibrinogen and endothelium, but blockade of fibrinolytic activity by tranexamic acid increased the deposition of fibrinogen at the endothelial surface. In the present study we administrated a drug containing the bioflavonoids diosmin and hesperidin, which may activate tissue plasminogen activator. Such pretreatment significantly decreased the accumulation of fibrinogen at the endo-endothelial surface of the venules. We therefore conclude that the endothelial plasma interface is characterized by accumulation of fibrinogen which is not affected by thrombin-mediated activation of the coagulation system. In contrast, interactions between fibrinogen and endothelium are influenced by the fibrinolytic system, both of plasmatic and endothelial origin, thus representing an important aspect of the antithrombotic potential of the endothelium.

Animals↗
PubMed1995

Stimulating effect on tissue-type plasminogen activator--a new and sensitive indicator of denatured fibrinogen.

A high clottability and a short thrombin clotting time have routinely been considered as evidence of genuineness of the fibrinogen molecule. Since denatured fibrinogen stimulates the t-PA-catalysed conversion of plasminogen to plasmin, it was of interest to study the sensitivity of t-PA-stimulation as evidence of fibrinogen denaturation. Therefore, fibrinogen was intentionally exposed to various denaturating conditions (freeze-drying, heating, EDTA, alkali), and the clottability, the thrombin clotting time and the t-PA-stimulating effect were recorded. We found that the clottability was a poor indicator of fibrinogen denaturation, whereas the t-PA-stimulating effect could detect even mild fibrinogen denaturation. The thrombin clotting time was shortened after freeze-drying or heating at 47 degrees C, in spite of what might have been expected. Thus, denaturation is not necessarily accompanied by a prolonged clotting time. In some instances therefore, the t-PA-stimulation is an even more sensitive and reliable indicator of fibrinogen denaturation than is the thrombin clotting time. Consequently, this parameter should be combined with the thrombin clotting time to characterise preparations of fibrinogen.

Blood Coagulation↗
PubMed1980

The polymerization of fibrinogen under the influence of diazomethane modification.

To study the effect of the acidic amino acid residues on the physiological polymerization and clot formation of fibrinogen, the fibrinogen system was polymerized by interaction with diazomethane, a specific group reagent which modifies the carboxylic acid residues via the process of methylation. The extent of methylation of fibrinogen by diazomethane was estimated by methoxyl determination on the modified fibrinogen. Under the present experimental conditions, no significant amounts of ammonia were detected as a result of amide hydrolysis concomitant with esterification of the fibrinogen. Chemical methylation of approximately 214 residues resulted in polymerization of the fibrinogen molecule to a product which resembled the physiological clot formation. The application of paper chromatographic techniques identified the modification of other amino acid residues in addition to the methylation of the carboxylic acid groups of glutamic and aspartic acids. These results are interpreted in terms of methylation of carboxylic acid groups in fibrinogen by diazomethane providing a reduction of both negative charge and intermolecular repulsion, thereby enabling the modified fibrinogen molecules to polymerize.

Animals↗
PubMed1982

Measurement of fibrinogen in dog liver cell fractions by electroimmunoassay and radioimmunoassay.

Dog liver was fractionated and the amount of fibrinogen, in the various cell fractions (organelles) involved in the secretory process, was determined both by the Laurell electroimmunoassay and by radioimmunoassay. An unequal distribution of fibrinogen was noted for each cell fraction after an appropriate correction was made. This involved the estimation of the level of contamination of each cell fraction by soluble (blood) fibrinogen. It was observed that significant amounts of added 125I-labeled fibrinogen could be found in each organelle following cell fractionation. This was especially true for the rough endoplasmic reticulum which contained as much as 31% of the added tracer. Both the smooth endoplasmic reticulum and the Golgi fractions contained much lower amounts of added tracer. Using this correction factor, it was found that the rough endoplasmic reticulum contains about 0.1-0.2 micrograms fibrinogen per mg organelle protein. On the other hand, the smooth endoplasmic reticulum and Golgi fractions contained much more fibrinogen. The fibrinogen concentration ranges found for the latter two organelles were 1.9-5.0 and 1.5-5.7 micrograms fibrinogen per mg organelle protein, respectively.

Animals↗
PubMed1991

Stimulation of the amidolytic activity of single chain tissue-type plasminogen activator by fibrinogen degradation products: possible fibrin binding sites on single chain tissue-type plasminogen activator molecule.

The steady-state kinetics of the amidolytic activity of single chain tissue-type plasminogen activator (tPA) were analyzed in the presence or absence of different molecular forms of fibrinogen degradation products. Single chain tPA showed a Km value of 1.6 mM and kcat value of 4.9/s toward the chromogenic substrate H-D-Ile-Pro-Arg-p-nitroanilide (S-2288). In the presence of infinite concentrations of fibrinogen, kinetic constant was calculated as about 8-times higher than that in the absence of fibrinogen, mainly caused by the decrease of Km value. The dissociation constant (Ka) for this stimulation by fibrinogen was 2.9 microM. When the same assay was conducted with fragment X or fragment D of fibrinogen, the kinetic constants increased 3.2 and 2.9-times, respectively, whereas no enhancement was obtained by fragment E. Neither lysine analogues nor monoclonal antibody toward domains of finger and epidermal growth factor of tPA quench the enhancement by fibrinogen. This enhancement was not observed in the case of the two chain form of tPA. These results indicate that fibrinogen enhances the amidolytic activity of single chain tPA by binding to kringle 2 domain or light chain through D domain of fibrinogen.

Binding Sites↗
PubMed1992

Significance of plasma fibrinogen in coronary arterial disease: marker or causative risk factor for arterial thrombosis?

The relationship between fibrinogen and severity of disease was measured in patients with coronary arterial disease (n = 301) prior to surgical coronary revascularisation. Platelet reactivity (shear-induced haemostasis) was measured from non-anticoagulated blood, in vitro. Coagulation was assessed by the clotting time of flowing native blood (dynamic) and by the conventional (stagnant) tube tests. Significantly enhanced platelet reactivity to shear-stress was observed when patients with one-vessel disease were compared to those with two- or three-vessel disease (P = 0.003). Neither coagulation nor fibrinogen were significantly related to the severity of disease. Furthermore, patients who had myocardial infarction (n = 144) showed enhanced platelet reactivity (P = 0.02) as compared to those who had not (n = 157). Again, neither coagulation nor fibrinogen discriminated between these groups of patients. Relationship between plasma fibrinogen and platelet reactivity was also investigated in vitro. Identical blood samples with normal (220-280 mg/dl) and elevated plasma fibrinogen (approximately 500 mg/dl) were compared by measuring platelet reactivity and coagulation from native blood and platelet aggregation in whole blood. The in vitro studies suggested that plasma fibrinogen and platelet reactivity are inversely associated. Furthermore, increased fibrinogen prolonged dynamic coagulation. These findings do not support the assertion that elevated plasma fibrinogen is a true causative factor for coronary arterial disease and arterial thrombosis.

Blood Coagulation↗
PubMed1982

Binding of fibrinogen molecules to pig platelets and their membranes.

Following addition of ADP, 125I-labelled fibrinogen binds specifically to pig platelets. This binding is completely inhibited by the unlabelled fibrinogen. Quantitative analysis indicates the presence of 12,400-25,000 molecules of fibrinogen which can be bound with an association constant of 5 . 10(8) M-1 to platelets. Fibrinogen receptors were found to be active in the isolated platelet membranes as well. Quantitative analysis of the saturable binding of fibrinogen to the platelet membranes showed that these receptors react with the same affinity with fibrinogen molecules. In contrast to the intact platelets, the platelet membranes can specifically bind fibrinogen in the absence of ADP. We conclude that a specific receptor for fibrinogen is exposed on the surface as a result of cell damage which is the first step of the platelet membrane isolation.

Adenosine Diphosphate↗
PubMed1984

Purification of three gamma-chains with different molecular weights from normal human plasma fibrinogen.

Three forms of the normal human plasma fibrinogen gamma-chain which differ in molecular weight have been purified. Plasma fibrinogen was separated by ion exchange chromatography on DEAE-Sephacel into three populations of molecules, each with a unique gamma-chain composition. Following reduction and S-carboxymethylation, the fibrinogen polypeptide chains in each chromatographic peak were separated by ion exchange chromatography on DEAE-Sephacel and identified following sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The A alpha, B beta and smallest gamma-chain (gamma 50) eluted at progressively higher ionic strengths, but the elution positions of A alpha, B beta and gamma 50 chains were identical for fibrinogen from each of the three different chromatographic fractions. The unique gamma chain of fibrinogen in the second chromatographic peak (gamma 55) eluted at an ionic strength higher than that of the gamma 50 chain, while the largest gamma-chain (gamma 57.5), which was contained only in the third chromatographic peak of fibrinogen, eluted at the highest ionic strength. The higher ionic strengths needed to elute fibrinogen in the second and third peaks was paralleled by the higher ionic strengths needed to elute the gamma-chains unique to them, suggesting that the gamma-chain composition of the three fibrinogen fractions accounted for their differential binding to the ion exchange resin. Following desialation with neuraminidase, the differences in electrophoretic mobilities between the three gamma-chain forms was maintained, indicating that differential migration on SDS-polyacrylamide gel electrophoresis was not due to variation in sialic acid content.

Chromatography, Affinity↗
PubMed1987

Protein synthesis and storage in human platelets: a defective storage of fibrinogen in platelets in Glanzmann's thrombasthenia.

In vivo metabolic labelling experiments were performed to investigate the ability of human platelets to synthesize and store fibrinogen and thrombospondin. Newly synthesized proteins were analyzed by SDS-polyacrylamide gel electrophoresis. Results were compared with those obtained for the platelets of a patient with Glanzmann's thrombasthenia where endogenous fibrinogen levels were severely reduced. Normal human platelets were able to synthesize the different subunits of fibrinogen and thrombospondin and to assemble them into native fibrinogen and thrombospondin molecules. This synthesis was inhibited by cycloheximide. Synthesis of both fibrinogen and thrombospondin was observed in the platelets of the Glanzmann's thrombasthenia patient. However, radiolabelled fibrinogen was no longer detected after an 18-h non-radioactive chase, although it was retained in the control platelets. Neosynthesized thrombospondin of the patient was normally preserved during the same chase period. When the fate of the radioactive fibrinogen was studied, it was found to be degraded in Glanzmann's thrombasthenia platelets to the same extent as neosynthesized cytoplasmic proteins, whereas in control platelets less degradation had occurred. We conclude that human platelets maintain a residual capacity to synthesize fibrinogen and that its deficiency in Glanzmann's thrombasthenia results from a storage abnormality and not from a synthesis defect.

Blood Platelet Disorders↗
PubMed1991

Inhibitory effects of fibrinogen on phagocytic killing of streptococcal isolates from humans, cattle and horses.

The effects of fibrinogen on phagocytic killing of Streptococcus dysgalactiae from cattle and S. equi from horses were studied in comparison to that of S. pyogenes from humans. Phagocytic killing was determined by a fluorometric microassay using glass adherent polymorphonuclear neutrophils (PMN) from the respective host species, preopsonization with homologous sera led to a dose-dependent increase in phagocytic killing of all streptococcal cultures, preincubation of streptococci with fibrinogen significantly inhibited their phagocytic killing. Fibrinogen had no effect on phagocytic killing of non-fibrinogen binding S. agalactiae cultures. Further characterization studies with S. dysgalactiae and S. pyogenes revealed that a partial inhibition of phagocytic killing could also be achieved by preincubation with monomeric beta-chains of fibrinogen. Digestion of the fibrinogen binding sites on streptococci with proteases resulted in an almost complete loss of the inhibitory effects of fibrinogen on phagocytic killing. It could thus be concluded that by binding fibrinogen animal pathogenic streptococci could evade phagocytic killing in a similar manner as M protein carrying S. pyogenes isolates from human infections.

Animals↗
PubMed1990

Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study.

Plasma fibrinogen was measured in a sample of 8824 men and women aged 40-59 years participating in the Scottish Heart Health Study, and related to cardiovascular risk factors. Women had higher fibrinogen levels than men. In both sexes, multivariate analysis showed that fibrinogen was positively associated with age, smoking, total cholesterol and body mass index and negatively associated with alcohol consumption. Among women, early menopause and systolic blood pressure were also associated with fibrinogen levels. Univariate analyses showed weak positive associations with fish consumption for both sexes although only male white fish consumption entered the final model. Women with a history of contraceptive pill usage had significantly lower fibrinogen levels. The relationship between fibrinogen and physical activity was complex, and could largely be explained by smoking. These findings support the hypothesis that raised fibrinogen is one mechanism by which several major risk factors may promote coronary heart disease. However, known risk factors explained, at most, 10% of the total variance in fibrinogen levels among the general population.

Adult↗
PubMed2004

Ischemic stroke and fibrinogen in the elderly.

Senescence is accompanied by an important increase in prevalence and incidence of ischemic stroke. The plasma level of fibrinogen tends to increase with age in the elderly similarly to the prevalence of stroke. The aim of our study was to evaluate the age-related increase in fibrinogen plasma level in the elderly and to assess the presence of eventual differences between normal subjects and patients with previous ischemic stroke associated with precerebral atherosclerosis. Eighty inpatients (41 males and 39 females), consecutively admitted to our Geriatric Unit, were included to this study. The patient group was formed 32 subjects (20 males and 12 females) aged 50-79 years, suffering from cerebrovascular disease with one or several previous ischemic stroke episodes, having occurred at least 1 year earlier. The control group consisted of 48 normal subjects (21 males and 27 females) aged 50-79 years. Both control and patient groups were subdivided into three subgroups, according to their age: Group 1 (50-59 years), Group 2 (60-69 years)and Group 3 (70-79 years). The statistical comparison was carried out by means of the Mann-Whithney nonparametric test. In normal controls, a mild age effect is evident because only Group 3 shows fibrinogen levels significantly higher than those of Group 1. On the contrary, in patients with ischemic stroke, an age effect is already evident between Group 2 and Group 1; of course, also the comparison between patient Group 3 and Group I shows a statistically significant difference. Moreover, the levels of fibrinogen were significantly increased in patient Group 2 and 3 when compared to those of their respective age-matched controls. Our data are in agreement with those already available in the literature and demonstrate that fibrinogen in normal aging changes with age and shows a 19 %increase between age Group 1 and Group 3. Patients with ischemic stroke show an earlier and more evident age-related increase in fibrinogen than normal controls. Even if it is not possible to know, if the increase in fibrinogen is a consequence or not of the ischemic stroke, we can affirm that certainly the increased levels of fibrinogen should be considered as an important risk factor in the elderly for cerebrovascular disease and deserve treatment.

Aged↗