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PubMed1975

Defective alpha-polymerization in the conversion of fibrinogen Baltimore to fibrin.

The subunit structure of fibrinogen Baltimore and fibrin formed from this inherited dysfibrinogenemia was analyzed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The molecular weights of the alpha-, b- and gamma-chains of fibrinogen Baltimore were found to be identical to those of normal fibrinogen. Noncross-linked fibrin formed from both purified fibrinogen Baltimore as well as normal fibrinogen contained two alpha-monomers (alpha1 and alpha2). alpha2 was presumed to be alpha-monomer from which fibrinopeptide A had been released. The evolution of alpha2 during clotting of fibrinogen Baltimore was delayed and appeared to be quantitatively reduced when compared to normal. Crosslinked fibrin formed from fibrinogen Baltimore possessed an abnormal subunit structure. alpha-polymers were not generated in thrombin-induced, factor XIII-rich clots of fibrinogen Baltimore under conditions of pH and calcium concentration suitable for complete alpha-polymerization in normal fibrin. If clotting was carried out with calcium concentrations twice that required for normal clots or at pH 6.4, fibrin from fibrinogen Baltimore was completely cross-linked. These structural analyses of fibrin formed from fibrinogen Baltimore substantiate earlier findings that indicate a defect in the alpha-chain of this dysfibrinogenemia.

Blood Coagulation Disorders↗
PubMed1979

Exposure of platelet fibrinogen receptors by ADP and epinephrine.

The role of fibrinogen as a cofactor for platelet aggregation was examined by measuring the binding of 125I-labeled human fibrinogen to gel-filtered human platelets both before and after platelet stimulation by ADP and epinephrine. Platelet stimulation by ADP resulted in the rapid, reversible binding of fibrinogen to receptors on the platelet surface. Fibrinogen binding increased as the concentration of ADP was increased from 0.1 to 2 microM, reaching a plateau at higher ADP concentrations. Binding occurred only after platelet stimulation and in the presence of divalent cations. However, fibrinogen binding did not occur to ADP-stimulated platelets from three patients with Glanzmann's thrombasthenia. Analysis of fibrinogen binding as a function of increasing fibrinogen concentration demonstrated that maximal platelet stimulation exposed approximately or equal to 45,000 binding sites per platelet with a dissociation constant of 80--170 nM. These fibrinogen binding parameters were essentially the same whether ADP or epinephrine was the platelet-stimulating agent. Thus, these studies demonstrate that platelet stimulation by ADP and epinephrine exposes a limited number of fibrinogen receptors on the platelet surface. Furthermore, these data suggest that the fibrinogen molecules bound to the platelet as a consequence of platelet stimulation are directly involved in the platelet aggregation response.

Adenosine Diphosphate↗
PubMed1985

Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.

Thrombin cleavage of blood coagulation Factor XIII (a2b2) and fibrinogen was studied during in vitro clotting to determine the physiologic sequence of these events. First, the time course of fibrin formation and cleavage of Factor XIII was measured in platelet-rich plasma. Cleavage of fibrinogen was measured by using a radioimmunoassay for fibrinopeptide A. Conversion of trace amounts of radioiodinated a-chains of 125I-Factor XIII to thrombin-modified a-chains was measured in unreduced 10% sodium dodecyl sulfate-polyacrylamide gels. During spontaneous clotting, a similar percentage of 125I-Factor XIII and fibrinogen was cleaved at each time point. Visible gelation of polymerized fibrin monomer occurred when 24 +/- 8% of fibrinogen was cleaved and 21 +/- 6% of Factor XIII was converted to Factor XIII'. Thrombin cleavage of Factor XIII and fibrinogen was also studied in platelet-poor plasma to which thrombin was added. In order to measure Factor XIIIa activity, fibrin polymerization was completely inhibited by the addition of Gly-Pro-Arg-Pro. Factor XIIIa formation was measured by the incorporation of [3H]putrescine into casein. The concentration of added thrombin required to cleave 50% of fibrinogen and Factor XIII was 0.65 U/ml and 0.35 U/ml, respectively. The rate of cleavage of fibrinogen by thrombin was 43-fold greater than cleavage of Factor XIII. Lower Gly-Pro-Arg-Pro concentrations were used to determine the effects of incompletely inhibiting fibrin polymerization on cleavage of Factor XIII and fibrinogen. Thrombin cleavage of Factor XIII but not fibrinogen was dependent on the extent of fibrin polymerization. The more marked the degree of inhibition of fibrin polymerization, the slower the rate of Factor XIIIa formation. Thus, in platelet-rich plasma, thrombin cleavage of Factor XIII and fibrinogen are closely related events during spontaneous clotting. Furthermore, cleavage of Factor XIII during clotting is enhanced by fibrin polymerization in platelet-poor plasma.

Binding Sites↗
PubMed2004

Fibrinogen in children undergoing cardiac surgery: is it effective?

There is speculation based on laboratory tests and biochemical data regarding the functional integrity of the fibrinogen in young children. Recent investigations in adults have demonstrated that their fibrinogen level correlates with the thromboelastogram maximum amplitude (MA) after modification with a glycoprotein IIb/IIIa receptor blocker that uncouples platelet-fibrinogen interactions. We postulate that if the fibrinogen of young children is functionally intact then their fibrinogen levels should also correlate with modified thromboelastogram MA values as they do in adults. We compared modified and unmodified thromboelastogram variables of 250 children <2 yr old undergoing cardiac surgery with their fibrinogen levels and platelet counts. Five age groups were distinguished to determine if and when correlations become significant (<1 mo, 1-3 mo, 3-6 mo, 6-12 mo, and 12-24 mo). Fibrinogen levels correlated with modified thromboelastogram MAs only in the 12-24 mo group. In this 12-24 mo age group other correlations between fibrinogen levels and thromboelastogram variables influenced by fibrinogen also became significant, as did correlations noted in adults between platelet counts and thromboelastogram variables. We conclude that the fibrinogen of children <12 mo old with congenital heart disease is qualitatively dysfunctional.

Abciximab↗
PubMed2004

Plasma fibrinogen.

Fibrinogen is the major plasma protein coagulation factor. Low plasma fibrinogen concentrations are therefore associated with an increased risk of bleeding due to impaired primary and secondary haemostasis. Fibrinogen is a classical positive acute-phase reactant protein and is an independent predictor of coronary heart disease events. This review considers available methods for measurement of fibrinogen and makes recommendations as to their appropriate use. Total clottable fibrinogen assays are the definitive and reference method for plasma fibrinogen measurement. However, they are time-consuming and are rarely required in clinical practice. Clotting rate assays remain the routine method of choice for investigation, monitoring and treatment of bleeding disorders associated with low plasma fibrinogen concentrations. They are appropriately sited in haematology or haemostasis laboratories, with facilities for further relevant investigations, and expert advice from consultant haematologists on appropriate management. They have also been used in the majority of studies investigating increasing fibrinogen concentrations as a cardiovascular risk factor. Prothrombin-time derived assays are widely used, because they are less expensive and come at no extra cost with prothrombin time assays. However, their results vary widely with analysers and reagents, show discrepancies with clotting rate assays for both low and normal plasma fibrinogen samples, and at present they are not recommended by routine clinical use. Immunoassays (radial immunodiffusion, enzyme-linked immunosorbent assay or nephelometric) are useful in (a) differentiating hypofibrinogenaemia from dysfibrinogenaemia, and (b) assessing cardiovascular risk and acute-phase reactions. Unlike clottable fibrinogen assays, immunoassays can be performed in dipotassium edetate anticoagulated samples.

Biomarkers↗
PubMed1987

Biochemical characterization of autologous fibrinogen adhesive.

Fibrinogen-based adhesive, derived from pooled human plasma, has been used in Europe with great success in otologic surgery, but has not been approved for use in the U.S. because of the risk of transmitting hepatitis. Autologous fibrinogen, derived by polyethylene glycol precipitation from the blood of an individual patient would avoid this risk, and has been shown to be relatively safe to the ear in animal studies. A study of the biochemical composition of this autologous fibrinogen concentrate derived from 15 human volunteer donors was performed. The mean starting plasma fibrinogen was 2.12 mg/ml (range 1.59-3.22 mg/ml). When 10% polyethylene glycol was used to precipitate the fibrinogen, the concentrate contained, on the average, 31.8 mg of fibrinogen/ml. The percent yield averaged 54.9%, and the protein in the final product was 91.9% fibrinogen. Increasing the polyethylene glycol concentration in the precipitation process to as high as 15% resulted in an increased yield as high as 91%, but the protein in the final product was only 42.5% fibrinogen. Polyacrylamide gel electrophoresis confirmed that the predominant protein in the 10% polyethylene glycol precipitate was fibrinogen. These data suggest that highly concentrated fibrinogen can be derived with relative ease from single donor human plasma, and that the product is relatively pure. When combined with thrombin and calcium chloride, this concentrate should provide an adhesive that avoids the risks associated with fibrinogen adhesive derived from pooled blood.

Aprotinin↗
PubMed2001

Do HMG-CoA reductase inhibitors affect fibrinogen?

OBJECTIVE: To review commonly used fibrinogen assay methods and the evidence demonstrating an association between fibrinogen and increased risk of coronary artery disease and to review the current literature to determine and assess the impact of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on fibrinogen. DATA SOURCES: Primary and review articles identified from a MEDLINE search (1966-December 1999); references obtained from these publications were subsequently reviewed for additional relevant articles. STUDY SELECTION AND DATA EXTRACTION: All articles were evaluated, and all relevant information was included in this review. DATA SYNTHESIS: The Clauss method is currently the preferred method for determining plasma fibrinogen concentrations, due to its high degree of accuracy and precision. Furthermore, unlike immunologic methods, its reliability is unaffected by change in triglycerides. The effects of four HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin, pravastatin) on fibrinogen have been evaluated. Atorvastatin has been shown to induce significant increases in fibrinogen (22% increase; p <0.05) by using the immunonephelometric method. This method also demonstrated that lovastatin use was associated with a 24.4% increase (p < 0.0001) in plasma fibrinogen concentration. Simvastatin has been shown in multiple studies using the Clauss method to have a neutral effect on fibrinogen. The majority of studies have revealed significant decreases (7-19%) in fibrinogen following treatment with pravastatin. CONCLUSIONS: Future studies need to be performed evaluating the effects of HMG-CoA reductase inhibitors on fibrinogen, but using direct comparisons and clotting assay methodology.

Animals↗
PubMed1997

Influence of fibrinogen on cardiovascular disease.

Results from prevalence, case-control, angiographic and echocardiographic investigations incriminate elevated fibrinogen levels as a strong independent risk factor for the occurrence of initial and recurrent cardiovascular events. Average fibrinogen levels are higher in women and persons with other risk factors including hypertension, diabetes, cigarette smoking, obesity, elevated haematocrit value and dyslipidaemia. Fibrinogen tends to cluster with most of these major atherogenic cardiovascular risk factors and further enhances their risk. Prospective data indicate a relationship between fibrinogen and the subsequent development of all the major atherosclerotic cardiovascular events including coronary heart disease, stroke and peripheral artery disease. Fibrinogen adds to the multivariate risk of cardiovascular events, especially in the high risk subset of the population. In the Framingham Heart Study, a comparison of risk gradients, exemplified by their regression coefficients, was similar for all outcomes (coronary heart disease, stroke, peripheral artery disease and cardiovascular disease) in men, whereas, in women, the risk gradient for fibrinogen appeared weakest for stroke. Fibrinogen exerts an independent influence on the frequency of cardiovascular disease in general, and coronary heart disease in particular. For example, in both men and women, each standard deviation increase in fibrinogen level (about 0.56 g/L) within the range of usual values is associated with about a 20% age- and risk factor-adjusted increase in the incidence of an initial cardiovascular event. Fibrinogen should be added to the list of major atherogenic cardiovascular risk factors; in addition, there is a need for intervention trials designed to test the efficacy of lowering fibrinogen in individuals at high risk for cardiovascular disease.

Cardiovascular Diseases↗
PubMed1999

Alcohol at moderate levels decreases fibrinogen expression in vivo and in vitro.

BACKGROUND: Consumption of moderate amounts of alcohol has been reported to exert a cardioprotective effect in individuals. The exact mechanism by which this occurs has not been fully explored. Circulating levels of the clotting protein fibrinogen have been unequivocally established as an independent risk factor for vascular diseases. This study examined the effects of moderate levels of ethanol on the expression of fibrinogen in an animal model and in hepatoma cells. METHODS: Out-bred Sprague-Dawley rats were fed 5% ethanol (v/v) in their water for 4 weeks, and circulating levels of fibrinogen were measured weekly via quantitative immunoassay. H4IIE rat hepatoma cells, which constitutively produce fibrinogen, were exposed to 10 and 20 mM ethanol, and fibrinogen production was determined. The effects of ethanol on fibrinogen messenger ribonucleic acids were determined by northern gel analyses. RESULTS: Our findings demonstrate that daily consumption of moderate amounts of ethanol decreases circulating levels of fibrinogen 18% to 20%. The decrease is reversible and is not gender specific. The exposure of hepatoma cells to ethanol also diminishes fibrinogen production by 20% by decreasing the transcription of fibrinogen genes. Alcohol concentration of 10 to 20 mM did not affect hepatoma cell viability or doubling time. CONCLUSIONS: The findings indicate that one likely positive benefit of moderate ethanol consumption is to diminish the production of fibrinogen, which reduces the potential risk exerted by this protein. The site of action of ethanol is, at least in part, exerted at the level of gene transcription.

Animals↗
PubMed1999

Increased plasma levels of fibrinogen in acute and chronic ischemic coronary syndromes.

BACKGROUND: The aim of this study was to evaluate the pathophysiological role of fibrinogen in patients with chronic or acute ischemic coronary syndromes on the basis of epidemiological and clinical evidences showing the importance of fibrinogen as a risk factor for cardiovascular diseases and atherosclerosis progression. METHODS: We evaluated the behavior of plasma fibrinogen in 310 hospitalized patients with 1) acute myocardial infarction (n = 98); 2) unstable angina (n = 87); 3) chronic ischemic heart disease (n = 75); and 4) in controls without myocardial ischemia (n = 50). Fibrinogen was evaluated, by using the Clauss method, on day 1 and 5 during in hospital-stay and at 6-month follow-up in patients suffering from acute myocardial infarction. RESULTS: Plasma levels of fibrinogen were higher in patients with chronic ischemic heart disease (335.3 +/- 81.2 mg/dl, p < 0.001) and especially in patients with acute myocardial infarction (454.72 +/- 69.5 mg/dl, p < 0.00001) and unstable angina (382.6 +/- 101.3 mg/dl, p < 0.00025) in comparison with controls (271.28 +/- 62.4 mg/dl). Q wave myocardial infarction showed higher levels of fibrinogen than non-Q wave (461.3 +/- 95.8 vs 422.5 +/- 71.3 mg/dl, p < 0.02). Patients with acute myocardial infarction showed a further increase in fibrinogen on day 5 in comparison with entry levels (525.88 +/- 87.3 vs 454.7 +/- 69.5 mg/dl, p < 0.00001) regardless of the fibrinolytic treatment. Patients who died (n = 6) or had severe arrhythmias (n = 4) during in-hospital stay as well as those with post-infarction angina (n = 20) showed higher fibrinogen levels. CONCLUSIONS: Our results confirm the role of fibrinogen as a risk factor for ischemic heart disease, especially in patients with unstable angina and acute myocardial infarction. In the latter, elevated fibrinogen values seem also to be associated with a worsen prognosis during hospitalization.

Acute Disease↗
PubMed1975

Cross-linking of fibrinogen and fibrin by fibrin-stablizing factor (factor XIIIa).

Factor XIIIa catalyzed intermolecular cross-linking of fibrinogen at initial rates that varied in direct (first order) proportion to the fibrinogen concentration, which differed from the well known zero order relationship in fibrin cross-linking. Preferential cross-linking of gamma-chains occurred with both substrates. The differences in rates and order of reaction were attributed mainly to effect of self-alignment of the gamma-chains in fibrin which enabled the cross-linking enzyme to interact with paired chains as a single rather than two independent entities. Studies on mixtures of fibrinogen and fibrin indicated factor XIIIa had near equal affinities for the two substrates. At low concentrations with which cross-linking of fibrinogen proceeded sluggishly compared to fibrin, fibrinogen inhibited stabilization of fibrin clots by competitively partitioning factor XIIIa away from the fribin. Additional inhibition arose from cross-linking of fibrin in soluble combination with fibrinogen in mixtures containing fibrinogen in large excess over fibrin. The observations demonstrate ways in which fibrinogen normally helps to suppress both polymerization and cross-linking of small amounts of fibrin produced within the circulation. At very high concentrations above 30 mg. per milliliter, fibrinogen underwent cross-linking at faster initial rates than the cross-linking of fibrin. Rapid cross-linking of concentrated fibrogen raises the possibility that filtration enrichment may be a factor contributing to abnormal formation of the highly insoluble fibrinogen deposits occurring in atheromatous tissue.

Animals↗
PubMed2002

Association of gammaA/gamma' fibrinogen levels and coronary artery disease.

GammaA/gamma' fibrinogen is a fibrinogen isoform that constitutes about 15% of total plasma fibrinogen. This isoform contains an additional binding site for zymogen factor XIII and for active thrombin, and forms fibrin clots that are resistant to fibrinolysis in vitro. Little is known about the variability of gammaA/gamma' fibrinogen levels in human populations, whereas total fibrinogen levels are known to increase with age and are higher in women than in men. In this report, evidence is presented that, in contrast to total fibrinogen levels, gammaA/gamma' fibrinogen levels showed no significant association with age or gender in a population of normal blood donors. A study of gammaA/gamma' fibrinogen levels in patients undergoing coronary angiography also showed that gammaA/gamma' fibrinogen levels were higher on average in coronary artery disease patients than in patients without coronary artery disease, and that this association was independent of total fibrinogen levels.

Adult↗
PubMed2002

The minimum concentration of fibrinogen needed for platelet aggregation using ADP.

OBJECTIVE: Determine the minimum concentration of plasma fibrinogen needed to stimulate the aggregation of platelets, collected from normal subjects, using ADP. DESIGN: Platelet rich plasmas (300 x 10(9) platelets/L) were made and adjusted to final fibrinogen concentrations of 75, 19, 5, and 0 mg/dL using fibrinogen free serum. Each fibrinogen concentration in all twelve subjects was aggregated with ADP SETTING: Research laboratory in the Department of Clinical Laboratory Science at Saint Louis University. PARTICIPANTS: Twelve healthy volunteers of both genders, between the ages of 18 and 60 years who were not pregnant and weighed at least 110 pounds were included in the study. Subjects were excluded from the study if they had ingested aspirin within one week prior to blood collection. In addition, subjects with a history of bleeding disorders such as afibrinogenemia, hypofibrinogenemia, von Willebrand disease, and Bernand-Soulier disease were rejected from the study. MAIN OUTCOME MEASURES: Platelet aggregation tracings were analyzed for amplitude and compared across plasma fibrinogen concentrations. In addition, the type of curve (monophasic vs. biphasic), smoothness and aggregation stability were also noted. RESULTS: The results show that aggregation occurred with every dilution of fibrinogen tested and that the amplitude of the aggregation curves appears not to be dependent on plasma fibrinogen. CONCLUSIONS: The results indicate that platelets from healthy individuals previously exposed to normal fibrinogen levels will aggregate equally well in decreasing plasma fibrinogen concentrations and even in the absence of plasma fibrinogen using ADP as the aggregator.

Adenosine Diphosphate↗
PubMed1992

Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461-610 (Lys 461 AAA-->stop TAA).

In the A alpha-chain gene coding for an abnormal fibrinogen (fibrinogen Marburg) we identified a single base substitution (A-->T) that changes the codon A alpha 461 AAA (Lys) to TAA (Stop). The propositus was found to be homozygous for the mutation, whereas the father and five siblings were heterozygous, and three other siblings contained only the normal sequence. The stop codon at position 461 results in the deletion of the carboxyl-terminal segment A alpha 461-610. Purified fibrinogen Marburg contained an A alpha-chain with a relative molecular weight of approximately 47,000. The FpA release by thrombin was not affected by this deletion, whereas the fibrin polymerization was strongly decreased. The binding of endothelial cells to immobilized fibrinogen Marburg was almost completely abolished compared with normal fibrinogen. Fibrinogen Marburg contained a substantial amount of albumin linked to the fibrinogen molecule by disulfide bonds, and these fibrinogen-albumin complexes were also present in plasma. The plasma fibrinogen concentration of the propositus was measured by three different methods: a functional method (< 0.25 mg/mL), an immunologic method using polyclonal antibodies (0.6 mg/mL), and an immunologic method based on two monoclonal antibodies specific for the amino-terminus and carboxyl-terminus of the A alpha-chain (< 0.05 mg/mL). Using the two immunologic methods, it appeared that only 10% to 15% of the plasma fibrinogen of the heterozygous siblings was abnormal.

Adult↗
PubMed1992

Recognition of platelet-associated fibrinogen by polyclonal antibodies: correlation with platelet aggregation.

Progressive decreases in platelet-bound fibrinogen accessibility to antibody and enzymes were recently reported to occur after adenosine diphosphate (ADP)-induced fibrinogen binding. Because previous studies also indicated that platelets that are activated but not aggregated by ADP in the presence of fibrinogen lose their ability to aggregate in a time-dependent manner despite negligible changes in fibrinogen binding, the present study examined the relationship between platelet aggregation and accessibility of platelet-bound fibrinogen to specific polyclonal antibody F(ab')2 fragments over a 60-minute time course. Although 125I-fibrinogen binding remained virtually unchanged, comparison of antifibrinogen antibody F(ab')2 binding and platelet aggregation 5 minutes and 60 minutes after platelet stimulation with ADP or thrombin showed decreases in F(ab')2 binding of 62% +/- 13% and 73% +/- 7% (mean +/- SD, n = 5), respectively, and decreases of 65% +/- 16% and 60% +/- 10% in platelet aggregation. In contrast, platelets stimulated with A23187 or chymotrypsin retained 87% +/- 16% and 76% +/- 12% of their ability to aggregate over the same time course, and lost only 39% +/- 14% and 36% +/- 12% of their ability to bind antifibrinogen antibody F(ab')2 fragments, respectively. Pretreatment of ADP-stimulated platelets with chymotrypsin largely prevented the progressive loss of platelet aggregability and the accompanying decreased recognition of bound fibrinogen by antifibrinogen F(ab')2 fragments. Preincubation of platelets with cytochalasin D (30 micrograms/mL) also inhibited the decrease in platelet aggregation after exposure of ADP-treated platelets to fibrinogen over a 60-minute time course. This was accompanied by only a 25% +/- 18% decrease in antifibrinogen antibody F(ab')2 binding. Present data support the hypothesis that qualitative changes in platelet-bound fibrinogen correlate with loss of the ability of platelets to aggregate, and implicate both the platelet cytoskeleton and chymotrypsin-sensitive surface membrane structures in modulating qualitative changes in bound fibrinogen on the platelet surface.

Adenosine Diphosphate↗
PubMed2005

Influence of fibrinogen levels on erythrocyte aggregation determined with the Myrenne aggregometer and the Sefam erythro-aggregometer.

Fibrinogen is one of the plasmatic proteins which has a major influence on erythrocyte aggregation. The level of fibrinogen at which erythrocyte aggregation does not further increase is not well established. Therefore we aim to determine erythrocyte aggregation with two devices: Myrenne aggregometer (M0 and M1) and Sefam erythro-aggregometer (Ta, AI10 and gammaD) in relation with fibrinogen levels, in patients with several diseases with fibrinogen levels ranging between 200-1100 mg/dl. With the Myrenne aggregometer a plateau can be observed for fibrinogen levels higher than 400 mg/dl, while with the Sefam erythro-aggregometer, aggregation increases proportionally with fibrinogen levels higher than 400 mg/dl. In addition, for fibrinogen values higher than 400 mg/dl, only statististically significant correlations could be observed between fibrinogen and erythrocyte aggregation parameters with the Sefam erythro-aggregometer: r(Ta)=-0.463; r(AI10)=0.624, r(gammaD)=0.817, p<0.01, but not with the Myrenne: r(M0)=0.01, r(M1)=0.02, ns. Although the Sefam erythro-aggregometer is a better tool for determining erythrocyte aggregation both at low and high fibrinogen levels, the Myrenne aggregometer may be useful for assessing the erythrocyte aggregation as an indicator of cardiovascular risk, as in such circumstances fibrinogen levels do not usually exceed values higher than 400 mg/dl.

Adolescent↗
PubMedDate not supplied

Antileukemic activity of glycated fibrinogen-methotrexate conjugates.

BACKGROUND: The aim of the study was to compare the antileukemic activity of methotrexate (MTX) conjugates with native and glycated fibrinogen. We expected that conjugates based on glycated fibrinogen would reveal higher antileukemic activity because of decreased plasmin digestibility and a higher retention rate of glycated fibrinogen in the body. MATERIALS AND METHODS: Fibrinogen was glycated using a high-temperature procedure at 65-85 degrees C. Glycated fibrinogens were examined with respect to their ability to clot and susceptibility to plasmin digestion. Native fibrinogen (F) and fibrinogens glycated at 65 and 73 degrees C (F65 and F73) were conjugated with MTX and tested in mice bearing P388 leukemia, at a dose of 40 mg of MTX per kg of body weight. RESULTS: Glycated fibrinogens retained their ability to clot. Compared to native fibrinogen, they were more resistant to digestion by plasmin. All tested conjugates revealed higher antitumor activity than the free drug. Increases in average lifespan over the control group were 34% for free MTX, 137% for F-MTX, 151% for F65-MTX and 91% for F73-MTX. The differences between the antitumor activities of all conjugates were not statistically significant. CONCLUSION: It seems necessary to compare the antitumor activities of MTX conjugates based on native and glycated fibrinogen in different tumor models, to demonstrate the expected differences.

Animals↗
PubMed1991

Fibrinogen is not synthesized by human megakaryocytes.

The origin of platelet fibrinogen is controversial. It may arise from two sources: (a) exogenously by endocytosis of plasma fibrinogen, or (b) endogenously by synthesis. We explored the second possibility because we previously demonstrated that the first mechanism does occur. Fibrinogen synthesis by human megakaryocytes (MK) was investigated by in situ hybridization and the polymerase chain reaction (PCR) applied to mRNA. MK differentiating from marrow CFU-MK were cultured in suspension. In situ hybridization using the 35S alpha and beta fibrinogen chain anti-sense riboprobes was totally negative in MK in comparison with negative controls (lambda phage and alpha and beta fibrinogen chain sense riboprobes). In contrast, synthesis of fibrinogen was detected by this technique in a hepatoma cell line (HepG 2). Furthermore, mRNA for alpha and beta chains of fibrinogen was not detected by the PCR performed on mRNA from cultured MK enriched to 90% purity, by the immunomagnetic bead technique, even after Southern blotting of the amplified products. In addition, fibrinogen mRNA was undetected in marrow MK and in platelets by the same technique, whereas a specific megakaryocyte gene transcript (GPIb alpha) was easily detected. These observations demonstrate that the only mechanism responsible for the presence of fibrinogen in platelets is endocytosis of fibrinogen from plasma.

Base Sequence↗