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PubMed1996

Fibrinogen, coronary heart disease and mortality from all causes in smokers and nonsmokers. The study of men born in 1933.

OBJECTIVES: To analyse the relation between fibrinogen concentration and incidence of coronary heart disease and mortality from all causes. A secondary aim was to investigate whether the effect of fibrinogen, as in previous cross-sectional analyses from this population, was restricted to nonsmokers. DESIGN: Prospective population study. SETTING: City of Göteborg, Sweden. SUBJECTS: A total of 664 men from a population sample of 1016 men aged 50 in 1983, without prior myocardial infarction. MAIN OUTCOME MEASURES: Development of coronary heart disease (myocardial infarction, coronary death or, in men with angina, revascularization, or scintigraphic evidence of coronary disease) and death from all causes, in relation to fibrinogen concentration and smoking status at baseline, during 9 years' follow-up. RESULTS: Rates of coronary heart disease during follow-up in the lowest, middle and highest third of the fibrinogen distribution were 4.6, 6.4 and 10.3%, respectively, but this did not remain significant after controlling for smoking and other risk factors (adjusted odds ratio [OR] for the highest, compared to the lowest third 1.5 [0.7-3.4]). Percentages of men who died from any cause were 3.2, 5.9 and 10.7 in the lowest, middle and highest thirds of fibrinogen, respectively. After adjustment for smoking and other risk factors, this difference remained significant (relative risk 2.6 [1.2-5.9]). In men who were smokers at baseline, fibrinogen was not significantly related to coronary heart disease or mortality. Men who did not smoke in the lowest, middle, and highest third of the fibrinogen distribution had rates of coronary heart disease of 1.8, 3.6 and 10.3%, respectively, and of deaths from all causes of 1.8, 2.9 and 8.4%, respectively. The adjusted OR remained significant at 5.4 (1.4-20.0) for coronary heart disease, as did the adjusted relative risk for mortality at 3.8 (1.01-14.4). CONCLUSION: Plasma fibrinogen is an independent predictor of premature death, and also of coronary heart disease, in middle-aged men and in nonsmokers. A high fibrinogen concentration, particularly in a nonsmoker, deserves attention.

Cause of Death↗
PubMed2005

Beta-fibrinogen haplotypes and the risk for cardiovascular disease in a dialysis cohort.

BACKGROUND: Elevated plasma fibrinogen levels are common in dialysis patients and may be related to an elevated risk for cardiovascular disease (CVD). We tested the hypothesis that genetic variation in the beta-fibrinogen ( FGB ) gene, shown to explain 1% to 5% of fibrinogen level variation in the general population, has an important role in elevated fibrinogen levels and excess CVD risk in dialysis patients. METHODS: Plasma fibrinogen was measured in 735 dialysis patients a median of 3 months from the start of dialysis therapy by using an automated clot-rate assay. Seven polymorphisms of the FGB gene were determined. Haplotype analysis was conducted using the Phase program to estimate haplotypes, with stratification for race. CVD events were ascertained from medical records. RESULTS: During a median follow-up of 2.1 years, 279 CVD events occurred. Genotype frequencies were in Hardy-Weinberg equilibrium. Four common haplotypes identified were not associated with fibrinogen levels or CVD risk in the entire cohort or after stratification by race. The -455A allele, known to increase gene expression in vitro, was marginally associated with fibrinogen levels only in patients without diabetes (regression coefficient [beta], 20 mg/dL [for +1 copy of the A allele; P = 0.06]), adjusted for age, sex, race, smoking, baseline dialysis modality, comorbidity, and history of diabetes and CVD. Post hoc analysis showed that -249C-->T (defining haplotype 3) was associated with greater fibrinogen levels and CVD risk among patients without diabetes and current smokers. CONCLUSION: The FGB gene likely does not have an important role in determining the variation in elevated plasma fibrinogen levels or excess CVD risk in dialysis patients.

Adult↗
PubMed1986

Fibrinogen mitogenic effect on hemopoietic cell lines: control via receptor modulation.

The possibility that the mitogenic effect of fibrinogen, a major plasma protein (3 mg/ml), is mediated by specific membrane receptors was studied. Specific binding analysis showed that fibrinogen receptors are present only on hemopoietic cell lines that respond to its mitogenic effect. The mitogenic fibrinogen receptor is not recognized by antibodies specific for the platelet fibrinogen receptor or is not competitively blocked by synthetic peptides containing the Arg-Gly-Asp sequence, which is common to fibronectin, fibrinogen, vitronectin, and other cell-attachment proteins. The lymphoma-derived pre-B-cells (Raji) have 149,000 receptors, whereas the lymphoma-derived T cells (JM), which are 3 times smaller, have 54,000 receptors. These receptors have a Kd of 2 X 10(-7) M. They are inducible by stimuli specific for the cell lineage: activators of the breakdown of phosphatidylinositol phosphates, such as platelet activating factor for Raji cells, and adenylate cyclase agonists and cAMP analogues for JM cells. The stimuli have no mitogenic effect in the absence of fibrinogen; they do not change the Kd. Each stimulus increases the number of fibrinogen receptors in a dose-dependent manner, which correlates strongly (r = -0.98, n = 5) with an increased growth rate of cells in the presence of fibrinogen. This correlation concludes that the mitogenic effect of fibrinogen is controlled via receptor modulation.

Adenosine Diphosphate↗
PubMed1997

A mitogenic action for fibrinogen mediated through intercellular adhesion molecule-1.

Intercellular adhesion molecule-1 (ICAM-1) is a cell surface ligand for alphaLbeta2 and alphaMbeta2 integrins and has a key role in leukocyte adhesion to the vascular endothelium. The plasma protein fibrinogen has also been shown to interact with ICAM-1. We have investigated the effect of fibrinogen binding to ICAM-1-expressing cells on cell proliferation. The inclusion of 200-800 nM fibrinogen but not fibronectin to the culture medium of Raji induced a 2-4-fold increase in [3H]thymidine incorporation after 8 h. Cell proliferation in cultures containing fibrinogen was also confirmed by direct cell counting. The proliferative response in Raji was abrogated by an anti-ICAM-1 mAb 84H10 which maps to the first Ig domain of ICAM-1. A purified truncated form of ICAM-1 containing the first two Ig-like domains and a peptide with amino acid sequence corresponding to ICAM-1 (8-22) was also able to block the proliferative action of fibrinogen on Raji. 200 nM fibrinogen induced a 3-fold increase in [3H]thymidine incorporation by 293 cells transfected with ICAM-1 cDNA but not control non-transfected 293 cells. Comparable mitogenic effects were achieved with fibrinogen fragments X and D100, and with a synthetic peptide with an amino acid sequence matching fibrinogen gamma chain (117-133). These results indicate that interaction between discrete sequences within ICAM-1 and fibrinogen result in cellular proliferation.

Amino Acid Sequence↗
PubMed1998

The fibrinogen-binding MSCRAMM (clumping factor) of Staphylococcus aureus has a Ca2+-dependent inhibitory site.

The clumping factor (ClfA) is a cell surface-associated protein of Staphylococcus aureus that promotes binding of fibrinogen or fibrin to the bacterial cell. Previous studies have shown that ClfA and the platelet integrin alphaIIbbeta3 recognize the same domain at the extreme C terminus of the fibrinogen gamma-chain. alphaIIbbeta3 interaction with this domain is known to occur in close proximity to a Ca2+-binding EF-hand structure in the alpha-subunit. Analysis of the primary structure of ClfA indicated the presence of a potential Ca2+-binding EF-hand-like motif at residues 310-321 within the fibrinogen-binding domain. Deletion mutagenesis and site-directed mutagenesis of this EF-hand in recombinant truncated ClfA proteins (Clf40, residues 40-559; and Clf41, residues 221-559) resulted in a significant reduction of affinity for native fibrinogen and a fibrinogen gamma-chain peptide. Furthermore, Ca2+ (or Mn2+) could inhibit the binding of the fibrinogen gamma-chain peptide to Clf40-(40-559) and the adhesion of S. aureus cells to immobilized fibrinogen with an IC50 of 2-3 mM. In contrast, Mg2+ (or Na+) at similar concentrations had no effect on the ClfA-fibrinogen interaction. Far-UV CD analysis of Clf40-(40-559) and Clf41-(221-559) in the presence of metal ions indicated Ca2+- and Mn2+-induced differences in secondary structure. These data suggest that Ca2+ binds to an inhibitory site(s) within ClfA and induces a conformational change that is incompatible with binding to the C terminus of the gamma-chain of fibrinogen. Mutagenesis studies indicate that the Ca2+-dependent inhibitory site is located within the EF-hand motif at residues 310-321.

Adhesins, Bacterial↗
PubMed2001

Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta.

Fibrinogen is a coagulation factor and an acute phase reactant up-regulated by inflammatory cytokines, such as interleukin 6 (IL-6). Elevated plasma fibrinogen levels are associated with coronary heart diseases. Fibrates are clinically used hypolipidemic drugs that act via the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). In addition, most fibrates also reduce plasma fibrinogen levels, but the molecular mechanism is unknown. In this study, we demonstrate that fibrates decrease basal and IL-6-stimulated expression of the human fibrinogen-beta gene in human primary hepatocytes and hepatoma HepG2 cells. Fibrates diminish basal and IL-6-induced fibrinogen-beta promoter activity, and this effect is enhanced in the presence of co-transfected PPAR alpha. Site-directed mutagenesis experiments demonstrate that PPAR alpha activators decrease human fibrinogen-beta promoter activity via the CCAAT box/enhancer-binding protein (C/EBP) response element. Co-transfection of the transcriptional intermediary factor glucocorticoid receptor-interacting protein 1/transcriptional intermediary factor 2 (GRIP1/TIF2) enhances fibrinogen-beta gene transcription and alleviates the repressive effect of PPAR alpha. Co-immunoprecipitation experiments demonstrate that PPAR alpha and GRIP1/TIF2 physically interact in vivo in human liver. These data demonstrate that PPAR alpha agonists repress human fibrinogen gene expression by interference with the C/EBP beta pathway through titration of the coactivator GRIP1/TIF2. We observed that the anti-inflammatory action of PPAR alpha is not restricted to fibrinogen but also applies to other acute phase genes containing a C/EBP response element; it also occurs under conditions in which the stimulating action of IL-6 is potentiated by dexamethasone. These findings identify a novel molecular mechanism of negative gene regulation by PPAR alpha and reveal the direct implication of PPAR alpha in the modulation of the inflammatory gene response in the liver.

Blotting, Northern↗
PubMed2005

A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism.

An elevated plasma fibrinogen level is an independent risk factor for cardiovascular disease. Therefore, an understanding of the regulation of fibrinogen expression is important. Inflammation and genetic variation of the fibrinogen beta gene regulate plasma fibrinogen levels, and there are indications that inflammation and genetic variation interact. The aim of our study was to gain more understanding of the regulation of the inflammatory response of the fibrinogen beta gene and to determine the effects of genetic variation. Luciferase reporter gene assays in hepatoma cells, mutation analysis, and electrophoretic mobility shift assays were used to investigate the transcriptional regulation of the fibrinogen beta promoter. We identified a hepatocyte nuclear factor-3 (HNF-3) site located just upstream of previously identified interleukin-6 (IL6)-responsive sequences. This HNF-3 site is essential for a full response of the promoter to IL6, which is a new function for HNF-3. The activity of the CCAAT box/enhancer-binding protein site (located 18 nucleotides downstream of the HNF-3 site and important to the IL6 response) depends on the integrity of the HNF-3 site and vice versa, explaining the necessity of HNF-3 in the IL6 response of the fibrinogen beta promoter. Furthermore, small interfering RNA to HNF-3 reduces the fibrinogen beta mRNA levels. The rare T allele of the -148C/T polymorphism, which is present between the binding sites of HNF-3 and CCAAT box/enhancer-binding protein, interferes with this mechanism, and this polymorphism is in our assay system the only genetic determinant of IL6-induced promoter activity among six polymorphisms in the fibrinogen beta promoter.

Alleles↗
PubMed1984

Redistribution of the fibrinogen receptor of human platelets after surface activation.

We investigated the whole cell distribution of the platelet membrane receptor for fibrinogen in surface-activated human platelets. Fibrinogen-labeled colloidal gold was used in conjunction with platelet whole mount preparations to visualize directly the fibrinogen receptor. Unstimulated platelets fail to bind fibrinogen, and binding was minimal in the stages of activation immediately following adhesion. The amount of fibrinogen bound per platelet increased rapidly during the shape changes associated with surface activation until 7,600 +/- 500 labels were present at saturation. Maximal binding of fibrinogen was followed by receptor redistribution. During the early stages of spreading, fibrinogen labels were uniformly distributed over the entire platelet surface, including pseudopodia, but the labels become progressively centralized as the spreading process continued. In well spread platelets, labels were found over the central regions, whereas peripheral areas were cleared of receptors. Receptor redistribution during spreading was accompanied by cytoskeletal reorganization such that a direct correlation was seen between the development of specific ultrastructural zones and the distribution of surface receptor sites suggesting a link between the surface receptors and the cytoskeleton. The association of fibrinogen receptors with contractile elements of the cytoskeleton, which permits coordinated receptor centralization, is important to the understanding of the role of fibrinogen in normal platelet aggregation and clot retraction.

Blood Platelets↗
PubMed1995

Fetal bleeding in neonatal alloimmune thrombocytopenia mediated by anti-PlAl is not associated with inhibition of fibrinogen binding to platelet GPIIb/IIIa.

Antibody directed against the platelet-specific alloantigen, PlAl, is the most frequently reported cause of two syndromes, post-transfusion purpura (PTP), and neonatal alloimmune thrombocytopenia (NAIT). Numerous reports have indicated that anti-PlAl also has the ability to block certain responses of platelets to stimulation, including fibrinogen binding, platelet aggregation, and serotonin release. Because the PlAl epitope is located on platelet membrane glycoprotein (GP) IIb/IIIa that also contains the fibrinogen receptor, these effects may be mediated by antibody binding at or near the fibrinogen receptor site. This study examines the capacity of anti-PlAl from patients with PTP and from mothers of infants affected by the NAIT to block the binding of radio-labeled fibrinogen to washed human platelets stimulated by ADP and epinephrine. In six of the seven PTP patients, there was inhibition of fibrinogen binding, ranging from 28% to 84% inhibition. In contrast, all anti-PlAl sera from nine mothers of infants with NAIT, including four with intracranial hemorrhage, failed to inhibit fibrinogen binding. Despite the generally higher anti-PlAl titers of the PTP sera, the ability to inhibit fibrinogen binding did not appear attributable to antibody titers. These results suggest that interference with fibrinogen binding to platelets by maternal anti-PlAl does not underlie the increased risk of bleeding in NAIT, whereas inhibitory activity directed against fibrinogen binding appears to be a characteristic feature of the sera from PTP patients.

Antigens, Human Platelet↗
PubMed2002

Increased fibrinogen levels among South Asians versus Whites in the United Kingdom are not explained by common polymorphisms.

Determinants of fibrinogen level among South Asians are not established. In 1997-1999, plasma fibrinogen levels and prevalences of the fibrinogen polymorphisms A alpha Thr312Ala, beta-445G/A, and B beta Arg448Lys and correlates were compared among 100 apparently healthy United Kingdom South Asians and 100 age- and sex-matched Whites. Mean fibrinogen levels were higher in South Asians (3.33 g/liter, 95% confidence interval (CI): 3.16, 3.51) than in Whites (2.84 g/liter, 95% CI: 2.72, 2.96) (p < 0.0001), but genotype distributions were similar. B beta Arg448Lys was related to fibrinogen in South Asians (RR (n = 67): 3.22 g/liter, 95% CI: 3.03, 3.43; RK (n = 26): 3.72 g/liter, 95% CI: 3.65, 4.11; KK (n = 7): 3.07 g/liter, 95% CI: 2.53, 3.72) (p = 0.04) and Whites (p = 0.06). beta-455G/A was related to fibrinogen in Whites (GG (n = 56): 2.68 g/liter, 95% CI: 2.56, 2.86; GA (n = 37): 2.97 g/liter, 95% CI: 2.79, 3.17; AA (n = 5): 3.22 g/liter, 95% CI: 2.85, 3.65) (p = 0.02) and South Asians (p = 0.07). After adjustment for age, gender, body mass index, hypertension, cholesterol, triglycerides, smoking, A alpha Thr312Ala, and beta-455G/A, fibrinogen levels remained significantly higher in South Asians (3.56 g/liter, 95% CI: 3.35, 3.77) than in Whites (3.03 g/liter, 95% CI: 2.85, 3.22) (p < 0.0001). These findings suggest that increased fibrinogen levels among South Asians versus Whites are not due to differences in the prevalence of genetic polymorphisms that encode for fibrinogen.

Adult↗
PubMed1995

Fibrinogen in ischaemic heart disease.

Fibrinogen contributes to both pathological and clinical manifestations of ischaemic heart disease (IHD). Several cross-sectional angiographic studies have shown correlations between the fibrinogen level and the extent of coronary artery disease. The largest of these studies suggests that this relationship is due mainly to luminal occlusion, strengthening the evidence that high fibrinogen levels are thrombogenic. The growing number of prospective studies that have included fibrinogen measurements consistently show a direct, independent and statistically significant association between fibrinogen level and the subsequent incidence of IHD, this association being about as strong as the relation between cholesterol and IHD, for example. The fibrinogen level is also associated with the recurrence of IHD in those who have survived a myocardial infarction and with the onset and recurrence or progression of cerebrovascular disease and lower extremity arterial disease. Besides a contribution to coronary artery changes, high fibrinogen levels predispose to IHD through influences on blood and plasma viscosity, platelet aggregability and the amount of fibrin produced when coagulation is initiated. Progress towards the standardization of methods for measuring fibrinogen increasingly justifies its inclusion in the IHD risk profile. Establishing the value of agents that lower fibrinogen levels is now a high research priority, mainly for clinical reasons but also as part of the evidence for clarifying the nature of the association of raised levels with arterial disease.

Blood Viscosity↗
PubMed1995

Fibrinogen and peripheral arterial disease.

Both hospital and epidemiological studies have reported elevated plasma fibrinogen levels in patients with intermittent claudication. Fibrinogen levels have also been positively related to the degree of asymptomatic peripheral arterial disease (PAD). In claudicants, raised fibrinogen is predictive of future cardiovascular events, particularly coronary death. These associations between plasma fibrinogen and PAD are independent of diabetes mellitus and serum lipid concentrations. Lifetime cigarette smoking and plasma fibrinogen interact synergistically in their association with PAD. However, most of the increased risk of PAD due to cigarette smoking is not mediated via plasma fibrinogen, and conversely the relationship between fibrinogen and PAD is not wholly dependent on smoking. The association between fibrinogen and PAD is stronger in men than in women, and in women does not occur independently of smoking. When comparing sex differences in a wide range of aetiological factors associated with PAD, plasma fibrinogen is one of the few factors showing a stronger relationship in men than in women, and may be important in explaining sex differences in susceptibility to disease.

Adult↗
PubMed1996

Plasma fibrinogen and its correlates in urban Japanese men.

BACKGROUND: The intention of the study was to examine determinants of plasma fibrinogen concentrations in Japanese men. METHODS: A cross-sectional study was conducted in 1991 among 995 male employees aged 40-59 years in two urban companies. RESULTS: The overall mean value (standard deviation) of plasma fibrinogen concentration was 257 (57) mg/dl. There was a strong dose-response relationship between cigarette smoking and plasma fibrinogen concentration. Plasma fibrinogen was positively associated with age and serum total cholesterol, and inversely associated with ethanol intake, dietary intake of sea foods such as squid, octopus or shrimp. Intake of other major protein and lipid resources such as meat, eggs and milk, or intake of vegetables was not related to plasma fibrinogen. An effect of dietary intake of sea foods on plasma fibrinogen was small but significant after controlling for the other covariates; an 80 g/week larger intake of sea foods was associated with a 3.9 mg/dl (95% confidence interval: 0.5, 7.3) lower fibrinogen concentration. CONCLUSIONS: This study confirms the relation of known coronary risk factors to plasma fibrinogen in Japanese men, and suggests that dietary intake of sea foods affects plasma fibrinogen concentrations.

Adult↗
PubMed1999

Association of plasma fibrinogen concentration with vascular access failure in hemodialysis patients.

BACKGROUND: Elevated plasma fibrinogen is an important risk factor for coronary artery disease in the general population and patients with chronic renal failure. High plasma fibrinogen may trigger thrombus formation in arteriovenous fistulas. We performed a prospective, cohort study to evaluate the association of plasma fibrinogen concentration with vascular access failure in patients undergoing long-term haemodialysis. METHODS: Between September 1989 and October 1995, 144 patients underwent a vascular access operation. In March 1997, 102 patients (56 M, 46 F) who had been followed up for more than 18 months (median; 37 months, range; 18-102 months) were included in the study. The median age of the patients was 52 years (range; 19-78 years). In 35 patients, renal disease was secondary to diabetes mellitus. The type of vascular access was a polytetrafluoroethylene (PTFE) graft in 17 patients. Seventy-seven patients received recombinant human erythropoietin (r-HuEPO) therapy during the follow-up period. Plasma fibrinogen, albumin, total cholesterol, hematocrit, platelets and creatinine were measured at the time of operation. Vascular access failure was defined as the occurrence of complications requiring transluminal angioplasty, thrombolytic therapy or surgical repair. RESULTS: Thirty-eight patients had at least one vascular access failure and the incidence was 0.3 (range; 0-2.4) episodes per patient-year. The survival rate of vascular access was 78% (native fistula; 80%, PTFE graft; 71%) after 12 months and 70% (native fistula; 73%, PTFE graft; 51%) after 24 months. Older age, a PTFE graft, r-HuEPO therapy, higher hematocrit, lower albumin and higher fibrinogen levels were significantly associated with vascular access failure, whereas gender, diabetes mellitus, total cholesterol and platelet count were not. Plasma fibrinogen was inversely correlated with albumin (r=-0.38, P=0.001). The cumulative vascular access survival was significantly lower in patients with high plasma fibrinogen levels (> or = 460 mg/dl) compared with patients with low levels (< 460 mg/dl) (P=0.007). Independent risk factors for vascular access failure analysed by Cox's proportional hazards model were older age (RR; 1.36 by 10-year increment), higher fibrinogen level (RR; 1.20 by 100 mg/dl increment), PTFE graft (RR; 2.28) and r-HuEPO therapy (RR; 3.79). CONCLUSION: High plasma fibrinogen level is an independent risk factor for vascular access failure in haemodialysis patients.

Adult↗
PubMed2000

Fibrinogen binds to integrin alpha(5)beta(1) via the carboxyl-terminal RGD site of the Aalpha-chain.

Fibrinogen interactions with vascular endothelial cells are implicated in various physiological and pathophysiological events, including angiogenesis and wound healing. We have shown previously that integrin alpha(5)beta(1) is a fibrinogen receptor on endothelial cells [Suehiro, K., Gailit, J., and Plow, E.F. (1997) J. Biol. Chem. 272, 5360-5366]. In the present study, we have characterized fibrinogen interactions with purified alpha(5)beta(1) and have identified the recognition sequence in fibrinogen for alpha(5)beta(1). The binding of fibrinogen to immobilized alpha(5)beta(1) was selectively supported by Mn(2+). Fibrinogen bound to purified alpha(5)beta(1) in a time-dependent, specific, and saturable manner in the presence of Mn(2+), and the binding was blocked completely by Arg-Gly-Asp (RGD)-containing peptides and by anti-alpha(5) and anti-alpha(5)beta(1) monoclonal antibodies. A monoclonal antibody directed to the C-terminal RGD sequence at Aalpha572-574 significantly inhibited the binding of fibrinogen to alpha(5)beta(1), whereas monoclonal antibodies directed to either the N-terminal RGD sequence at Aalpha95-97 or the C-terminus of the gamma-chain did not. Furthermore, substituting RGE for RGD at position Aalpha95-97 in recombinant fibrinogen had a minimal effect on binding, whereas substituting RGE for RGD at position Aalpha572-574 decreased binding by 90%. These results demonstrate that the C-terminal RGD sequence at Aalpha572-574 is required for the interaction of fibrinogen with alpha(5)beta(1).

Amino Acid Sequence↗
PubMed1991

Interaction of hementin with fibrinogen and fibrin.

The giant Amazon leech Haementeria ghilianii manufactures blood anticoagulant which is present in the posterior and anterior salivary glands. The mechanism of blood anticoagulation by Haementeria ghilianii is completely different from that used by Hirudo medicinalis. The anticoagulant is mostly associated with a fibrinogen-degrading proteinase, hementin. However, other inhibitors of blood coagulation are also present in the salivary glands. The salivary gland extract inhibits platelet aggregation that is mostly attributable to the degradation of fibrinogen. Hementin purified by various methods has a molecular weight in the range of 80,000-120,000 and appears to be a metalloproteinase that is regulated by calcium ions. The enzyme degrades both fibrinogen and fibrin. The Michaelis constant for human fibrinogen is 1 microM. The cleavage of the isolated chains of fibrinogen is inefficient implying that the native conformation of the substrate may play a role in the recognition mechanism. The pattern of fibrinogen degradation by hementin resembles that caused by plasmin since products analogous to fragments Y, D and E are generated. However, the unique action of hementin on fibrinogen is in the initial proteolytic attack in the coiled-coil connector region while proteolysis of the alpha-chain is very slow. In consequence, unique fibrinogen fragments are formed that contain the entire COOH-terminus of the alpha-chain. The mechanism of blood anticoagulation by hementin is very efficient since the cleavage of only three peptide bonds in the fibrinogen molecule disassembles its bivalent structure and renders it non-functional.

Animals↗
PubMed2004

The effect of fibrinogen concentrate administration on coagulation abnormalities in a rat sepsis model.

Disseminated intravascular coagulation is a disorder that affects the function of the clotting system and is frequently associated with sepsis or septic shock. One of its leading symptoms is the decrease in circulating fibrinogen. We investigated the effect of fibrinogen concentrate (Haemocomplettan P) on fibrinogen plasma levels, coagulation parameters and mortality in a rat model of sepsis-induced disseminated intravascular coagulation. The disseminated intravascular coagulation was characterized by elevated thrombin-antithrombin complex and a sharp drop in circulating fibrinogen. Coagulation abnormalities were evaluated by thrombelastography. Plasma fibrinogen levels decreased from 2.06 +/- 0.2 to 0.16 +/- 0.1 g/l following administration of bacterial lipopolysaccharide. Thrombelastographic measurements revealed a concurrent decrease in maximum amplitude and an increase in reaction time. Treatment with fibrinogen concentrate (Haemocomplettan P, 25-200 mg/kg body weight intravenously) resulted in a statistically significant dose-dependent increase in fibrinogen plasma levels and amelioration of the measured coagulation abnormalities. Fibrinogen plasma concentrations were restored to normal levels when 200 mg/kg body weight fibrinogen concentrate was administered. A significant decrease in sepsis-induced mortality was observed in animals treated with Haemocomplettan P.

Animals↗
PubMed1980

Studies on circulating soluble fibrin: separation of 125I-Des-AB fibrin and 131I-fibrinogen by gel filtration.

The behaviour of labelled des-AB fibrin in plasma was studied by gel filtration after it had been injected into rabbits. Purified rabbit [125I]des-AB fibrin was prepared by clotting of [125I]fibrinogen by thrombin and solubilizing the formed clot in buffered 3 M urea. Gel filtration of this material on urea-equilibrated columns showed a single peak identical to the elution profile of fibrinogen. This indicated the existence of monomeric des-AB fibrin. When plasma from rabbits injected with monomeric [125I]des-AB fibrin and [131I]fibrinogen was gel-filtered through plasma-equibrated columns, two separate peaks of radioactivities were obtained. The first peak eluted mainly with the void volume and contained [125I]des-AB fibrin whereas the second peak eluting within the fractionation range contained [131I]fibrinogen. Identical elution profiles were obtained in in vitro studies when monomeric [125I]des-AB fibrin was mixed with plasma containing [131I]fibrinogen and gel-filtered through plasma-equilibrated columns. We conclude from these studies that monomeric des-AB fibrin formed high-molecular weight aggregates or changed its conformation posing as a larger molecule than fibrinogen when injected into rabbits. No complex formation between des-AB fibrin and fibrinogen was observed as [131I]fibrinogen was not incorporated into des-AB fibrin aggregates. Thus, soluble des-AB fibrin can circulate in the blood without forming fibrin-fibrinogen complexes.

Animals↗