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PubMed2003

Relation of fibrinogen to cardiovascular events is independent of preclinical cardiovascular disease: the Strong Heart Study.

BACKGROUND: It is unclear whether fibrinogen predicts cardiovascular events independently of echocardiographic cardiovascular abnormalities and traditional risk factors. METHODS: We studied 2671 American Indians who participated in the second Strong Heart Study examination (1993-1995) and were observed for an average of 50 +/- 6 months. Participants with baseline overt coronary artery disease or a plasma creatinine level > or =3 mg/dL were excluded. Left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial contractility were assessed by echocardiography. RESULTS: Prevalences of echocardiographic abnormalities and cardiovascular event rates were higher with higher fibrinogen levels. Incident cardiovascular events (n = 158) and deaths (n = 64) were more frequent in participants with elevated fibrinogen levels (>400 mg/dL) than in participants with lower fibrinogen levels, as was the prevalence of echocardiographic abnormalities (both P <.01). Incident cardiovascular fatal and nonfatal events and cardiovascular deaths were 4 and 8 times higher, respectively, in participants with both elevated fibrinogen levels and echocardiographic abnormalities than in participants with neither echocardiographic abnormalities nor elevated fibrinogen levels. However, participants with fibrinogen levels >400 mg/dL had a 2 times greater relative risk of cardiovascular events or mortality, independent of both risk factors and echocardiographic abnormalities. CONCLUSIONS: In a population-based sample of adults without clinical evidence of coronary artery disease at baseline, fibrinogen levels predicted cardiovascular events independent of traditional risk factors, left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial systolic function.

Cardiovascular Diseases↗

PubMed1973

Discriminating neoantigenic differences between fibrinogen and fibrin derivatives.

Discrimination between the physiological cleavage fragments of fibrinogen and fibrin offers an approach to differentiation between fibrinogenolytic processes and fibrinolysis after coagulation. By use of the cleavage-associated neoantigen of fibrinogen (fg-D(neo)) as a molecular marker, characteristic differences between the D regions of fibrinogen derivatives and fibrin derivatives can be demonstrated. The expression of fg-D(neo) by X, Y, D:E complex, and D-fragments of fibrinogen or fibrin is shown to be quantitative and unitary. Characteristic differences between fg-D(neo) sites present on fibrinogen cleavage fragments, as contrasted to fibrin cleavage fragments, are indicated by different competitive inhibition slopes, and appear to reflect differential binding affinity of selected anti-fg-D(neo) antibodies for the specific molecular site. There is a linear relationship between the slope of quantitative competitive inhibition and the relative molar ratio of fibrinogen and fibrin derivatives. Identical immunochemical expressions are observed in vitro and in vivo, and support the thesis that cleavage in vivo is produced by plasmin. The differential immunochemical features of fg-D(neo) expression may be the result of stable conformational and/or subtle structural differences between the D region of fibrinogen and fibrin cleavage fragments and suggest that precise changes in the D region are associated with the fibrin transition. These molecular features not only provide additional insight into the molecular immunology and structure of fibrinogen, but also appear to offer a new molecular approach to discrimination between fibrinogenolytic mechanisms as contrasted to fibrinolysis secondary to coagulation.

Abruptio Placentae↗

PubMed1978

Fibrinogen synthesis in serum-free hepatocyte cultures: stimulation by glucocorticoids.

Fibrinogen synthesis was investigated in cultures of chicken embryo hepatocytes initiated and maintained in chemically defined, serum-free medium. 11-Hydroxy glucocorticoids caused a 3-fold stimulation of fibrinogen synthesis. Half-maximal stimulation was achieved with 1 nM corticosterone or hydrocortisone, as compared with only 0.1 nM dexamethasone. Increased fibrinogen production in the presence of these glucocorticoids was characterized by a 4-hr delay in onset, a sensitivity to actinomycin D, and a requirement for the continuous presence of the steroid. Crossed immunoelectrophoresis permitted analysis of the simultaneous effects of glucocorticoids on the synthesis of more than 20 plasma proteins secreted in culture. The absence of an effect on the synthesis of most of these proteins was in sharp contrast to the 3-fold increase in fibrinogen production. Sera from a variety of animals also stimulated an increase in fibrinogen synthesis that was similar in degree but less specific than that due to glucocorticoids and that partially masked the response of the cells to the steroid hormones. The presence of an anticoagulant in the medium was found to be necessary for detection of the fibrinogen secreted in culture. Although insulin was routinely included in the chemically defined medium, the cells synthesized fibrinogen and responded to glucocorticoids in the absence of hormonal supplementation of the medium. These findings are consistent with the thesis that variations in glucocorticoid levels contribute to the regulation of fibrinogen production in the intact animal.

Animals↗

PubMed1982

gamma and alpha chains of human fibrinogen possess sites reactive with human platelet receptors.

Fibrinogen, a clottable plasma protein, agglutinates both prokaryotic cells (e.g., staphylococci) and eukaryotic cell fragments (e.g., platelets) through interaction with specific receptors. To identify the region of the fibrinogen molecule responsible for its interaction with human platelets, we prepared polypeptide chain subunits (alpha, beta, and gamma) of human fibrinogen by reduction and carboxymethylation. A mixture of the chains induced aggregation (clumping) of human platelets separated from plasma proteins and treated with ADP. When individual chains of fibrinogen were tested, gamma-chain multimers caused platelet aggregation at a molar concentration comparable with that of intact human fibrinogen. The beta chain remained inactive, and the alpha chain was 1/4th to 1/5th as reactive as the gamma chain. Monospecific antibody fragments against the gamma chain inhibited binding of 125I-labeled fibrinogen to the human platelet receptor and blocked aggregation of platelets induced by ADP in the presence of fibrinogen or gamma-chain multimers. These results indicate that the gamma chain of human fibrinogen bears the main site for interaction with the platelet receptor.

Antigen-Antibody Reactions↗

PubMed1983

Inhibition of fibrinogen binding to stimulated human platelets by a monoclonal antibody.

Fibrinogen binding to receptors on stimulated platelets is a prerequisite for platelet aggregation. To gain further insight into the role of fibrinogen in platelet aggregation and to identify the platelet fibrinogen receptor, we developed a monoclonal anti-platelet antibody that inhibited platelet aggregation. The purified antibody, designated A2A9, inhibited platelet aggregation stimulated by 10 microM ADP, 10 microM epinephrine, and thrombin at 1 unit/ml without inhibiting platelet shape change or platelet secretion. A2A9 was also a competitive inhibitor of fibrinogen binding to ADP-stimulated platelets. Fifty percent inhibition of fibrinogen binding occurred at 65 nM A2A9. Direct binding studies using radiolabeled A2A9 demonstrated 47,000 A2A9 binding sites on unstimulated platelets, with a dissociation constant of 60 nM. Platelets from two individuals with Glanzmann thrombasthenia bound essentially no A2A9. Therefore, these data support the hypothesis that receptor-bound fibrinogen mediates platelet aggregation. In order to identify the platelet fibrinogen receptor, A2A9 immobilized on agarose was used for affinity chromatography. Two platelet polypeptides with Mr = 140,000 and 93,000 were recovered from the immobilized A2A9. After disulfide reduction, these Mr values were altered to 125,000 and 116,000. The smaller polypeptide was also found to contain the PlA1 antigen. These data localize the epitope recognized by A2A9 to the platelet membrane glycoprotein IIb-IIIa complex and suggest that this complex forms the physiologic platelet fibrinogen receptor.

Adenosine Diphosphate↗

PubMed1984

ADP-dependent common receptor mechanism for binding of von Willebrand factor and fibrinogen to human platelets.

Human von Willebrand factor (vWF) and fibrinogen are adhesive plasma glycoproteins essential for formation of a platelet hemostatic plug. We investigated the role of ADP and fibrinogen in binding of vWF to platelets in vitro. Binding of 125I-labeled vWF to human platelets separated from plasma proteins and treated with ADP was specific, and time and concentration dependent, reaching equilibrium at 20 min and approaching saturation at 12 micrograms/ml. The binding was inhibited by EDTA and by prostaglandin I2, a known activator of platelet adenylate cyclase. A purine nucleotide affinity analog, 5'-p-fluorosulfonylbenzoyl adenosine (FSBA), which covalently modifies the ADP binding sites on the human platelet membrane, prevented binding of vWF induced with ADP, as well as with human thrombin and with ionophore A23187, agents known to cause platelet ADP secretion. By comparison, FSBA did not inhibit binding of vWF induced by ristocetin, indicating that the ristocetin mechanism is not dependent on ADP. Human fibrinogen inhibited in a competitive manner the ADP-induced binding of 125I-labeled vWF (9 micrograms/ml) with an IC50 of 25 micrograms/ml. Conversely, unlabeled vWF inhibited ADP-induced binding of 125I-labeled fibrinogen (60 micrograms/ml) with an IC50 of 16 micrograms/ml. A synthetic dodecapeptide (Mr, 1188), analogous with the specific platelet receptor recognition site of human fibrinogen gamma chain (gamma 400-411), inhibited binding of both 125I-labeled vWF and 125I-labeled fibrinogen to ADP-treated platelets, whereas it was without effect on binding of 125I-labeled vWF to ristocetin-treated platelets. These data indicate that vWF and fibrinogen have a common receptor mechanism for their interaction with human platelets that is dependent on ADP occupancy of its binding sites and is recognized by the sequence of 12 amino acid residues at the carboxyl terminus of the human fibrinogen gamma chain.

Adenosine Diphosphate↗

PubMed1988

Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen.

Human polymorphonuclear leukocytes (PMN) have previously been shown to bind to aggregates of fibrin and to fibrinogen-coated surfaces. During their interactions with fibrinogen-coated surfaces, PMN make such close contact with the surface that a portion of the secreted elastase activity is protected from macromolecular protease inhibitors in the surrounding medium. Here we show that the receptor on PMN that mediates this interaction is complement receptor type 3 (CR3; CD11b/CD18), a molecule previously identified as a receptor for the complement protein fragment C3bi. Monoclonal antibodies against CR3 that block the binding of C3bi also block the binding of PMN to fibrinogen-coated surfaces and the formation of a protected compartment. The region of fibrinogen recognized by CR3 lies at the carboxyl terminus of the gamma chain, since peptides based on this sequence effectively inhibit the binding of PMN to fibrinogen-coated surfaces. These peptides also block the binding of C3bi-coated erythrocytes to CR3, thus indicating that a single binding site is used for binding both C3bi and fibrinogen. Sequence analysis shows strong structural similarity between this region of fibrinogen and other known ligands of CR3. These studies thus indicate that CR3 functions as a receptor not only for C3bi but also for fibrinogen.

Antibodies, Monoclonal↗

PubMed1989

Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin.

Lipoprotein (a) [Lp(a)] is a plasma component whose concentration is related to the development of atherosclerosis, although the underlying mechanisms are not known. Lp(a) contains a unique structure, apolipoprotein (a), that shares partial homology with plasminogen. We now report that plasmin catalyzes the binding of Lp(a) to both immobilized fibrinogen and fibrin in a manner analogous to our previously reported studies with plasminogen. Plasmin treatment of immobilized fibrinogen induces a 3.7-fold increase in Lp(a) binding. Low density lipoprotein, molecules similar to Lp(a) but lacking apolipoprotein (a), bind poorly to immobilized fibrinogen and binding is not increased by plasmin. Trypsin but not neutrophil elastase also increases the binding of Lp(a) to fibrinogen. Lp(a) also complexes to plasmin-fibrinogen digests, and binding increases in proportion to the time of plasmin-induced fibrinogen degradation. Lp(a) binding is lysine-binding site dependent as it is inhibited by epsilon-aminocaproic acid. Lp(a) inhibits the binding of plasminogen to plasmin-modified immobilized fibrinogen, indicating that both molecules compete for similar lysine-binding sites. These findings demonstrate an affinity between Lp(a) and protease-modified fibrinogen or fibrin and thereby provide a potential mechanism to explain the association between thrombosis, coronary atherosclerosis, and increased blood concentrations of Lp(a).

Arteriosclerosis↗

PubMed1995

Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition.

Although primarily recognized for its role in hemostasis, fibrinogen is also required for competent inflammatory reactions in vivo. It is now shown that fibrinogen promotes adhesion to and migration across an endothelial monolayer of terminally differentiated myelomonocytic cells. This process does not require chemotactic/haptotactic gradients or cytokine stimulation of the endothelium and is specific for the association of fibrinogen with intercellular adhesion molecule 1 (ICAM-1) on endothelium. Among other adhesive plasma proteins, fibronectin fails to increase the binding of leukocytes to endothelium, or transendothelial migration, whereas vitronectin promotes the binding but not the migration. The fibrinogen-mediated leukocyte adhesion and transendothelial migration could be inhibited by a peptide from the fibrinogen gamma-chain sequence N117NQKIVNL-KEKVAQLEA133, which blocks the binding of fibrinogen to ICAM-1. This interaction could also be inhibited by new anti-ICAM-1 monoclonal antibodies that did not affect the ICAM-1-CD11a/CD18 recognition, thus suggesting that the fibrinogen binding site on ICAM-1 may be structurally distinct from regions previously implicated in leukocyte-endothelium interaction. Therefore, binding of fibrinogen to vascular cell receptors is sufficient to initiate (i) increased leukocyte adhesion to endothelium and (ii) leukocyte transendothelial migration. These two processes are the earliest events of immune inflammatory responses and may also contribute to atherosclerosis.

Amino Acid Sequence↗

PubMed1996

In vitro assembly of the component chains of fibrinogen requires endoplasmic reticulum factors.

Human fibrinogen (340 kDa) is a dimer, with each identical half-molecule composed of three different polypeptides (Aalpha, 66 kDa; Bbeta, 55 kDa; and gamma, 48 kDa). To understand the mechanisms of chain assembly, a coupled in vitro transcription translation system capable of assembling fibrinogen chains was developed. Fibrinogen chain assembly was assayed in an expression system coupled to rabbit reticulocyte lysate in the presence or absence of dog pancreas microsomal membranes. Fibrinogen chain assembly required microsomal membranes and oxidized glutathione. Co-expression of two of the chains, Bbeta and gamma or Aalpha and gamma, yielded free chains and two-chain complexes. Unlike combinations of Aalpha with gamma and Bbeta with gamma, co-expression of Aalpha and Bbeta did not form a single two-chain complex but produced a mixture of two-chain complexes. Co-expression of all three chains yielded free chains, two-chain complexes, and higher molecular weight complexes that corresponded to a half-molecule and to fully formed fibrinogen. Upon treatment of this mixture with thrombin and factor XIIIa, a gamma.gamma dimer, similar to that obtained from cross-linked human fibrin, was produced, indicating that properly folded fibrinogen was formed in vitro. Molecular chaperones may participate in fibrinogen assembly, since antibodies to resident proteins of the endoplasmic reticulum (BiP, Hsp90, protein disulfide isomerase, and calnexin) co-precipitated the chaperones together with nascent fibrinogen chains and complexes.

Animals↗

PubMed1997

Fibrinogen is a ligand for integrin alpha5beta1 on endothelial cells.

Previous studies have shown that fibrinogen can associate with endothelial cells via an Arg-Gly-Asp (RGD) recognition specificity. In the present study, we have characterized the specificity of fibrinogen binding to endothelial cells under different cation conditions. Fibrinogen binding to suspended endothelial cells was selectively supported by Mn2+ and was suppressed by Ca2+. The Mn2+-supported interaction was completely inhibited by RGD peptides but not by alphavbeta3 blocking monoclonal antibodies. In contrast, the interaction was completely blocked by two alpha5beta1 monoclonal antibodies. This interaction was not mediated by fibronectin bound to the integrin; could be demonstrated with purified alpha5beta1; and also was observed with a second alpha5beta1-bearing cell type, platelets. The binding of fibrinogen to alpha5beta1 on endothelial cells in the presence of Mn2+ was time-dependent, specific, saturable, and of high affinity (Kd = 65 nM). By employing anti-peptide monoclonal antibodies, the carboxyl-terminal RGD sequence at Aalpha 572-574 was implicated in fibrinogen recognition by alpha5beta1. Two circumstances were identified in which alpha5beta1 interacted with fibrinogen in the presence of Ca2+: when the receptor was activated with monoclonal antibody (8A2) or when the fibrinogen was presented as an immobilized substratum. These results identify fibrinogen as a ligand for alpha5beta1 on endothelial and other cells, an interaction which may have broad biological implications.

Cells, Cultured↗

PubMed1998

Binding of basic fibroblast growth factor to fibrinogen and fibrin.

Fibrin is formed at sites of tissue injury and provides the temporary matrix needed to support the initial endothelial cell responses needed for vessel repair. Basic fibroblast growth factor (bFGF) also acts at sites of injury and stimulates similar vascular cell responses. We have, therefore, investigated whether there are specific interactions between bFGF and fibrinogen and fibrin that could play a role in coordinating these actions. Binding studies were performed using bFGF immobilized on Sepharose beads and soluble 125I-labeled fibrinogen and also using Sepharose-immobilized fibrinogen and soluble 125I-bFGF. Both systems demonstrated specific and saturable binding. Scatchard analysis indicated two classes of binding sites for each with Kd values of 1.3 and 260 nM using immobilized bFGF; and Kd values of 0.9 and 70 nM using immobilized fibrinogen. After conversion of Sepharose-immobilized fibrinogen to fibrin by treatment with thrombin, bFGF also demonstrated specific and saturable binding with two classes of binding sites having Kd values of 0.13 and 83 nM. Fibrin binding was also investigated by clotting a solution of bFGF and fibrinogen, and two classes of binding sites were demonstrated using this system with Kd values of 0.8 and 261 nM. The maximum molar binding ratios of bFGF to fibrinogen were between 2.0 and 4.0 with the four binding systems. We conclude that bFGF binds specifically and saturably to fibrinogen and fibrin with high affinity, and this may have implications regarding the localization of its effect at sites of tissue injury.

Cell Adhesion↗

PubMed2001

Structural organization of the fibrinogen-binding region of the clumping factor B MSCRAMM of Staphylococcus aureus.

The clumping factor B (ClfB) of Staphylococcus aureus is a surface protein that binds to fibrinogen (Ni Eidhin, D., Perkins, S., Francois, P., Vaudaux, P., Hook, M., and Foster, T. J., 1998 Mol. Microbiol. 30, 245-257). The ligand-binding activity is located in the approximately 500-residue A-region (residues 44-542), which represents the N-terminal half of the MSCRAMM protein. We now hypothesize that the ClfB A-region is composed of three subdomains, which we have named N1, N2, and N3, respectively. To examine this hypothesis, we expressed recombinant forms of the individual putative subdomains, the tandem motifs N12 and N23, and the full-length A-region N123. Far UV circular dichroism spectra showed that each subdomain is composed mainly of beta-sheets with little or no discernible alpha-helices. Heat-induced unfolding of individual subdomains occurred with a single state transition and was reversible, indicating that the subdomains can fold as discreet units. Gel permeation chromatography indicated that N2, N3, and N23 are globular. In contrast, domain N1 appeared to be elongated and conferred a somewhat elongated structure on segments containing this subdomain (i.e. N12 or N123). N123, N12, and N23 all bound to fibrinogen, but N23 had a higher affinity for fibrinogen than that observed for the full-length A-region; N123 or for N12. However, an extended N terminus of N23 was required for ligand binding. A form of N23 that was generated by proteolytic processing and lacked the N-terminal extension was unable to bind fibrinogen. Recombinant forms of individual subdomains did not bind fibrinogen. The addition of recombinant N23 effectively inhibited ClfB-mediated bacterial adherence to fibrinogen, and N123 caused some reduction in bacterial attachment, whereas N12 was essentially inactive. Antibodies raised against the central N2 domain of the A-region were the most effective at inhibiting bacterial adhesion to immobilized fibrinogen, although anti-N3 or anti-N1 antibodies also caused some reduction in ClfB-mediated adherence to fibrinogen.

Adhesins, Bacterial↗

PubMedDate not supplied

Peroxynitrite-mediated modification of fibrinogen affects platelet aggregation and adhesion.

The reaction of peroxynitrite with fibrinogen resulted in both structural modifications and altered biological properties of this glycoprotein. SDS-PAGE analysis of peroxynitrite-treated fibrinogen, performed under non-reducing conditions, showed some aggregated material on the top of the gel (5-10% of total staining bands) and the presence of nitrotyrosine. The amount of nitrotyrosine, detected by immunoassay with anti-nitrotyrosine antibodies, was dependent on peroxynitrite concentration. In comparison with native molecule, peroxynitrite-treated fibrinogen subjected to SDS-PAGE under reducing conditions revealed not only three bands corresponding to Aalpha, Bbeta and gamma chains, but the existence of additional high molecular bands probably due to the formation of dityrosine crosslinking between fibrinogen subunits. The different susceptibility in tyrosine nitration of fibrinogen subunits was also observed. The Aalpha chain was the most intensely nitrated, while Bbeta and gamma chains were nitrated much less? Peroxynitrite-treated fibrinogen in comparison with native molecule had a distinct capability to mediate platelet adhesion and aggregation. Both unstimulated and ADP-activated platelets showed a reduced ability to adhere to peroxynitrite-modified fibrinogen. The percentage of ADP-induced platelet aggregation decreased as a function of peroxynitrite-mediated modification of fibrinogen molecule.

Adenosine Diphosphate↗

PubMed2006

Fibrinogen is a co-antioxidant that supplements the vitamin E analog trolox in a model system.

OBJECTIVE: It appears that the atherosclerotic plaque is a prooxidant environment where some molecules that are normally antioxidants, including vitamins C and E, may act as prooxidants that contribute to atherosclerosis by oxidizing LDL. Some molecules can act as co-antioxidants to eliminate this prooxidant effect by recycling or other mechanisms of supplementation. Fibrinogen and other acute phase proteins found in the plaque are antioxidants. We hypothesized that fibrinogen can act as a co-antioxidant to supplement vitamin E thereby eliminating its oxidative effect under prooxidant conditions. We tested a model system for this hypothesis using the vitamin E analogue Trolox in a cell free system. METHODS: LDL was oxidized using 5 umol/l copper. Antioxidant conditions were achieved by adding the antioxidants immediately with LDL, while prooxidant conditions were created by adding antioxidants after a 40 min delay. Oxidation was monitored as the lag phase at 234 nm. RESULTS: Under antioxidant conditions, the protective effect of fibrinogen and Trolox combined together were about equal to the sum of the anitioxidant effects of each alone (additive), while under prooxidant conditions the combined protection was 54-200% greater (synergistic). These effects were different than those of vitamin C with Trolox in that under antioxidant conditions fibrinogen and Trolox were additive while vitamin C and Trolox showed strong synergistic effects, and in that unlike vitamin C and Trolox fibrinogen showed no prooxidant tendencies under prooxidant reaction conditions. CONCLUSIONS: The data indicated that fibrinogen did act as a co-antioxidant to supplement Trolox and eliminate its prooxidant effect, most probably, by directly quenching the phenoxyl radical, because unlike vitamin C, fibrinogen did not appear to recycle vitamin E. But fibrinogen may act as a universal antioxidant, since unlike Trolox and vitamin C, it showed little tendency toward becoming a prooxidant.

Antioxidants↗

PubMed1984

Common protective antigens of group A streptococcal M proteins masked by fibrinogen.

The influence of fibrinogen on the opsonization of Group A streptococci by type-specific and cross-reactive anti-M protein antisera was investigated. As previously reported for type 24 streptococci, fibrinogen inhibited the complement-mediated opsonization of types 5, 6, and 19 organisms. Rabbit antisera against large peptide fragments of purified homologous M proteins (pep M proteins) overcame the anti-opsonic effect of fibrinogen in a dose-dependent manner. In the presence of optimal amounts of antibody, bacterial uptake by PMN was equal in serum and plasma, and greater than could be obtained in serum in the absence of antibody. Polyclonal anti-pep M sera contained antibodies directed against fibrinogen-binding as well as fibrinogen-nonbinding sites or regions of the M protein molecule. Three cross-reactive anti-pep M sera included antibodies directed against fibrinogen binding sites or regions of the cross-reacting M proteins. In the two sera studied in detail, these antibodies accounted for a large part of the cross-reacting anti-M antibody present in the sera. We suggest that fibrinogen binding sites on different serotypes of M protein may be structurally and therefore antigenically similar. Conservation of fibrinogen binding sites on M proteins may be related to their protective anti-opsonic function.

Animals↗

PubMed1985

Inhibition of complement-mediated opsonization and phagocytosis of Streptococcus pyogenes by D fragments of fibrinogen and fibrin bound to cell surface M protein.

The biological effects of the binding of fibrin(ogen) degradation products to M protein-bearing group A streptococci were investigated. Type 24 group A streptococci bind fibrinogen degradation products of the D family, but not fragment E. Binding appears to be mediated by M protein, since a large peptide of this molecule (pep M24) bound to fragments containing the terminal domains of the fibrinogen molecule (D, X, and Y), but not fragment E, and pep M24 inhibited the binding of digested fibrinogen to streptococcal cells. An M protein-binding site occurs on fragment D3 and, therefore, differs from several functional sites present on D1 but not D3, including the fibrin polymerization site, the two gamma chain crosslink sites, and the bindings sites for platelet fibrinogen receptor, staphylococcal clumping factor, and ionized calcium. Bound fibrinogen degradation products prevented deposition of C3 on the streptococcal cell surface, and, in consequence, prevented phagocytosis by neutrophils in nonimmune blood. The average affinity of D fragments for the streptococcal cell surface was approximately 30 times lower than that of native fibrinogen, and a terminal plasmic digest was approximately 50 times less potent in inhibiting opsonization by C3. However, physiologic concentrations of digested fibrinogen sufficed to inhibit opsonization and phagocytosis completely. Digests of crosslinked fibrin clot also inhibited opsonization, although slightly less effectively than did fibrinogen digests. The antiopsonic effect of fibrin(ogen) degradation products may be relevant to circumstances in which fibrin(ogen)olysis is occurring, e.g., exudation and suppuration.

Antigens, Bacterial↗

PubMed2000

Plasma fibrinogen and coronary heart disease in urban Japanese.

There is little information on the relation of plasma fibrinogen concentration to the risk of coronary heart disease in Asians, including Japanese, whose plasma fibrinogen concentration has been reported to be low by Western standards. The authors conducted a prospective study with 4.8 years of follow-up of 11,977 men and women aged 21-89 years (mean value of fibrinogen = 267 mg/dl) living or working in Osaka, Japan, in 1990-1996 to examine the relation of plasma fibrinogen with the incidence of coronary heart disease (myocardial infarction and angina pectoris). Mean fibrinogen concentration was 293.6 mg/dl for men who developed coronary heart disease (n = 35) compared with 261.6 mg/dl for men free of coronary heart disease (n = 8,094; difference, p < 0.01), and 355.2 mg/dl for women who developed coronary heart disease (n = 6) compared with 276.8 mg/dl for women free of coronary heart disease (n = 3,842; difference, p < 0.01). With a Cox proportional hazards model to adjust for cardiovascular risk factors, the relative risk for the highest fibrinogen quartile (> or =295 mg/dl) compared with the lowest (<228 mg/dl) was 4.8 (95% confidence interval: 1.4, 16.8, p = 0.01) for coronary heart disease, and 3.8 (95% confidence interval: 1.1, 13.4, p = 0.04) for myocardial infarction. Plasma fibrinogen is useful to predict the risk of coronary heart disease among urban Japanese, whose mean plasma fibrinogen is relatively low.

Adult↗