Role Of Fibrinogen Research Articles

Fibrinogen is a predictor of mortality in coronary heart disease patients. The Bezafibrate Infarction Prevention (BIP) Study Group.

Results of epidemiological studies have indicated that fibrinogen is an important primary cardiovascular risk factor. The role of fibrinogen as a predictor of mortality in coronary heart disease (CHD) patients is unclear. We investigated the association between fibrinogen and mortality in a large cohort of CHD patients screened for participation in a secondary prevention clinical trial. Of the total investigated, 3092 men who were not included in the trial and for whom vital status was known were followed up for a mean period of 3.2 years. In 54.4% of the 111 men who died, mortality was attributed to CHD. Mean baseline plasma fibrinogen levels were 29.4 mg/dL higher in patients who died than in the survivors. All-cause and CHD mortality rates increased with increasing fibrinogen levels. This relationship was also demonstrated within categories of the primary variables predicting mortality in these patients. The contribution of fibrinogen to CHD and all-cause mortality was assessed by multivariate analysis adjusting for age, CHD severity, and comorbidity. Risk of CHD and all-cause mortality for patients in the highest fibrinogen tertile were 1.67 and 1.75, respectively, relative to patients in the lowest tertile, and an increase of about 1 SD of plasma fibrinogen level (75 mg/dL) was found to increase risk of CHD and all-cause mortality 29% and 31%, respectively. These results indicate clearly that fibrinogen level is associated with significantly increased mortality in CHD patients. Implementation of a standardized measuring method is required to allow assessment of risk in CHD patients on the basis of fibrinogen levels.

The role of fibrinogen D domain intermolecular association sites in the polymerization of fibrin and fibrinogen Tokyo II (gamma 275 Arg-->Cys).

Intermolecular end-to-middle domain pairing between a thrombin-exposed 'A' polymerization site in the central 'E' domain of fibrin, and a constitutive complementary 'a' site in each outer 'D' domain ('D:E'), is necessary but not alone sufficient for normal fibrin assembly, as judged from previous studies of a congenital dysfibrinogen, Tokyo II (gamma 275 arg-->cys), which showed defective fibrin clot assembly and a normal D:E interaction (Matsuda, M., M. Baba, K. Morimoto, and C. Nakamikawa, 1983. J. Clin. Invest. 72:1034-1041). In addition to the 'a' polymerization site, two other constitutive intermolecular association sites on fibrinogen D domains have been defined: between gamma chain regions containing the carboxy-terminal factor XIIIa crosslinking site ('gamma XL:gamma XL'); and between sites located at the outer ends of each molecule ('D:D') (Mosesson, M. W., K. R. Siebenlist, J. F. Hainfeld, and J. S. Wall, manuscript submitted for publication). We evaluated the function of these sites in Tokyo II fibrinogen, and confirmed that there was a normal fibrin D:E interaction, as determined from a normal fibrin crosslinking rate in the presence of factor XIIIa. We also found a normal gamma XL: gamma XL interaction, as assessed by a normal fibrinogen crosslinking rate. Judging from electron microscopic images, factor XIIIa-crosslinked Tokyo II fibrinogen failed to form elongated double-stranded fibrils like normal fibrinogen. Instead, it formed aggregated disordered collections of molecules, with occasional short fibrillar segments. In addition, Tokyo II fibrin formed an abnormal, extensively branched clot network containing many tapered terminating fibers. These findings indicate that the Tokyo II fibrinogen defect results in a functionally abnormal D:D self-association site, and that a normal D:D site interaction is required, in addition to D:E, for normal fibrin or fibrinogen assembly.

Recent progress in the clinical aspects of fibrinogen.

This article provides an overview of recently accumulated evidence on the pathogenetic role of fibrinogen in various vascular beds; and tries to elucidate determinants for patients' susceptibility so that subgroups at particular risk of severe clinical complications can be characterized more accurately. Based on the considerably elevated risk of cardiovascular complications associated with increased levels of plasma fibrinogen, the potential value of lowering fibrinogen in the primary or secondary prevention of atherosclerotic disease is now recognized as an important topic for consideration. Recent progress in this field will also be reviewed.

F166. Role of fibrinogen and erythrocyte sialic acid content on red blood cell aggregation in hypercholesterolemia

F166. Role of fibrinogen and erythrocyte sialic acid content on red blood cell aggregation in hypercholesterolemia

Antiphospholipid Antibodies, Haemostatic Variables and Thrombosis – A Survey of 144 Patients

Several clotting abnormalities have been put forth to explain the thrombotic tendency of the antiphospholipid syndrome, but a possible role for fibrinogen and von Willebrand factor has been poorly investigated. The present cross-sectional retrospective study evaluated the relationship of IgG anticardiolipin antibodies, lupus anticoagulants, fibrinogen and von Willebrand factor with the occurrence of arterial and venous thromboses in patients with antiphospholipid antibodies. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell's viper venom time correlated with a history of venous thrombosis more strongly than activated partial thromboplastin time (p < 0.0002 vs p < 0.009) and was the only test which correlated with a history of arterial thrombosis (p < 0.01), also at low levels of IgG anticardiolipin antibodies (p = 0.003). By regression analysis, and after correction for confounders, serum levels of IgG anticardiolipin antibodies were found to be positively associated with the number of venous events (p < 0.001). Plasma levels of fibrinogen and von Willebrand factor were associated with each other (p < 0.0001; r: 0.48) and with the occurrence of arterial and venous thromboses (p < 0.001). Moreover, plasma levels of fibrinogen and von Willebrand factor in thrombotic patients with antiphospholipid antibodies were significantly higher than those of a control group of thrombotic patients who suffered thrombosis for other reasons (p < 0.0001 and p = 0.0008 respectively). Titres of IgG anticardiolipin antibodies correlated with plasma levels of von Willebrand factor (p < 0.0001; r: 0.42).(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinogen, arterial risk factor, in clinical practice

Easil y measured in lar ge series of sam p les , fibrinogen has been extensively studied in the epidemiology of cardiovascular risk factors. Ten large stu­ dies have concluded that fibrinogen is a risk factor of equal or higher value than total cholesterol. In coronary diseases, fibrinogen is an independent risk factor and has a pro­ gnostic value. After stroke, high fibrinogen level is an index of severity. In peripheral arterial disease, it indicates the risk of reocclusion after surgery. The role of fibrinogen in arterial occlusion is multiple: composition of the atheroma plaque, thrombi formation, endothelial injury, hyperviscosity. Many parameters increase fibrinogen: inflammation, ageing, smoking. Genetic control of fibrinogen is a promising field for future research in epi­ demiology. Many drugs decrease fibrinogen: fibrates, platelet inhibitor ticlopidin and should be used for this purpose. Lastly, physical exercise, if sustained enough, effectively reduces fibrinogen.

Fibrinogen Plasma Levels as a Marker of Thrombin Activation: New Insights on the Role of Fibrinogen as a Cardiovascular Risk Factor

Fibrinogen has recently emerged as a major risk factor for atherothrombosis. However, the pathophysiologic mechanism linking high fibrinogen concentration to cardiovascular disease is unclear. In this study 136 subjects (75 males, 61 females, age 51.7 +/- 14.4 years, mean +/- standard deviation, range 17-82) were tested for total and HDL-cholesterol, total triglycerides, apolipoprotein AI, apolipoprotein B, fibrinogen, prothrombin fragment and D-dimer. Moreover, 5 subjects who had hyperfibrinogenemia (range 450 to 950 mg/dl) for at least 6 months by repeated measurements, were treated with a short 7-day course of heparin 12,500 U/day subcutaneously. The effect of heparin on all the above mentioned parameters was observed at the end of treatment and after 7 days of wash-out. Simple regression analysis detected a positive correlation between fibrinogen and age, prothrombin fragment and D-dimer, and a negative correlation between fibrinogen and HDL-cholesterol and apolipoprotein AI. A direct correlation between age and both prothrombin fragment and D-dimer was also demonstrated. Multivariate analysis showed a persistent correlation between fibrinogen and prothrombin fragment, D-dimer and age, that was not influenced by sex, smoking habit and body mass index. In the 5 hyperfibrinogenemic subjects, heparin administration significantly reduced fibrinogen (625.4 +/- 211.1 vs 455.2 +/- 112.3 mg/dl, p < 0.03), prothrombin fragment (0.97 +/- 0.1 vs 0.63 +/- 0.2 nM, p < 0.002) and D-dimer (336 +/- 101.8 vs 275.2 +/- 78.5 ng/ml, p < 0.03). All these parameters returned to baseline after 7 days of wash-out (fibrinogen 632.5 +/- 198.2 mg/dl, prothrombin fragment 0.96 +/- 0.2 nM, D-dimer 325.8 +/- 98.65 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of fibrinogen in complement inhibition by streptococcal M protein.

M protein, the major virulence factor of group A streptococci, has antiopsonic activity in that it inhibits activation of the alternative complement pathway on the streptococcal surface. Two properties of M protein have been claimed to account for the inhibitory activity, namely, (i) its binding affinity for complement factor H, which is an inhibitor of alternative pathway activation, and (ii) its high binding affinity for fibrinogen. We have recently shown that fibrinogen, like M protein, inhibits alternative pathway activation by possessing binding affinity for factor H. Here we report that fibrinogen effectively competes with factor H for binding to M protein but retains its own binding affinity for factor H. The presence of fibrinogen did not significantly affect alternative pathway inhibition on the streptococcal surface.

The role of fibrinogen in mediating staphylococcal adherence to fibers

The use of tampons and surgical gauze pads and colonization with Staphylococcus aureus have been established as risk factors for the development of toxic shock syndrome. To elucidate the role of blood factors in the mediation of staphylococcal adherence to fibers used in tampons and surgical packing, an adherence assay with cotton fibers was developed. Results demonstrated that cotton disks precoated with fibrinogen in the presence of human serum albumin bound a significant percentage of the inoculum for both staphylococcal strains tested when compared to human serum albumin controls. Likewise, fibers pretreated with plasma or defibrinated blood containing a small amount of fibrin revealed comparable staphylococcal adherence to that of fibrinogen. In contrast, fibers pretreated with serum, fibronectin, or vitronectin did not exhibit significant augmentation in staphylococcal attachment in comparison to human serum albumin controls. The attachment of staphylococci to fibrinogen and/or fibrin appeared to be specific and is blocked by goat anti-human fibrinogen antibody, but not fibronectin, vitronectin, or nonimmune goat IgG. Thus, our data indicate that fibrinogen/fibrin is the dominant blood component in the mediation of staphylococcal adherence to fibers used in tampons and surgical gauze pads.

The Role of Fibrinogen in Staphylococcal Adherence to Catheters In Vitro

A study was conducted to examine the factors involved in adherence of Staphylococcus aureus to various catheter materials. Staphylococcal adherence to catheters coated with fibrinogen was specific and significantly increased compared with that to control catheters (preincubated in phosphate-buffered saline). The adherence of S. aureus to fibrinogen-coated catheters was blocked by goat anti-human fibrinogen antibody, but not fibronectin, vitronectin, or nonimmune goat IgG. Adherence to catheter tubings coated with fibrin did not differ markedly from that to those coated with fibrinogen alone, suggesting the conservation of the staphylococcal binding domain during the conversion of fibrinogen to fibrin. Plasma proteins such as fibronectin or factor XIII that interacted with fibrin did not modify staphylococcal adherence to fibrin. Adherence studies with staphylococcal cells treated with proteinases revealed that staphylococcal surface protein(s) were responsible for fibrinogen binding. These data indicate that fibrinogen or fibrin is the dominant plasma mediator of staphylococcal adherence to intravascular catheters.

The Role of Fibrinogen A α Chains in ADP-Induced Platelet Aggregation in the Presence of Fibrinogen Molecules Containing γ' x2018;Chains

Human plasma fibrinogen (Fgn) is heterogenous with respect to the size of its gamma chains, which differ in that residues 408 to 411 of gammaA chains (93% of total) are replaced in gamma' chains by a unique 20 amino acid sequence (gamma408 to gamma427). In this study, we compared the contribution to adenosine diphosphate (ADP)-induced platelet aggregation of the A alpha chains in Fgn molecules containing predominantly (fraction 1-2) or exclusively (peak 1 Fgn) gammaA chains with that of molecules containing approximately 50% gamma' chains (peak 2 Fgn). Using washed human platelets, we confirmed that the number of peak 2 Fgn molecules binding to platelets in the presence of ADP was about half the number of peak 1 Fgn molecules (18,962 +/- 2,298 v 44,366 +/- 16,096 molecules per platelet), and that isolated S-carboxymethylated (SCM) gammaA chains supported ADP-induced platelet aggregation nearly as well as peak 1 Fgn. In contrast, SCM-gamma' chains alone supported aggregation poorly, whereas a mixture of SCM-gammaA and gamma' chains (1:1 ratio) gave intermediate results. Despite the findings with isolated SCM-gamma' chains, we found that peak 2 Fgn supported platelet aggregation nearly as well as peak 1 Fgn. However, peak 2 Fgn from which carboxy (COOH)-terminal A alpha chain segments had been removed by digestion with plasmin showed a markedly decreased platelet aggregation potential. Peak 1 Fgn core fraction from an 88% to 90% coagulable plasmin digest, or Fgn fraction 1-9, which has a high gammaA/gamma' chain ratio (93:7), but lacks COOH-terminal regions of A alpha chains, supported platelet aggregation to the same extent as did intact peak 2 Fgn. These findings indicate that Fgn molecules containing gamma' chains can approach the aggregation potential of Fgn molecules containing predominantly or exclusively gammaA chains only if intact A alpha chains are also present.

The role of fibrinogen A alpha chains in ADP-induced platelet aggregation in the presence of fibrinogen molecules containing gamma' chains

Human plasma fibrinogen (Fgn) is heterogenous with respect to the size of its gamma chains, which differ in that residues 408 to 411 of gammaA chains (93% of total) are replaced in gamma' chains by a unique 20 amino acid sequence (gamma408 to gamma427). In this study, we compared the contribution to adenosine diphosphate (ADP)-induced platelet aggregation of the A alpha chains in Fgn molecules containing predominantly (fraction 1–2) or exclusively (peak 1 Fgn) gammaA chains with that of molecules containing approximately 50% gamma' chains (peak 2 Fgn). Using washed human platelets, we confirmed that the number of peak 2 Fgn molecules binding to platelets in the presence of ADP was about half the number of peak 1 Fgn molecules (18,962 +/- 2,298 v 44,366 +/- 16,096 molecules per platelet), and that isolated S- carboxymethylated (SCM) gammaA chains supported ADP-induced platelet aggregation nearly as well as peak 1 Fgn. In contrast, SCM-gamma' chains alone supported aggregation poorly, whereas a mixture of SCM- gammaA and gamma' chains (1:1 ratio) gave intermediate results. Despite the findings with isolated SCM-gamma' chains, we found that peak 2 Fgn supported platelet aggregation nearly as well as peak 1 Fgn. However, peak 2 Fgn from which carboxy (COOH)-terminal A alpha chain segments had been removed by digestion with plasmin showed a markedly decreased platelet aggregation potential. Peak 1 Fgn core fraction from an 88% to 90% coagulable plasmin digest, or Fgn fraction 1–9, which has a high gammaA/gamma' chain ratio (93:7), but lacks COOH-terminal regions of A alpha chains, supported platelet aggregation to the same extent as did intact peak 2 Fgn. These findings indicate that Fgn molecules containing gamma' chains can approach the aggregation potential of Fgn molecules containing predominantly or exclusively gammaA chains only if intact A alpha chains are also present.

Immunocytochemical Localization of Fibrinogen During Thrombin-Induced Aggregation of Washed Human Platelets

Because thrombin aggregates afibrinogenemic platelets and platelets from patients with the gray platelet syndrome and because antibodies to fibrinogen inhibit thrombin-induced aggregation only at low concentrations of thrombin, the role of fibrinogen in the formation of thrombin-induced aggregates was investigated further with human platelets washed and resuspended in Tyrode-albumin solution containing apyrase, either with or without added Ca2+ (2 mmol/L). Samples for immunocytochemical assessment of fibrinogen distribution were taken at several times (up to five minutes) after aggregation induced by 0.5 U/mL of thrombin. Glutaraldehyde-fixed samples were embedded in Lowicryl K4M, sectioned, incubated with goat antihuman fibrinogen, washed, reacted with gold-labeled antigoat IgG, and prepared for electron microscopy. By 10 seconds, small aggregates formed, and granules were centralized; alpha granules were heavily labeled with immunogold, but the platelet surface was not. As large aggregates formed, granule swelling or fusion occurred, and in some areas granule material seemed to be in contact with the exterior. In these experiments with no added fibrinogen, there were some clusters of gold particles on the platelet surfaces remote from sites of granule discharge, but there were large areas where platelets were in close contact with little or no fibrinogen detectable between them. No fibrin was visible up to five minutes after the addition of thrombin, which indicated that fibrinogen from the granules does not readily become available for fibrin formation in the ambient fluid. Similar results were obtained in media with and without added Ca2+. Thus at least some aggregation in response to thrombin can occur without the participation of released fibrinogen, and much of the granule fibrinogen appears to remain localized at sites where granules fuse with the plasma membrane or the open canalicular system. Incubation of unstirred samples with thrombin for ten minutes resulted in the formation of small aggregates, extensive gold label in regions connected to the exterior of the platelets, but very little gold labeling of the platelet membrane and no visible fibrin formation. When the platelets were aggregated in the presence of external fibrinogen, the morphological changes within the platelets were the same, but fibrinogen rapidly became associated with the entire platelet surface, and visible fibrin formed within 30 seconds in the medium containing 2 mmol/L Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunocytochemical localization of fibrinogen during thrombin-induced aggregation of washed human platelets

Because thrombin aggregates afibrinogenemic platelets and platelets from patients with the gray platelet syndrome and because antibodies to fibrinogen inhibit thrombin-induced aggregation only at low concentrations of thrombin, the role of fibrinogen in the formation of thrombin-induced aggregates was investigated further with human platelets washed and resuspended in Tyrode-albumin solution containing apyrase, either with or without added Ca2+ (2 mmol/L). Samples for immunocytochemical assessment of fibrinogen distribution were taken at several times (up to five minutes) after aggregation induced by 0.5 U/mL of thrombin. Glutaraldehyde-fixed samples were embedded in Lowicryl K4M, sectioned, incubated with goat antihuman fibrinogen, washed, reacted with gold-labeled antigoat IgG, and prepared for electron microscopy. By 10 seconds, small aggregates formed, and granules were centralized; alpha granules were heavily labeled with immunogold, but the platelet surface was not. As large aggregates formed, granule swelling or fusion occurred, and in some areas granule material seemed to be in contact with the exterior. In these experiments with no added fibrinogen, there were some clusters of gold particles on the platelet surfaces remote from sites of granule discharge, but there were large areas where platelets were in close contact with little or no fibrinogen detectable between them. No fibrin was visible up to five minutes after the addition of thrombin, which indicated that fibrinogen from the granules does not readily become available for fibrin formation in the ambient fluid. Similar results were obtained in media with and without added Ca2+. Thus at least some aggregation in response to thrombin can occur without the participation of released fibrinogen, and much of the granule fibrinogen appears to remain localized at sites where granules fuse with the plasma membrane or the open canalicular system. Incubation of unstirred samples with thrombin for ten minutes resulted in the formation of small aggregates, extensive gold label in regions connected to the exterior of the platelets, but very little gold labeling of the platelet membrane and no visible fibrin formation. When the platelets were aggregated in the presence of external fibrinogen, the morphological changes within the platelets were the same, but fibrinogen rapidly became associated with the entire platelet surface, and visible fibrin formed within 30 seconds in the medium containing 2 mmol/L Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS).

Oleic acid-induced lung injury in rabbits: effect of fibrinogen depletion with Arvin.

The role of fibrinogen in the evolution of the increased permeability after oleic acid-induced lung injury was studied in New Zealand White rabbits. Animals depleted of fibrinogen by treatment with Malayan pit viper venom were compared with untreated rabbits immediately and at 1 and 24 h after injury. The increased permeability to albumin and elevated extravascular lung water (EVLW) associated with lung injury returned to control values by 24 h in untreated animals. Fibrinogen-depleted animals had a higher mortality (10/25 vs. 2/17, P less than 0.02) and showed a greater immediate increase in permeability to albumin that returned to control values at 1 and 24 h after injury, as well as trends toward elevated blood-free dry lung weight and larger increases in EVLW that persisted for 24 h. These findings indicate that fibrinogen-related proteins play an important role in controlling the microvascular injury that is produced by oleic acid. However, when these proteins are depleted, other mechanisms partially control the leak at later stages of the repair process.

Role of fibrinogen in activation of platelets by artificial surfaces.

Role of fibrinogen in activation of platelets by artificial surfaces.

Role of A alpha chain of fibrinogen in coagulation and platelet interaction investigated with a monoclonal antibody.

A murine monoclonal antibody (anti-C2G7), reactive with fibrinogen, was used to analyse the structure and function of the fibrinogen epitope C2G7. Anti-C2G7 was found to be reactive with fibrinogen but not with fibronectin, Factor VIII-von Willebrand Factor (FVIII-vWF), beta-thromboglobulin (beta TG), platelet factor 4 (PF4) nor with a range of normal cells and cell lines. Biochemical and plasmin digestion studies of fibrinogen revealed that C2G7 is present on the carboxy-terminal end of the alpha chain on a fragment with a Mr approximately 30-40 K. Functional studies, on the role of fibrinogen in coagulation and platelet function, demonstrated the importance of C2G7 (or a closely associated region) for thrombin-associated fibrin polymerization and collagen induced fibrinogen binding to platelets.

Immunocytochemical localization of in vitro binding of human fibrinogen to Candida albicans germ tube and mycelium

In vitro fixation of human fibrinogen to different morphological stages of Candida albicans was examined immunocytochemically. When detected by fibrinogen latex microspheres or gold particles by scanning electron microscopy, fibrinogen-binding sites were found on the surface of germ tubes and mycelium, but not on blastospores. With transmission electron microscopy, fibrinogen-binding sites appeared associated with the flocculent surface layer, and increased during growth of germ tubes. Prefixation of C. albicans with formaldehyde decreased binding of fibrinogen, and pretreatment with mercaptoethanol and pronase abolished it. On thin sections of low temperature ⪡Lowicryl K4M⪢-embedded organisms, gold particles were arranged in the form of clusters which extended from the surface through the cell wall. In contrast, the inner cell wall layers were weakly labelled. Labelling was also detected in the cytoplasm of germ tube, suggesting that fibrinogen receptors were synthesized during germ tube formation. In view of the importance of filamentous forms in host tissue adherence and colonization, the role of fibrinogen as a ligand for binding of C. albicans to epithelial cells was postulated.

The Role of Fibrinogen in Platelet Interaction with Methacrylate Polymers

AbstractWhen blood comes in contact with a foreign surface, protein adsorption occurs within seconds and precedes the arrival of blood cells. Since a layer of plasma proteins is laid down on any surface in contact with blood before the platelets arrive, differences in platelet reactivity with different surfaces must result from variations in the nature of the protein-surface interactions. These interactions may vary in terms of which proteins bind to the surfaces, the amounts bound, and the various changes in protein conformation induced by surface contact.

Possible Role of Fibrinogen in the Aggregation of White Blood Cells

In order to verify whether leukocyte aggregation correlated with aggregation of other cellular elements during inflammation, we examined the state of leukocyte adhesiveness/aggregation (LAA) in the peripheral blood and red cell aggregation. Correlation was found to be significant as was the correlation between LAA and fibrinogen, and with the fibrin/fibrinogen degradation products concentration during various inflammatory states. In vitro leukocyte aggregation was decreased when the cells were suspended in autologous heat defibrinogenated plasma as compared to cells suspended in autologous native plasma. Heat aggregated fibrinogen but not native fibrinogen caused leukocyte aggregation in vitro. Finally, Arvin defibrinogenation in rabbits reduced the state of LAA in endotoxinemic rabbits. Integrating all this information, we assume that fibrinogen participates not only in the aggregation phenomena of red cells and platelets, but also in those of leukocytes.