Increased Plasma Fibrinogen Levels Research Articles

Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.

Mechanism of the haemostatic effect of ethanolamine oleate in the injection sclerotherapy for oesophageal varices.

Changes in coagulation and fibrinolysis were investigated in 20 patients with oesophageal varices, who underwent endoscopic injection sclerotherapy (EIS) with 5 per cent ethanolamine oleate (EO), by means of serial determination of plasma fibrinopeptide A (FPA) and fibrinopeptide B beta 15-42 (B beta 15-42). One hour after the completion of EIS, the value of FPA was significantly increased to 38.1 +/- 11.1 ng/ml (mean +/- s.e.m.) from a pre-EIS value of 7.1 +/- 1.4 ng/ml (P less than 0.01) and it gradually returned to normal range by 48 h after EIS. A very similar change was observed in the value of B beta 15-42 (P less than 0.01). These observations indicated that EIS provokes transient activation of coagulation and fibrinolysis. In vitro studies, however, revealed that EO inhibits fibrin clot formation because of the Ca2+-chelating ability of its constituent ethanolamine, although oleate or benzyl alcohol exhibited procoagulant activity in FPA formation in vitro. Nevertheless, an external application of EO or oleate over decapsulized kidney of rat resulted in a significant accumulation of 125I-labelled fibrin(ogen). From these results it was suggested that intravascular injection of EO, which exerts an inhibitory effect on coagulation in vitro, activates the local coagulation system. The activation may be accelerated by an acute inflammatory process provoked by oleate, which is supported by such clinical manifestations as mild fever, retrosternal pain leukocytosis and an increase in plasma fibrinogen level which was observed in all during the period.

Le fibrinogène a-t-il une place pour évaluer le risque d’accident cardiovasculaire ischémique ?

Most cardiovascular events result from a thrombotic complication of an atherosclerotic lesion. Inflammation plays a central role in both the pathogenesis of atherosclerosis and the progression of its complications (especially plaque rupture). Fibrinogen, on the one hand a marker of inflammation and on the other a major determinant in thrombosis and haemorrheology, plays a central role in atherosclerosis and its thrombotic complications. The clinical data are in agreement with epidemiological data, and show that increased plasma fibrinogen levels (compared with values in paired controls) are predictive of the risk of cardiovascular events – both primary cardiovascular events in the general population and recurrence in patients. Determining the plasma fibrinogen level in terms of genetic predisposition and environmental factors provides a good example of the interrelationship between genes and the environment. It must be recognised that a minimal increase in the fibrinogen level (within the plasma reference values) is an indicator of a significantly increased risk. This shows why epidemiological data are not useful for determining cardiovascular risk in individual patients in daily clinical practice (with the exception of the very high levels that are infrequently observed).

Homocysteine as a risk factor for CVD mortality in men with other CVD risk factors: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study

Based on case-control and prospective studies elevated blood total homocysteine (tHcy) has been suggested to be an independent risk factor for cardiovascular diseases (CVD). The purpose of the study was to explore the joint effect of increased serum tHcy concentration and other risk factors on the risk of CVD mortality in middle-aged men without a history of heart disease or stroke. A prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Eastern Finland. Subjects. A total of 802 men aged 46-64 years, examined in 1991-93. CVD mortality event. The mean serum tHcy concentration was 10.8 micromol L(-1) (SD 3.3). During the average follow-up time of 10.8 years 50 men experienced a CVD death. The hazard rate ratio for CVD mortality was 1.80 (95% confidence interval: 1.02-3.19) in men in the highest serum tHcy third versus lower thirds after adjustment for cardiovascular risk factors. Furthermore, elevated serum tHcy concentration appeared to increase the risk of CVD death in men who smoke or who have high circulating concentrations of serum total or LDL cholesterol, apo-B apolipoprotein or plasma fibrinogen. We conclude that homocysteine may increase the risk of CVD mortality in middle-aged men from Eastern Finland, and it may especially increase the risk when present with other risk factors for CVD.

Effect of L-NAME on the Synthesis of Plasma Fibrinogen in Mice

The effect of nitric oxide (NO) on plasma fibrinogen was investigated by treating mice with oral NG-nitro-L-arginine-methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor. Treatment with L-NAME significantly increased the concentration of plasma fibrinogen and hepatic expression of the α- and β-chains of fibrinogen, whereas plasma NO2− level and hepatic expression of endothelial NOS (eNOS) mRNA were significantly decreased. These results suggest that L-NAME treatment can increase plasma fibrinogen levels via an increase in expression of fibrinogen mRNA in the liver, and NO may be involved in plasma fibrinogen increase.

Antiplatelet Agents and Bleeding After Cardiac Surgery: In Response

We acknowledge the comments of Shore-Lesserson et al. concerning our recent paper. We believe that our interpretation of the data, suggesting reduced microembolic activity with a combination of antiplatelet and anticoagulant therapy, is justified in view of the observed favorable outcomes, and more plausible than their proposed explanation for reduction of postoperative bleeding. On that basis, we cited the PRISM-PLUS trial (1) that found decreased evidence of myocardial ischemia (probably in large part related to microvascular events) with a combination of platelet inhibition and heparin therapy. The authors of the letter note differences in what we consider to be outcomes among the treatment groups, as preexisting differences. (One of the differences they noted, temperatures perioperatively, did not take place.) If one follows the contention of Shore-Lesserson et al., the favorable outcomes that we found, i.e., decreased postoperative blood loss, decreased surgical times and extracorporeal circulation times, and trends toward decreased intraoperative blood loss and reduced levels of prothrombin fragment 1.2, are the simple consequence of increased fibrinogen, as a result of the patients’ acute coronary syndromes. We favor our stated interpretation of improved or maintained hemostatic competency perioperatively, as resulting from decreased microembolic activity with the combined treatment of ADP-receptor antagonist and heparin. We believe that our explanation is more plausible than one that proposes such improved outcome arising from the proinflammatory state of acute coronary syndrome. However, the issue can probably be resolved only by further studies. Shore-Lesserson et al. question the exclusion of five patients that had extensive requirements for blood products perioperatively. Since blood product use is intended to reduce bleeding, we considered it more appropriate to exclude these patients from a comparison of blood loss. We were interested in publishing our findings with the hope that they would contribute a possible approach to minimizing the risks associated with the use of antiplatelet drugs in the near-preoperative period. The results were also consistent with our earlier preliminary observations of increased plasma fibrinogen levels and reduced postoperative bleeding in patients who received heparin infusions preoperatively (2). Suryanarayana Pothula, MD Vajubhai T. Sanchala, MD Basavaraj Nagappala, MD Department of Anesthesiology Mario A. Inchiosa, Jr., PhD Department of Pharmacology, New York Medical College, Valhalla, NY

Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD.

Chronic obstructive pulmonary disease (COPD) is characterised by sputum production, bacterial colonisation, neutrophilic bronchial airway inflammation and poor health status. The aim of this study was to determine the impact of sputum potentially pathogenic microorganisms (PPMs) on bronchial airway inflammation, health status and plasma fibrinogen levels in subjects with moderate-to-severe COPD during the clinical stable state. Sputum total cell and neutrophil counts, supernatant interleukin-8, leukotriene B4, tumour necrosis factor-alpha and neutrophil elastase levels, neutrophil chemotaxis and plasma fibrinogen levels were estimated. Health status was determined using the St George's Respiratory Questionnaire and the 36-item Short-Form Health Survey questionnaire. Twenty-seven (40%) subjects had PPMs and 40 (60%) non-PPMs in their sputum. Both groups were of similar age, body mass index, smoking history and lung function. The PPMs group showed significantly higher levels of interleukin-8, leukotriene B4, tumour necrosis factor-a, neutrophil elastase and increased neutrophil chemotaxis. They also exhibited worse health status and raised plasma fibrinogen levels compared to the non-PPMs group. In conclusion, subjects with clinically stable moderate-to-severe chronic obstructive pulmonary disease who had potentially pathogenic microorganisms in their sputum demonstrated an exaggerated airway inflammatory response, poorer health status and increased plasma fibrinogen levels than those who had nonpotentially pathogenic microorganisms.

Plasma fibrinogen and its association with cardiovascular risk factors in apparently healthy Japanese subjects.

Recent evidence has shown the association of increased plasma fibrinogen levels with subsequent coronary heart disease or stroke. Fibrinogen is an acute-phase inflammatory reactant as well as a clotting factor. The authors investigated an association between fibrinogen levels and cardiovascular risk factors in apparently healthy Japanese subjects, while considering C-reactive protein (CRP) levels, a marker of the inflammatory status. Plasma fibrinogen and serum CRP from 2 706 participants in an annual mass screening examination, held in Matsukawa, Nagano, Japan were measured. A total of 2 355 subjects (816 men and 1 539 women) were analyzed after excluding individuals with a history of diabetes mellitus, heart disease, or stroke. Plasma fibrinogen was strongly correlated with CRP levels. After adjusting the CRP levels, fibrinogen was positively associated with age, smoking status, total cholesterol, and hemoglobin A(1c) (HbA(1c)) in men, and with age, total cholesterol, and HbA(1c) in women. On the other hand, high-density lipoprotein (HDL) cholesterol was a strong negative correlate of fibrinogen in both genders. Fibrinogen levels also tended to be associated positively with body mass index in both genders and negatively with exercise habits in men. The present multiple regression analysis has shown that plasma fibrinogen levels are correlated with conventional cardiovascular risk factors even after adjusting for the CRP levels. Persons with cardiovascular risk factors tended to have higher fibrinogen levels, suggesting that all elevated plasma fibrinogen concentration in those with risk factors may further increase the risk of the development of atherothrombosis and subsequent cardiovascular disease through the blood coagulation system.

P2.27: Periodontal disease but not edentulism is independently associated with increased plasma fibrinogen levels ‐ Results from a population‐based study.

P2.27: Periodontal disease but not edentulism is independently associated with increased plasma fibrinogen levels ‐ Results from a population‐based study.

Periodontal disease, but not edentulism, is independently associated with increased plasma fibrinogen levels. Results from a population-based study.

The systemic response to periodontal disease was analyzed in the cross-sectional Study of Health in Pomerania (SHIP). The completed data of 2,738 subjects aged 20 to 59 years were used for logistic regression analysis with an increased plasma fibrinogen level (> or =3.25 g/L according to Clauss) as the dependent variable. Participants were divided into four groups according to the number of periodontal pockets > or =4 mm (0, 1-7, 8-14, > or =15 pocketing). An additional group comprised the 52 edentulous subjects. The adjusted odds ratio (OR) of > or =15 periodontal pockets for increased plasma fibrinogen levels was 1.88 (95% CI: 1.25-2.83). Edentulism per se was not associated with increased plasma fibrinogen levels but was contained in a two-way interaction with the number of cigarettes/day in current smokers (p = 0.031). For edentulous nonsmokers the adjusted OR was 1.10 (95% CI: 0.51-2.39). Furthermore, body mass index, the interaction between gender and body mass index, serum LDL cholesterol, medication, the interaction between LDL cholesterol and medication, aspirin, smoking, school education, chronic bronchitis, and the interaction between alcohol consumption and chronic gastritis were associated with plasma fibrinogen levels. Our results show that periodontal disease but not edentulism per se is associated with an increased plasma fibrinogen level.

Fibrinogen: biochemistry, epidemiology and determinants.

Plasma fibrinogen is an important component of the coagulation cascade, as well as a major determinant of blood viscosity and blood flow. Increasing evidence from epidemiological studies suggests that elevated plasma fibrinogen levels are associated with an increased risk of cardiovascular disorders, including ischaemic heart disease (IHD), stroke and other thromboembolism.1,,2 This increase in plasma fibrinogen levels may promote a prothrombotic or hypercoagulable state, and may in part explain the risk of stroke and thromboembolism in conditions such as atrial fibrillation (AF). Nevertheless, the relationship between hyperfibrinogenemia, atherosclerosis and thrombosis is complicated. As the process of thrombogenesis is very closely related to atheroma formation (atherogenesis), it follows that specific thrombogenic factors such as fibrinogen (with important effects on blood rheology) may play key roles in the process of atherosclerotic lesion formation, with subsequent effects on cardiovascular diseases (Figure 1). However, knowledge about the precise determinants of plasma fibrinogen levels in health and disease is as yet incomplete, and many paradoxes are still present. For example, it is known that plasma fibrinogen is higher in Black than in White patients,3 but (in the UK at least) coronary artery disease is less common in Blacks than in White patients, while hypertension and stroke are conversely more common.4,,5 Plasma fibrinogen is also influenced by many factors: it increases with age, body mass index, smoking, diabetes and post menopause and is related to fasting serum insulin, low-density-lipoprotein (LDL) cholesterol lipoprotein(a) and leukocyte count. Conversely, it decreases with moderate alcohol intake, physical activity, increased high-density-lipoprotein (HDL) cholesterol, and with hormone replacement therapy (HRT).6–,8 Figure 1. Plasma fibrinogen, thrombogenesis and atherogenesis. We review the biochemistry, epidemiology, and genetic and extrinsic influences on plasma fibrinogen levels, as well as the close association between plasma fibrinogen and various vascular disorders. … Address correspondence to Professor G.Y.H. Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH. e-mail: g.y.h.lip{at}bham.ac.uk

Fibrinogen--marker or mediator of vascular disease?

Fibrinogen plays a key role in platelet aggregation, the final step of the coagulation cascade, i.e. the formation of fibrin, and it is a major determinant of plasma viscosity and erythrocyte aggregation. It is both constitutively expressed and inducible during an acute phase reaction. Increased plasma fibrinogen levels are associated with an increased risk of coronary heart disease and myocardial infarction. The question as to whether fibrinogen is only a marker of the inflammatory process involved in atherosclerosis or a mediator, i.e. a pathogenic factor, has not yet been answered. Human in vivo studies do not permit a conclusive answer to this question. If it is a pathogenic factor, fibrinogen lowering would be a therapeutic option. Selective fibrinogen-lowering agents do not exist however. All agents that lower fibrinogen also have other cardiovascular effects such as a decrease in cholesterol or inflammation. Newer information stems from molecular biology. Polymorphisms in the human fibrinogen gene with higher fibrinogen levels do not increase the risk for myocardial infarction. Fibrinogen knockout mice crossed with an atherosclerosis-susceptible strain (apoprotein E null mice) did not show a decreased extent of atherosclerosis despite the absence of fibrinogen, and a mouse strain over-expressing fibrinogen did not show an increased degree of atherosclerosis. Thus, fibrinogen seems to be a marker rather than a mediator of vascular disease, which would make selective fibrinogen lowering a useless preventive or therapeutic strategy.

Fibrinogen gene promoter -455 A allele as a risk factor for lacunar stroke.

Elevated fibrinogen levels are suggested to increase the risk of myocardial infarction and stroke. Carriers of the A allele of the fibrinogen -455G/A polymorphism have increased plasma fibrinogen levels. We studied the association of this polymorphism with stroke subtype in the Stroke Aging Memory (SAM) cohort. The SAM cohort comprises 486 consecutive patients 55 to 85 years of age who, 3 months after ischemic stroke, completed a detailed stroke assessment. Stroke subtypes were examined with MRI. -455G/A genotype was determined by polymerase chain reaction. MRI and genotype data were available for the 299 patients who constitute the present study population. Genotype distributions were 64.9% (GG), 31.8% (GA), and 3.3% (AA). In a logistic regression model with age, sex, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, myocardial infarction, arrhythmia, atrial fibrillation, peripheral arterial disease, and smoking as possible confounders, there was a significant association between A+ genotype and >or=3 lacunar infarcts (odds ratio [OR], 2.57; 95% CI, 1.23 to 5.36; P=0.01). Hypertensive patients carrying the A allele had increased risk (OR, 4.24; 95% CI, 1.29 to 13.99; P=0.02) for >or=3 lacunar infarcts. A similar increase in risk was observed among smokers with the A+ genotype (OR, 2.67; 95% CI, 0.92 to 7.77; P=0.07). Stroke patients carrying the A allele of the Bbeta-fibrinogen -455G/A polymorphism frequently presented with multiple lacunar infarcts. This association was stronger among hypertensives and smokers. These associations suggest that the A allele may predispose to atherothrombotic events in cerebrovascular circulation.

Importance of LDL/HDL cholesterol ratio as a predictor for coronary heart disease events in patients with heterozygous familial hypercholesterolaemia: a 15-year follow-up (1987-2002)

SUMMARYThis study evaluated the prognostic significance of several risk factors on the outcome of coronary heart disease (CHD) in 639 cardiovascular disease-free subjects with heterozygous familial hypercholesterolaemia (FH). During the 15-year follow-up, 53 (18%) men and 34 (9.8%) women had a CHD event (men vs women, p < 0.001). The age-adjusted 15-year event rate was 3% (87 events/2915 person-years). Smoking increased the CHD risk (hazard ratio = 2.45, p < 0.001), women had a 74% lower risk of a vascular event, compared to men, after controlling for the post-menopausal status (hazard ratio = 0.26, p < 0.001). A one-unit difference in low density lipoprotein (LDL)/high density lipoprotein cholesterol (HDL) cholesterol ratio was associated with a 17% higher risk (hazard ratio = 1.17, p < 0.05); hypertension increased the risk for an adverse event (hazard ratio = 3.02, p < 0.05) and a 1 mg/dl increase in plasma fibrinogen level was associated with a 4% higher CHD risk (hazard ratio = 1.04, p < 0.05).With the power of the 15 years of prospective evaluation, the study shows that increased smoking, hypertension and LDL cholesterol levels eight times more than HDL cholesterol predicts an adverse CHD event, in patients with FH.

High plasma fibrinogen level is associated with poor clinical outcome in DIC patients.

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.

Mutation in the promoter region of the beta-fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis.

Polymorphisms in the promoter region of the beta-fibrinogen gene are associated with increased plasma fibrinogen levels. We investigated whether the distribution of the C148T polymorphism is associated with an increase in cardiovascular risk. In a nested case-control design, the distribution of the C148T polymorphism was investigated among 751 participants in the Physicians' Health Study who subsequently developed myocardial infarction, stroke or venous thromboembolism (cases) and among 751 age- and smoking-matched controls over follow-up of 8.6 years. Frequency of the T allele was similar among men who had myocardial infarction (22.7%, P=0.5), stroke (18.4%, P=0.2) or venous thromboembolism (17.0%, P=0.1) compared with those with no cardiovascular events (21.5%). The relative risk for any vascular event among men homozygous or heterozygous for the T allele compared with men homozygous for the C allele was 0.94 (95% CI 0.76-1.16). We found no evidence of an association between the T allele and myocardial infarction (relative risk 1.06; 95% CI 0.82-1.36), stroke (0.87, 0.63-1.21) or venous thromboembolism (0.75; 0.51-1.08). Analysis adjusted for aspirin use and traditional cardiovascular risk factors had no significant effect on these findings. In a large prospective cohort, carriage of the T allele for the C148T mutation in the beta-fibrinogen promoter gene was not associated with an increased subsequent risk of cardiovascular events.

Plasma fibrinogen level is an important determinant of prolonged euglobulin clot lysis time in hemodialysis patients.

The euglobulin clot lysis time (ECLT), a traditional measure of plasminogen activation, directly depends on plasma fibrinogen (FBG) level. This fact was neglected in studies concluding that prolonged ECLT in chronic hemodialysis (HD) patients pointed exclusively to impaired fibrinolysis. We studied the relations between ECLT and plasma FBG levels in HD patients in relation to certain hepatic and inflammatory markers. Median ECLT of 320 minutes (range, 150 to 620 minutes) and plasma FBG of 306 mg/dL (range, 171 to 553 mg/dL) were higher in 75 HD patients than in 60 healthy controls (Mann-Whitney p < 0.0001). There were positive associations between these parameters both in the patients (Spearman p = 0.273, p = 0.018) and the controls (p = 0.672, p < 0.0001). The FBG-corrected ECLT (plasma FBG/ECLT) (in mg/[min x dL]) in the patients (0.92 [range, 0.47 to 2.43]) was not different (p = 0.065) from that in the controls (1.08 [0.58 to 1.67]). In the patients, serum alanine aminotransferase inversely correlated with ECLT (p = -0.306, p = 0.008) and FBG (p = -0.310, p = 0.007), whereas serum C-reactive protein was associated positively with these variables (p = 0.383, p = 0.0007; p = 0.477, p < 0.0001, respectively). The FBG-corrected ECLT was not related to either marker. In conclusion, increased plasma FBG level, a continuum between liver dysfunction and stimulation by chronic inflammation, is an important determinant of prolonged ECLT in HD patients. The FBG-corrected ECLT value suggests that baseline activation of fibrinolysis is normal in these patients, and that this simple index could be useful in its laboratory assessment.

Socioeconomic status, workplace characteristics and plasma fibrinogen level of Japanese male employees.

This study examined the relationships between workplace characteristics and plasma fibrinogen level and assessed the possibility of socioeconomic differences in plasma fibrinogen level being accounted for by workplace characteristics. Cross-sectional questionnaire data from 4343 Japanese male employees were examined with Karasek's demand-control model, as was sedentary job and overtime work. Less overtime work, a less sedentary job, and to a less extent, lower job control and low worksite support were related to increased plasma fibrinogen levels. Adjusting for employment grade strongly attenuated or eliminated these relationships. The association of job demands or job strain with plasma fibrinogen level was weak. High plasma fibrinogen in lower socioeconomic groups remained largely unchanged after adjustment for workplace characteristics. Workplace characteristics are not significantly related to the plasma fibrinogen levels of male Japanese employees after adjustment for socioeconomic status, and they do not explain socioeconomic differences in plasma fibrinogen levels among these employees.

Inflammatory response to abdominal irradiation stimulates hemopoiesis

Purpose : The connection between inflammation and hemopoiesis was studied in the context of abdominal irradiation. Materials and methods : Male C57BL6/J mice received localized irradiation of 20 Gy either to 70% of the liver or to the intestine (most of ileum and caecum). Results : Irradiation of liver induced a rapid increase in intercellular adhesion molecule-1 mRNA expression in the liver. In serum/plasma, an increase in positive acute phase proteins (serum amyloid-P and fibrinogen) and a decrease in albumin occurred during the second and third week following liver irradiation. Similarly, intestinal irradiation induced an increase in plasma fibrinogen level. A transient elevation in neutrophil and platelet counts was observed that was maximal during the second and third week with similar kinetics for intestinal and liver irradiation. Moreover, intestinal irradiation enhanced hemopoietic progenitors in bone marrow. IL-6, which is known to be an agonist in the regulation of acute phase protein expression as well as hemopoietic cell production, was increased in plasma from intestinal- and liver-irradiated mice. Administration of an anti-IL-6mAb to intestinal-irradiated mice abrogated the elevation of fibrinogen and the increase in hemopoietic progenitors. Conclusions : Abdominal irradiation provokes an inflammatory response which in turn stimulates hemopoiesis. IL-6 may play a major role in controlling these events.

Increased Hepatic Fibrinogen Bβ-gene Transcription Is not enough to Increase Plasma Fibrinogen Levels

The fibrinogen Aalpha, Bbeta, and gamma polypeptides are encoded by three separate genes, which are arranged in the order gamma-alpha-beta. In order to study the biosynthesis of fibrinogen in vivo we generated a line of transgenic mice carrying extra copies of the fibrinogen beta-gene. To clone the mouse fibrinogen Bbeta-chain gene, a mouse 129 Sv/Ev genomic cosmid library was screened, using the mouse fibrinogen Aalpha-, Bbeta-chain cDNA. A clone containing the complete fibrinogen Bbeta-chain gene including approximately 11-kb of the natural promoter region was identified and subsequently microinjected into mice. Southern blot analysis identified a founder that carried additional copies of the fibrinogen Bbeta-chain gene. Transgenic offspring of this founder were interbred and heterozygous and homozygous transgenic mice were obtained. Northern blot analysis demonstrated approximately a 3-fold increase in fibrinogen Bbeta mRNA in heterozygous mice as compared to wild-type, whereas homozygous transgenic mice showed approximately a 9-fold increase. The levels of the Aalpha and gamma mRNAs in transgenic homozygous mice were not changed as compared to those in wild-type mice. Fibrinogen levels in plasma were not significantly increased in transgenic mice as compared to wild-type mice. These results indicate that: additional copies of the fibrinogen Bbeta-chain gene lead to increased levels of the Bbeta-chain mRNA in the liver; the increased levels of Bbeta-chain mRNA in homozygous overexpression mice do not change the transcription levels of the two other fibrinogen mRNAs in vivo; the absence of an increased plasma fibrinogen level in the transgenic mice indicates that this level is not regulated solely by transcription of the Bbeta-chain gene.