Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1368-1377

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maresca, G.
Right arrow Articles by Di Minno, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maresca, G.
Right arrow Articles by Di Minno, G.
Related Collections
Right arrow Risk Factors
Right arrow Acute myocardial infarction
Right arrow Acute Stroke Syndromes
Right arrow Coagulation and fibronolysis
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1368-1377.)
© 1999 American Heart Association, Inc.


Brief Reviews

Measuring Plasma Fibrinogen to Predict Stroke and Myocardial Infarction

An Update

Giulio Maresca; Anna Di Blasio; Roberto Marchioli; Giovanni Di Minno

From the Clinica Medica, Dipartimento di Medicina Clinica e Sperimentale (G.M.), Ateneo "Federico II" Napoli; Laboratoro di Epidemiologia Clinica Cardiovascolare, Istituto di Ricerche Farmacologiche Mario Negri (A.D.B., R.M.), Consorzio Mario Negri Sud, S. Maria Imbaro (CH); Istituto di Medicina Interna e Geriatria (G.D.M.), Università di Palermo, Italy.

Correspondence to Giovanni Di Minno, MD, Clinica Medica, Dipartimento di Medicina, Clinica e Sperimentale, Via S. Pansini 5, 80131 Napoli, Italy. E-mail diminno{at}unina.it


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowReferences
 
Abstract—Plasma fibrinogen is a major determinant of platelet aggregation and blood viscosity. The decrease in plasma fibrinogen by bezafibrate is associated with a decrease in the risk of reinfarctions. To strengthen the predictive value of plasma fibrinogen with respect to cardiovascular risk, we performed a meta-analysis of studies conducted between 1984 and 1998. Emphasis has been put on the relationship between high levels of plasma fibrinogen and fatal and/or nonfatal cardiovascular events in both the general population and in patients with previous cardiovascular events. Twenty-two studies (13 prospective, 5 cross-sectional, and 4 case-control) addressing the association between fibrinogen plasma concentrations and cardiovascular disease were analyzed. The overall estimate of risk of cardiovascular event in subjects with plasma fibrinogen levels in the higher tertile, was twice as high as that of subjects in the lower one (odds ratio, 1.99; 95% confidence interval, 1.85 to 2.13). High plasma fibrinogen levels were associated with an increased risk of cardiovascular disease in healthy as much as in high-risk individuals. A metaregression showed no confounding effects attributable to selected characteristics of retrieved studies. A subgroup analysis (study design, follow up, mean fibrinogen levels, percentage of smokers, and mean age) allowed us to conclude that fibrinogen is an independent risk factor for cardiovascular disease; that it interacts with major determinants of myocardial and cerebrovascular ischemia; and that, in secondary prevention studies, it enhances by 8% the prediction of future events by established risk factors. Thus, fibrinogen measurements should be encouraged to refine the overall risk profiles of individuals and to better tailor preventive interventions.


Key Words: fibrinogen • risk factor • stroke • myocardial ischemia • meta-analysis


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowReferences
 
Stroke and myocardial infarction are major thrombotic complications of atherosclerosis and leading causes of morbidity and mortality in western countries. Many studies have established the involvement in atherosclerosis of blood lipids and lipoproteins, hypertension, diabetes mellitus, and smoking, as well as the active role of endothelial injury, smooth muscle cell proliferation, and inflammation.1 2 3 The role of hypercoagulability and of plasma fibrinogen, the central protein of the coagulation system, in this complex scenario has been suspected for many years, and has recently been documented by experimental and clinical evidence: human gelatinous and fibrous plaques are rich in fibrinogen and its degradation products4 5 6 7 8 9 ; thrombin, fibrinogen, and fibronectin are involved in cell proliferation3 7 8 9 10 ; fibrinogen is involved in mechanisms (platelet aggregation, endothelial cell injury, and plasma viscosity) that play a central role in the formation of thrombi10 ; and thrombosis is a major determinant of myocardial ischemia.11 12 13 Early epidemiological evidence has associated high levels of plasma fibrinogen with cardiovascular disease (CVD).10 14 15 Moreover, drugs that lower the progression of coronary heart disease also reduce plasma fibrinogen levels in young postinfarction males.16

Recommendations for the management of CVD in the general population as well as for people with previous cardiovascular events were recently formulated jointly by various medical associations. These recommendations focus on preventive interventions based on the summation of risks rather than addressing the individual who is a carrier of an isolated high-risk factor (the philosophy being that individuals with a combination of borderline risks may actually be at considerably greater risk than subjects with a single very high risk factor). Thus, these recommendations for the primary prevention of coronary heart disease in clinical practice focus only on cholesterol, hypertension, and smoking habits.17 18 19 Because patients at risk for the development of fibrinogen-related ischemic complications of atherosclerosis can be easily identified and treatment strategies have been developed to protect against these complications, clinically oriented prevention recommendations should consider the role of fibrinogen in CVD. In an effort to strengthen the clinical impact of measuring plasma fibrinogen, we performed a meta-analysis to answer the following questions: (1) Is epidemiological evidence still supporting plasma fibrinogen as an independent risk factor for cardiovascular disease? (2) Is plasma fibrinogen measurement improving prediction of future ischemic events by established risk factors? (3) What areas of uncertainty remain with respect to the association between fibrinogen and CVD?


*    Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowReferences
 
Twenty-two studies20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 (MEDLINE search from 1984 to September 1998) (Tables 1Down and 2Down), in which the association of plasma fibrinogen concentrations with the risk of CVD had been evaluated, were scrutinized. Other relevant studies were identified by resuming recent reviews.10 14 15 42 Studies not providing enough information as to the criteria adopted for the present meta-analysis (ie, odds ratios [ORs], confidence intervals [CIs], and/or the possibility of recalculating crude ORs) were not used.


View this table:
[in this window]
[in a new window]
 
Table 1. Fibrinogen and CVD: Prospective Studies


View this table:
[in this window]
[in a new window]
 
Table 2. A. Fibrinogen and CVD: Cross-Sectional Studies

Statistical Analysis
Data from different studies were combined using the general variance-based method.43 44 45 46 47 48 49 50 51 52 53 This method requires only information on the OR estimate and 95% CI of each study.44 95% CIs were used to assess the variance of each study effect. When provided by the authors, adjusted ORs and their CIs were preferred. Crude ORs and their 95% CIs were used when an adjusted estimate was not provided. These estimates were used to carry out the overview for all studies as well as for the subgroups. To examine the strength of the association between total cardiovascular events and the different subgroups, we fitted a multivariate inverse variance–weighed linear regression of the logarithmic ORs for total events as dependent variable against the variables. The weights that were obtained with the variance-based method were adopted for the regression analysis.

{chi}2 was used to assess the magnitude of heterogeneity among studies, ie, the within-group heterogeneity (Het-w).44 The {chi}2 with degrees of freedom 1 less than the number of groups was used to assess the magnitude of the heterogeneity of the ORs between the subgroups of studies, ie, the between-group heterogeneity (Het-b).45 46

Subgroup Analysis
Duration of follow-up, mean plasma fibrinogen values at baseline, percentage of current smokers, mean age of the study population, and study design (prospective, cross-sectional, and case-control) were taken into consideration to stratify for potential confounders (subgroup analyses). Continuous variables were dichotomized according to their approximate median values. The criteria used for subgroup analysis according to different study designs (prospective, cross-sectional, and case-control) are given below.

Prospective Studies
Cardiovascular events were presented according to tertiles of fibrinogen in the majority of the studies.20 22 23 24 25 26 28 32 The relationship between fibrinogen levels and cardiovascular events was determined by comparing higher and lower tertiles of fibrinogen. The results of 3 prospective studies (Gothenburg and Scottish Heart Health Study, Caerphilly-Speedwell)20 25 26 published as quintiles were recalculated into tertiles using a conservative approach that assumes a linear increase in events within quintiles. This method tends to underestimate the risk associated to fibrinogen tertiles.15

Cross-Sectional Studies
The effect of fibrinogen level in cross-sectional studies was evaluated by comparing upper and lower quartiles. Three studies presented their results as quartiles of fibrinogen.33 34 37 In the Prevention Cardiovasculaire en Medecine du Travail study, tertiles of fibrinogen were used because the results were presented only as unadjusted estimates of the OR of the higher tertile of plasma fibrinogen level compared with the lower one.35 Sharp et al36 presented their results as quintiles of fibrinogen. These were recalculated.

Case-Control Studies
OR and 95% CI values were computed by comparing higher quartiles of fibrinogen to lower ones38 40 41 In 1 case, it was not possible to recalculate risk estimates into quartiles; thus the unadjusted estimate according to the median value, as presented by the authors, was used.39


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowReferences
 
Is the Epidemiological Evidence Still Supporting Plasma Fibrinogen as an Independent Risk Factor for Cardiovascular Disease?
Of the 22 studies contributing to this analysis, 63 736 individuals were included and 5712 cardiovascular (CV) events were observed. The end points available for the analysis were fatal and nonfatal coronary heart disease (CHD) for 10 studies,20 22 24 26 27 28 31 32 34 36 fatal and nonfatal CV events for 4 studies,23 37 38 39 arterial plaque progression for 2 studies,35 40 deep vein thrombosis for 1 study,41 and myocardial infarction for 4 studies.21 25 29 33

Thirteen prospective studies evaluated a total of 47 323 subjects (Table 1Up); 5 cross-sectional and 4 case-control studies recruited 15 537 and 1625 subjects, respectively (Table 2Up). Figure 1Down summarizes of OR estimates and their 95% CIs. The overall OR estimate from all studies was 1.99 (95% CI, 1.85 to 2.13). The Het-w test was statistically significant (P<0.05).



View larger version (24K):
[in this window]
[in a new window]
 
Figure 1. Risk of cardiovascular disease for high versus low plasma fibrinogen values. The studies are arranged according to study design (ie, prospective, cross-sectional, and case-control) and year of publication. Separate results are given for individual studies. Each OR and its 95% CI is plotted as a back square and a line. The solid vertical line represents an OR of 1.0 and the broken vertical line indicates the overall OR estimate for all combined studies. The results of the ARIC study are presented separately for white men, black men, white women, and black women. M, data on men; WM, data on white men; BM, data on black men; W, data on women; WW, data on white women; and BW, data on black women. Cutoff values were as follows: Prospective studies–Northwich Park Heart Study (NPHS), 270 and 319 mg/dL; Framingham Study, 265 and 311 mg/dL; Gottingen Risk Incidence and Prevalence Study (GRIPS), 326 and 395 mg/dL; Prospective Cardiovascular Muster Study (PROCAM), 236 and 277 mg/dL; Atherosclerosis Risk in Communities Study (ARIC), 270 and 319 mg/dL; European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study (ECAT), 271 and 331 mg/dL; Bezafibrate Infarction Prevention Study (BIP), 308 and 368 mg/dL; Toss et al,32 338 and 400 mg/dL; Gothenburg, The Caerphilly and Speedwell Collaborative Heart Disease Studies (CSCHDS), the Scottish Heart Health Study (SHHS), and the study by Fowkes28 et al did not provide cutoff values. Cross-sectional studies–Sharp et al,36 256 and 351 mg/dL; Prevention Cardiovasculaire en Medecine du Travail (PVCMETRA), 288 and 347 mg/dL; The Scottish Heart Health Study (SHHS), the Finrisk Hemostasis Study, and the Monica Study did not provide cutoff values. Case-control studies–Oxfordshire Study, 300 and 430 mg/dL; ARIC, 256 and 337 mg/dL; Resch et al,39 median value of fibrinogen was 350 mg/dL; Leiden Thrombophilia Study (LETS), 300 and 500 mg/dL. Results: Prospective studies–All OR, 2.35 (95% CI, 2.14 to 2.57; Het-w, NS); General population OR, 2.46 (95% CI, 2.22 to 2.72; Het-w, NS); Healthy men OR, 2.44 (95% CI, 2.20 to 2.72; Het-w, NS); Healthy women OR, 2.62 (95% CI, 1.92 to 3.58; Het-w, NS); High risk patients OR, 1.94 (95% CI, 1.58 to 2.38; Het-w, NS); Het-b test, General population versus High risk patients, NS; Het-b test, Healthy men versus Healthy women, NS. Cross-sectional studies–OR, 1.52 (95% CI, 1.37 to 1.69; Het-w, NS). Case-control studies–OR, 3.03 (95% CI, 2.14 to 4.29; Het-w, NS). All studies–(prospective, cross-sectional, and case-control) OR, 1.99 (95% CI, 1.85 to 2.13; Het-w, P<0.05). Heterogeneity test between groups (Het-b) were all NS, except for the study design (P<0.05).

When all the prospective studies were considered, a total of 2581 events in 47 323 subjects was observed and the estimate of risk of CVD was more than doubled when comparing the higher tertile to the lower one. Eight prospective studies were conducted in general populations and 1910 CV events were found in 37 684 subjects.20 21 22 23 24 25 26 27 The overall estimate of risk of cardiovascular events in subjects in the higher tertile of fibrinogen was more than doubled compared with that of subjects in the lower tertile.

Eight prospective studies were carried out on healthy men and a total of 1587 CV events in 24 983 subjects was observed.20 21 22 23 24 25 26 27 Three studies on healthy women reported 404 CV events in 13 803 individuals.20 23 26 No difference in the estimate of CV risk was found after separate analyses for men and women (Het-b test, not significant [NS]). Five prospective studies on high-risk subjects recruited 9639 individuals who experienced 671 events.26 29 31 32 Subjects in the higher tertile of fibrinogen had a 92% greater risk of CV events. No difference in CV risk was evident between studies in the general population and those in high-risk subjects (Het-b test, NS). No effect modification emerged from studies on subjects with or without previous CVD.

In cross-sectional and case-control studies, the overall estimates of risk in subjects with higher levels of fibrinogen compared with those in the lower tertile were 1, 5, and 3 times higher, respectively.

Subgroup Analysis
Duration of follow-up was analyzed only for prospective studies (Figure 2ADown). Studies with duration of follow-up above and below 5.2 years had comparable ORs (2.5 versus 2.24; Het-b, NS). Similar results were obtained by examining the effect of duration of follow-up in studies that recruited high-risk subjects. In studies in general populations, subjects had an {approx}6.0 year (median) follow-up. Studies with duration of follow up above and below the median value had a similar risk of CV events (OR, 2.40 versus 2.70). Duration of follow up did not influence the results of studies in healthy men as well as in high-risk subjects.



View larger version (40K):
[in this window]
[in a new window]
 
Figure 2. (A) Risk of cardiovascular disease related to length of follow-up. Prospective studies were divided into subgroups according to the median length of follow-up. (B) Risk of cardiovascular disease related to mean plasma fibrinogen values of examined populations. Studies were divided into subgroups according to the median of mean fibrinogen values of the studies. (C) Risk of cardiovascular disease related to the percentage of current smokers. Studies were divided into subgroups according to the median percentage of smokers included in each study. (D) Risk of cardiovascular disease related to age. Studies were divided into subgroups according to the median of the means of age observed in each study.

Mean fibrinogen values of the subjects recruited in each study were used as rough estimates of the fibrinogen level of the population of origin (Figure 2BUp). When all the studies were taken into consideration, the risk of CV events was almost twice as high in studies with mean fibrinogen values above 303 mg/dL. No difference in the estimates of risk were apparent when mean fibrinogen values measured in the patients recruited were examined according to study design (ie, cross-sectional and case-control studies).

The percentage of smokers in each study was used as an index of the interplay between smoking habits and fibrinogen levels in determining the level of CV risk (Figure 2CUp). No difference was apparent between studies according to the prevalence of smokers above and below the median value of 36% when all studies were considered. Similar results were obtained by evaluating all prospective studies or prospective studies on males, on the general population or high risk populations alone.

The prevalence of smoking in cross-sectional studies did not change the estimate of risk attributable to fibrinogen levels. It was not possible to evaluate the role of smoking habits in case-control studies.

Mean age of subjects recruited in each study was used to evaluate the role of fibrinogen levels in younger and older patients (Figure 2DUp). Comparable results were found in the whole study group, in prospective studies of general populations, in prospective studies of high-risk individuals, in cross-sectional studies, and in case-control studies, all of which showed no effect modification.

Meta Regression
To examine the strength of the association between total cardiovascular events and the selected subgroups, an inverse variance-weighed multiple linear regression of the logarithmic ORs for total events were used as dependent variables against study design, percentage of smokers, age, and mean plasma fibrinogen values as explanatory variables (Table 3Down). Cross-sectional studies behaved differently. Mean fibrinogen values and percentage of smokers at baseline did not influence the risk estimates.


View this table:
[in this window]
[in a new window]
 
Table 3. Analysis of Confounding by Fitting Univariate Inverse Variance-Weighed Multiple Linear Regression

Limitations of the Present Meta-Analysis
Publication biases and different study designs may have overestimated the risk related to high plasma fibrinogen levels. The somewhat lower estimates of CV risk in cross-sectional studies is likely to be caused by inherent selection biases. This can be because of specific characteristics of this type of study (ie, selection of subjects with better prognosis). Conversely, because of the type of studies or the use of fibrinogen values measured close to the index event (ie, more representative of the hemostatic state before the event), there might have been emphasis in the role of fibrinogen as a CV risk factor in case-control studies. However, the results of the present meta-analysis are strengthened by those of the Scottish Heart Health Study,25 in which no interaction between fibrinogen levels and other cardiovascular risk factors occurs. On the other hand, despite differences in the analytical procedures used for their meta-analysis, Danesh et al42 achieved results similar to ours. Finally, on the bases of meta-regression analysis, it is unlikely that the selection characteristics of the studies retrieved (mean age, healthy/high-risk subjects, smoking habits, duration of follow-up, and mean plasma fibrinogen values) may have affected the estimates of the risk associated with quantiles of fibrinogen values.

Because different methods with differences in variability, accuracy, precision, and agreement among different laboratories have been used to measure plasma fibrinogen in the studies retrieved (Table 4Down). This may have hampered the accuracy of the risk estimates. However, the net results of each study–the association between high plasma fibrinogen and stroke and myocardial infarction–were unequivocal. Each method used different cutoff values (see legend of Figure 1Up). However, comparisons between higher and lower figures (as in the present analysis) reduce the disadvantages inherent to the differences in the methods used.


View this table:
[in this window]
[in a new window]
 
Table 4. Methods to Measure Plasma Fibrinogen

Is Plasma Fibrinogen Measurement Improving Prediction of Future Ischemic Events By Established Risk Factors?
1. Fibrinogen Interaction With Other Risk Factors
In the Prospective Cardiovascular Muster study, fibrinogen plasma levels of 277 mg/dL increased by 2-fold the risk of myocardial infarction in subjects with LDL cholesterol >163 mg/dL.23 In the Framingham study, fibrinogen levels of 312 mg/dL increased by 6-fold the risk of myocardial infarction in smokers.22 In the Gotheburg study, fibrinogen levels >500 mg/dL increased by 12-fold the risk of stroke in subjects with systolic blood pressure >180 mm Hg.20

2. Attributable Risk
In the Atherosclerosis Risk in Communities study, the role of fibrinogen was marginal, albeit significant, when the data were corrected for major cardiovascular risk factors.27 However in the Scottish Heart Health Study, which examined various factors, fibrinogen was the second most important factor for predicting causes of death in men and the sixth most important factor for women.61 Based on the data from >1300 individuals who had experienced recurrence of a coronary event, the Gruppo Italiano per lo Studio della Sopravvivenza Nell'Infarto Miocardico (GISSI) Prevention Group prepared a Coronary Risk Chart for the secondary prevention of CHD. In addition to using fibrinogen levels to determine the overall risk of individual patients, this chart assesses attributable risks for established CV risk factors.62 Fibrinogen levels higher than median values (371 mg/dL) predicted myocardial reinfarction in younger as much as in older individuals. The prognostic role of fibrinogen for the evaluation of the global risk for CVD was comparable with that of major CV risk factors. Furthermore, prediction of CVD by established factors was improved by 8% when fibrinogen was added to the analysis. Under the same conditions of analysis, cholesterol improved prediction by 5%, hypertension by 5%, and diabetes mellitus by 7% (Figure 3Down).



View larger version (28K):
[in this window]
[in a new window]
 
Figure 3. GISSI Prevenzione Study: attributable risk estimates.

What Areas of Uncertainty Remain With Respect to the Association Between Fibrinogen and CVD?
1. Methods to Measure Plasma Fibrinogen
Taking into account accuracy (as evaluated with reference to the gravimetric method), precision (as evaluated by determining the inter- and intra-assay coefficients of variations), and agreement of methods (among different laboratories), the (semiquantitative) Clauss clotting method has been suggested to be a reliable manner of measuring very low and very high plasma fibrinogen levels in short- and long-term studies of repeatability.10 Recent data support the notion that the nephelometric method may provide a prediction comparable to that of the Clauss method.63 Although requiring further confirmation, these observations raise the possibility that commonly recognized reference methods other than the Clauss may be recommended for future epidemiological studies. However, the potential availability of a simpler, easier, and more reproducible method by no means hampers the clinical impact of measuring plasma fibrinogen levels.

2. Pathogenetic Significance
Similar to other acute-phase proteins, expression of fibrinogen (ie, its plasma level) is regulated by interleukin-6 and impaired by transforming growth factor-ß.10 64 65 C-reactive protein (CRP) is also an acute-phase reactant; its baseline levels predicted the risk of a first myocardial infarction and stroke independently of other risk factors in apparently healthy men as well as in patients with unstable angina.42 66 67 68 Fibrinogen correlates with CRP both in men and women.42 Thus, the question is whether raised plasma fibrinogen is the epiphenomenon of the severity of the vascular damage taking place. Vascular injury, response to vascular injury, and plaque rupture and fissuring are major stages of the development and progression of atherosclerosis.1 2 3 Presently, it is unclear whether plasma fibrinogen is related to 1 or more of these stages. However, although relevant from a therapeutic point of view (ie, measuring plasma fibrinogen to identify subjects in whom interventions on established risk factors affecting specific stages in atherosclerosis have to be greatest), the question is of little relevance from a prognostic point of view.

3. Gene–Environment Interaction
High fibrinogen levels have been reported to be accounted for by environmental and genetic differences.69 70 71 72 73 74 75 Some polymorphisms modulate the response of genes to environmental stimuli, ie, the same stimulus may cause different levels of fibrinogen in subjects with different polymorphisms.76 This is consistent with the possibility that a theoretical level (determined by genes) and a real level (because of the interaction of genes with the environment) of fibrinogen may play a role in the intra- and inter-population variability of fibrinogen levels and may explain, at least in part, differences in CVD frequency and cardiovascular death between Japan and USA. However, despite its pathophysiological relevance, this information is unlikely to affect the clinical impact of plasma fibrinogen levels.

Areas of Future Research
The gradient of CHD death rate across European countries has been associated with a different distribution of some genotypes affecting plasma levels of factor VII.77 78 Similar to fibrinogen, the latter is a known determinant of hypercoagulability and of the risk of CVD.21 23 79 Whether a similar gradient for fibrinogen is also present also is unclear.

In 2 studies,70 74 molecular variations of plasma fibrinogen have been related to arterial thrombosis regardless of their effect on plasma fibrinogen. Whether the analysis of these markers should be included in the cardiovascular risk factor profile regardless of plasma fibrinogen measurements remains to be clarified. Interleukin-6 gene variants have been reported.80 Their effect on plasma fibrinogen levels and, in turn, CVD, deserves proper investigation.

With 1 exception,16 the lack of clinical trials demonstrating the effectiveness of lowering fibrinogen levels on hard clinical end points is hampering the clinical impact of measuring plasma fibrinogen levels. Plasma levels of fibrinogen are lowered by drugs commonly used in clinical practice (Table 5Down). Clinical trials with these drugs should be encouraged to implement knowledge on the correlation between fibrinogen and CVD.


View this table:
[in this window]
[in a new window]
 
Table 5. Factors Affecting Plasma Fibrinogen Levels

Within the area of cerebrovascular disease, it is presently possible to identify groups of subjects who will take advantage of therapies, including antiplatelet agents, antihypertensive therapy (or a combination of both), carotid endoarteriectomy, and anticoagulation. To improve the impact of plasma fibrinogen and address some of the issues raised above, future prospective observational or interventional studies in vascular medicine should include the measurement of fibrinogen (and its genotypes) at the beginning of and at some time during the trials. This would be particularly relevant in large studies, with appropriate statistical power, that include individuals from different geographic areas. We believe that this attitude may refine the overall individual risk, and provide the individual patient with a tailor-made intervention based on a specific mechanism and/or stage of the atherosclerotic vascular disease.


*    Acknowledgments
 
We thank Drs Giovanni de Gaetano, Maria Benedetta Donati, and Licia Iacoviello for their help during the preparation of the manuscript; and Rosa Maria Marfisi and Anna Polidoro for assistance with data analysis and figure elaboration.

Received August 14, 1998; accepted December 1, 1998.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*References
 
1. Munro JM, Costran RS. The pathogenesis of atherosclerosis: Atherogenesis and inflammation. Lab Invest. 1988;58:249–261.[Medline] [Order article via Infotrieve]

2. Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]

3. Ross R. The pathogenesis of atherosclerosis. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia: Saunders; 1997:1105–1125.

4. Henschen A, McDonagh J. Fibrinogen, fibrin and factor XIII. In: Zwaal RFA, Hemker HC, eds. Blood Coagulation. Amsterdam: Elsevier Science Pub Co; 1986:171–241.

5. Atherosclerosis Risk in Community Study. Operation Manual, No. 9: Hemost Determinations. Bethesda, MD: National Heart, Lung, and Blood Institute; April 28, 1987. Version 1.0.

6. Bini A, Kudrik BJ. Fibrin and its derivatives in the normal and disease vessel wall. In: Plasminogen activation in fibrinolysis, in tissue remodeling and in development. Ann N Y Acad Sci. 1992;667:112–126.[Medline] [Order article via Infotrieve]

7. Constantinides P. Cause of thrombosis in human atherosclerotic arteries. Ann J Cardiol. 1990;66:37G–40G.

8. Smith EL, Thompson WD. Fibrin as cofactor in atherogenesis. Thromb Res. 1994;73:1–19.[Medline] [Order article via Infotrieve]

9. Schwartz CJ, Valente AJ, Kelley JL, Sprague EA, Edwards EH. Thrombosis and development of atherosclerosis: Rokitansky revisited. Semin Thromb Hemost. 1988;14:189–195.[Medline] [Order article via Infotrieve]

10. Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arteriosclerosis. 1990;10:1–7.[Abstract/Free Full Text]

11. Falk E. Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. 1985;71:699–708.[Abstract/Free Full Text]

12. Davies MJ, Thomas CA. Plaque fissuring: The cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J. 1985;53:363–373.[Free Full Text]

13. Saffitz JE, Schwartz CJ. Coronary atherosclerosis and thrombosis underlying acute myocardial infarction. Cardiol Clin. 1987;5:21–30.[Medline] [Order article via Infotrieve]

14. Cook NS, Ubben D. Fibrinogen as a major risk factor for cardiovascular disease. Trends Pharmacol Sci. 1990;11:444–451.[Medline] [Order article via Infotrieve]

15. Ernst E., Resch K. L. Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med. 1993;118:956–963.[Abstract/Free Full Text]

16. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996;347:849–853.[Medline] [Order article via Infotrieve]

17. Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile: A Statement for health professionals. Circulation. 1991;83:356–362.[Free Full Text]

18. Pyorala K, De Baker G, Graham I, Poole-Wilson P, Wood D on behalf of the Task Force: Prevention of coronary heart disease in clinical practice: Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J. 1994;15:1300–1331.[Free Full Text]

19. 27th Bethesda Conference. Matching the intensity of risk factor management with the hazard for coronary disease events. J Am Coll Cardiol. 1996;27:957–1047.[Medline] [Order article via Infotrieve]

20. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505.[Abstract]

21. Meade TW, Brozovic M, Chakrabarti RR, Haines AP, Iameson JD, Mellows S, Miller GJ, North WRS, Striling Y, Thompson SG. Haemostatic function and ischemic heart disease: The Northwick park heart study. Lancet. 1986;I:533–537.

22. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease: The Framingham study. JAMA. 1987;258:1183–1186.[Abstract/Free Full Text]

23. Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: Results from the PROCAM study in healthy men. Arterioscler Thromb. 1994;14:54–59.[Abstract/Free Full Text]

24. Cremer P, Nagel D, Labrot B, Mann H, Muche R, Elster H, Seidel D. Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL Cholesterol and other risk factors: Results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Europ J Clin Invest.. 1994;24:444–453.[Medline] [Order article via Infotrieve]

25. Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe. Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women: Scottish Heart Health Study. Eur Heart J. 1998;19:55–62.[Abstract/Free Full Text]

26. Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker IA, Elwood PC. Fibrinogen viscosity and the ten year incidence of ischaemic heart disease: The Caerphilly and Speedwell Studies. Eur Heart J. 1996;17:1814–1820.[Abstract/Free Full Text]

27. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997;96:1102–1108.[Abstract/Free Full Text]

28. Fowkes FGR, Lowe GDO, Housley E, Rattray A, Rumley A, Elton RA, MacGregor IR, Dawes J. Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet. 1993;342:84–86.[Medline] [Order article via Infotrieve]

29. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo J, for the European Concerted Action on Thrombosis, and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.[Abstract/Free Full Text]

30. Thompson SG, Calori G, Thomson JM, Haverkate F, Duckert F. The Impact of Sequential quality assessment exercises on laboratory performance: The Multicentre ECAT Angina Pectoris Study. Report from the European Concerted Action on Thrombosis, and Disabilities (ECAT). Thromb Haemost. 1991;65:149–152.[Medline] [Order article via Infotrieve]

31. Benderly M, Graff E, Reicher-Reiss H, Behar S, Brunner D, Goldbourt U, for the Benzafibrate Infarction Prevention (BIP) Study Group. Fibrinogen is a predictor of mortality in coronary heart disease patients. Arterioscler Thromb Vasc Biol. 1996;16:351–356.[Abstract/Free Full Text]

32. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation. 1997;96:4204–4210.[Abstract/Free Full Text]

33. Lee A. J., Lowe GDO, Woodward M., Tunstall-Pedoe H. Fibrinogen in relation to history of prevalent hypertension, diabetes, stroke, intermittent claudicatio, coronary heart disease and family history: The Scottish Heart Health Study. Br Heart J. 1993;69:338–342.[Abstract/Free Full Text]

34. Salomaa V, Rasi V, Pekkanen J, Vahtera E, Jauhiainen M, Vartiainen E, Myllyla G, Ehnholm C. Haemostatic factors and prevalent coronary heart disease: The FINRISK haemostasis study. Eur Heart J. 1994;15:1293–1299.[Abstract/Free Full Text]

35. Levenson J, Giral P, Raziavian M, Gariepy J, Simon A. Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 1995;15:1263–1268.[Abstract/Free Full Text]

36. Sharp DS, Abbott RD, Burchfiel CM, Rodriguez BL, Tracy RP, Yano K, Curb D. Plasma fibrinogen and coronary heart disease in elderly Japanese-American men. Arterioscler Thromb Vasc Biol. 1996;16:262–268.[Abstract/Free Full Text]

37. Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H, Philippou H, Lane DA, Morrison CE. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey II. Relationships to cardiovascular disease. Br J Haematol. 1997;97:785–797.[Medline] [Order article via Infotrieve]

38. Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischemic attacks and minor ischemic strokes. BMJ. 1991;303:605–609.

39. Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med. 1992;117:371–375.

40. Wu KK, Folsom AR, Heiss G, Davis CE, Conlan MG, Barnes R, for the ARIC Study Investigators. Association of coagulation factors and inhibitors with carotid Artery Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 1992;2:471–480.[Medline] [Order article via Infotrieve]

41. Koster T, Rosendaal FR, Reitsma PH, van der Valden PA, Briet E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis: A case-control study of plasma levels and DNA polymorphisms: the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994;71:719–722.[Medline] [Order article via Infotrieve]

42. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analysis of prospective studies. JAMA. 1998;279:1477–1482.[Abstract/Free Full Text]

43. Petitti DB. Meta-Analysis, Decision Analysis, and Cost-effectiveness Analysis. Oxford, England: Oxford University Press; 1994.

44. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;39:1–30.

45. D'Agostino RB, Weintraub M. Meta-analysis: A method for synthesizing research. Clin Pharmacol Ther. 1995;58:605–616.[Medline] [Order article via Infotrieve]

46. Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to Meta-analysis. Am J Epidemiol. 1992;135:1301–1309.[Abstract/Free Full Text]

47. Laird NM, Mosteller F. Some statistical methods for combining experimental results. Epidemiol Rev. 1987;9:1–30. International Journal of Technology Assessment in Health Care 1990;6:5–30.[Free Full Text]

48. Jenicek M. Meta-analysis in medicine where we are and where we want to go. J Clin Epidemiol. 1989;42:34–44.

49. Greenland S, Salvan A. Bias in the one-step method for pooling study results. Stat Med. 1991;9:247–252.

50. Olkin I. A critical look at some popular meta-analytic methods [Invited commentary]. Am J Epidemiol. 1994;140:297–299.[Free Full Text]

51. Rosner B, Spiegelman D, Willet WC. Correction of logistic regression relative risk estimates and confidence intervals for random within-person measurement error. Am J Epidemiol. 1992;136:1400–1413.[Abstract/Free Full Text]

52. Gibaldi M. Meta-analysis: a review of its place in therapeutic decision making. Drugs. 1993;46:805–818.[Medline] [Order article via Infotrieve]

53. L'Abbè KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Ann Intern Med. 1987;107:224–233.

54. Ingram GIC. The determination of plasma fibrinogen by the clot-weight method. Biochem J. 1952;51:583–585.[Medline] [Order article via Infotrieve]

55. Ellis BC, Stransky A. A quick and accurate method for the determination of fibrinogen in plasma. J Lab Clin Med. 1961;58:477–488.[Medline] [Order article via Infotrieve]

56. Blomback B, Blomback M. Purification of human bovine fibrinogan. Arkh Kem. 1956;10:415–443.

57. von Clauss A. Gerinnungphysiologische Schnellmethode zur bestimmung des fibrinogen. Acta Haematol. 1957;17:237–246.[Medline] [Order article via Infotrieve]

58. Brittin GM, Rafinia H, Ravel D, Werner M, Brown B. Evaluationof single radial immunodiffusion for quantitation of plasma fibrinogen. Am J Pathol. 1972;57:89–94.

59. Ernst E, Resch KL, Saradeth T, Maier A, Matrai A. A viscometric method of measuring plasma fibrinogen concentrations. J Clin Pathol. 1992;45:534–535.[Abstract/Free Full Text]

60. Dessert J, Bocquet P, Belleville J, Later R, Quincy C. An automated immunonephelometric method for the quatitiative determination of plasma fibrinogen. Hamostasis. 1973;1:215.

61. Tunstall-Pedoe H, Woodward M, Taverdale R, A'Brook R, McCluskey MK. Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study: Cohort study. BMJ. 1997;315:722–729.[Abstract/Free Full Text]

62. Marchioli R, Bomba E, Di Pasquale A, Geraci E, Giannuzzi C, Marfisi RM, Pede S, Schweiger C, Tavazzi L, Tognoni G, Valagussa F, a nome dei Ricercatori GISSI-Prevenzione. La carta del rischio post-IMA: Risultati dei primi 18 mesi di follow-up del GISSI-Prevenzione. G Ital Cardiol. 1998;28:416–433.[Medline] [Order article via Infotrieve]

63. Sweetnam PM, Yarnell WG, Lowe GDO, Baker LA, O'Brein JR, Rumley A, Etherinton MD, Whitehead PJ, Elwood PC. The relative power of heat-precipitation nephelometric and clottable (Clauss) fibrinogen in the prediction of ischaemic heart disease: The Caerphilly and Speedwell Studies. Br J Haematol. 1998;100:552–558.

64. Fey GH, Fuller GM. Regulation of the acute phase gene expression by inflammatory mediators. Mol Biol Med. 1987;4:323–328.[Medline] [Order article via Infotrieve]

65. Hassan J, Chelucci C, Peschle C, Sorrentino V. Transforming growth factor b (TGF-b) inhibits expression of fibrinogen and factor VII in a hepatoma cell line. Thromb Haemost. 1992;67:478–483.[Medline] [Order article via Infotrieve]

66. Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB, for the ECAT Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet. 1997;349:462–466.[Medline] [Order article via Infotrieve]

67. Maseri A. Inflammation, atherosclerosis, and ischemic events: Exploring the hidden side of the moon. N Engl J Med. 1997;336:1014–1016.[Free Full Text]

68. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.[Abstract/Free Full Text]

69. Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the b fibrinogen gene is associated with plasma fibrinogen levels in smokers and in non-smokers. Thromb Haemost. 1991;65:487–490.[Medline] [Order article via Infotrieve]

70. Fowkes FGR, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet. 1992;339:693–696.[Medline] [Order article via Infotrieve]

71. Connor JM, Fowkers FGR, Wood J, Smith FB, Donnan PT, Lowe GDO. Genetic variation at fibrinogen loci and plasma fibrinogen levels. J Med Genet. 1992;29:480–482.[Medline] [Order article via Infotrieve]

72. Scarabin PY, Bara L, Ricard S, Poirier O, Cambou JP, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the b-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction: The ECTIM study. Arterioscler Thromb. 1993;13:886–891.[Abstract/Free Full Text]

73. de Maat MPM, de Knijff P, Green FR, Thomas AE, Jespersen J, Kluft C. Gender-related association between b-fibrinogen genotype and plasma fibrinogen levels and linkage disequilibrium at the fibrinogen locus in Greenland Inuit. Arterioscler Thromb Vasc Biol. 1995;15:856–860.[Abstract/Free Full Text]

74. Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou JP, Scarabin PY, Bara L, Green F, Cambien F. Beta-fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: The ECTIM study. Circulation. 1996;93:440–449.[Abstract/Free Full Text]

75. Margaglione M, Cappucci G, Colaizzo D, Pirro L, Vecchione G, Grandone E, Di Minno G. Fibrinogen plasma levels in an apparently healthy general population: Relation to environmental and genetic determinants. Thromb Haemost. 1998;80:805–810.[Medline] [Order article via Infotrieve]

76. Di Minno G, Grandone E, Margaglione M. Clinical relevance of polymorphic markers of arterial thrombosis. Thromb Haemost. 1997;78:462–466.[Medline] [Order article via Infotrieve]

77. Bernardi F, Arcieri P, Bertina RM, Chiarotti F, Corral J, Pinotti M, Prydz H, Samama M, Sanset PM, Strom R, Vincente Garcia V, Mariani G. Contribution of factor VII genotype to activated FVII levels: Differences in genotype frequencies between northern and southern European populations. Arterioscler Thromb Vasc Biol. 1997;17:2548–2553.[Abstract/Free Full Text]

78. Iacoviello L, Di Castelnuovo A, De Knijff P, D'Orazio A, Amore C, Arboretti R, Kluft C, Donati MB. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med. 1998;338:79–85.[Abstract/Free Full Text]

79. Ballestein L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiological study on factor VII, Factor VIII and fibrinogen in an industrial population: I Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Thromb Haemost. 1985;54:475–479.[Medline] [Order article via Infotrieve]

80. Fishman D, Foulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo D. The effect of novel polymorphisms in the Interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic- onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–1376.[Medline] [Order article via Infotrieve]




This article has been cited by other articles:


Home page
CirculationHome page
D. S. Frankel, J. B. Meigs, J. M. Massaro, P. W.F. Wilson, C. J. O'Donnell, R. B. D'Agostino, and G. H. Tofler
Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease: The Framingham Offspring Study
Circulation, December 9, 2008; 118(24): 2533 - 2539.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
W. Koch, P. Hoppmann, J. Biele, J. C. Mueller, A. Schomig, and A. Kastrati
Fibrinogen Genes and Myocardial Infarction: A Haplotype Analysis
Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 758 - 763.
[Abstract] [Full Text] [PDF]


Home page
HeartHome page
O Rogowski, I Shapira, A Shirom, S Melamed, S Toker, and S Berliner
Heart rate and microinflammation in men: a relevant atherothrombotic link
Heart, August 1, 2007; 93(8): 940 - 944.
[Abstract] [Full Text] [PDF]


Home page
CMAJHome page
L. Pilote, K. Dasgupta, V. Guru, K. H. Humphries, J. McGrath, C. Norris, D. Rabi, J. Tremblay, A. Alamian, T. Barnett, et al.
A comprehensive view of sex-specific issues related to cardiovascular disease
Can. Med. Assoc. J., March 13, 2007; 176(6): S1 - S44.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
M. J. Maxwell, E. Westein, W. S. Nesbitt, S. Giuliano, S. M. Dopheide, and S. P. Jackson
Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation
Blood, January 15, 2007; 109(2): 566 - 576.
[Abstract] [Full Text] [PDF]


Home page
Hum ReprodHome page
J. Y.-P. Ho, M.-J. Chen, W. H.-H. Sheu, Y.-C. Yi, A. C.-W. Tsai, H.-F. Guu, and E. S.-C. Ho
Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women
Hum. Reprod., October 1, 2006; 21(10): 2715 - 2720.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
S. Sato, H. Iso, H. Noda, A. Kitamura, H. Imano, M. Kiyama, T. Ohira, T. Okada, M. Yao, T. Tanigawa, et al.
Plasma Fibrinogen Concentrations and Risk of Stroke and Its Subtypes Among Japanese Men and Women
Stroke, October 1, 2006; 37(10): 2488 - 2492.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
R. von Kanel, U. Hepp, C. Buddeberg, M. Keel, L. Mica, K. Aschbacher, and U. Schnyder
Altered Blood Coagulation in Patients With Posttraumatic Stress Disorder
Psychosom Med, July 1, 2006; 68(4): 598 - 604.
[Abstract] [Full Text] [PDF]


Home page
ANGIOLOGYHome page
A. Ziakas, S. Gavrilidis, G. Giannoglou, E. Souliou, K. Gemitzis, D. Kalampalika, M. A. Vayona, I. Pidonia, G. Parharidis, and G. Louridas
In-Hospital and Long-Term Prognostic Value of Fibrinogen, CRP, and IL-6 Levels in Patients with Acute Myocardial Infarction Treated with Thrombolysis
Angiology, May 1, 2006; 57(3): 283 - 293.
[Abstract] [PDF]


Home page
J Am Coll CardiolHome page
A. A. Quyyumi
Women and Ischemic Heart Disease: Pathophysiologic Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study and Future Research Steps
J. Am. Coll. Cardiol., February 7, 2006; 47(3_Suppl_S): S66 - S71.
[Abstract] [Full Text] [PDF]


Home page
Eur J EndocrinolHome page
L. M C. S M Leao, M. P. C Duarte, D. M. B Silva, P. R. V Bahia, C. M. Coeli, and M. L. F. de Farias
Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study
Eur. J. Endocrinol., January 1, 2006; 154(1): 131 - 139.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. Smith, C. Patterson, J. Yarnell, A. Rumley, Y. Ben-Shlomo, and G. Lowe
Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke?: The Caerphilly Study
Circulation, November 15, 2005; 112(20): 3080 - 3087.
[Abstract] [Full Text] [PDF]


Home page
JAMAHome page
Fibrinogen Studies Collaboration*
Plasma Fibrinogen Level and the Risk of Major Cardiovascular Diseases and Nonvascular Mortality: An Individual Participant Meta-analysis
JAMA, October 12, 2005; 294(14): 1799 - 1809.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
D. Feinbloom and K. A. Bauer
Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events
Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2043 - 2053.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
G. D. Smith, R. Harbord, J. Milton, S. Ebrahim, and J. A.C. Sterne
Does Elevated Plasma Fibrinogen Increase the Risk of Coronary Heart Disease?: Evidence from a Meta-Analysis of Genetic Association Studies
Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2228 - 2233.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
M. Woodward, G. D.O. Lowe, D. J. Campbell, S. Colman, A. Rumley, J. Chalmers, B. C. Neal, A. Patel, A. J. Jenkins, B. E. Kemp, et al.
Associations of Inflammatory and Hemostatic Variables With the Risk of Recurrent Stroke
Stroke, October 1, 2005; 36(10): 2143 - 2147.
[Abstract] [Full Text] [PDF]


Home page
ANGIOLOGYHome page
K. I. Paraskevas, S. S. Daskalopoulou, M. E. Daskalopoulos, and C. D. Liapis
Secondary Prevention of Ischemic Cerebrovascular Disease. What Is the Evidence?
Angiology, September 1, 2005; 56(5): 539 - 552.
[Abstract] [PDF]


Home page
StrokeHome page
H. J. Milionis, E. Rizos, J. Goudevenos, K. Seferiadis, D. P. Mikhailidis, and M. S. Elisaf
Components of the Metabolic Syndrome and Risk for First-Ever Acute Ischemic Nonembolic Stroke in Elderly Subjects
Stroke, July 1, 2005; 36(7): 1372 - 1376.
[Abstract] [Full Text] [PDF]


Home page
Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
R. Elosua, B. Bartali, J. M. Ordovas, A. M. Corsi, F. Lauretani, L. Ferrucci, and on Behalf of the InCHIANTI Investigators
Association Between Physical Activity, Physical Performance, and Inflammatory Biomarkers in an Elderly Population: The InCHIANTI Study
J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2005; 60(6): 760 - 767.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
J. M. Soria, L. Almasy, J. C. Souto, A. Buil, M. Lathrop, J. Blangero, and J. Fontcuberta
A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels
Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1287 - 1292.
[Abstract] [Full Text] [PDF]


Home page
CLIN APPL THROMB HEMOSTHome page
E. Arikan and S. Sen
Endothelial Damage and Hemostatic Markers in Patients with Uncomplicated Mild-to-Moderate Hypertension and Relationship with Risk Factors
Clinical and Applied Thrombosis/Hemostasis, April 1, 2005; 11(2): 147 - 159.
[Abstract] [PDF]


Home page
Eur J EndocrinolHome page
A M Smith, K M English, C J Malkin, R D Jones, T H Jones, and K S Channer
Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina
Eur. J. Endocrinol., February 1, 2005; 152(2): 285 - 291.
[Abstract] [Full Text] [PDF]


Home page
Mayo Clin Proc.Home page
I. J. Kullo and C. M. Ballantyne
Conditional Risk Factors for Atherosclerosis
Mayo Clin. Proc., February 1, 2005; 80(2): 219 - 230.
[Abstract] [PDF]


Home page
J. Neurol. Neurosurg. PsychiatryHome page
M P J van Goor, E B Gomez-Garcia, F W G Leebeek, G J Brouwers, P J Koudstaal, and D W J Dippel
The - 148 C/T fibrinogen gene polymorphism and fibrinogen levels in ischaemic stroke: a case-control study
J. Neurol. Neurosurg. Psychiatry, January 1, 2005; 76(1): 121 - 123.
[Abstract] [Full Text] [PDF]


Home page
StrokeHome page
P. M. Rothwell, S. C. Howard, D. A. Power, S. A. Gutnikov, A. Algra, J. van Gijn, T. G. Clark, M. F.G. Murphy, C. P. Warlow, and for the Cerebrovascular Cohort Studies Collaborati
Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke
Stroke, October 1, 2004; 35(10): 2300 - 2305.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
J. F Viles-Gonzalez, V. Fuster, and J. J Badimon
Atherothrombosis: A widespread disease with unpredictable and life-threatening consequences
Eur. Heart J., July 2, 2004; 25(14): 1197 - 1207.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Clin. Nutr.Home page
D. J Baer, J. T Judd, B. A Clevidence, and R. P Tracy
Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study
Am. J. Clinical Nutrition, June 1, 2004; 79(6): 969 - 973.
[Abstract] [Full Text] [PDF]


Home page
HeartHome page
D Zeltser, O Rogowski, S Berliner, T Mardi, D Justo, J Serov, M Rozenblat, D Avitzour, and I Shapira
Sex differences in the expression of haemorheological determinants in individuals with atherothrombotic risk factors and in apparently healthy people
Heart, March 1, 2004; 90(3): 277 - 281.
[Abstract] [Full Text] [PDF]


Home page
Arch NeurolHome page
K. Kang, K. Chu, and J.-K. Roh
POEMS Syndrome, Fibrinogen, and Ischemic Stroke: A Critical Point of View--Reply
Arch Neurol, January 1, 2004; 61(1): 155 - 156.
[Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen
Atherosclerotic Plaque Rupture: Local or Systemic Process?
Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2123 - 2130.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
R. von Kanel and J. E. Dimsdale
Hemostatic Alterations in Patients With Obstructive Sleep Apnea and the Implications for Cardiovascular Disease
Chest, November 1, 2003; 124(5): 1956 - 1967.
[Abstract] [Full Text] [PDF]


Home page
QJMHome page
S. Kamath and G.Y.H. Lip
Fibrinogen: biochemistry, epidemiology and determinants
QJM, October 1, 2003; 96(10): 711 - 729.
[Full Text] [PDF]


Home page
Diabetes CareHome page
V. Palmieri, R. P. Tracy, M. J. Roman, J. E. Liu, L. G. Best, J. N. Bella, D. C. Robbins, B. V. Howard, and R. B. Devereux
Relation of Left Ventricular Hypertrophy to Inflammation and Albuminuria in Adults With Type 2 Diabetes: The Strong Heart Study
Diabetes Care, October 1, 2003; 26(10): 2764 - 2769.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
S. E. Bojesen, K. Juul, P. Schnohr, A. Tybjaerg-Hansen, and B.o. G. Nordestgaard
Platelet glycoprotein IIb/IIIa PlA2/PlA2 homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: The Copenhagen City Heart Study
J. Am. Coll. Cardiol., August 20, 2003; 42(4): 661 - 667.
[Abstract] [Full Text] [PDF]


Home page
JAMAHome page
D. G. Hackam and S. S. Anand
Emerging Risk Factors for Atherosclerotic Vascular Disease: A Critical Review of the Evidence
JAMA, August 20, 2003; 290(7): 932 - 940.
[Abstract] [Full Text] [PDF]


Home page
QJMHome page
C.J. Malkin, P.J. Pugh, T.H. Jones, and K.S. Channer
Testosterone for secondary prevention in men with ischaemic heart disease?
QJM, July 1, 2003; 96(7): 521 - 529.
[Full Text] [PDF]


Home page
Am J EpidemiolHome page
K. Kain, J. M. Blaxill, A. J. Catto, P. J. Grant, and A. M. Carter
Increased Fibrinogen Levels among South Asians versus Whites in the United Kingdom Are Not Explained by Common Polymorphisms
Am. J. Epidemiol., July 15, 2002; 156(2): 174 - 179.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
C. G.C. Spencer, D. Gurney, A. D. Blann, D. G. Beevers, and G. Y.H. Lip
Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension: A Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
Hypertension, July 1, 2002; 40(1): 61 - 66.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Acevedo, G. L. Pearce, K. Kottke-Marchant, and D. L. Sprecher
Elevated Fibrinogen and Homocysteine Levels Enhance the Risk of Mortality in Patients From a High-Risk Preventive Cardiology Clinic
Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 1042 - 1045.
[Abstract] [Full Text] [PDF]


Home page
LupusHome page
P R J Ames, A Margarita, J D. Alves, C Tommasino, L Iannaccone, and V Brancaccio
Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies
Lupus, April 1, 2002; 11(4): 208 - 214.
[Abstract] [PDF]


Home page
Eur Heart JHome page
R Marchioli, F Avanzini, F Barzi, C Chieffo, A Di Castelnuovo, M.G Franzosi, E Geraci, A.P Maggioni, R.M Marfisi, N Mininni, et al.
Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations; GISSI-Prevenzione mortality risk chart
Eur. Heart J., November 2, 2001; 22(22): 2085 - 2103.
[Abstract] [PDF]


Home page
HypertensionHome page
L. Iacoviello, M. Vischetti, F. Zito, and M. Benedetta Donati
Genes Encoding Fibrinogen and Cardiovascular Risk
Hypertension, November 1, 2001; 38(5): 1199 - 1203.
[Abstract] [Full Text] [PDF]


Home page
ANGIOLOGYHome page
H. J. Milionis, E. Rizos, and D. P. Mikhailidis
Smoking Diminishes the Beneficial Effect of Statins: Observations from the Landmark Trials
Angiology, September 1, 2001; 52(9): 575 - 587.
[Abstract] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
K. Yano, J. S. Grove, R. Chen, B. L. Rodriguez, J. D. Curb, and R. P. Tracy
Plasma Fibrinogen as a Predictor of Total and Cause-Specific Mortality in Elderly Japanese-American Men
Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1065 - 1070.
[Abstract] [Full Text] [PDF]


Home page
Exp. Biol. Med.Home page
M. S. Williams and P. F. Bray
Genetics of Arterial Prothrombotic Risk States
Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419.
[Abstract] [Full Text]


Home page
CirculationHome page
S. C. Clarke, P. M. Schofield, A. A. Grace, J. C. Metcalfe, and H. L. Kirschenlohr
Tamoxifen Effects on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis
Circulation, March 20, 2001; 103(11): 1497 - 1502.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
L. F. Bielak, G. G. Klee, P. F. Sheedy II, S. T. Turner, R. S. Schwartz, and P. A. Peyser
Association of Fibrinogen With Quantity of Coronary Artery Calcification Measured by Electron Beam Computed Tomography
Arterioscler. Thromb. Vasc. Biol., September 1, 2000; 20(9): 2167 - 2171.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maresca, G.
Right arrow Articles by Di Minno, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maresca, G.
Right arrow Articles by Di Minno, G.
Related Collections
Right arrow Risk Factors
Right arrow Acute myocardial infarction
Right arrow Acute Stroke Syndromes
Right arrow Coagulation and fibronolysis