This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yano, K. Articles by Tracy, R. P. Search for Related Content PubMed PubMed Citation Articles by Yano, K. Articles by Tracy, R. P. Related Collections Calcium cycling/excitation-contraction coupling Fibrinogen/fibrin Epidemiology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1065.)
© 2001 American Heart Association, Inc.

Thrombosis

Plasma Fibrinogen as a Predictor of Total and Cause-Specific Mortality in Elderly Japanese-American Men

Katsuhiko Yano; John S. Grove; Randi Chen; Beatriz L. Rodriguez; J. David Curb; Russell P. Tracy

From the Honolulu Heart Program, Kuakini Medical Center (K.Y., R.C., B.L.R., J.D.C.), Honolulu, Hawaii; the Division of Clinical Epidemiology, Department of Medicine (K.Y., R.C., B.L.R., J.D.C.), and the Biostatistics Program, Department of Public Health (J.S.G.), John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii; and the Department of Pathology (R.P.T.), University of Vermont, Laboratory for Clinical Biochemistry Research, Colchester.

Correspondence to Katsuhiko Yano, MD, Pacific Health Research Institute, 846 S Hotel St, Suite 306, Honolulu, HI 96813. E-mail yano{at}phri.hawaii-health.com

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—The relation between plasma fibrinogen and total and cause-specific mortality was investigated in a cohort of 3571 Japanese-American men aged 71 to 93 years during a median follow-up of 4.4 years. There were a total of 728 deaths, of which 37% were accounted for by cardiovascular disease and 27% by cancer. The age-adjusted relative risk (RR) for total mortality in the top quintile of fibrinogen (>3.51 g/L) compared with the bottom quintile (<2.57 g/L) was 4.3 (P<0.0001) in the first year of follow-up. RR was reduced to 1.7 in the second year but remained significantly and slightly increased in subsequent years. After adjustment for age and confounding risk factors, the RRs (and 95% confidence intervals) associated with a 1-SD increment of fibrinogen (0.64 g/L) for all-cause, cardiovascular disease, cancer, and other-cause mortality were 1.3 (1.2 to 1.4), 1.2 (1.1 to 1.4), 1.3 (1.2 to 1.5), and 1.3 (1.2 to 1.5), respectively. Preexisting diseases did not influence the significant association of fibrinogen with mortality. There was a significant interaction of fibrinogen with white blood cell count but not with cigarette smoking. We conclude that plasma fibrinogen is an independent risk factor for mortality from a broad spectrum of diseases in elderly men and that this universal effect of fibrinogen on mortality may be mediated partly through inflammation.

Key Words: Asian Americans • cancer • cardiovascular disease • fibrinogen • mortality

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The ability of standard risk factors, including hypertension, elevated blood cholesterol, cigarette smoking, and diabetes mellitus, to predict coronary heart disease (CHD) is limited.^{1 2} There is growing evidence for the important roles of new risk factors related to hemostasis, blood rheology, inflammation, and infection in the pathogenesis of atherosclerotic vascular diseases.^{2 3 4 5 6} Plasma fibrinogen is a major factor affecting blood coagulation, viscosity, smooth muscle proliferation, and endothelial function.⁷ It is also an acute-phase reactant that is a sensitive marker for systemic inflammation.⁸

Since publication of the reports from the Northwick Park Heart Study in the 1980s,^{9 10} an elevated level of plasma fibrinogen has been identified as a major independent risk factor for ischemic cardiovascular disease (CVD). In 3 recent review articles,^{11 12 13} meta-analyses of 6 to 18 prospective studies have consistently shown predictive values of fibrinogen for CHD and stroke incidence and mortality that are independent of standard risk factors.

However, most of the available data are based on middle-aged men, and there is a relative lack of information on the relation of fibrinogen to both total and CVD mortality in elderly people. In this report, we present results of a prospective investigation of the association between baseline levels of plasma fibrinogen and subsequent total and cause-specific mortality during a median follow-up of 4.4 years among 3571 Japanese-American men aged 71 to 93 years.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The Honolulu Heart Program (HHP) is a long-term prospective study of CVD among Japanese-American men who were living on Oahu island, Hawaii, in 1965. A total of 8006 eligible men aged 45 to 68 years participated in the initial examination between 1965 and 1968. Details of the cohort selection process were previously published.¹⁴ This cohort was reexamined 2, 6, and 26 years later. Plasma fibrinogen levels were first determined in the fourth HHP examination (1991 to 1993) on 3571 men aged 71 to 93. These men represented 80% of the surviving members of the original cohort. This analysis was based on the data obtained from the follow-up of these 3571 men through the end of 1996. The Kuakini Medical Center institutional review committee approved the study protocol, and informed consent was obtained from all participants.

Data Collection
The fourth HHP examination included demographic questions, medical history, anthropometry, standard blood pressure measurements, smoking habits, alcohol intake, physical activity assessment, resting 12-lead electrocardiogram, pulmonary function tests, and collection of fasting blood specimens to measure levels of plasma fibrinogen, total cholesterol, HDL cholesterol, triglyceride, glucose, insulin, and hematological values. A standard oral glucose tolerance test was performed. Diabetes mellitus was defined by a fasting glucose level >126 mg/dL, a 2-hour glucose level 200 mg/dL, or active treatment with insulin or oral hypoglycemic agents. Hypertension was defined as a systolic blood pressure 160 mm Hg, a diastolic blood pressure 95 mm Hg, or use of antihypertensive drugs. Body mass index was calculated as weight (kg)/square of height (m²). A summary measure of physical activity was estimated by the method used in the Framingham Study.¹⁵ The number of hours spent per 24-hour period in 5 different activity levels was recorded, and the weighted sum of hours spent for each activity was used as the physical activity index.

Plasma fibrinogen levels were determined at the Laboratory for Clinical Biochemistry Research, University of Vermont, Colchester, as the rate of clot formation by a semiautomated modification of the Clauss method,¹⁶ as determined on a BBL fibrometer (Becton Dickinson). Details of the calibration and quality control data were previously published.¹⁷ Other laboratory measurements were conducted by standardized procedures.

Mortality data were obtained through a comprehensive surveillance system that has been used successfully since the beginning of the HHP.¹⁸ All deaths were ascertained by continuous monitoring of obituaries in local newspapers, mortuary notices, hospital discharge records, and death certificates. The underlying cause of death was determined by a panel of study physicians at bimonthly conferences and was based on all available information, including HHP examinations, hospital records, death certificates, autopsy reports, and telephone inquiries to physicians and families. Three major categories were used to classify the underlying cause according to the eighth revision of the International Classification of Disease: CVD (codes 390 to 459), cancer (codes 140 to 208), and all other causes combined.

Statistical Analysis
Rates of survival through the end of 1996 by quintile of baseline fibrinogen level were calculated by using the Kaplan-Meier method.¹⁹ Significant differences in survival among the quintile groups were evaluated by the log-rank test. Temporal changes in the relation between fibrinogen and mortality were examined by estimating age-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for total mortality in each of the second to the fifth quintiles of fibrinogen, compared with the first quintile, by using Cox proportional-hazards regression models²⁰ for separate follow-up years.

The independent role of fibrinogen as a predictor of total and cause-specific mortality was evaluated by using Cox regression models, with separate adjustments for age, potentially confounding factors, and preexisting diseases. Confounding factors were selected on the basis of previously reported cross-sectional analyses in this study cohort^{17 21} and other studies.^{22 23 24} These factors included body mass index, total and HDL cholesterol, triglyceride, hematocrit, white blood cell (WBC) count, smoking (pack-years), alcohol intake (oz/mo), physical activity index, and the presence or absence of hypertension and diabetes mellitus (as defined above). Preexisting diseases included CHD, stroke, and cancer, which were identified at the baseline examination.

In these analyses, predictive values of fibrinogen for total and cause-specific mortality were evaluated by RRs in each of the second through the fifth quintiles of baseline fibrinogen compared with the first quintile. In a separate analysis, fibrinogen was treated as a continuous variable, and standardized relative risks (SRRs) for total and cause-specific mortality associated with an increment of 1 SD of fibrinogen (0.64 g/L) were estimated.

Possible interactions between fibrinogen and other variables were examined by including fibrinogen (continuous variable), age, each variable one at a time, and the product of fibrinogenxeach variable simultaneously in Cox regression models. For statistical significance, 2-sided probability values <0.05 were used throughout the analysis.

	Results

Top Abstract Introduction Methods Results Discussion References

 
For the 3571 participants, during the follow-up through the end of 1996 (median 4.4 years), a total of 728 men had died. Table 1 shows the number of total and cause-specific deaths by quintile of baseline fibrinogen level. CVD accounted for 37% of all deaths, which included 124 cases of CHD, 102 cases of stroke, and 32 cases of other circulatory diseases. Cancer was the second most frequent cause, accounting for 27% of deaths. Among the 273 remaining deaths, senile dementia, chronic obstructive pulmonary disease, pneumonia, liver cirrhosis, diabetes, and accidents/suicide were relatively common causes. None of the deaths due to these miscellaneous causes exceeded 50.

View this table: [in this window] [in a new window]   Table 1. Baseline Levels of Plasma Fibrinogen (1991–1993) and the Number of Total and Cause-Specific Deaths During the Follow-Up Period (Through 1996) by Quintile of Fibrinogen Among 3571 Japanese-American Men Living in Hawaii, Aged 71–93 Years

Figure 1 illustrates survival curves by quintile of fibrinogen. Among the lower 3 quintile groups, survival curves were very similar and showed much better survival rates than those for the upper 2 quintiles. The fifth quintile group showed the worst survival. This result was evident from the first year of follow-up. Overall differences in survival among quintile groups of fibrinogen were highly significant (P<0.0001).

View larger version (20K): [in this window] [in a new window]   Figure 1. Survival rates during a median follow-up of 4.4 years by quintile of baseline fibrinogen levels in 3571 Japanese-American men aged 71 to 93 years.

Figure 2 shows age-adjusted RRs and 95% CIs of total mortality for each of the second through the top quintiles of fibrinogen compared with the lowest quintile by year of follow-up. Because of the similarity in patterns of RRs, the follow-up years after the second were combined. There were substantial decreases in RRs for every quintile group between the first and second year of follow-up. The reduction was greatest for the top quintile group, dropping from 4.3 to 1.7. However, the RRs tended to increase consistently in subsequent years, with an average of 1.9 for the top quintile. The RRs for the top quintile group were significantly greater than 1.0 in every year of follow-up, whereas those for the fourth quintile group were significant only after the second year. None of the RRs for the second and third quintile groups were significant in any of the follow-up years. Exclusion of preexisting diseases (1187 men; 349 deaths) altered these temporary patterns of RR over time.

View larger version (15K): [in this window] [in a new window]   Figure 2. Age-adjusted RRs for total mortality in each of the second through the fifth quintiles of baseline fibrinogen levels compared with the first quintile during different periods of follow-up. Circles indicate RRs, and bars indicate 95% CIs.

Figure 3 shows age-adjusted RRs and 95% CIs of total and cause-specific mortality during the entire follow-up period for each of the second through the top quintiles of fibrinogen compared with the lowest quintile. There were significant increases in mortality for the top quintile of fibrinogen (>3.51 g/L) compared with the lowest quintile (<2.57 g/L): 2.1 times in all causes, 2.4 times in CVD, 2.8 times in cancer, and 1.6 times in all other causes. Significant increases in mortality (1.5 times in all causes and 2.1 times in cancer) were also noted for the fourth quintile of fibrinogen (3.14 to 3.51 g/L). On the other hand, there was no significant increase in mortality for the second and third quintiles of fibrinogen, except that the second quintile had a 1.6-fold increase in cancer mortality. Thus, there might be a threshold of fibrinogen above which mortality risk is increased. However, when fibrinogen level was treated as a continuous variable in Cox regression models, a test for nonlinearity was not significant. These results suggest that the difference in risk increases exponentially with fibrinogen level, a curve that mimics a threshold effect.

View larger version (17K): [in this window] [in a new window]   Figure 3. Age-adjusted RRs for total and cause-specific mortality in each of the second through fifth quintiles of baseline fibrinogen levels compared with the first quintile during the entire follow-up period. Circles indicate RRs, and bars indicate 95% CIs. Other indicates combined causes other than CVD and cancer.

Table 2 shows SRRs and 95% CIs for total and cause-specific mortality associated with an increment of baseline fibrinogen by 1 SD (0.64 g/L). In this analysis, effects of fibrinogen as a continuous variable on mortality were evaluated by Cox regression models. Three models were used, with adjustments for (1) age alone; (2) age and standard risk factors for CVD; and (3) age, risk factors, and preexisting diseases (CHD, stroke, and cancer). When the adjustment was made only for age, the SRR was greatest for CVD mortality (1.40), followed by cancer (1.38), all causes (1.36), and other causes (1.31). All of these SRRs were statistically significant. After adjustment for risk factors, however, there was a substantial reduction in the SRR for CVD (1.21), a relatively small reduction for cancer (1.32) and all-cause mortality (1.28), and a slight increase for other causes (1.32). The reduction in SRR for CVD mortality suggests greater confounding effects of these risk factors on CVD mortality. Further adjustment for preexisting diseases slightly reduced the SRR for CVD mortality but left the other SRRs unchanged.

View this table: [in this window] [in a new window]   Table 2. Standardized Relative Risks for Total and Cause-Specific Mortality Associated With an Increment of Baseline Fibrinogen Levels by 1 SD (0.64 g/L)

When these analyses were repeated after excluding deaths that occurred within 1 year of the follow-up, all SRRs remained significant, although their values tended to be smaller. In particular, there was a 10 percentage point decrease (from 1.38 to 1.28) in the age-adjusted SRR for cancer mortality. These findings are consistent with the reduction of RRs for total mortality between the first and second year of follow-up that was shown in Figure 2.

Figure 4 illustrates interactions between fibrinogen and 2 other variables for the association with total mortality. The figure on the left shows age-adjusted mortality rates for 9 subgroups classified by combinations of fibrinogen tertiles (<2.76, 2.76 to 3.22, and >3.22 g/L) and WBC tertiles (<5.4, 5.4 to 6.6, and >6.6x10⁹/L). Within the lowest tertile of WBC, there was only a small increase in mortality with increasing fibrinogen level. In contrast, there were clearly greater increases in mortality between the second and the third tertiles of fibrinogen within the higher 2 tertiles of WBC. The ß coefficient for the interaction term (fibrinogenxWBC) in the Cox regression was highly significant (P<0.0001). The right side of the figure shows age-adjusted mortality rates by combinations of fibrinogen tertiles and smoking status (never, past, and current smoker). There were similar increases in mortality with increasing fibrinogen levels within each group of smoking. The ß coefficient for the interaction term was not significant. When the amount of lifetime smoking (pack-years) was used instead of smoking status, similar results were obtained. There was no significant interaction between fibrinogen and the remaining variables except for alcohol intake, which showed a weakly significant negative interaction (P=0.04).

View larger version (18K): [in this window] [in a new window]   Figure 4. Age-adjusted total mortality rates by combinations of fibrinogen tertiles and WBC tertiles or smoking status.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this report, we demonstrated that plasma fibrinogen was a strong predictor of total and cause-specific mortality, independent of standard risk factors, in a large cohort of elderly Japanese-American men who were known to have a low risk for ischemic CVD and a long life expectancy.²⁵ It is remarkable that an increased level of fibrinogen was universally associated with increasing risk of mortality from diverse causes, including CVD, cancer, and other miscellaneous diseases. The association was strongest with cancer and weakest with CVD after adjustment for confounding risk factors. This result may simply be due to the fact that the risk factors selected are, by and large, CVD risk factors and not necessarily cancer-related risk factors (except for smoking and alcohol intake).

It is interesting to note that the association of fibrinogen with mortality, especially cancer mortality, was greater in the first year of follow-up than in subsequent years. This finding might imply that elevated levels of fibrinogen were consequences of subclinical disease or underlying conditions. However, this hypothesis explains only partly the fibrinogen-mortality association because the higher mortality in men with increased levels of fibrinogen persisted after exclusion of early deaths, not only for total mortality but also for every category of cause-specific death. Tracy⁴ observed similar findings in the Cardiovascular Health Study and postulated the concept of "proximate pathophysiology," in which it was hypothesized that individuals with chronic diseases might enter a time of destabilization and rapid worsening and decline 6 months to 2 years before an event (or death).

These findings also suggest that 1 of the main pathophysiological mechanisms of the increased all-cause mortality associated with elevated levels of fibrinogen may be an inflammatory process.⁸ Acute or chronic inflammation is a common underlying condition of many diseases leading to death.⁴ Older individuals are most vulnerable to inflammatory conditions, and predictive values of fibrinogen for mortality from a variety of causes are particularly important in old age.^{4 26}

C-reactive protein is known to be a sensitive marker for chronic systemic inflammation.^{3 4 12} Although direct information on C-reactive protein was not available in the present analysis, fibrinogen was found to be highly correlated with C-reactive protein (r=0.59) in a random sample of this study cohort.²⁷ Furthermore, in a separate report from the HHP,²¹ there was a significant correlation (r=0.24) of fibrinogen with WBC count, another marker for inflammation/infection.²¹ Nonetheless, both fibrinogen and WBC count were independently associated with total mortality in the present study. Also, there was a significant interaction between fibrinogen and WBC count, which indicates joint effects of these 2 markers of inflammation. Simultaneously elevated levels of both variables might simply mean an increased severity of the underlying inflammatory process, or it might reflect multiple causal pathways of the inflammation. It is known from other prospective studies^{28 29 30 31} that WBC is an independent predictor of CVD, cancer, and total mortality.

There are a few prospective studies showing a significant association of fibrinogen with total mortality, independent of standard risk factors. In the Northwick Park Heart Study,¹⁰ plasma fibrinogen predicted 10-year total and ischemic heart disease mortality among 1511 men aged 40 to 64 years. However, there was no significant association of fibrinogen with cancer mortality. According to the 18-year follow-up data of the Framingham Study cohort (1274 men and women aged 47 to 79 years),³² an increment of baseline fibrinogen by 1 SD (0.56 g/L) increased the age-adjusted risk for both all-cause mortality and CVD mortality in men by 30%. After adjustment for other risk factors, the increased risks were reduced to 20%. These results are very similar to those in our study. In a 21-year follow-up of CVD and total mortality among Swedish men aged 54 to 75,³³ plasma fibrinogen was a strong predictor of all-cause, CHD, stroke, and non-CVD mortality when smoking was excluded from the analysis. In the 8-year follow-up data of the Scottish Heart Health Study (5095 men and 4860 women aged 40 to 59 years),³⁴ fibrinogen was a strong predictor of CHD and total mortality, even after adjustment for smoking in both sexes and with or without preexisting CHD. There appeared to be a threshold effect, with individuals in the fifth quintile of fibrinogen having a much increased risk of total and CHD mortality. In the Atherosclerosis Risk in Communities Study,³⁵ a 5.2-year follow-up of 14 477 men and women aged 45 to 64 years who were free of CHD showed that both fibrinogen and WBC count were significantly associated with total mortality in men, with multivariate-adjusted RRs (per 1-SD increment) of 1.30 and 1.15, respectively. However, there was no interaction between fibrinogen and WBC count. These findings in other studies are generally consistent with those in our study.

Cigarette smoking is the strongest known determinant of fibrinogen levels⁷ and is 1 of the most important risk factors for CVD and all-cause mortality.^{36 37} The Framingham Study provided detailed analyses of the interrelation of fibrinogen with smoking and CVD.³⁸ It was estimated that half of the increased risk of CVD due to smoking was mediated through its effects on increasing fibrinogen. In our study, however, both fibrinogen and smoking were significant predictors of total mortality, independent of each other. These 2 variables were weakly but significantly correlated (r=0.07, P<0.001),^{7 21} yet there was no interaction of fibrinogen with smoking on mortality. Similar findings have been shown in another prospective study.³⁰

Although a causal relation between fibrinogen and mortality can be determined only by clinical trials, the clinical importance of plasma fibrinogen as a potent and independent predictor of mortality from a broad spectrum of chronic diseases appears to be clear. In old age, when the association of traditional risk factors with mortality is weakened, this relatively inexpensive test should provide a useful measure to identify high-risk persons. Whether or not lowering fibrinogen levels can reduce mortality risk awaits further studies.

	Acknowledgments

 
This study was supported by the National Heart, Lung, and Blood Institute contract N01-HC-05102 and grant U01HL-56274.

Received November 1, 2000; accepted February 19, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Heller RF, Chinn S, Tunstall-Pedoe M, Rose G. How well can we predict coronary heart disease? findings in the United Kingdom Heart Disease Prevention Project. BMJ. 1984;288:1409–1411.
2. Braunwald E. Shattuck lecture: cardiovascular medicine at the turn of the millennium: triumphs, concerns and opportunities. N Engl J Med. 1997;337:1360–1369.[Free Full Text]
3. 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]
4. Tracy RP. Epidemiological evidence for inflammation in cardiovascular disease. Thromb Haemost. 1999;82:826–831.[Medline] [Order article via Infotrieve]
5. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126.[Free Full Text]
6. Nieto FJ. Infections and atherosclerosis: new clues from old hypothesis? Am J Epidemiol. 1998;148:937–948.
7. Ernst E. Fibrinogen: an important risk factor for atherothrombotic diseases. Ann Med. 1994;26:15–22.[Medline] [Order article via Infotrieve]
8. Ernst E. Fibrinogen as a cardiovascular risk factor: interrelationship with infections and inflammation. Eur Heart J. 1993;14(suppl K):82–87.
9. Meade TW, North WRS, Chakrabarti R, Stirling Y, Haines AP, Thompson SG. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet. 1980;1:1050–1054.[Medline] [Order article via Infotrieve]
10. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thomson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533–537.[Medline] [Order article via Infotrieve]
11. Ernst E, Resh KL. 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]
12. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477–1482.[Abstract/Free Full Text]
13. Maresa G, Blasio AD, Marchioli R, Minno GD. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999;19:1368–1377.[Abstract/Free Full Text]
14. Worth RM, Kagan A. Ascertainment of men of Japanese ancestry in Hawaii through World War II Selection Service registration. J Chronic Dis. 1970;23:389–397.[Medline] [Order article via Infotrieve]
15. Kannel WB, Sorlie P. Some health benefits of physical activity: the Framingham Study. Arch Intern Med. 1979;139:857–861.[Medline] [Order article via Infotrieve]
16. Clauss A. Gerinnungs physiologishe schenellmethode zur bestimmungs des fibrinogens. Acta Haematol. 1957;17:237–246.[Medline] [Order article via Infotrieve]
17. Sharp DS, Abbott RD, Burchfiel CM, Rodriguez BL, Tracy RP, Yano K, Curb JD. Plasma fibrinogen and coronary heart disease in elderly Japanese-American men. Arterioscler Thromb Vasc Biol. 1996;16:262–268.[Abstract/Free Full Text]
18. Rhoads GG, Kagan A, Yano K. Usefulness of community surveillance for the ascertainment of coronary heart disease and stroke. Int J Epidemiol. 1975;4:265–270.[Abstract/Free Full Text]
19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481.
20. Cox DR. Regression models and life tables. J R Stat Soc [B]. 1972;34:187–202.
21. Yano K, Kodama K, Shimizu Y, Chyou P-H, Sharp DS, Tracy RP, Rodriguez BL, Curb JD, Kusumi S. Plasma fibrinogen and its correlates in elderly Japanese men living in Japan and Hawaii. J Clin Epidemiol. 1999;52:1201–1206.[Medline] [Order article via Infotrieve]
22. Folsom AR, Conlan MG, Davis CE, Wu KK. Relations between hemostasis variables and cardiovascular risk factors in middle-age adults. Ann Epidemiol. 1992;2:481–494.[Medline] [Order article via Infotrieve]
23. Cushman M, Yanez D, Psaty BM, Fried LP, Heiss G, Lee M, Polak JF, Savage PJ, Tracy RP. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Am J Epidemiol. 1996;143:665–676.[Abstract/Free Full Text]
24. Sato S, Iso H, Naito Y, Kiyama M, Kitamura A, Iida M, Shimamoto T, Komachi Y. Plasma fibrinogen and its correlates in urban Japanese men. Int J Epidemiol. 1996;25:521–527.[Abstract/Free Full Text]
25. Curb JD, Reed DM, Miller FD, Yano K. Health status and lifestyle in elderly Japanese men with a long life expectancy. J Gerontol. 1990;45:S206–S211.[Medline] [Order article via Infotrieve]
26. Hamerman D, Berman JW, Albers GW, Brown DL, Silver D. Emerging evidence for inflammation in conditions frequently affecting older adults: report of a symposium. J Am Geriatr Soc. 1999;47:1016–1025.[Medline] [Order article via Infotrieve]
27. Rodriguez BL, Curb JD, Sakkinen P, Bild DE, Burchfiel CM, Abbott R, Schatz I, Yano K, Tracy R. The association between C-reactive protein, diabetes, and other CVD risk factors among Japanese-American men: the Honolulu Heart Program. Circulation. 1999;99(suppl I):I-1120. Abstract.
28. Grimm RH, Neaton JD, Ludwig W. Prognostic importance of the white blood cell count for coronary, cancer, and all-cause mortality. JAMA. 1985;254:1932–1937.[Abstract]
29. DeLabry LO, Campion EW, Glynn RJ, Vokonas PS. White blood cell count as a predictor of mortality: results over 18 years from the Normative Aging Study. J Clin Epidemiol. 1990;43:153–157.[Medline] [Order article via Infotrieve]
30. Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, Elwood PC. Fibrinogen viscosity, and white blood cell count are major risk factor for ischemic heart disease: the Caerphilly and Speedwell Collaborative Heart Study.Circulation. 1991;83:836–844.[Abstract/Free Full Text]
31. Kannel WB, Anderson K, Wilson PWF. White blood cell count and cardiovascular disease: insight from the Framingham Study. JAMA. 1992;267:1253–1256.[Abstract]
32. Kannel WB, D’Agostino RB, Belanger AJ. Update on fibrinogen as a cardiovascular risk factor. Ann Epidemiol. 1992;2:457–466.[Medline] [Order article via Infotrieve]
33. Tibblin G. 21-year follow-up of CVD and total mortality among men born in 1913. In: Ernst E, Koenig W, Maede TW, eds. Fibrinogen: a "New" Cardiovascular Risk Factor. Oxford, England; Blackwell-MZV: 1992:115–119.
34. Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H. Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women: the Scottish Heart Health Study. Eur Heart J. 1998;19:55–62.[Abstract/Free Full Text]
35. Folsom AR, Wu KK, Rosamond WD, Sharett 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]
36. Tunstall-Pedoe H, Woodward M, Tavendale 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]
37. Yusurf HR, Giles WH, Croft JB, Anda RF, Casper ML. Impact of multiple risk factor profiles on determining cardiovascular disease risk. Prev Med. 1998;27:1–9.[Medline] [Order article via Infotrieve]
38. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insight from the Framingham Study. Am Heart J. 1987;113:1006–1010. [Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				L. Jorgensen, I. Heuch, T. Jenssen, and B. K. Jacobsen Association of Albuminuria and Cancer Incidence J. Am. Soc. Nephrol., May 1, 2008; 19(5): 992 - 998. [Abstract] [Full Text] [PDF]

				W. Koenig, N. Khuseyinova, J. Baumert, and C. Meisinger Prospective Study of High-Sensitivity C-Reactive Protein as a Determinant of Mortality: Results from the MONICA/KORA Augsburg Cohort Study, 1984-1998 Clin. Chem., February 1, 2008; 54(2): 335 - 342. [Abstract] [Full Text] [PDF]

				S. Shinkai, P. H. M. Chaves, Y. Fujiwara, S. Watanabe, H. Shibata, H. Yoshida, and T. Suzuki {beta}2-Microglobulin for Risk Stratification of Total Mortality in the Elderly Population: Comparison With Cystatin C and C-Reactive Protein Arch Intern Med, January 28, 2008; 168(2): 200 - 206. [Abstract] [Full Text] [PDF]

				N. S. Jenny, N. D. Yanez, B. M. Psaty, L. H. Kuller, C. H. Hirsch, and R. P. Tracy Inflammation Biomarkers and Near-Term Death in Older Men Am. J. Epidemiol., March 15, 2007; 165(6): 684 - 695. [Abstract] [Full Text] [PDF]

				J. A. Tice, A. Kanaya, T. Hue, S. Rubin, D. S. M. Buist, A. LaCroix, J. V. Lacey Jr, J. A. Cauley, S. Litwack, L. A. Brinton, et al. Risk Factors for Mortality in Middle-aged Women Arch Intern Med, December 11, 2006; 166(22): 2469 - 2477. [Abstract] [Full Text] [PDF]

				D. Mazhar and S. Ngan C-reactive protein and colorectal cancer. QJM, August 1, 2006; 99(8): 555 - 559. [Full Text] [PDF]

				K. Miura, H. Nakagawa, H. Ueshima, A. Okayama, S. Saitoh, J. D. Curb, B. L. Rodriguez, K. Sakata, N. Okuda, K. Yoshita, et al. Dietary Factors Related to Higher Plasma Fibrinogen Levels of Japanese-Americans in Hawaii Compared With Japanese in Japan Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1674 - 1679. [Abstract] [Full Text] [PDF]

				A. Shankar, J. J. Wang, E. Rochtchina, M. C. Yu, R. Kefford, and P. Mitchell Association Between Circulating White Blood Cell Count and Cancer Mortality: A Population-Based Cohort Study Arch Intern Med, January 23, 2006; 166(2): 188 - 194. [Abstract] [Full Text] [PDF]

				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]

				S. B. Kritchevsky, M. Cesari, and M. Pahor Inflammatory markers and cardiovascular health in older adults Cardiovasc Res, May 1, 2005; 66(2): 265 - 275. [Abstract] [Full Text] [PDF]

				E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]

				T. P. Erlinger, P. Muntner, and K. J. Helzlsouer WBC Count and the Risk of Cancer Mortality in a National Sample of U.S. Adults: Results from the Second National Health and Nutrition Examination Survey Mortality Study Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 1052 - 1056. [Abstract] [Full Text] [PDF]

				T. P. Erlinger, E. A. Platz, N. Rifai, and K. J. Helzlsouer C-Reactive Protein and the Risk of Incident Colorectal Cancer JAMA, February 4, 2004; 291(5): 585 - 590. [Abstract] [Full Text] [PDF]

				T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]

				M. Haim, D. Tanne, V. Boyko, T. Reshef, U. Goldbourt, J. Leor, Y. A. Mekori, and S. Behar Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease: Data from the Bezafibrate Infarction Prevention (BIP) Study J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1133 - 1138. [Abstract] [Full Text] [PDF]

				W. Koenig and M. B. Pepys C-Reactive Protein Risk Prediction: Low Specificity, High Sensitivity Ann Intern Med, April 2, 2002; 136(7): 550 - 552. [Full Text] [PDF]

				V. Salomaa, V. Rasi, S. Kulathinal, E. Vahtera, M. Jauhiainen, C. Ehnholm, and J. Pekkanen Hemostatic Factors as Predictors of Coronary Events and Total Mortality: The FINRISK '92 Hemostasis Study Arterioscler. Thromb. Vasc. Biol., February 1, 2002; 22(2): 353 - 358. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yano, K. Articles by Tracy, R. P. Search for Related Content PubMed PubMed Citation Articles by Yano, K. Articles by Tracy, R. P. Related Collections Calcium cycling/excitation-contraction coupling Fibrinogen/fibrin Epidemiology