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(Circulation. 2007;115:996-1003.)
© 2007 American Heart Association, Inc.

Epidemiology

Diurnal, Seasonal, and Blood-Processing Patterns in Levels of Circulating Fibrinogen, Fibrin D-Dimer, C-Reactive Protein, Tissue Plasminogen Activator, and von Willebrand Factor in a 45-Year-Old Population

From the Division of Community Health Sciences (A.R.R., D.P.S.), St George’s, University of London, London; and the Division of Cardiovascular and Medical Sciences (A.R., G.D.O.L.), University of Glasgow, Royal Infirmary, Glasgow, UK.

Correspondence to Dr Alicja R. Rudnicka, Division of Community Health Sciences, St George’s, University of London Cranmer Terrace, London, SW17 0RE, United Kingdom. E-mail arudnick{at}sgul.ac.uk

Received May 17, 2006; accepted December 27, 2006.

	Abstract

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Background— Circulating levels of fibrinogen, fibrin D-dimer, C-reactive protein (CRP), tissue plasminogen activator antigen (t-PA) and von Willebrand factor are associated with incident coronary heart disease. We describe cross-sectional diurnal, seasonal, and blood-processing patterns for these variables, and assess whether they represent important sources of variability that should be taken into account in epidemiological studies or for additional risk prediction in individuals.

Methods and Results— A total of 9377 men and women aged 45 years were visited in their homes and blood-sampled for fibrinogen, D-dimer, CRP, t-PA, and von Willebrand factor. These variables were examined in relation to the time of blood sample collection, day of the year, and delay in processing. All variables exhibited statistically significant diurnal sinusoidality (P0.02). Our models predicted a peak rise for fibrinogen and von Willebrand factor at midday, with overall diurnal variations of 3% and 10%, respectively, after adjustment for standard cardiovascular risk factors. D-dimer exhibited a peak at 14:00 hours, CRP at 15:00 hours, and t-PA at 10:00 hours with diurnal variations of 10%, 34%, and 55%, respectively, after full adjustment. All variables except CRP showed seasonal heterogeneity. Greater delays in processing blood samples were associated with higher levels of t-PA in particular. The proportion of variation attributed to the diurnal, seasonal, and processing effects was 2% for fibrinogen and von Willebrand factor; 9% for D-dimer, 1% for CRP, and 16% for t-PA.

Conclusions— Temporal variations are important sources of heterogeneity that may bias the analysis of epidemiological studies and coronary heart disease risk prediction in individuals. Sample-processing delay is particularly important for t-PA.

Key Words: coagulation • fibrin • fibrinogen • plasminogen activators • von Willebrand factor • seasons

	Introduction

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Circulating levels of hemostatic and inflammatory variables have been associated with risk of coronary heart disease in meta-analyses of prospective studies including fibrinogen,¹ fibrin D-dimer,² C-reactive protein (CRP),³ von Willebrand factor (vWF),^4,5 and tissue plasminogen activator antigen (t-PA).⁵ Several studies have shown seasonal variation in fibrinogen, with the highest levels in the winter months,^6–14 although 1 study demonstrated a peak in early summer¹⁵ and 3 studies did not find a seasonal effect for fibrinogen.^16–18 Variable reports exist for seasonality of CRP,^6,7,11,19 while t-PA shows a winter peak^12,16 and there is no data for vWF or D-dimer. One postulated cause for these seasonal effects is an increase in respiratory infections that leads to a rise in levels of acute-phase reactant proteins such as fibrinogen and CRP^6,7 in the colder months, which produces a hyper-coagulable and inflammatory state that may be partly responsible for the rise in cardiovascular morbidity and mortality in the winter months, especially in the elderly.^6,16

Clinical Perspective p 1003

In some reports, however, seasonality of fibrinogen or CRP was not related to markers of infection.^11,20 Fibrinogen was also found to be negatively correlated with both personal and environmental temperature⁶; the elderly have impaired thermoregulation compared with younger people²¹ and may be more prone to seasonal metabolic changes. A study, based on fibrinogen measurements in 2325 subjects >55 years of age found that the seasonal difference increased with age and was independent of outdoor temperature.⁸ This is supported by other smaller studies.^7,16

As well as seasonal effects, variable reports exist of a diurnal pattern in fibrinogen^12,22,23 and D-dimer,^24–26 whereas t-PA shows a morning peak with levels that tend to decline during the day;^12,24,27,28 vWF has been reported to show no diurnal variation in 1 small study.²⁸ Diurnal variation may be an important source of heterogeneity or bias, and standardization for sampling time may be important in population-based studies, as well as in using these variables for additional coronary heart disease risk prediction in individuals.

Most studies of seasonal or diurnal fluctuations in these markers performed repeat measures on a relatively small number of subjects, typically <100 subjects. In the present study we describe one of the largest cross-sectional studies of seasonal and diurnal fluctuations in fibrinogen, fibrin D-dimer, CRP, t-PA, and vWF in >7000 men and women. We also examine the influence of delay in processing the samples after blood collection, the use of conventional needles or winged needles with plastic tubing on the levels of these variables, and hemolysis status as observed by laboratory workers after centrifugation of blood samples.

	Methods

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Study Design
All persons born in England, Scotland, and Wales during 1 week in March 1958 were recruited for the National Child Development Study and have been followed up periodically from birth into adulthood. All surviving cohort members still in contact with the study team and resident in Britain were invited to participate in a clinical examination by a trained research nurse who visited their home during 2002 to 2004 when cohort members were 44 to 45 years old. From a target sample of 12 069 persons, 9377 (78%) cohort members were visited in their home by a team of 122 specially trained nurses from the National Centre for Social Research, who conducted the annual Health Surveys of England and Scotland. Ethical approval for the medical examination of the British 1958 Birth Cohort was obtained from South East Multicenter Research and Ethics Committee.

Blood Collection and Measurement
Venipuncture was performed with seated subjects and nonfasting venous blood samples were drawn into Sarstedt polypropylene tubes that contained citrate anticoagulant. Samples were taken between 9:00 and 22:00 hours and transported to the laboratory at ambient temperature. The samples were centrifuged and the aliquots of plasma stored at –70°C. Fibrinogen was determined by the Clauss method²⁹ (MDA 180 coagulometer, Biomerieux, Basingstoke, UK). CRP was measured by high-sensitivity nephelometric analysis of latex particles coated with CRP monoclonal antibodies (BN ProSpec protein analyzer, Dade Behring, Marburg, Germany). t-PA and vWF were measured by ELISA assays that used a double-antibody sandwich (Biopool, Umea, Sweden, and DAKO, Copenhagen, Denmark, respectively). Fibrin D-dimer was measured on stored samples at the end of the field study period by ELISA assay (Hyphen, Paris, France) and standardized for interbatch variation. All analytes were monitored for internal quality control by Levey-Jennings plots during the assay period.

Statistical Analysis
Fibrinogen, D-dimer, CRP, t-PA, and vWF were log-transformed to normalize their distributions before any analyses were performed. Multiple linear regression was used to simultaneously assess the heterogeneity of each outcome with each of the following factors: hour of blood sample collection, month of examination, delay in processing blood sample (determined as number of days between the date the sample was taken and the date it arrived at the laboratory), use of standard versus winged needles for blood extraction, and gender (the latter adjustment was made because time of examination varied between males and females). From the multiple linear regression models, adjusted geometric means of the hemostatic/inflammatory markers are presented with 95% CI. Patterns by time of day and day of the year were further explored with the following sinusoidal model: equation

Y(t) is the level of factor of interest at time t, a is the overall mean (also termed rhythm-adjusted mean), and n is the number of intervals of time over which measurements are taken. For diurnal variations, t is the hour of day, and n would be 24. For seasonal variations, t is the day of the year and n becomes 365. Statistical significance of the sinusoidal parameters was determined by the F-test. If there is no sinusoidal seasonal (or diurnal) variation both b and c are zero, and the seasonal difference is zero. The seasonal amplitude is the square root of (b² +c²) and the seasonal variation is 2x amplitude.

ß_k are the associated effects with covariates X_k: delay in processing blood sample, use of standard versus winged needles for blood extraction, gender (all included as categorical variables); systolic blood pressure, total and high-density lipoprotein cholesterol (all included as continuous variables); quintiles of body mass index; current smoking status (current smoker, ex-smoker, or never smoker); self report of a diagnosis or treatment for diabetes and treatment for a heart problem or hypertension. Investigations of the seasonal patterns were always adjusted for hour of blood collection (as a categorical variable) and diurnal patterns were adjusted for month (as a categorical variable).

_i is the residual error from the regression model assumed to be normally independently and identically distributed with zero mean and variance .² Normal plots of the residuals showed some evidence of more outliers than expected from the normal distribution but were otherwise respectable (data not shown). All analyses were adjusted for assay batch. Statistical analyses were performed with STATA version 9.2 (STATA Corporation, College Station, Texas).

The authors had full access to take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

	Results

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Mean plasma levels of fibrinogen and D-dimer were higher in women, whereas t-PA and vWF were higher in men after adjustment for all factors listed in Table 1; there was no difference in levels of CRP between men and women (Table 1; see online-only Data Supplement for crude means). There was statistically significant heterogeneity by time of blood sample collection for fibrinogen, CRP, vWF, and t-PA (Table 1), and after further adjustment for established cardiovascular risk factors the sinusoidal parameters for these diurnal patterns were statistically significant in all instances (P<0.001). Fibrinogen rises to a peak at midday and gradually declines throughout the day (Figure); the diurnal amplitude from the sinusoidal model is 1.5%, and the overall diurnal variation is 3%. A similar pattern was observed for vWF with a predicted peak at 13:00 hours and total diurnal variation of 10% (Table 1, Figure). For CRP the predicted maximum is at 15:00 hours (Table 1, Figure) with 17% diurnal amplitude (total diurnal variation 34%). For t-PA the sinusoidal pattern is different, with higher levels in the early morning that gradually declined to a minimum at 19:00 hours and diurnal amplitude of 27% (total diurnal variation 54%). Although D-dimer did not initially exhibit diurnal heterogeneity (Table 1), the sinusoidal terms with adjustment for cardiovascular risk factors were statistically significant (P=0.02) with levels rising to a peak at 14:00 hours and declining throughout the day (total diurnal variation 10%).

View larger version (23K): [in this window] [in a new window]   Adjusted geometric means along with 95% CIs for fibrinogen, fibrin D-dimer, CRP, t-PA, and vWF by time of day and month. For diurnal variation, means are adjusted for month, delay in sample arrival at the laboratory, assay batch, gender, smoking status, blood pressure, total cholesterol, high-density lipoprotein cholesterol, body mass index, and self-reported diagnosis or treatment for heart problems, hypertension, or diabetes. Seasonal means are adjusted for time of day instead of month. The vertical scale is logarithmic in all instances.

All markers exhibited seasonal heterogeneity except CRP (Table 1). For fibrinogen the seasonal heterogeneity was of borderline statistical significance after full adjustment for cardiovascular risk factors (P=0.06). Although there was a tendency for higher values in the winter months compared with the summer months (3.0% seasonal difference), fibrinogen did not exhibit any statistically significant sinusoidality (or curvature) throughout the year (Figure). After adjustment for cardiovascular risk factors, CRP was on average higher in the winter months compared with summer months (Figure) with 9% seasonal sinusoidality, which was of borderline statistical significance (P=0.10). For D-dimer, t-PA, and vWF the seasonal heterogeneity remained after full adjustment. The sinusoidal terms were of borderline statistical significance for D-dimer, however (P=0.08), with predicted peak values between February and March and seasonal variation of 4%. For both t-PA and vWF, the sinusoidal terms were statistically significant (P<0.01), with 17% seasonal variation in t-PA and a predicted peak in November, and 6% seasonal variation for vWF with a peak in May (Figure).

In general, the diurnal and seasonal patterns were only marginally changed with the extra adjustment for cardiovascular risk factors, and men and women exhibited similar patterns.

The delay in processing the sample did not influence fibrinogen levels. A marginal effect was observed on D-dimer and CRP levels. t-PA levels increased by 25% if the sample reached the laboratory after 4 or more days compared with arriving within 24 hours, and for vWF the increase was 6%.

Venipuncture performed with a winged needle was 37% less likely to exhibit hemolysis (assessed subjectively as the sample arrived at the laboratory) compared with a conventional needle (risk ratio, 0.63; 95% CI, 0.42 to 0.94; P=0.025). Also, an increase in sample delay increased the risk of hemolysis: 2.3% for samples received within 1 day exhibited hemolysis; 3.7%, within 2 days; 4.7%, within 3 days; and 8.3% for samples delayed by 4 or more days.

The proportion of the variation (partial R² value) in each analyte explained by gender, time of day, season, sample delay, cardiovascular risk factors, and treatment for cardiovascular disease is summarized in Table 2. Adjustment for gender, time of day, month, and delay in sample processing explained 2.4% of variance in fibrinogen levels, 8.9% for D-dimer, 0.8% for CRP, 16.3% for t-PA, and 2.1% for vWF (Table 2). A considerable proportion of the variation in t-PA can be attributed to the diurnal component of variation, which to some extent is linked with the gender differences because there was a difference in the time of day that men and women were examined. A similar pattern of results is shown for men and women separately. For fibrinogen, CRP, and t-PA, a considerable proportion of the variation can be attributed to established cardiovascular risk factor and treatment for cardiovascular disease (Table 2).

Phase of menstrual cycle explained a small but statistically significant proportion of the variation in fibrinogen, D-dimer, and CRP levels (1% for fibrinogen and CRP, and 3% for D-dimer) in women but it did not confound the patterns reported in the tables and figure. Self-reported use of hormone replacement therapy explained 2% of the variation in CRP and 0.3% for t-PA but it did not affect levels of fibrinogen, D-dimer, or vWF. Hormone replacement therapy did not confound the patterns reported in Table 1 and the Figure.

	Discussion

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Gender Effects
The observed differences between men and women in levels of fibrinogen,¹ D-dimer,³⁰ t-PA,^5,30 and vWF,^3,4,30 and the lack of difference in CRP^3,30 are consistent with previous reports.

Diurnal Variations
The diurnal variation in fibrinogen in middle-aged adults agrees with previous studies on much smaller samples^22,23,31 and shows a peak in the early afternoon, with values that decrease throughout the rest of the day. Previous studies of D-dimer on a small number of subjects (n<15) did not find a diurnal variation in D-dimer,^24,25 although another small study did report a morning peak.²⁶ The present study is the first to report a diurnal pattern in CRP, which was not observed in a previous study of only 13 healthy young volunteers.³² The diurnal variation in t-PA has been confirmed, with a morning high and levels that decrease during the day.^26–28,33 One study showed a peak t-PA between 16:00 and 20:00 hours with lowest levels at 8:00 hours,³⁴ but that study included only 10 subjects. The same study did not find a diurnal variation in vWF,³⁴ whereas we find vWF rises to a peak at midday and then gradually declines.

The present study is the largest study to examine diurnal patterns in fibrinogen, D-dimer, CRP, t-PA, and vWF. In relative terms the diurnal variations for t-PA and CRP are larger than the diurnal amplitudes for fibrinogen, D-dimer, or vWF. The existence of a diurnal pattern is not only a potentially important confounder in analyses of epidemiological studies, but is possibly also of biological interest because it appears that the diurnal pattern of fibrinogen and vWF may be absent in patients with cardiovascular disease.^35,36 If the type of individuals sampled varies in relation to the time of the day, this may be an important source of bias in epidemiological studies. For example, employed persons are more likely to be examined in the evening or very early in the morning, whereas individuals with poor health or not currently employed are more likely to be sampled during the day. In the current study, women were more likely to be examined during the typical working day than men, who were more likely to be examined in the evening. Although nonfasting samples were taken in the present study, the diurnal patterns did not materially change with adjustment for time since food was last consumed.

Seasonal Variation
With regard to seasonal variation, the winter peak and summer low in fibrinogen is confirmed. Reported values for the seasonal amplitude for fibrinogen vary from 0.13 g/L in 100 subjects aged 65 to 74 years adjusted for age, sex, smoking, and assay drift⁷ to 1.26 g/L in a study of 24 subjects aged >75 years of age (crude difference not adjusted for assay drift).¹¹ The study most similar in design to the present study is the Rotterdam Study, which found a seasonal difference of 0.34 g/L in 2325 subjects aged 55 years and over⁸ and that adjustment for body mass index, cholesterol, and blood pressure did not materially alter this result. The maximum difference in mean fibrinogen levels in the present study is 0.4 g/L (Table 1) which, although heterogeneity was statistically significant a sinusoidal model as advocated by others,^7,8,11 was not statistically significant in our data. In general the seasonal pattern was the same with or without adjustment for established cardiovascular risk factors. It is possible that the seasonal pattern is a phenomenon of aging because it is not observed in young or early middle-aged healthy adults.^16,17,19 Van der Bom et al showed that the seasonal amplitude for fibrinogen was 0.29 g/L in those aged 55 to 75 years but increased to 0.43 g/L in those aged 75 years and older.⁸

The seasonal heterogeneity in D-dimer (Table 1) was also small, with only 4% seasonal variation. A previous study on small numbers of subjects did not report a seasonal variation in D-dimer.²⁰ Although some studies have reported a seasonal variation in CRP on smaller numbers of subjects, the magnitude of the effect was small in relation to the amplitude of change observed with acute infection and chronic inflammation (between 1.8 and 3.7 mg/L).^7,11,37 Evidence of seasonality in CRP in the present study was borderline, and this challenges the suggestion that raised levels of fibrinogen in the winter are part of a generalized, hepatic, acute-phase response to respiratory infections.⁷ Similarly, seasonal variation in fibrinogen has not been found to be related to other markers of infection, which include white cell count, interleukin-6, or soluble P-selectin.^11,20 The present study confirms that t-PA levels are higher in the colder months.^12,16 As with fibrinogen, the seasonality of t-PA may be age-related because it is not present in healthy young adults.¹⁶ We are unaware of any previous publication on the seasonality of vWF.

The biological relevance of seasonal variation is uncertain but may reflect exposure to seasonal infections or a physiological response to changes in daylight hours or indoor or outdoor temperature. It has been shown both cross-sectionally and longitudinally that relatively higher levels of physical activity are associated with lower levels of fibrinogen, fibrin D-dimer, CRP, vWF, and t-PA.³⁸ Seasonal variations in physical activity may contribute to the seasonal variations observed.

Blood Sample Processing
Although the effect of blood sample–processing delay was statistically significant for D-dimer, CRP, t-PA, and vWF (Table 1), this effect was minimal up to 3 days. The increases in t-PA and vWF most likely result from platelet granule release.³⁹ Use of a conventional needle versus a winged needle with plastic tubing did not influence levels of these variables, but it appeared to affect the hemolysis status of blood samples. Previous studies also reported no effect of the use of winged versus standard needles on the levels of fibrinogen, D-dimer, and clotting times.⁴⁰

The total variation attributed to time of blood collection, season, and sample-processing delay is 16% for t-PA, 9% for D-dimer, 2% for both fibrinogen and vWF, and 1% for CRP. A similar pattern emerges for men and women considered separately. Incorporation of these explanatory factors is probably only of practical benefit for t-PA, and possibly D-dimer, in the reduction of the random error and the resultant improvement of the precision of associations with other biological variables (and clinical outcomes). If variables are to be used for additional coronary heart disease risk prediction in individuals, which is controversial,^41,42 standardization of the time of blood collection (eg, 9:00 hours to 18:00 hours) and of sample processing delay (eg, <4 days) may be considered.

Although phase of menstrual cycle was related to fibrinogen, D-dimer, and CRP levels, and hormone replacement therapy use was related to CRP and t-PA, neither of these 2 factors confounded the patterns reported in Table 1 and the Figure. In agreement with previous work, a considerable proportion of the variation in fibrinogen,³⁰ CRP,³⁰ t-PA,^5,30 and to a lesser extent D-dimer^2,30 and vWF^4,30 can be attributed to variation in standard cardiovascular risk factors. These effects will be addressed in further reports on the present study cohort.

Conclusions
The present study has shown that significant diurnal variations exist for fibrinogen, D-dimer, CRP, t-PA, and vWF, and seasonal variations are present for t-PA and vWF. The amplitude of the diurnal variation for all analytes is greater than the seasonal variation. The diurnal variations may be important sources of bias in the analyses (and meta-analyses^1,3–5) of epidemiological studies or coronary heart disease risk prediction. Such variations may be partly physiological, and partly caused by work or health status (eg, it is possible that individuals who are employed are more likely to be examined in the evening or early in the morning, whereas individuals with poor health or currently unemployed would be sampled midday). Such systematic differences between individuals may lead to bias in the analysis of epidemiological studies if not taken into account. In addition, delay in processing blood samples may introduce bias into population-based studies and appears to be of particular importance for t-PA.

	Acknowledgments

 
We wish to thank the cohort members for their participation in the present study and the nurses for their performance of measurements in the field.

Sources of Funding

The medical examination in adulthood and related statistical analyses were funded by Medical Research Council grant G0000934, awarded under the Health of the Public initiative. The Medical Research Council played no role in study design, collection, analysis, or interpretation of data, in the writing of the report, or the submission of the manuscript for publication. Dr Rudnicka was funded by the Medical Research Council (grant no. G0000934).

Disclosures

None.

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	Footnotes

 
The online-only Data Supplement, consisting of a table, is available with this article at http://circ.ahajournals.org/cgi.content/full/CIRCULATIONAHA.106.635169/DC1.

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