© 1996 American Heart Association, Inc.
Articles |
Interindividual and Intraindividual Variability in Plasma Fibrinogen, TPA Antigen, PAI Activity, and CRP in Healthy, Young Volunteers and Patients With Angina Pectoris
the Gaubius Laboratory, TNO-PG, Leiden (M.P.M. de M., A.C.W. de B., B.C.H., P.M., A.C.H., C.K.), and the Departments of Internal Medicine II (M.P.M. de M.) and Epidemiology and Biostatistics (P.G.H.M.), Erasmus University, Rotterdam, the Netherlands.
Correspondence to M.P.M. de Maat, Gaubius Laboratory, TNO-PG, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail M.deMaat@pg.tno.nl.
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Abstract |
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We compared intraindividual and interindividual variability in the plasma levels of fibrinogen, tissue-type plasminogen activator (TPA) antigen, plasminogen activator inhibitor (PAI) activity, and C-reactive protein (CRP) in 20 healthy, young individuals and 26 patients with stable angina pectoris (AP) who were at higher risk for cardiovascular disease. For each of the four parameters, the contribution of the intraindividual variation to the total variance (13% and 9% for fibrinogen, 3% and 5% for TPA antigen, 4% and 20% for ln[PAI activity], and 14% and 9% for ln[CRP] for the healthy volunteers and AP patients, respectively) was smaller than the contribution from the interindividual variation. These results indicate that single sampling is sufficient to assess an individual level for TPA antigen and PAI activity, whereas duplicate sampling for fibrinogen and triplicate sampling for CRP are recommended. In an epidemiological study the sample sizes, based on the variances found in the transverse part of the study, needed to detect a 15% difference between the two groups (with
=.01 and a statistical power=.90) are 31 and 40 for fibrinogen, 568 and 146 for TPA antigen, 603 and 119 for PAI activity, and 1490 and 2263 for CRP in healthy volunteers and patients with AP, respectively. Additionally, we studied the contribution of genetic polymorphisms of the Bß-fibrinogen (Bcl I and G
A-455) and PAI activity (HindIII and CA-repeat) genes to intraindividual and interindividual variation. Fibrinogen genotypes were associated with plasma fibrinogen levels in the volunteers but not in the AP patients. No effects of fibrinogen or PAI polymorphisms on intraindividual variation were observed in either healthy individuals or AP patients. In this study intraindividual variation in plasma levels of the cardiovascular risk indicators fibrinogen, TPA antigen, PAI activity, and CRP was small when compared with the interindividual variation in healthy, young volunteers and patients with stable AP.
Key Words: fibrinogen • tissue-type plasminogen activator • plasminogen activator inhibitor • C-reactive protein • DNA polymorphism
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Introduction |
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Fibrinogen1 2 3 4 5 6 7 as well as TPA,5 8 9 10 PAI,11 and CRP5 are variables that have been identified as risk indicators for cardiovascular disease in various epidemiological studies. Interest is growing in the measurement procedures for these factors because accurate and specific knowledge of plasma fibrinogen, PAI activity, and CRP levels will increase their worth as risk indicators.
The plasma levels of fibrinogen, TPA antigen, PAI activity, and CRP are influenced by various lifestyle aspects. Fibrinogen levels can be raised by smoking, obesity, older age, and oral contraceptive use.12 13 However, a negative association has been found between moderate alcohol intake and plasma fibrinogen concentration.14 TPA antigen levels are positively associated with age, BMI, and systolic blood pressure,15 whereas PAI activity is raised by smoking,16 older age,17 18 pregnancy,19 regular alcohol intake,20 21 and dietary consumption of fish oil.22 Exercise23 and use of oral contraceptives or anabolic steroids24 can reduce PAI activity in plasma. Furthermore, plasma levels of PAI activity are subject to diurnal variation.25 CRP levels are higher in smokers,5 26 27 in those under physiological stress,28 and in the obese.5
The acute-phase reaction can increase plasma fibrinogen and PAI-1 levels 2-fold to 4-fold and CRP levels 100-fold. However, when using these factors as long-term risk indicators, we are interested in habitual levels and not short-time fluctuations induced by transient, acute-phase reactions. In most epidemiological studies, only one blood sample from each subject is typically taken and is then accepted as representative of the habitual level. Although blood samples are withdrawn when the participants are healthy, multiple sampling may be required for optimal risk assessment.
Several investigators have reported genetic polymorphisms of the fibrinogen and PAI-1 genes, and these genotypes appear to be associated with plasma fibrinogen and PAI levels.29 30 31 32 Humphries et al30 have also reported that individuals who carry the rare allele of the Bcl I polymorphism of the Bß-fibrinogen gene have a larger longitudinal variation in their fibrinogen levels.
In this study we investigated the intraindividual and interindividual variations in and the need for multiple samples of fibrinogen, TPA antigen, PAI activity, and CRP in healthy, young volunteers and patients with stable AP. We also documented the contribution of genetic polymorphisms of fibrinogen and PAI to habitual plasma levels and their longitudinal variation.
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Methods |
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Healthy Individuals
Twenty apparently healthy volunteers with a median age of 31 years (range, 24 to 58) were included in the longitudinal study. Of the 10 men and 10 women, 2 were smokers. The median BMI was 22.3 kg/m2 (range, 16.9 to 28.7). Blood samples were collected every 3 weeks for 6 months. At each visit the volunteers completed a questionnaire on those factors that influence fibrinogen, PAI activity, and CRP levels (ie, BMI, age, sex, smoking habits, diet, alcohol use, medication [use of contraceptives], illnesses [only the common flu was reported], and stage of the menstrual cycle).
For the transverse study, the first blood sample from the volunteers in the longitudinal study was used and supplemented with blood samples from 39 healthy, male volunteers from whom only 1 blood sample had been drawn. In the transverse study group (n=59) the median age was 38 years (range, 24-58) and the median BMI 25.1 kg/m2 (range, 16.9 to 31.5); 22 participants were smokers.
Patients With AP
Twenty-six consecutive patients who were seen at the outpatient cardiology department of the Medical Centre Alkmaar (n=18) or the University Hospital Rotterdam (n=8) and who had AP (New York Heart Association class 2-3/4) with evidence of coronary artery disease as shown by coronary angiography, documented myocardial infarction, or a positive exercise test formed the patient group. There were 24 men and 2 women with a median age of 66 years (range, 46 to 80) and a median BMI of 25.6 kg/m2 (range, 21.6 to 30.1). For the longitudinal study blood was collected five times at 4-week intervals between May 1992 and August 1993. For the transverse study results from the first visit were used. Informed consent was obtained from all participants, and the study was performed in accordance with the Declaration of Helsinki.
Blood Collection
Venous blood was collected between 8 AM and 10 AM into CTAD (Becton Dickinson) or sodium citrate (final concentration, 0.011 mol/L) and immediately placed in an ice-water bath. The blood was then centrifuged for 30 minutes at 2000g and 4°C, and the resulting plasma was collected and stored in aliquots at -70°C until assayed.33
Assays
Fibrinogen levels were determined according to the method of Von Clauss34 and expressed in grams per liter; the standard was pooled, citrated plasma for which the fibrinogen level had been determined gravimetrically.35 TPA antigen levels were determined with an EIA (Imulyse t-PA, Biopool AB). PAI activity levels were obtained from CTAD/plasma by using the method of Verheijen et al36 and expressed as international units per milliliter, with pooled plasma (7.6 IU/mL, calibrated against the NIBSC international standard) as the standard. CRP levels were measured with an EIA that used rabbit antibodies to CRP (Dako) as both the capture and the tagging antibody and expressed in milligrams per liter. CRP standard serum (Behringwerke) was used for calibration.
The within-day and between-day CVs were 1.7% and 6.3% for fibrinogen, 10% and 15% for TPA antigen, 6% and 12% for PAI activity, and 2.9% and 7.2% for CRP.
Detection of Polymorphisms
The Bcl I RFLP of the Bß-fibrinogen gene was assessed by Southern blot analysis of Bcl I–digested genomic DNA with a ß-fibrinogen cDNA probe (a gift from Dr S. Lord) as previously described.30 The GA-455 RFLP of the Bß-fibrinogen gene was determined by amplification of the polymorphic region by the polymerase chain reaction, followed by digestion with the restriction enzyme Hae III as described by Thomas et al.29 The HindIII RFLP of the PAI-1 gene37 was assessed by Southern blot analysis of HindIII-digested DNA with a PAI-1 cDNA probe (a gift from Dr P. Bosma).
Determination of the genotype of the polymorphic (CA)n region in the PAI-1 gene was performed as described before.31 The most frequent allele was designated z, and the other alleles were designated by their base-pair differences from z. Thus, allele types z, z+2, z+4, z+8, and z+10 could be identified.
Statistical Evaluation
The geometric mean of all values for each parameter for each subject was used as the habitual level. Because of the positively skewed distribution of PAI activity and CRP values, we used (natural) logarithmically transformed data. The distribution of fibrinogen and TPA antigen levels did not significantly deviate from normal, and therefore these values were not transformed. Thus, the arithmetic mean is given for fibrinogen and TPA antigen, whereas the geometric mean is given for PAI activity and CRP.
In the longitudinal study an ANOVA was performed to separate the sources of variation. We applied an additive-variance component model in which
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i, deviation from the true mean of the ith person (i=1, 2, 3, . . . 20). The residual, 
ij, thus comprises the intraindividual variation and the intraserial analytic variation. The random terms i and ij were assumed to be independent and normally distributed with zero expectations. The measurement number was not added as a factor because its deviations from the true mean were assumed to be independent of sampling time.
The within-subject component of the variance can be reduced by using the mean of m repeated measurements and the formula
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=.01 and a statistical power (1-ß) of .90.
A similar ANOVA was performed to calculate the analytic portion of the intraindividual variation. The number of measurements needed to reduce the contribution from the analytic variation, ie, so that 
analytic/intraindividual 
.5, which has been accepted as an analytic goal,38 was calculated.
In the transverse study an ANCOVA with multiple linear regression was performed to evaluate the effect of Bß-fibrinogen and PAI genotypes on plasma levels of fibrinogen and PAI activity, respectively. Age, BMI, and sex were added as covariables, and means and SEMs were calculated. For those individuals who also participated in the longitudinal study, results from the first sampling were used in the transverse analysis. The SOLO statistical package was used for the analyses, and values of P<.05 were considered significant.
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Results |
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Healthy Volunteers
Figs 1 through 4
show the data for plasma fibrinogen, TPA antigen, PAI activity, and CRP in 20 healthy individuals (for whom multiple [as many as 9] samples were available) over a period of 6 months. Both intraindividual and interindividual variations are obvious for all variables. The estimated contributions of intraindividual and interindividual variations to the total variance are given in Tables 1 and 2. The contributions of intraindividual variation in each parameter to its total variation were 13% for fibrinogen, 3% for TPA antigen, 4% for ln(PAI activity), and 14% for ln(CRP), which were much smaller for each parameter than were the interindividual variations, which ranged between 86% and 97%.
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The information from the questionnaire did not contribute to the variation. When the analyses were performed for nonsmokers only (n=18), in men and women separately, after excluding periods of reported disease (common flu), or for nonusers of contraceptives, the contribution of intraindividual variation to the total variation did not change. Also, adjustments for BMI, age, or stage in the menstrual cycle did not affect the intraindividual variation.
The descriptive statistics of analyses for the transverse-study group are presented in Table 3. The plasma levels observed in this larger group (n=59) were comparable to the levels in the longitudinal group (n=20). The sample sizes that would be needed to detect differences of 10% and 15% between parameter levels in the two groups with single and duplicate sampling are presented in Table 4. The number of measurements that would be needed to reduce the contribution from analytic variation to the intraindividual variation to an acceptable size are given in Table 5.
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Individuals with the rare allele of the Bcl I and GA-455 polymorphisms of the ß-fibrinogen gene have higher plasma levels of fibrinogen (Table 6), but the intraindividual variation is comparable for all genotypes. The Bcl I and GA-455 fibrinogen polymorphisms were closely linked in this group. If one considers the habitual levels (mean of all longitudinal samplings) from the individuals in the longitudinal study, a slightly larger effect of the polymorphism on plasma fibrinogen levels is observed.
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The HindIII PAI polymorphism was not associated with either the levels of or the intraindividual variation in PAI activity. The CA-repeat polymorphism of the PAI gene showed many different genotypes, as expected for a multiple-allele polymorphism. No effect of any allele was detected for either the (habitual) level of or the intraindividual variation in PAI activity.
Patients With AP
Figs 5 through 8 show the data for plasma fibrinogen, TPA antigen, PAI activity, and CRP in 26 patients with stable AP (for whom 5 samples were available) over a period of 5 months. Both intraindividual and interindividual variations were obvious for all variables. The estimated contributions of intraindividual and interindividual variation to the total variance is given in Table 1
. The contributions of intraindividual variation in each parameter to its total variation were 9% for fibrinogen, 5% for TPA antigen, 20% for ln(PAI activity), and 9% for ln(CRP), which were much smaller for each parameter than were the interindividual variations, which ranged between 80% and 95%. These variations are comparable to those observed in the healthy volunteers.
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The sample sizes that would be needed to detect differences of 10% and 15% in parameter levels between the two groups with single and duplicate sampling are presented in Table 3. The number of measurements that would be needed to reduce the contribution of analytic variation to the intraindividual variation to an acceptable size are given in Table 4.
In Table 5 the influence of the Bcl I and GA-455 polymorphisms on plasma levels of fibrinogen are shown. In the patient group no relation could be found between the Bcl I and GA-455 fibrinogen polymorphisms. In the longitudinal-group analysis we found no association between intraindividual variation and fibrinogen genotypes by ANOVA.
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Discussion |
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Because elevated fibrinogen, TPA antigen, PAI activity, and CRP levels have gained interest as risk indicators for cardiovascular disease,1 2 3 4 5 6 7 8 it has become important to accurately know the habitual levels of these parameters. Until now, single measurements of these variables have been assumed to represent habitual levels. However, this assumption may be inaccurate, because plasma levels of these proteins are influenced by transient events, eg, the acute-phase reaction, which may cause temporary variations in plasma levels. In the present study we documented the intraindividual and interindividual variations in plasma levels and the number of samples required to obtain accurate estimates of habitual plasma levels of fibrinogen, TPA antigen, PAI activity, and CRP.
In a longitudinal study involving 9 blood samples from 20 healthy individuals and 5 blood samples from 26 patients with stable AP, we showed that for plasma fibrinogen levels, intraindividual variation contributed 13% and 9%, respectively, to the total variance. Multiple sampling of healthy volunteers is required to decrease the contribution of this intraindividual variation and to obtain an accurate estimate of the habitual level when compared with interindividual variation. With 2 random samplings for plasma fibrinogen, the contribution from intraindividual variation will be reduced to <10%, thereby yielding a correlation between interindividual variance and total variance of >.90, which we used as an arbitrary limit. In the patient group intraindividual variation is <10%, and therefore multiple sampling is not needed. In this study the period between samplings was 3 and 4 weeks for volunteers and patients, respectively. Peak values were not consistent for consecutive samplings, thus indicating that a sampling interval of 3 weeks is sufficient to negate peak effects.
To compare the interindividual variation in our group with that reported in other studies, we calculated the CV in the transverse portion of our study (59 healthy individuals, single sampling). We found that the CV was 0.15, which agrees well with the results of Marckmann et al39 and Thompson et al.40 We calculated that a sample size of either 68 healthy individuals or 91 patients would be needed to differentiate the two groups with a 10% difference. We choose the 10% value because that is the average difference between event and no-event groups in epidemiological studies.1 2 3 4 5 6 7
The variation in TPA antigen values can be ascribed to the interindividual variation of 97% in healthy volunteers and 95% in patients with AP. The intraindividual variations for this parameter are well below 10%, and therefore single sampling is sufficient. For TPA antigen, PAI activity, and CRP, the association between higher levels and cardiac disease risk is not so well established as for fibrinogen. In the ECAT Angina Pectoris Study,5 TPA activity was 19% higher in the event group, and Hamsten et al11 reported a 15% higher log(PAI) level in men who developed a myocardial infarction. Therefore, we calculated the necessary sample sizes for both 10% and 15% differences between groups.
When we studied the variation in logarithmically transformed PAI activity data, we observed that most of the variance could be ascribed to the interindividual variation in the healthy volunteers. Therefore, single sampling is also sufficient for PAI activity. In the patient group intraindividual variation is relatively larger than it is in the healthy volunteers, and triplicate sampling is thus needed to reduce the intraindividual variation to <10%.
Because the distribution of untransformed data was positively skewed, we analyzed logarithmically transformed data for PAI activity and CRP. These transformed data had a gaussian distribution. Clark and Fraser41 also studied the biologic variation in CRP, but although they reported comparable intraindividual and interindividual CVs, their results cannot be directly compared with ours because they did not use logarithmically transformed data.
For the logarithmically transformed CRP levels, we found contributions of 14% and 9% for intraindividual variation to the total variance in healthy volunteers and patients, respectively. The mean of two samplings will yield a reasonable estimate of the habitual level. However, Figs 4 and 8 contain a number of outliers, which we frequently observed. Therefore, for assessing habitual levels, we suggest that at least three measurements be taken to identify and exclude these outliers. For the same reasons as for fibrinogen, a 3-week period between sampling is sufficient.
In this study the contribution of analytic variance in fibrinogen measurements by the Von Clauss method was only a small part of the intraindividual variation. This finding is in accordance with that of Thompson et al40 but not of Rosenson et al.42 If duplicate sampling is performed, then the required sample size of the healthy volunteer group will decrease from 68 to 60 for fibrinogen and from 3236 to 2799 for CRP. In patients comparably small reductions in sample size can be obtained by multiple sampling (from 91 to 83 for fibrinogen and from 4911 to 4479 for CRP). This implies that when intraindividual variation is relatively low, multiple sampling will hardly influence the number of individuals who need to be enrolled in an epidemiological study. However, for reliable determination (10% criterion) of the habitual level for an individual, multiple sampling will be necessary.
The genetic polymorphisms of the Bß-fibrinogen gene were associated with plasma fibrinogen levels obtained by simple sampling in the transverse healthy-volunteer group. These findings are in agreement with those of other studies of healthy volunteers.30 31 The association between habitual levels (mean of as many as 9 samplings) of healthy individuals in the longitudinal study and genotypes of the Bß-fibrinogen RFLP were more significant and the differences between levels somewhat larger than expected. Since the association was already significant with single sampling, multiple sampling will not essentially improve it. In the patient group no association between fibrinogen polymorphisms and plasma levels was observed, but that may be due to small group size. No association was found between fibrinogen genotypes and intraindividual variation in either healthy volunteers or patients.
The genotypes of the HindIII and CA-repeat polymorphisms of PAI were not associated with either habitual plasma levels or intraindividual variation. The association was also not significant when habitual ln(PAI activity) levels of individuals in the longitudinal study were evaluated. It might be interesting to study the contributions of genetic elements to the variations in fibrinogen and PAI activity levels in a larger study, because there are reports of different reactions to acute-phase stimuli (eg, smoking) in individuals with different GA-455 genotypes of the Bß-fibrinogen RFLP.
In conclusion, we observed that the contribution of intraindividual variation to the total variance in a longitudinal study of fibrinogen, PAI activity, and CRP values was lower than that of interindividual variation. The relation between intraindividual and interindividual variation was comparable between healthy, young volunteers and those at greater risk for cardiac disease, namely, patients with stable AP. However, multiple sampling is advised for fibrinogen assays to decrease the contribution of intraindividual variation to <10% and for CRP EIAs to exclude outliers. A contribution of genetic polymorphisms of the Bß-fibrinogen gene to interindividual but not intraindividual variation was observed in healthy volunteers but not in patients with AP.
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Selected Abbreviations and Acronyms |
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Received February 28, 1995;
revision received April 25, 1996;
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References |
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1. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson 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]
2.
Kannell WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA. 1987;258:1183-1186.
3.
Yarnell JWG, Fehily AM, Milbunk J, Kubicki AJ, Eastham R, Hayes TM. Determinants of plasma lipoproteins and coagulation factors in men from Caerphilly, South Wales. J Epidemiol Community Health. 1983;37:137-140.
4. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501-505.[Abstract]
5. Haverkate F. Thrombosis and disabilities. In: Baya C, ed. Advances in Medical Biology. Amsterdam, Netherlands: IOS Press; 1994:81-103.
6. Stone MC, Thorpe JM. Plasma fibrinogen: a major coronary risk factor. J R Coll Gen Pract. 1985;35:565-569.[Medline] [Order article via Infotrieve]
7.
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.
8. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet. 1993;341:1165-1168.[Medline] [Order article via Infotrieve]
9.
Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J. 1991;12:157-161.
10. Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulin characterizes a risk group among young survivors of acute myocardial infarction. Thromb Haemost. 1987;57:137-139.[Medline] [Order article via Infotrieve]
11. Hamsten A, De Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3-9.[Medline] [Order article via Infotrieve]
12. Meade TW, Chakrabarti RR, Haines AP, North WRS, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J. 1979;1:153-156.
13.
Meade TW, North WRS. Population based distribution of haemostatic variables. Br Med Bull. 1977;33:283-288.
14. Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiology 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]
15. Siegert G, Bergmann S, Jaross W. Relationship of plasminogen activator inhibitor activity and tissue-type plasminogen activator concentration with age, sex, risk factors for coronary heart disease and life style. Fibrinolysis. 1994;4(suppl 2):34-36.
16. Haire WD, Goldsmith JC, Rasmussen J. Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors. Am J Hematol. 1988;31:36-40.
17. Hashimoto Y, Kobayashi A, Yamazaki N, Sugawara Y, Takada Y, Takada A. Relationship between age and plasma t-PA, PA-inhibitor and PA activity. Thromb Res. 1987;46:625-633.[Medline] [Order article via Infotrieve]
18. Aillaud MF, Pignol F, Alessi MC, Harle JR, Escande M, Mongin M, Juhan-Vague I. Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor VIII, protein C and in erythrocyte sedimentation rate with age. Thromb Haemost. 1986;55:330-332.[Medline] [Order article via Infotrieve]
19.
Kruithof EK, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, Welti H, Bachmann F. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69:460-466.
20. Kluft C, Veenstra J, Schaafsma G, Pikaar NA. Regular moderate wine consumption for five weeks increases plasma activity of the plasminogen activator inhibitor-1 (PAI-1) in healthy young volunteers. Fibrinolysis. 1990;4(suppl 2):69-70.
21. Mullertz A, Hølmer G, Grøndahl-Hansen J. Increased concentration of plasminogen activator inhibitor type-1 in plasma after intake of fish oil. Fibrinolysis. 1990;4(suppl 2):86-88.
22.
Emeis JJ, Houwelingen AC, van den Hoogen CM, Hornstra G. A moderate fish intake increases plasminogen activator inhibitor type-1 in human volunteers. Blood. 1989;74:233-237.
23. De Geus EJC, Kluft C, De Bart ACW, van Doornen LJP. The effects of exercise training on plasminogen activator inhibitor activity, body fat, blood pressure and the lipid profile. Med Sci Sports Exerc. 1992;24:1210-1219.[Medline] [Order article via Infotrieve]
24. Verheijen JH, Rijken DC, Chang GTG, Preston FE, Kluft C. Modulation of rapid plasminogen activator inhibitor in plasma by stanazolol. Thromb Haemost. 1984;51:396-397.[Medline] [Order article via Infotrieve]
25. Andreotti F, Davies GJ, Hackett D, Khan MI, De Bart ACW, Dooijewaard G, Maseri A, Kluft C. Circadian variation of fibrinolytic factors in normal human plasma. Fibrinolysis. 1988;2(suppl 2):90-92.
26. Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta. 1985;153:9-13.[Medline] [Order article via Infotrieve]
27.
Allen RA, Kluft C, Brommer EJP. Effect of chronic smoking on fibrinolysis. Arteriosclerosis. 1985;5:443-452.
28. Dugue B, Leppanen EA, Teppo AM, Fyhrquist F, Grasbeck R. Effects of psychological stress on plasma interleukins-1 beta and 6, C-reactive protein, tumour necrosis factor alpha, anti-diuretic hormone and serum cortisol. Scand J Clin Lab Invest. 1993;53:555-561.[Medline] [Order article via Infotrieve]
29. Thomas EA, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the ß fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost. 1991;65:487-490.[Medline] [Order article via Infotrieve]
30. Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet. 1987;1:1452-1455.[Medline] [Order article via Infotrieve]
31. Dawson SJ, Hamsten A, Wiman B, Henney AM, Humphries SE. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb. 1991;1:183-190.
32. Dawson SJ, Hamsten A, Wiman B, Henney AM, Humphries SE. Genetic variation at the plasminogen activator inhibitor-1 (PAI-1) locus. Fibrinolysis. 1990;4(suppl 2):51-53.
33. Kluft C, Verheijen JH. Blood collection and handling procedures. Fibrinolysis. 1990;4(suppl 2):155-161.
34. Von Clauss A. Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol. 1957;17:237-246.[Medline] [Order article via Infotrieve]
35. Astrup T, Brakman P, Nissen U. The estimation of fibrinogen: a revision. Scand J Clin Invest. 1965;17:57-65.[Medline] [Order article via Infotrieve]
36. Verheijen JH, Chang GTG, Kluft C. Evidence for the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemost. 1984;51:392-395.[Medline] [Order article via Infotrieve]
37.
Klinger K, Winqvist R, Riccio A, Andreasen PA, Sartorio R, Nielsen LS, Stuart N, Stanislovitis P, Watkins P, Douglas R, Grzeschik K-H, Alitalo K, Blase F, Danø K. Plasminogen activator inhibitor type-1 is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci U S A. 1987;84:8548-8552.
38. Fraser CG, Harris EK. Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci. 1989;27:409-437.[Medline] [Order article via Infotrieve]
39. Marckmann P, Sandstrom B, Jespersen J. The variability of and associations between measures of blood coagulation, fibrinolysis and blood lipids. Atherosclerosis. 1992;96:235-244.[Medline] [Order article via Infotrieve]
40. Thompson SG, Martin JC, Meade TW. Sources of variability in coagulation factor assays. Thromb Haemost. 1987;58:1073-1077.[Medline] [Order article via Infotrieve]
41. Clark GH, Fraser CG. Biological variation of acute phase protein. Ann Clin Biochem. 1993;30:373-376.
42.
Rosenson RS, Tangney CC, Hafner JM. Intraindividual variability of fibrinogen levels and cardiovascular risk profile. Arterioscler Thromb. 1994;14:1928-1932.
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 M. P.M. de Maat, E. M. Bladbjerg, J. von Bornemann Hjelmborg, L. Bathum, J. Jespersen, and K. Christensen Genetic Influence on Inflammation Variables in the Elderly Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2168 - 2173. [Abstract] [Full Text] [PDF]
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 R. Kleemann, L. Verschuren, B.-J. de Rooij, J. Lindeman, M. M. de Maat, A. J. Szalai, H. M. G. Princen, and T. Kooistra Evidence for anti-inflammatory activity of statins and PPAR{alpha} activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro Blood, June 1, 2004; 103(11): 4188 - 4194. [Abstract] [Full Text] [PDF]
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 C. J. Hukshorn, J. H. N. Lindeman, K. H. Toet, W. H. M. Saris, P. H. C. Eilers, M. S. Westerterp-Plantenga, and T. Kooistra Leptin and the Proinflammatory State Associated with Human Obesity J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1773 - 1778. [Abstract] [Full Text] [PDF]
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 G. Tsirpanlis, P. Bagos, D. Ioannou, A. Bleta, I. Marinou, A. Lagouranis, S. Chatzipanagiotou, and C. Nicolaou The variability and accurate assessment of microinflammation in haemodialysis patients Nephrol. Dial. Transplant., January 1, 2004; 19(1): 150 - 157. [Abstract] [Full Text] [PDF]
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 T. Hoekstra, J. M. Geleijnse, C. Kluft, E. J. Giltay, F. J. Kok, and E. G. Schouten 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly Stroke, December 1, 2003; 34(12): 2822 - 2828. [Abstract] [Full Text] [PDF]
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 W. Koenig, M. Sund, M. Frohlich, H. Lowel, W. L. Hutchinson, and M. B. Pepys Refinement of the Association of Serum C-reactive Protein Concentration and Coronary Heart Disease Risk by Correction for Within-Subject Variation over Time: The MONICA Augsburg Studies, 1984 and 1987 Am. J. Epidemiol., August 15, 2003; 158(4): 357 - 364. [Abstract] [Full Text] [PDF]
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 W. M. R. Broekmans, I. A. A. Klopping-Ketelaars, J. A. Weststrate, L. B. M. Tijburg, G. van Poppel, A. A. Vink, T. T.J.M Berendschot, M. L. Bots, W. A. M. Castenmiller, and A. F. M. Kardinaal Decreased Carotenoid Concentrations Due to Dietary Sucrose Polyesters Do Not Affect Possible Markers of Disease Risk in Humans J. Nutr., March 1, 2003; 133(3): 720 - 726. [Abstract] [Full Text] [PDF]
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R. Kleemann, P. P. Gervois, L. Verschuren, B. Staels, H. M. G. Princen, and T. Kooistra Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation Blood, January 15, 2003; 101(2): 545 - 551. [Abstract] [Full Text] [PDF]
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I. M. van der Meer, M. P.M. de Maat, M. L. Bots, M. M.B. Breteler, J. Meijer, A. J. Kiliaan, A. Hofman, and J. C.M. Witteman Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 838 - 842. [Abstract] [Full Text] [PDF]
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 I. S. Ockene, C. E. Matthews, N. Rifai, P. M. Ridker, G. Reed, and E. Stanek Variability and Classification Accuracy of Serial High-Sensitivity C-Reactive Protein Measurements in Healthy Adults Clin. Chem., March 1, 2001; 47(3): 444 - 450. [Abstract] [Full Text] [PDF]
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 J.C. Kaski, X. Garcia-Moll, W. K. Lagrand, C. A. Visser, H. W. M. Niessen, C. E. Hack, W. T. Hermens, F. W. A. Verheugt, G.-J. Wolbink, and C. E. Hack C-Reactive Protein as a Clinical Marker of Risk Response Circulation, August 29, 2000; 102 (9): e63 - e64. [Full Text] [PDF]
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E. S. Ford and W. H. Giles Serum C-Reactive Protein and Self-Reported Stroke : Findings From the Third National Health and Nutrition Examination Survey Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1052 - 1056. [Abstract] [Full Text] [PDF]
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W. K. Lagrand, C. A. Visser, W. T. Hermens, H. W. M. Niessen, F. W. A. Verheugt, G.-J. Wolbink, and C. E. Hack C-Reactive Protein as a Cardiovascular Risk Factor : More Than an Epiphenomenon? Circulation, July 6, 1999; 100(1): 96 - 102. [Abstract] [Full Text] [PDF]
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M. P. M. de Maat, J. J. P. Kastelein, J. W. Jukema, A. H. Zwinderman, H. Jansen, B. Groenemeier, A. V. G. Bruschke, and C. Kluft -455G/A Polymorphism of the ß-Fibrinogen Gene is Associated With the Progression of Coronary Atherosclerosis in Symptomatic Men : Proposed Role for an Acute-Phase Reaction Pattern of Fibrinogen Arterioscler Thromb Vasc Biol, February 1, 1998; 18(2): 265 - 271. [Abstract] [Full Text] [PDF]
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