© 1999 American Heart Association, Inc.
Thrombosis |
Subunit Antigen and Activity Levels of Blood Coagulation Factor XIII in Healthy Individuals
Relation to Sex, Age, Smoking, and Hypertension
From the Unit of Molecular Vascular Medicine, University of Leeds, Leeds, UK.
Correspondence to Robert A.S. Ariëns, BSc, PhD, Unit of Molecular Vascular Medicine, University of Leeds, G Floor, Martin Wing, Leeds General Infirmary, Leeds LS1 3EX, UK. E-mail r.a.s.ariens{at}leeds.ac.uk
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Abstract |
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Abstract—Factor (F) XIII covalently cross-links and stabilizes the fibrin-clot. Recent evidence suggests a role for FXIII in atherothrombotic diseases, but no information is available regarding the association of FXIII with common risk factors. The aim of this study was to investigate the relationship of FXIII with age, sex, smoking, and hypertension. Plasma levels of FXIII A-subunit antigen, FXIII B-subunit antigen, and FXIII cross-linking activity were measured in 612 healthy individuals (250 men and 362 women). FXIII A- and B-subunit levels were correlated significantly with age in both men (r=0.21, P=0.001, and r=0.17, P=0.008, respectively) and women (r=0.20, P<0.0005, and r=0.13, P=0.011, respectively). FXIII B-subunit levels and activity were correlated significantly with FXIII A-subunit levels (r=0.60, P<0.0005, and r=0.14, P<0.0005, respectively) and fibrinogen (r=0.26, P<0.0005, and r=0.14, P=0.001, respectively). Women had higher levels of FXIII A-subunit (111.8% versus 105.2%, P<0.01) and B-subunit (109.5% versus 103.8%, P<0.01) than did men. FXIII A-subunit was significantly increased in smokers (117.0% versus 104.6%, P<0.0005) and in subjects with hypertension (114.9% versus 107.8%, P<0.05). In a multiple regression model, FXIII A-subunit was significantly increased by female sex (+6.4%, P<0.007), smoking (+12.3%, P<0.0005), and increasing age (+3.7% per 10 years, P<0.0005). FXIII B-subunit was significantly related to female sex and fibrinogen, and FXIII activity was significantly related to fibrinogen levels. In conclusion, the FXIII A-subunit level increases significantly with female sex, age, and smoking, whereas FXIII B-subunit and FXIII activity are associated with FXIII A-subunit level and fibrinogen. Although evidence for a causal relationship between FXIII A-subunit and vascular disease is not available, these results might suggest a role for elevated FXIII A-subunit levels in the pathogenesis of vascular disease.
Key Words: factor XIII • sex • age • smoking • hypertension
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The transglutaminase blood coagulation factor XIII (FXIII) covalently cross-links and therefore stabilizes the fibrin clot, which initially is held together solely by electrostatic interactions.1 2 The mature proenzyme circulates as a tetramer consisting of 2 A-subunits containing the active site and 2 B-subunits serving as carriers of the A-subunits in plasma. In addition to introducing peptide bonds between aligned fibrin
- and
-chains, FXIII incorporates
2-antiplasmin,3 4 von
Willebrand factor,5 thrombospondin,6
and fibronectin7 8 into the fibrin network. Through these
cross-linking reactions, the mechanical, chemical, and proteolytic
vulnerability of the fibrin clot is decreased by FXIII. Because a
deficiency of FXIII leads to severe bleeding, the critical role of
FXIII in blood clotting has long been acknowledged. The involvement of
FXIII in thrombotic disease is instead starting to emerge only now. It
has been shown that FXIII levels were increased in
non–insulin-dependent diabetic patients with microangiopathy and
macroangiopathy9 and in patients with obliterative
atherosclerosis of the lower limbs.10
Increased cross-linking of fibrin -chains has been found in patients
with acute myocardial infarction.11 In addition, plasma
samples from men with myocardial infarction at a young age formed
fibrin gel structures that were more tight and rigid than did plasma
samples from normal subjects.12 Recently, we have shown
that a common genetic polymorphism in the FXIII A-subunit, coding
for a substitution of valine with leucine at residue 34, is protective
against myocardial infarction.13 These studies suggest
that FXIII may be a risk factor for the development of atherothrombotic
disorders. To date, there is no information available regarding the
relation of FXIII with other known risk factors of
cardiovascular disease, such as age and smoking. The
aim of the present study was to investigate the influence of sex,
age, smoking, and hypertension on FXIII activity and subunit antigen
levels in a population of healthy individuals. |
Methods |
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Subjects
Plasma samples were obtained from 612 healthy, white northern Europeans, 250 men and 362 women, aged between 22 and 93 years. The subjects were recruited from large employers in Leeds, randomly selected from the registers of Leeds Health care, and invited by letter to participate in the study. A clinical history was recorded for each subject, and all were apparently free from vascular disorders, thrombosis, and other diseases. Subjects were classified as smokers if they were current, regular smokers. All other individuals were classified as nonsmokers. The presence of hypertension was defined as a blood pressure of 160/95 mm Hg or greater as recorded before blood sample withdrawal, or as previously diagnosed and currently treated hypertension. Characteristics of the study population are depicted in Table 1
. All subjects gave
informed consent according to a protocol approved by the Research
Ethics Committee of the United Leeds Teaching Hospitals NHS
Trust.
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Blood Sampling and Processing
Venous blood was collected in 0.1 mol/L trisodium citrate, 9
parts blood to 1 part trisodium citrate. Within 1 hour after
collection, the samples were centrifuged at 2560g
for 20 minutes at room temperature to obtain platelet-poor plasma,
frozen in aliquots in LN2, and stored at -40°C
until analysis. Pooled normal plasma was obtained from 47
healthy donors (different from the subjects of the study population) at
the local blood transfusion center and was used as reference plasma
throughout the study.
Fibrinogen Assay
Fibrinogen levels were measured with a clotting assay according
to Clauss.14 The intra-assay CV was 2.0% (n=10) and the
interassay CV 3.5% (n=10).
FXIII Activity Assay
FXIII activity was determined with a microtiter assay using
fibrinogen and 5-(biotinamido)pentylamine as substrates, based on a
method described by Song et al.15 Nunc Immuno Maxisorp
microtiter plates (Nunc A/S) were coated with 100 µL fibrinogen at 40
µg/mL in 40 mmol/L Tris-HCl, 140 mmol/L NaCl, and 0.02%
(wt/vol) NaN3, pH 8.3 (TBS1), for 45 minutes at
room temperature. The microtiter plate was emptied and blocked with 150
µL of 0.5% (wt/vol) nonfat dried milk in TBS1 for 20 minutes at
37°C and washed twice with 200 µL of TBS1. Ten microliters of
citrated plasma samples, diluted 1/10 in TBS1, was added in 2
duplicates to the wells, and the cross-linking reaction was started by
addition of 90 µL of reaction mixture: 1.11 IU/mL -thrombin (Sigma
Chemical Co), 1.11 mmol/L 5-(biotinamido)pentylamine (Pierce
Chemical Co), 0.56 mmol/L DTT (Sigma), and 0.11 mol/L
CaCl2 in TBS1. After incubation at room
temperature, the reaction was stopped at 3 and 10 minutes by addition
of 200 µL of 0.2 mol/L EDTA. Wells were washed twice with 200 µL
TBS1 and incubated with 100 µL of 10 µg/mL streptavidin–alkaline
phosphatase (Sigma) in 0.5% (wt/vol) nonfat dried milk/TBS1 for 1 hour
at 37°C. After 2 washes with 200 µL of TBS1 containing 0.01%
(vol/vol) Triton X-100 and 2 washes with 200 µL of TBS1, color was
developed by incubation with 100 µL of 1 mg/mL
p-nitrophenyl phosphate (Sigma) in 1 mol/L
diethanolamine–0.5 mmol/L MgCl2, pH 9.8,
for 10 to 30 minutes at room temperature. The development reaction was
stopped by the addition of 100 µL of 4 mol/L NaOH to the wells.
Absorbance was measured at 405 nm, and at 550 nm as a reference, on a
Titertek absorbance reader (Flow Laboratories). FXIII activities were
determined from the change in absorbance after 3 and 10 minutes and
expressed as a percentage of pooled normal plasma. The intra-assay CV
was 3.9% (n=20) and the interassay CV 10.0% (n=10).
FXIII A- and B-Subunit Antigen Assays
FXIII A- and B-subunit antigen levels were determined by
sandwich-ELISA. Microtiter plates (Nunc Immuno Maxisorp) were coated
overnight at 4°C with 100 µL of polyclonal sheep anti-human FXIII
per well (Binding Site Ltd) at a concentration of 5 µg/mL in 50
mmol/L sodium carbonate, pH 9.6, followed by washing and overcoating
with 150 µL of 50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L
NaCl, and 1.0% BSA for 1 hour at room temperature. The polyclonal
sheep anti-human FXIII antibody binds both purified FXIII A-subunit and
purified FXIII B-subunit. After the plates were washed, 100 µL of
plasma samples, diluted 1/4000 for the A-subunit and 1/16000 for the
B-subunit assays in 50 mmol/L Tris-HCl, pH 7.5, 150 mmol/L
NaCl, and 0.1% BSA (TBS2), were loaded into the wells in duplicate and
incubated for 1 hour at room temperature. Plates were next washed and
incubated with 100 µL of polyclonal rabbit anti-human FXIII A- or
FXIII B-subunit (both from Diagnostica Stago) at a dilution
of 1/1000 in TBS2 for 1 hour at room temperature, followed by washing
and incubation with 100 µL of polyclonal alkaline
phosphatase–labeled goat anti-rabbit IgG (Sigma) at a dilution of
1/1000 in TBS2 for 1 hour at room temperature. Every washing step was
performed by 5 cycles of 150 µL per well of 50 mmol/L Tris-HCl,
pH 7.5, 150 mmol/L NaCl, and 0.1% Tween-20. After a last washing
step, color was developed by incubation for 10 minutes at room
temperature with 100 µL of 1 mg/mL p-nitrophenyl phosphate
(Sigma) in 1 mol/L diethanolamine, pH 9.8, containing 0.5 mmol/L
MgCl2. The reaction was stopped by the addition
of 100 µL of 4 mol/L NaOH, and absorbance was read at 405 nm, and at
550 nm as a reference, on a Titertek absorbance reader (Flow
Laboratories). A standard curve was obtained with pooled normal plasma,
diluted from 1/1000 to 1/16000 for the A-subunit and from 1/4000 to
1/64000 for the B-subunit, and sample levels were interpolated from
this standard curve and expressed as percentages. Testing a sample from
a patient with homozygous FXIII A-subunit deficiency showed that
there was no cross-reactivity with other proteins for the A-subunit
antigen assay. Incubation with purified A-subunit and/or purified
B-subunit showed that the A-subunit ELISA reacts with purified
A-subunit only and that the B-subunit ELISA reacts with purified
B-subunit only. Incubation with solutions of purified B-subunit with or
without purified A-subunit showed that the FXIII B-subunit ELISA
equally measures both the free form of the B-subunit as well as the
B-subunit in complex with the A-subunit. The intra-assay CVs (n=20)
were 5.4% for the A-subunit antigen assay and 6.2% for the B-subunit
antigen assay. The interassay CVs (n=12) were 9.3% for the A-subunit
antigen assay and 9.8% for the B-subunit antigen assay.
Statistical Analysis
Results were analyzed using the SPSS for
Windows software package (version 6.0, SPSS Inc). Levels of FXIII
activity, FXIII A-subunit antigen, and FXIII B-subunit antigen were not
normally distributed and were positively skewed toward higher values.
Logarithmic transformation resulted in a sufficient fit of the data to
the normal distribution (Kolmogorov-Smirnov test) to validate
parametric statistical analysis. Accordingly,
between-group differences were analyzed with Student's
t test for unpaired data by using logarithmically
transformed values and expressed as geometric means and 95% CIs.
Bivariate correlations between variables were analyzed with
Pearson's correlation coefficient, and trendlines were calculated with
linear regression analysis on logarithmically transformed data.
Multiple regression modelling was used to test
multivariate relationships of variables with
logarithmically transformed FXIII levels. Regression coefficients were
reverse-transformed to geometric values and expressed as percentage
changes to allow interpretation and assessment of effect. Significance
was taken as P<0.05.
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Results |
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Correlation of FXIII With Age
Plasma levels of FXIII A-subunit (log10FXIIIA=1.66x 10-3age+1.93, r=0.21, P<0.0005) and FXIII B-subunit antigen (log10FXIIIB=0.95x10-3age+1.97, r=0.16, P<0.0005) but not FXIII activity showed a significant correlation with age. When the regression coefficients were transformed to geometric values, a 10-year increase in age was associated with a 3.9% increase in A-subunit levels and a 2.2% increase in B-subunit levels. The correlation of FXIII A-subunit and FXIII B-subunit antigen levels with age was found in both male and female part of the population (the Figure
).
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FXIII B-subunit antigen and FXIII activity levels were correlated significantly with fibrinogen levels (6.8% per 1-g/L fibrinogen increase, r=0.26, P<0.0005, and 5.7% per 1-g/L fibrinogen increase, r=0.14, P=0.001, respectively). There was a strong correlation between FXIII A-subunit and FXIII B-subunit antigen levels (r=0.60, P<0.0005), and both FXIII A- and B-subunit antigen levels showed a relatively weak but significant correlation with FXIII activity (r=0.14, P<0.0005, and r=0.18, P<0.0005, respectively).
Association of FXIII With Sex, Smoking, and Hypertension
FXIII A-subunit antigen levels and FXIII B-subunit antigen levels
were higher in women than in men (Table 2). There were no significant differences
for FXIII activity levels between women and men. Smokers had markedly
increased FXIII A-subunit antigen levels when compared with nonsmokers,
and subjects with hypertension had significantly higher FXIII A-subunit
antigen than did subjects without hypertension. No significant
differences were found for the FXIII B-subunit antigen and FXIII
activity levels when comparing smokers with nonsmokers or subjects with
hypertension versus those without.
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Multiple Regression Analysis
Multiple regression models were constructed with FXIII A-subunit
antigen, FXIII B-subunit antigen, or FXIII activity as the dependent
variable and age, sex, smoking, hypertension, and fibrinogen as
independent predictor variables. In this model, smoking, age, and
female sex were significantly related to FXIII A-subunit antigen levels
(Table 3). The regression coefficient
between A-subunit levels and age in this model (3.7% increase per 10
years) was very similar to that found with bivariate analysis
(3.9%). Smoking had the most marked relationship with FXIII A-subunit
antigen levels, increasing them by 12.3%. The univariate
association of elevated FXIII A-subunit levels in subjects with
hypertension was not confirmed in this model.
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On a similar multivariate analysis, female sex and fibrinogen levels were significantly related to levels of FXIII B-subunit. The correlation of FXIII B-subunit antigen levels with age was no longer significant after adjustment for confounding effects in this model. FXIII activity levels were related significantly to fibrinogen levels only in the multivariate model. The regression coefficients between fibrinogen and B-subunit levels or activity levels (5.5% and 6.7% increase per 1-g/L fibrinogen) were similar to those found with bivariate analysis (6.8% and 5.7%, respectively).
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Discussion |
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We found that age, female sex, and smoking were significantly related to increased circulating levels of the A-subunit, which contains the activation peptide and the active site of FXIII. Individuals with hypertension also had higher FXIII A-subunit levels in univariate analysis, but this increase was not confirmed in a multiple regression model. It is known that fibrinogen levels increase with age and smoking,16 and increased fibrinogen levels are thought to be a risk factor for vascular disease.17 In the present study, we found that FXIII A-subunit levels also increase with age and smoking, which, together with previous studies that have reported an increase of FXIII in patients with atherosclerotic disorders,9 10 11 12 might suggest a role of the fibrin cross-linking enzyme FXIII in the pathogenesis of vascular disease. However, this cross-sectional study offers no evidence to support a causal relationship between FXIII levels and vascular disease. An elevation of FXIII measurements in subjects with a higher risk for vascular disease, such as smokers and the elderly, may therefore also be an epiphenomenon of systemic effects associated with the disease state.
One previous study has reported that FXIII is correlated significantly with age in healthy individuals who were enrolled as control group for a study of patients with diabetic angiopathy.9 The authors found that FXIII A-subunit, B-subunit (both measured with rocket immunoelectrophoresis), and FXIII activity (measured with a dansylcadaverine-into-casein incorporation assay) were all correlated significantly with age in their control group of 35 subjects. The regression lines between the measurements and age were much steeper than in our study. However, the number of subjects studied by Kloczko et al9 was too small to provide conclusive evidence regarding the regression lines and significance of the correlation between FXIII and age. Another study has reported on the relation of FXIII to smoking in pregnant women.18 van Wersch et al18 found that FXIII activity levels, measured with a commercially available photometric assay, were higher in women in the second half of pregnancy who were smoking than in those who were not. Also in that study, the number of subjects studied was rather small: 35 smoking, pregnant women were compared with 27 nonsmoking, pregnant women.
Both FXIII A- and B-subunit antigen levels were significantly higher in women than in men, even after adjusting for the confounding effects of smoking, hypertension, fibrinogen levels, and age. Because of the lower incidence of vascular disease in women, this finding appears contrary to the speculation that increased FXIII A-subunit levels may be a risk factor for vascular disease. However, levels of fibrinogen, FVII, and total cholesterol are also higher in women than in men, particularly after the menopause.16 19 20 The cause of these higher FXIII antigen levels in women is not clear, although it has been suggested that changes in female hormone metabolism are related to changes in other clotting factors. Further studies on the effect of menopausal status and estrogen replacement therapy on FXIII levels are needed to investigate whether or not FXIII levels are related to female hormone metabolism.
A correlation between FXIII B-subunit levels and age was found, but
this association was not confirmed by multivariate
regression analysis. It has been proposed that levels of
circulatory A-subunit control the total concentration of the
B-subunit,21 which mainly serves as a carrier protein of
the A-subunit in plasma. This idea is in agreement with the highly
significant correlation between the A-subunit and B-subunit levels we
found in the present study. It therefore appears that levels of the
FXIII B-subunit show a significant correlation with age through its
association with the A-subunit, which significantly increases with age
in both sexes. Besides being correlated with the A-subunit, FXIII
B-subunit levels were significantly associated with fibrinogen levels.
This result is in agreement with previous studies that have shown a
strong affinity between the FXIII B-subunit and
fibrinogen.22 One might expect that FXIII activity plasma
levels would increase significantly with age, smoking, and female sex,
in a manner similar to the A-subunit, which contains the active site of
the enzyme. However, we found that FXIII activity was associated
significantly with fibrinogen levels only. We have previously shown
that FXIII activity levels were markedly affected by a polymorphism
in the FXIII A-subunit with an allele frequency of 
25% that
codes for a substitution of valine with leucine only 3 amino acids away
from the thrombin activation site.23 It appears that FXIII
activity, as measured with a pentylamine-into-fibrin incorporation
assay, is particularly sensitive to the thrombin activation step and
hence, to the common polymorphism FXIII Val34Leu. Owing to this
sensitivity of the FXIII activity assay to the Val34Leu
polymorphism, a high variability of FXIII activity levels is
present in the normal population.24 This variability
in activity may lead to the relatively weak correlation between FXIII
activity levels and FXIII A-subunit antigen levels as found in the
present study and may explain why, in contrast to FXIII A-subunit,
FXIII activity levels were not associated significantly with age,
smoking, and female sex.
In conclusion, FXIII A-subunit antigen levels are increased significantly by age, female sex, and smoking. FXIII B-subunit antigen levels and FXIII activity levels are correlated significantly with FXIII A-subunit and fibrinogen levels. Although there is no evidence for a causal relationship between increased FXIII A-subunit and vascular disease or thrombosis, the association of FXIII A-subunit with the cardiovascular risk factors of age and smoking might suggest that increased FXIII A-subunit levels are involved in the pathogenesis of vascular disease.
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Acknowledgments |
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The work described in this article was supported by a grant-in-aid from Shield Diagnostics, Dundee, Scotland. H.P. Kohler was funded by the Swiss Foundation for Medical-Biological Grants.
Received September 21, 1998; accepted January 6, 1999.
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References |
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