© 2000 American Heart Association, Inc.
Thrombosis |
Polymorphisms in the 5' Regulatory Region of the Tissue Factor Gene and the Risk of Myocardial Infarction and Venous Thromboembolism
The ECTIM and PATHROS Studies
From Laboratoire d’Hémostase and Service des Maladies Vasculaires, Hôpital Broussais—AP-HP, and Unité INSERM 428, Faculté de Pharmacie, Université René Descartes, Paris (E.A., J.E., J.-N.F., M.A.); Société bioMérieux, Marcy-l’Etoile (V.B.); and Unité INSERM 525, Paris (V.N., F.C.), France; and the MONICA Project: Belfast, Northern Ireland, UK (A.E.); Glasgow, Scotland, UK (C.M.); and Strasbourg (D.A.), Lille (G.L.), and Toulouse (J.-B.R.), France.
Correspondence to Dr Emmanuel Arnaud, Laboratoire d’Hémostase, Hôpital Broussais, 96 rue Didot, F-75674 Paris Cedex 14, France. E-mail emmanuel.arnaud{at}brs.ap-hop-paris.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in monocytes and endothelial cells and is present in atherosclerotic plaque to initiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced the 5' domain of the gene up to nucleotide 2732 and found 6 different polymorphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patients with myocardial infarction in a case-control study involving 2354 subjects showed no association between the polymorphisms and nonfatal coronary thrombosis. In another study involving 255 patients with venous thromboembolism and 1204 controls, allele D was less common in the cases (P=0.022). The odds ratio associated with the presence of at least 1 D allele was 0.72 (P=0.031). Comparison of subgroups of control subjects who were homozygous for the D or I allele demonstrated a lower plasma TF concentration in DD homozygotes. These results indicate that the TF gene promoter exists in 2 major forms differing at 4 sites. The 1208 D haplotype is not associated with coronary thrombosis but is associated with reduced plasma TF levels and a lower risk of venous thrombosis.
Key Words: tissue factor • gene polymorphisms • venous thromboembolism • myocardial infarction
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Tissue factor (TF) is a 47-kD membrane protein expressed in a wide variety of tissues, including the vascular adventitia, where it rapidly activates coagulation in response to vessel disruption.1 2 Binding of circulating activated factor VII to TF triggers the so-called TF pathway, with rapid generation of thrombin and multiple feedback reactions that amplify the hemostatic response.3 TF is not normally expressed by circulating blood cells or by vascular endothelial cells, but its expression can be induced in monocytes and endothelial cells by a variety of stimuli such as proinflammatory cytokines.
The human TF gene spans 12.4 kb and is organized into 6 exons separated
by 5 introns.4 The promoter domain has been fully
sequenced 798 bp upstream from the transcription start site. The
mechanism underlying transcriptional activation of TF in human
monocytes and endothelial cells has been extensively
studied.5 The proximal promoter domain encompasses
consensus binding sites for the transcription factors
activator protein-1, nuclear factor-
B, and
Egr-1/Sp1.6 7 In endothelial cells,
mononuclear phagocytes, and smooth muscle cells, TF gene transcription
can be induced by growth factors,2 8 mechanical
injury,9 10 heart ischemia and
reperfusion,11 and shear stress,12 which
define the TF gene as a "primary response" gene.
It is generally accepted that atherosclerotic plaque rupture exposes vascular TF to flowing blood, leading to coagulation activation, thrombosis, and subsequent artery occlusion. In human carotid plaque, TF mRNA is expressed in macrophage foam cells and smooth muscle cells.13 Interestingly, TF activity was recently shown to be expressed on shed membrane microparticles arising from apoptosis in atherosclerotic carotid plaque.14 Quantification of TF in coronary atherosclerotic plaque suggests that high levels of TF are highly thrombogenic.15 16 17 The role of circulating TF may also be important, as suggested by increased expression of TF in monocytes from patients with unstable angina18 and increased plasma TF levels in patients with acute coronary syndromes.19 The presence of active circulating TF in normal subjects is reflected by the generation of prothrombin fragment 1+2, which is released after factor X activation by the TF pathway.20 21 The potentially important role of circulating TF in thrombosis was recently supported by the observation that encrypted leukocyte TF can become rapidly available to generate thrombosis in an experimental model.22 Taken together, these observations argue for an important role of TF in both arterial and venous thrombosis.
Genetic polymorphisms associated with modifications of the circulating levels or activities of coagulation proteins or with variations in platelet receptor expression have been suggested to favor thrombosis.23 24 25 26 27 28 Sequence variations in the TF gene promoter could modulate TF expression in endothelial cells, circulating monocytes, and macrophages.
We extensively screened the TF gene promoter over 2732 nucleotides in 40 unrelated subjects and identified 6 novel polymorphisms. The frequencies of these 6 polymorphisms were analyzed in 2 case-control studies, called ECTIM (Etude Cas-Témoins de l’Infarctus du Myocarde) and PATHROS (Paris Thrombosis case-control Study), to determine whether the TF promoter genotype is linked to the risk of myocardial infarction (MI) and venous thromboembolism (VTE), respectively.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sequencing the TF Gene Promoter
The human promoter finder DNA walking kit (Clonetech, Ozyme) was used to sequence upstream nucleotide -798 bp, after amplifying fragments from the 5 human DNA libraries provided by the manufacturer, by using the gene-specific primer 5'-TCA GGC ATC GCC CGG TAC GAC CAG AGA T-3' and the adaptor primer 5'-GTA ATA CGA CTC ACT ATA GGG C-3' (provided with the kit) on a Perkin Elmer DNA thermal cycler 480 (Perkin Elmer Cetus). One µL of each primary polymerase chain reaction (PCR) product was diluted in 49 µL of sterile water before nested PCR was performed with a second gene-specific primer (5'-TGA CTG AGG AAG AGC AGC CTC ACA T-3') and a second adaptor primer (5'-ACT ATA GGG CAC GCG TGG T-3'). The PCR products obtained with each of the 5 libraries were analyzed on 1.5% agarose gels stained with ethidium bromide.
Nested-PCR products were cloned with the TA kit (Invitrogen). Clones containing the insert were then incubated in 2 mL of Luria-Bertani medium containing 50 mg/mL ampicillin at 37°C overnight. The culture medium (1.5 mL) was then centrifuged for 10 minutes at 1000g and 4°C, and the sediment was dissolved in GTE medium (50 mmol/L glucose; 25 mmol/L Tris HCl, pH 8; and 10 mmol/L EDTA) and added to 1% SDS and 0.2 mol/L NaOH. Bacterial DNA was insolubilized with 2.55 mol/L potassium acetate and 100% acetic acid, pH 4.8. After centrifugation at 18 000g for 5 minutes at 4°C, the supernatant was mixed with 3 mL of RNase (Boehringer Mannheim) at 37°C for 60 minutes. Plasmid DNA containing the insert was then purified by means of a classic phenol-chloroform method.
Each plasmid DNA was directly sequenced with the universal M13 reverse
primer and M13 forward primer by using the ABI prism dye terminator
cycle sequencing ready-reaction kit (Perkin Elmer) under conditions
recommended by the manufacturer and was then loaded onto a 377 ABI
prism apparatus (Perkin Elmer). With the use of different
primers (listed in Table 1
) in different
steps, the promoter sequence was determined up to
nucleotide -2718.
|
Screening for Polymorphisms
The 5' regulatory region of the TF gene was screened by direct
sequencing by using the PE protocol described above on a 377 ABI
prism device. Forty alleles from 40 unrelated individuals (blood
donors) were first amplified as 9 different fragments, as described in
Table 1
. The PCR amplification mixture contained 10 pmol of each
primer, 200 µmol/L dNTP, 10 mmol/L Tris HCl (pH 8.8),
10 mmol/L KCl, 1.0 mmol/L MgCl2, 0.1%
Triton X-100, 0.2 mg/mL BSA, 0.25 U of Taq polymerase (Super
Taq, ATGC Biotechnologie), and 200 ng of DNA. The reaction was run in a
Techne PHC-3 thermal cycler (Techne, Ozyme) with a 5-minute
denaturation at 95°C followed by 35 cycles of a 1-minute denaturation
at 95°C, 1-minute annealing at a temperature given in Table 1, and 1-minute extension at 72°C. PCR fragments were then purified and
sequenced in both directions by using amplification primers.
Genotyping
DNA was prepared from white blood cells by using a standard
technique29 and was stored at 4°C until
analysis. The factor V Arg506Gln and prothrombin gene G20210A
mutations were identified as previously described.30
All of the subjects participating in the ECTIM and PATHROS studies were
genotyped by using allele-specific
oligonucleotides (ASOs).31 The PCR
product (15 µL) was denatured in 150 µL of 0.5 mol/L NaOH and
1.5 mol/L NaCl and blotted onto nylon membranes (ICN). ASOs for each
allele were labeled with 50 µCi of
[
-32]ATP by T4 kinase (Biolabs, Ozyme) at
37°C for 20 minutes. Membranes were incubated for 4 hours with 20
pmol of labeled probe at a melting temperature of -5°C, washed twice
at room temperature in 1x SSC for 5 minutes followed by 5 minutes in
0.5x SSC at melting temperature-3°C, and autoradiographed overnight
at -80°C with an intensifying screen. The ASOs are listed in
Table 1.
The TF concentration was measured with the Imubind tissue factor ELISA kit (American Diagnostica Inc) in a subsample of PATHROS controls homozygous for the D (n=28) and I (n=28) alleles and who were matched for age, sex, smoking status, and oral contraceptive use in women.
Study Populations
ECTIM is a study of patients with MI from regions covered by
World Health Organization MONICA (MONItoring trends and determinants in
CArdiovascular disease) registers and controls
representative of each geographic area. The following
resisters were used in the ECTIM study: Belfast (northern Ireland);
Glasgow (Scotland); and Lille, Strasbourg, and Toulouse (France). The
design of the study has been described in detail
elsewhere.32 In brief, men aged 25 to 64 and women aged 25
to 69 years were recruited between 1988 and 1990 for the original ECTIM
study and from 1997 to 1998 for its extension in Belfast and Glasgow.
Cases were recruited 3 to 9 months after the event and had to meet the
MONICA criteria for definite acute MI (category I). Controls were
randomly recruited from the same geographic areas as the cases (lists
of general practitioners in the United Kingdom and
electoral rolls in France), and stratification by age was used to
approximately match the age distribution of the control subjects with
that of the cases. The participants were white; the parents of the
cases and controls had to have been born in the same region; and their
4 grandparents had to have been born in Europe. All subjects gave their
informed consent, completed a questionnaire, and gave a venous blood
sample.
PATHROS was started in our center in November 1995 to identify genetic risk factors for VTE.30 Two hundred fifty-five patients <61 years old were included. All had had at least 1 episode of objectively diagnosed deep venous thrombosis (compression and ventilation lung ultrasonography or venography) and/or pulmonary embolism (perfusion and ventilation lung scan, conventional pulmonary angiography, or computed tomographic angiography).
The controls were 1214 healthy subjects matched for age and sex and recruited from a health center to which they had been referred for a routine checkup. On the basis of a medical questionnaire, subjects with a history of VTE, arterial disease (stroke, MI, angina, or peripheral vascular disease) or known malignancy were excluded. All subjects gave their informed consent, and the study was approved by the local ethics committee.
Statistical Analysis
Data were analyzed by using SAS statistical
software (SAS Institute Inc). The clinical characteristics of the cases
and controls were compared by using a 
2 test
with 1 df except for age, which was tested by ANOVA.
Hardy-Weinberg equilibrium was tested for by 2
with 1 df separately in cases and controls from the
different recruitment centers. Allele frequencies were deduced from
the genotype frequencies, and differences between the cases and
controls were identified by means of a 2 test
(1 df). In the ECTIM study, controls with coronary
heart disease were excluded.
The odds ratios (ORs) and 95% confidential intervals (95% CIs) associated with the -1208 ID and DD genotypes were calculated by using a logistic regression procedure (SAS PROC LOGIST), together with the OR associated with at least 1 copy of the D allele. The homogeneity of the OR associated with -1208 I/D was tested between men and women and across age by entering the corresponding interaction terms in the logistic regression equation. Differences in TF levels according to the -1208 I/D genotype were identified by ANOVA. Differences were considered significant when P<0.05
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Identification of 6 Novel Polymorphisms in the TF Gene Promoter -2718 to +14 Domain
On the basis of the published sequence of the TF promoter region,4 the distal region was sequenced between -798 and -2718 nucleotides upstream from the transcription start site (cap site) by using the DNA walking kit described in Methods. The sequence is depicted in Figure 1
. The
entire 5' regulatory region (-2718 to +14) of the TF gene was directly
sequenced on 80 alleles from 40 blood donors to identify
polymorphisms. Six polymorphisms were found at positions -1812
(C
T), -1442 (GC), -1322 (CT), -1208 (DI), -603 (AG),
and -21 (CT). The -1208 polymorphism was a deletion/insertion
(D/I) of 18 nucleotides (5'-none-AGCTAAACGAGATATGTA-3'). To
determine their frequencies and possible haplotypes, all of these
polymorphisms were first investigated in the ECTIM study (1191
cases and 1163 controls). The 4 polymorphisms at positions -1812,
-1322, -1208, and -603 were found to be completely concordant in the
2354 individuals, with 2 haplotypes of similar frequencies: -1812
C/-1322 C/-1208 D/-603 A and -1812 T/-1322 T/-1208 I/-603 G,
designated -1208 D and -1208 I, respectively.
|
The other 2 variants observed at positions -21 and -1442 were rare. Only 2 ECTIM controls were heterozygous for the -21 T allele, and 2 MI cases and 3 controls were heterozygous for the -1442 C allele. In the PATHROS study, 1 control was heterozygous for -21 T, and 3 VTE cases were heterozygous for -1442 C. Only the 2 frequent haplotypes were tested for their association with thrombosis.
TF Promoter Genotypes According to MI in the ECTIM Study
and VTE in the PATHROS Study
The characteristics of the patients and controls in the 2 study
populations are shown in Table 2. In
ECTIM, the mean age (±SD) of the cases and controls was 56.3±8.1
years, versus 57.3±8.0 (P=0.017) in the United Kingdom and
54.0±8.2 and 52.6±8.4 (P=0.014) in France. In the United
Kingdom, where both men and women were included, the cases and controls
were correctly matched for sex. As expected in the United Kingdom and
France, there were significant differences between the cases and
controls regarding the frequencies of smokers and subjects with a
family history of MI. The distribution of the genotypes and
allele frequencies are shown in Table 3. The frequencies of the
polymorphisms showed no significant deviation from Hardy-Weinberg
equilibrium, in any of the centers, among controls. The overall
genotype and allele frequencies were similar in cases and
control subjects, with an allele -1208 D frequency of
0.516 and 0.505 in cases and controls, respectively. There was no
heterogeneity according to the country of recruitment
nor any sex heterogeneity in the subgroup from the
United Kingdom.
|
|
Given the complete concordance of the 4 polymorphisms in ECTIM,
only 1 polymorphism, -1208 (DI), was screened in PATHROS. There
was no significant deviation from Hardy-Weinberg equilibrium. The cases
and controls did not differ significantly according to age, sex, or
smoking habit (Table 2). Oral contraceptive use was
significantly more frequent among the cases than the controls.
Spontaneous thrombosis and recurrent thrombosis occurred in 40.3% and
28.3% of cases, respectively. Pulmonary embolism had been
diagnosed in 31.6% of cases. The frequencies of the 2 most common
genetic risk factors for venous thrombosis, factor V Arg506Gln and
factor II G20210A, were within the expected range for a white
population. Factor V Arg506Gln was observed in 20.7% of cases and
3.5% of controls (P<0.001) and the prothrombin G20210A
mutation in 12.2% and 3.5% (P<0.001), respectively.
The frequency of the -1208 D allele was lower among VTE
cases than among controls (0.480 versus 0.536, P=0.022;
Table 3). No association with the occurrence of
pulmonary embolism, recurrence, or age at the first
thrombotic event was observed according to genotype. The OR
associated with the presence of at least 1 copy of the -1208
D allele was 0.72 (95% CI, 0.53 to 0.97;
P=0.031), suggesting a weak protective effect of this
allele on VTE (Table 3). After exclusion of subjects bearing
the factor V Arg506Gln or prothrombin gene G20210A mutation, the OR was
of similar magnitude but was no longer significant (0.75, with 95% CI
0.53 to 1.06; P=0.11).
Because levels of circulating TF might reflect intravascular TF gene
expression, we selected 28 subjects homozygous for the -1208
D haplotype and 28 subjects homozygous for the -1208
insertion among the PATHROS control subjects. The 2 groups were well
matched for age and sex. As shown in Table 4 and Figure 2, the control subjects homozygous for
allele D had a significantly lower circulating TF
concentration than did subjects homozygous for allele I
(mean of 165.0±66.9 and 124.2±61.5 pg/mL for -1208 II and
-1208 DD, respectively; P=0.021).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
TF plays a primary role in initiating blood coagulation, and the TF pathway may thus be involved in arterial and/or venous thrombosis. Genetic polymorphisms that increase TF gene expression by affecting the binding of transcription factors may lead to an increased risk of thrombosis. In this study, we screened for TF gene promoter polymorphisms in subjects from 2 large case-control studies involving patients with MI (ECTIM) and patients with VTE (PATHROS). Previous studies of the TF gene promoter have focused on the proximal region (up to nucleotide -798) encompassing cis-acting sequences required for constitutive and inducible TF gene transcription. To study the TF gene promoter more extensively, we determined its sequence up to nucleotide -2718 and screened the entire domain (+14 to -2718) of 80 alleles in 40 blood donors. This strategy detected 6 novel sequence variations, 4 of which were frequent and completely concordant (-1812 C/T, -1322 C/T, -1208 D/I, and -603 A/G), whereas the remaining 2 were rare (-1442 G/C and -21 C/T). Statistical analysis of the -1442 and -21 sequence variations could not be done because of their very low frequencies in the 2 study populations. The -21 polymorphism is close to the TATA box and may affect expression.
It is noteworthy that only 2 major haplotypes, -1208 D and -1208 I, resulted from the combination of 4 polymorphisms in the entire population of >2000 subjects. Complete concordance among polymorphisms within a gene is frequently observed and suggests the existence of ancestral haplotypes having survived to the present time through complex population-historical processes.33
In the ECTIM study population, we found similar haplotype frequencies
in the patients with MI and the control subjects, ruling out the
possibility that 1 of the haplotypes is predisposing individuals to
nonfatal coronary thrombosis. In PATHROS, the -1208 D
haplotype tended to be less frequent in cases than in control subjects,
with an OR of 0.72 associated with the presence of at least 1 copy
(P=0.031). However, the effect was no longer significant
after excluding the 73 patients carrying the factor V Arg506Gln and
factor II G20210A mutations. The weak or absent association between the
TF gene promoter polymorphisms and thrombosis in these 2
case-control studies might be due to the absence of a haplotype effect
on transcription factor binding. Indeed, none of the identified
polymorphisms is located in the proximal promoter region, which has
been shown to drive transcriptional activity.6 34 35
Potential transcription factor binding sites like Sp1, Egr-1,
activator protein-1, and nuclear factor-B, which are
active in the proximal promoter, were searched for by using the
transcription factor database program36 in the promoter
domain encompassing the polymorphisms. None appeared or was
disrupted by any of the 4 linked polymorphisms.
The lack or a weak effect of TF gene promoter polymorphisms on the risk of thrombosis (nonfatal MI and VTE) does not exclude the possibility that TF interacts with other thrombogenic factors. The baseline circulating TF level, assessed with an ELISA that measures soluble TF and possibly TF associated with microvesicle membranes,14 was significantly lower in subjects bearing two -1208 D alleles than in subjects bearing two -1208 I alleles, with mean values of 124.2±61.5 and 165.0±66.9 pg/mL, respectively (P=0.021). This argues for an effect of the polymorphisms on TF gene expression, but further experiments are required to support or reject this possibility. The lower TF concentration observed in -1208 D homozygotes is in keeping with the weak protective effect observed in patients with VTE.
Because these polymorphisms had little if any effect in a large series of patients with MI or VTE, the moderate increase in circulating TF levels associated with the -1208 I allele might be insufficient to favor thrombosis. Many genetic and circumstantial risk factors could interact in the onset of thrombosis. The polymorphism might play a role in patients with other genetic or acquired risk factors. Larger studies will be needed to check these interactions between TF gene polymorphisms and circumstantial risk factors.
|
Acknowledgments |
|---|
This work was supported by grants from Program Hospitalier de Recherche Clinique No. AO94031 "Evaluation clinique et biologique du risque thrombotique," Center Claude Bernard de Recherche sur les Maladies Vasculaires Périphériques and bioMérieux Laboratory (No. 95119 and 95116). Recruitment to the ECTIM study was supported by grants from Squibb Laboratory, the British Heart Foundation, INSERM, and the Lille Pasteur Institute (France). The authors acknowledge Dr Nigel Mackman for helpful discussion and careful review of the manuscript We thank Christiane Souriau for extracting DNA in the ECTIM study, Véronique Remones and Richard Casseron for their excellent technical assistance, and José Bon-Deguingand for her skillful secretarial assistance.
Received July 23, 1999; accepted August 31, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ruf W, Edgington TS. Structural biology of tissue factor, the initiator of thrombogenesis in vivo. FASEB J. 1994;8:385–390.[Abstract]
2. Camerer E, Kolsto A-B, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res. 1996;81:1–41.[Medline] [Order article via Infotrieve]
3. Mann GK, Kalafatis M. The coagulation explosion. Cerebrovasc Dis. 1995;5:93–97.
4. Mackman N, Morrissey JH, Fowler B, Edgington TS. Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade. Biochemistry. 1989;28:1755–1762.[Medline] [Order article via Infotrieve]
5. Mackman N. Regulation of the tissue factor gene. FASEB J. 1995;9:883–889.[Abstract]
6.
Mackman N, Fowler BJ, Edgington TS, Morrissey JH.
Functional analysis of the human tissue factor promoter and
induction by serum. Proc Natl Acad Sci U S A. 1990;87:2254–2258.
7.
Cui M-Z, Parry GN, Oeth P, Larson H, Smith M, Huang
R-P, Adamson ED, Mackman N. Transcriptional regulation of the tissue
factor gene in human epithelial cells is mediated by Sp1 and EGR-1.
J Biol Chem. 1996;271:2731–2739.
8.
Samad F, Pandey M, Loskutoff DJ. Tissue factor gene
expression in the adipose tissues of obese mice. Proc Natl Acad
Sci U S A. 1998;95:7591–7596.
9. Marmur JD, Rossikhina M, Guha A, Fyfe B, Friedrich V, Mendlowitz M, Nemerson Y, Taubman MB. Tissue factor is rapidly induced in arterial smooth muscle after balloon injury. J Clin Invest. 1993;91:2253–2259.
10.
Speidel CM, Eisenberg PR, Ruf W, Edgington TS,
Abendschein DR. Tissue factor mediates prolonged procoagulant activity
on the luminal surface of balloon-injured aortas in rabbits.
Circulation. 1995;92:3323–3330.
11. Golino P, Ragni M, Cirillo P, Avvedimento VE, Feliciello A, Esposito N, Scognamiglio A, Trimarco B, Iaccarino G, Condorelli M, Chiariello M, Ambrosio G. Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. Nat Med. 1996;2:35–40.[Medline] [Order article via Infotrieve]
12. Lin MC, Almus-Jacobs F, Chen HH, Parry GC, Mackman N, Shyy JY, Chien S. Shear stress induction of the tissue factor gene. J Clin Invest. 1997;99:737–744.[Medline] [Order article via Infotrieve]
13.
Wilcox JN, Smith KM, Schwartz SM, Gordon D.
Localization of tissue factor in the normal vessel wall and in the
atherosclerotic plaque. Proc Natl Acad Sci
U S A.. 1989;86:2839–2843.
14.
Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM,
Tedgui A. Shed membrane microparticles with procoagulant potential in
human atherosclerotic plaques: a role for apoptosis in plaque
thrombogenicity. Circulation. 1999;99:348–353.
15.
Annex BH, Denning SM, Channon KM, Sketch MHJ,
Stack RS, Morrissey JH, Peters KG. Differential expression of tissue
factor protein in directional atherectomy specimens from patients with
stable and unstable coronary syndromes. Circulation. 1995;91:619–622.
16.
Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD,
Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V,
Badimon JJ. Tissue factor modulates the thrombogenicity of human
atherosclerotic plaques. Circulation. 1997;95:594–599.
17.
Moreno PR, Bernardi VH, Lopez-Cuellar J, Murcia AM,
Palacios IF, Gold HK, Mehran R, Sharma SK, Nemerson Y, Fuster V, Fallon
JT. Macrophages, smooth muscle cells, and tissue factor in
unstable angina: implications for cell-mediated thrombogenicity in
acute coronary syndromes. Circulation. 1996;94:3090–3097.
18.
Jude B, Agraou B, McFadden EP, Susen S,
Bauters C, Lepelley P, Vanhaesbroucke C, Devos P, Cosson A, Asseman P.
Evidence for time-dependent activation of monocytes in the systemic
circulation in unstable angina but not in acute myocardial infarction
or in stable angina. Circulation. 1994;90:1662–1668.
19. Nishiyama K, Ogawa H, Yasue H, Soejima H, Misumi K, Takazoe K, Yoshimura M, Kugiyama K, Tsuji I, Kumeda K. Simultaneous elevation of the levels of circulating monocyte chemoattractant protein-1 and tissue factor in acute coronary syndromes. Jpn Circ J. 1998;62:710–712.[Medline] [Order article via Infotrieve]
20.
Bauer KA, Mannucci PM, Gringeri A, Tradati F, Barzegar
S, Kass BL, ten Cate H, Kestin AS, Brettler DB, Rosenberg RD. Factor
IXa-factor VIIIa-cell surface complex does not contribute to the basal
activation of the coagulation mechanism in vivo. Blood. 1992;79:2039–2047.
21.
Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ,
Rosenberg RD. Detection of factor X activation in humans.
Blood. 1989;74:2007–2015.
22.
Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M,
Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne
tissue factor: another view of thrombosis. Proc Natl Acad Sci
U S A.. 1999;96:2311–2315.
23.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A
common genetic variation in the 3'-untranslated region of the
prothrombin gene is associated with elevated plasma prothrombin levels
and an increase in venous thrombosis. Blood. 1996;88:3698–3703.
24.
Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma
PH. Genotypic variation in the promoter region of the protein C gene is
associated with plasma protein C levels and thrombotic risk.
Arterioscler Thromb Vasc Biol. 1995;15:214–218.
25.
Bernardi F, Faioni EM, Castoldi E, Lunghi B, Castaman
G, Sacchi E, Mannucci PM. A factor V genetic component differing from
factor V R506Q contributes to the activated protein C
resistance phenotype. Blood. 1997;90:1552–1557.
26.
Carlsson LE, Santoso S, Spitzer C, Kessler C,
Greinacher A. The 
2 gene coding sequence T807/A873 of the
platelet collagen receptor integrin 2ß1 might be a genetic
risk factor for the development of stroke in younger patients.
Blood. 1999;93:3583–3586.
27.
Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann
A. Association of the platelet glycoprotein Ia C807T
gene polymorphism with nonfatal myocardial infarction in younger
patients. Blood. 1999;93:2449–2453.
28.
Gonzalez-Conejero R, Lozano ML, Rivera J, Corral J,
Iniesta JA, Moraleda JM, Vicente V. Polymorphisms of platelet
membrane glycoprotein Ib associated with
arterial thrombotic disease. Blood. 1998;92:2771–2776.
29.
Miller SA, Dykes DD, Polesky HF. A simple salting out
procedure for extracting DNA from human nucleated cells. Nucleic
Acids Res. 1988;16:1215.
30. Alhenc-Gelas M, Arnaud E, Nicaud V, Aubry ML, Fiessinger JN, Aiach M, Emmerich J. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost. 1999;81:506–510.[Medline] [Order article via Infotrieve]
31.
Saiki RK, Walsh PS, Levenson CH, Erlich HA. Genetic
analysis of amplified DNA with immobilized
sequence-specific oligonucleotide probes. Proc
Natl Acad Sci U S A. 1989;86:6230–6234.
32.
Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng
DM, Nutt RF, Shafer JA, Gould RJ, Connolly TM. An antibody against the
exosite of the cloned thrombin receptor inhibits experimental
arterial thrombosis in the African green monkey.
Circulation. 1995;91:2961–2971.
33. Cambien F, Poirier O, Nicaud V, Herrmann SM, Mallet C, Ricard S, Behague I, Hallet V, Blanc H, Loukaci V, Thillet J, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L. Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet. 1999;65:183–191.[Medline] [Order article via Infotrieve]
34.
Oeth P, Parry GC, Mackman N. Regulation of the tissue
factor gene in human monocytic cells: role of AP-1, NF-B/Rel,
and Sp1 proteins in uninduced and lipopolysaccharide-induced
expression. Arterioscler Thromb Vasc Biol. 1997;17:365–374.
35. Mackman N. Regulation of the tissue factor gene. Thromb Haemost. 1997;78:747–754.[Medline] [Order article via Infotrieve]
36.
Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel
AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA,
Podkolodny NL, Kolchanov NA. Databases on transcriptional regulation:
TRANSFAC, TRRD and COMPEL. Nucleic Acids Res. 1998;26:362–367.
This article has been cited by other articles:
 |
|
 |
|
  P. V. Giannoudis, M. van Griensven, E. Tsiridis, and H. C. Pape The genetic predisposition to adverse outcome after trauma J Bone Joint Surg Br, October 1, 2007; 89-B(10): 1273 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. Smith, L. A. Hindorff, S. R. Heckbert, R. N. Lemaitre, K. D. Marciante, K. Rice, T. Lumley, J. C. Bis, K. L. Wiggins, F. R. Rosendaal, et al. Association of Genetic Variations With Nonfatal Venous Thrombosis in Postmenopausal Women JAMA, February 7, 2007; 297(5): 489 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Campo, M. Valgimigli, P. Ferraresi, P. Malagutti, M. Baroni, C. Arcozzi, D. Gemmati, G. Percoco, G. Parrinello, R. Ferrari, et al. Tissue Factor and Coagulation Factor VII Levels During Acute Myocardial Infarction: Association With Genotype and Adverse Events Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2800 - 2806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malarstig, T. Tenno, N. Johnston, B. Lagerqvist, T. Axelsson, A.-C. Syvanen, L. Wallentin, and A. Siegbahn Genetic Variations in the Tissue Factor Gene Are Associated With Clinical Outcome in Acute Coronary Syndrome and Expression Levels in Human Monocytes Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2667 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-M. Herrmann, H. Funke-Kaiser, K. Schmidt-Petersen, V. Nicaud, M. Gautier-Bertrand, A. Evans, F. Kee, D. Arveiler, C. Morrison, H.-D. Orzechowski, et al. Characterization of Polymorphic Structure of Cathepsin G Gene: Role in Cardiovascular and Cerebrovascular Diseases Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1538 - 1543. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||