© 2000 American Heart Association, Inc.
Cellular Biology |
Release of Active Tissue Factor by Human Arterial Smooth Muscle Cells
From the Cardiovascular Institute (A.D.S., M.R., J.T.F., E.A.F., M.B.T.), Division of Thrombosis Research (P.L.A.G., V.B., Y.N.), Division of Pulmonary Medicine (L.M.S.), Department of Medicine (A.D.S., B.S., M.R., P.L.A.G., V.B., J.T.F., E.A.F., L.M.S., Y.N., M.B.T.), and Department of Pathology (J.T.F.), Mount Sinai School of Medicine, New York, NY.
Correspondence to Mark B. Taubman, Mount Sinai School of Medicine, Box 1269, One Gustave L. Levy Place, New York, NY 10029. E-mail mark.taubman{at}mssm.edu
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Abstract |
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Abstract—Tissue factor (TF), the initiator of coagulation, is thought to function predominantly at the cell surface. Recent data have suggested that active TF is present extracellularly in atherosclerotic plaques, the arterial wall, and the blood. This study was conducted to determine whether smooth muscle cells (SMCs), a major source of arterial TF, could generate extracellular TF. Active TF accumulated in the medium of cultured human SMCs, representing
10% of that measured
in the underlying cells at 24 hours. Platelet-derived growth
factor, phorbol ester, and tumor necrosis factor-
caused 3-fold
increases in TF activity in the medium. Release of TF into the medium
was dependent on the presence of the TF transmembrane domain but not
the cytoplasmic domain. Antibodies to TF precipitated most of the
activity from the culture medium, whereas antibodies to the
ß1-integrin subunit precipitated 33% of the activity.
Treatment with detergent or
phosphatidylserine:phosphatidylcholine did not
increase activity, suggesting that all TF released by SMCs was in the
appropriate lipid milieu and not encrypted. Western blotting showed
that the medium contained full-length TF protein. Fluorescent
cytometry showed that extracellular TF was present largely in
particles 
200 nm, which had a density of 1.10 g/mL. We hypothesize
that active extracellular TF found in the injured arterial
wall and atherosclerotic plaques derives, in part, from SMC
microparticles. (Circ Res. 2000;87:126-132.)
Key Words: smooth muscle • tissue factor • thrombosis • microparticles
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue factor (TF) is the principal initiator of the clotting cascade and is considered to be a major regulator of hemostasis and thrombosis.1 2 Minimal TF activity is found in quiescent cultures of smooth muscle cells (SMCs), endothelial cells, fibroblasts, and macrophages. TF is induced by a variety of agonists, including growth factors and cytokines.2 3 4 In animal models of arterial injury, TF is rapidly induced in the medium and accumulates in the neointimal SMCS.5 6 7 8 TF is also abundant in macrophages and SMCs of atherosclerotic plaques.9 10 11 12 13 14
TF consists of a short cytoplasmic tail, single transmembrane domain, and large extracellular domain. The extracellular domain binds factors VII and VIIa, and the resulting complex acts as a catalyst for the conversion of factors IX and X to IXa and Xa, respectively, triggering coagulation.2 15 To be active, TF must reside in the appropriate phospholipid environment, such as that provided by plasma membranes containing phosphatidylserine or phosphatidylethanolamine. It has been thought that TF is exclusively cell-associated and that physiologically relevant TF is induced on the cell surface.
Recent data suggest that active TF may be present extracellularly. In atherosclerotic plaques, TF antigen is detected in the extracellular matrix and is most abundant in the acellular lipid-rich core.10 14 TF antigen is also present in the extracellular space surrounding intimal SMCs of injured vessels.14 We have recently found that the intimal TF activity accumulating after balloon injury of rat aortas can be washed off the surface under low shear conditions.16 TF antigen and activity also have been detected in circulating blood.17 18 19 20 Although it has been assumed that the blood TF is located on leukocytes, particularly monocytes, active TF has been identified in the cell-free plasma,19 where it seems to reside in small particles. The source and the mechanism by which extracellular TF is generated remain to be determined.
We now report that active TF is released into the medium of cultured
arterial SMCs. This activity exists largely in
microparticles (200 nm). We hypothesize that the extracellular TF
found in the injured arterial wall and atherosclerotic
plaques derives in part from these SMC-derived particles.
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Materials and Methods |
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Cell Culture
Human coronary arteries and aortic SMCs were prepared as previously described.21 Wild-type human melanoma cells and cells overexpressing TF were provided by Dr Michael Bromberg (Yale University, New Haven, Conn) and grown as described.22
Plasmid Construction
The coding region of human TF cDNA (GenBank accession No. J0293)
was ligated into the pEGFP-N3 vector (accession No. U57609). Construct
TF:TM- contained only the extracellular domain
of TF (bases 112 to 865). For TF:PI, the transmembrane and cytoplasmic
domains (bases 865 to 996) were substituted with a sequence encoding
the carboxy-terminal 37 amino acids of decay-accelerating factor, a
phosphatidylinositol-anchored protein.23
Transient Transfection Assays
Cells were transfected with 10 µg of TF constructs by
CaCl2 precipitation as
described.24
Determination of TF Activity
Confluent SMCs were washed twice and incubated with fresh
defined medium (DM).21 At various times, 160-µL aliquots
of the medium were assayed for TF, as described.21 Human
recombinant factor VIIa was a gift from Novo Nordisk A/S, (Gentoffe,
Denmark). Factor X was purified from human plasma.25
Cellular TF was measured after lysis in 15 mmol/L
octyl-ß-D-glycopyranoside (BOG), as
described.21
Sucrose Gradient Centrifugation
Medium was harvested from cells, clarified at 2000g
for 10 minutes, and spun at 265 000g for 1 hour onto a 1-mL
sucrose cushion (60% wt/wt). A 1-mL fraction directly overlying the
cushion (containing >95% of the total TF activity) was made 60% in
sucrose and overlayered with sucrose gradients. The gradients were
centrifuged for 80 hours at 265 000g. Fractions of
0.60 mL were collected and assayed for TF activity, density, and total
protein by Bradford assay.
Western Blot Analysis
Medium from monolayers of SMCs (100 mL) or melanoma cells (30
mL) was clarified at 2000g and spun at 265 000g
for 30 minutes. Then the pellet was washed once in 10 mmol/L HEPES
(0.14 mol/L NaCl, pH 7.5) and resuspended in 50 µL of gel-loading
buffer containing 10% (wt/vol) ß-mercaptoethanol. Western blotting
was performed as described.26
Flow Cytometry
Mean fluorescent intensity was determined at 488 nm
using an EPICS Profile II flow cytometer with Elite software (Coulter
Electronics). Background cell autofluorescence was assessed by
omitting the primary antibody. Particle size was determined by
comparison with carboxylate-modified fluorescent
microspheres (FluoSpheres, Molecular Probes).
Immunoprecipitation of TF Activity
The medium was concentrated on a 1-mL sucrose cushion, as
described above. Aliquots of 100 µL were incubated for 24 hours at
room temperature with antibodies coupled to protein A sepharose beads.
The mixture was centrifuged at 2000g, and the
supernatants were assayed for TF activity. The beads were washed in PBS
and incubated for 1 hour in 100 µL of 15 mmol/L BOG before
assay.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Active TF Is Present in the Medium of SMCs and Melanoma Cells
Aortic SMCs were washed and incubated with fresh DM.21 Minimal TF activity was detectable immediately after washing but subsequently accumulated in the medium (Figure 1A
). Similar results were obtained with
coronary artery SMCs (not shown). Phorbol 12-myristate
13-acetate (PMA), tumor necrosis factor-, and platelet-derived
growth factor (PDGF), activators of TF synthesis, caused
3-fold increases in TF activity in the medium (Figure 2). Interleukin-1 (IL-1) alone or
in combination with indomethacin, which potentiates the
mitogenic activity of IL-1 in SMCs,27 did
not increase TF activity in the medium or cell lysates (not shown). At
24 hours, TF activity in the medium was 10% of that measured in
lysates of the underlying cells whether incubated in DM or treated with
agonists. Agonist-mediated increases in TF activity in the medium seem
related to changes in TF synthesis rather than enhancement of TF
release from SMCs. High levels of TF accumulated in the medium of
melanoma cells overexpressing wild-type TF or TF lacking its
cytoplasmic domain22 (Figure 1B) and
represented 15% of cellular TF activity.
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Rat aortic SMCs and human melanoma cells were transiently transfected with full-length human TF cDNA, and TF activity was assayed in the medium at 24 hours (SMC, 1.5±0.21; melanoma, 0.8±0.15 fmol/mL±SD; n=3 experiments). Cells transfected with TF lacking the transmembrane domain (TF:TM-) displayed minimal TF activity in the medium (SMC, 0.2±0.03; melanoma, 0.1±0.04; P<0.001 compared with wild type). In contrast, cells transfected with TF containing an alternative transmembrane and cytoplasmic domain (TF:PI) had levels comparable to wild type (SMC, 0.8±0.3; melanoma, 0.6±0.08; n=3, P=not significant compared with wild type). Thus, insertion into the plasma membrane seems critical for release of active TF.
Extracellular TF Is Not Inhibited by Tissue Factor Pathway
Inhibitor or Encrypted
Tissue factor pathway inhibitor (TFPI) is a
circulating inhibitor of TF28 and has been
shown to attenuate TF activity in atherosclerotic
plaques.29 Antibodies to TFPI had no effect on the levels
of TF activity accumulating in DM (Figure 3A), suggesting that TF activity is not
reduced by the presence of TFPI secreted by the underlying SMCs. Less
TF activity was measured when cells were incubated in medium containing
10% FBS; after treatment with antibody to TFPI, levels were identical
to those measured in DM. Thus, FBS does contain TFPI, which attenuates
TF activity in the medium.
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TF is present on the surface of many cells in a largely inactive,
encrypted form.21 Release of the cells from the culture
dish or treatment with detergent deencrypts TF. To determine whether
there is encrypted TF in the medium, activity was measured in the
presence and absence of detergent. BOG did not increase TF activity in
the medium but, rather, decreased it by 50% (Figure 3B
). In
contrast, BOG caused an 10-fold increase in TF activity in intact
SMCs, consistent with deencryption. In the medium, TF may be
oriented only on the outside of microparticles. Detergent could cause a
rearrangement of TF molecules such that they would be dispersed
randomly on both sides of the microparticles, leading to a 50%
decrease in activity. Alternatively, BOG could directly affect the
measurement of TF activity. As shown in the inset, BOG in the
concentrations used for these experiments had no direct effect on TF
activity measured using a TF standard inserted randomly in 30%
phosphatidylserine and 70% phosphatidylcholine
vesicles.
The medium was also treated with 35 µmol/L (final concentration)
of 20% phosphatidylserine and 80%
phosphatidylcholine.30 This relipidation protocol did not
result in a significant increase in TF activity (Figure 3C),
indicating that all of the released TF was associated with appropriate
lipids.
Characterization of TF in the Culture Medium
Minimal TF activity (10%) was removed from the medium by
low-speed centrifugation (20 000g). In
contrast, virtually all of the activity (>95%) was precipitated at
100 000g. On Western blots (Figure 4), the size of the TF in the medium was
identical to the major band identified from human brain extracts (the
higher molecular weight band represents TF dimers). A slightly
smaller band was purified from the medium of melanoma cells expressing
the cytoplasmic domain mutant, commensurate with its smaller size. This
shows that TF in the medium is not derived from enzymatic cleavage of
the extracellular domain.
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Flow cytometry (Figure 5) showed that the
medium contained microparticles that migrated predominantly with a bead
size 200 nm, as indicated by the log of forward scatter. As shown in
the Table, 53% of these particles were positive for TF. Similarly,
59% of the underlying SMCs were positive for TF. TFPI was not
detected on the cells or microparticles. Although
v and ß1 were
expressed on the majority of SMCs, they were present on a much
smaller fraction of microparticles. In addition,
5 was not detected on microparticles, although
it was detectable on approximately one third of cells.
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When the medium was spun at 245 000g, virtually all of the
activity (>95%) was recovered in a 0.6-mL fraction overlying a 60%
sucrose bed. This fraction was overlayered with a stepwise sucrose
gradient and centrifuged for 80 hours at 245 000g.
All of the TF activity (Figure 6A) was
found at the top. TF-overexpressing melanoma cells yielded similar
results (not shown). As determined using a continuous 40% to 20%
sucrose gradient (Figure 6B), the TF activity migrated with a
density of 1.10 g/mL, consistent with its association with a
lipid-containing particle.
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To determine whether TF is associated with an LDL-like particle, the
medium was treated with antibodies to apolipoprotein B under conditions
shown previously to precipitate LDL31 ; this had no effect
on TF activity (Figure 7). Precipitating
antibodies to apolipoprotein A1, a major component of HDL also had no
effect. Antibodies to TF removed 90% of TF activity from the
medium. TF activity was not precipitated from the medium with
antibodies to v or 5.
However, 33% of TF activity was removed from the medium with
antibody to ß1. This activity was recovered
quantitatively from the immunoprecipitate. Similar results were
obtained from the medium of SMCs treated for 24 hours with PDGF.
Precipitating antibodies to annexin V, commonly found on
apoptotic vesicles, had no effect on the levels of TF activity.
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P<0.001 compared with
medium alone; and #P<0.005 compared with beads. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously reported that TF is present in SMCs in 3 distinct cellular pools.21 The appearance of surface TF activity was transient, peaking 4 to 6 hours after growth factor stimulation. The majority (
80%) of the TF was present in an
intracellular pool and encrypted on the cell surface. In the
present study, active TF was found to accumulate in the culture
medium, representing 10% of the activity measured from
total cell extracts at 24 hours. The TF activity in the medium may
represent a more stable source of SMC-derived procoagulant
activity than that found on the cell surface.
The centrifugation and fluorescent cytometric
studies suggest that the majority of TF activity is in a small
microparticle (200 nm) with a very low density consistent
with a high lipid content. It has recently been reported that
apolipoprotein B–containing lipoproteins of various densities can be
secreted by extrahepatic cells.32 TFPI has also been shown
to associate with LDL particles.33 34 However, TF could
not be precipitated from the culture medium by antibodies to the
apolipoprotein B moiety of LDL or the apolipoprotein A1 moiety of
HDL.
Another potential source of TF activity in the medium is apoptotic vesicles, in which procoagulant activity has been found.35 36 In addition, TF-containing microparticles, thought to be derived from apoptotic macrophages and lymphocytes, have recently been identified in atherosclerotic plaques.37 The SMCs used in these studies have very low levels of apoptosis (<1% after 24 hours of incubation in DM as determined by fluorescent cytometric analysis [A.D.S., M.R., M.B.T., unpublished observations, 2000]). In addition, TF activity in the medium could not be precipitated with antibodies to annexin V, a common component of apoptotic vesicles.38
In response to trypsin and calcium ionophore, TF-containing vesicles
bud off the surface of fibroblasts and WISH amnion
cells.39 40 TF has also been found in monocyte-derived
microparticles in response to endotoxin.41 Similarly,
vesicles containing TF may bud off the surface of SMCs as a normal
concomitant of cell activation. Such vesicles would also be expected to
have a high lipid content. Flow cytometry showed that approximately
half of the SMCs expressed surface TF. This is in keeping with our
previous finding that although virtually all SMCs stain for TF antigen,
expression of surface TF is transient.21 Approximately
half of the microparticles also had detectable TF antigen. Although the
vast majority of SMCs expressed v- and
ß1-containing integrins, a much smaller
percentage of microparticles were positive for these antigens. These
data support the concept that although TF-containing particles may be
derived by budding from the cell surface, they seem to be enriched for
TF relative to surface integrins.
Only antibody to ß1 was capable of
precipitating TF activity from the medium. Of note was that
approximately one third of the microparticles expressed
ß1 by flow cytometry, and antibody to
ß1 precipitated approximately one third of the
TF activity. This suggests that there is no selection for or against
ß1 in TF-containing microparticles. In
contrast, although 20% of microparticles have detectable
v by flow cytometry, antibody to
v failed to precipitate TF activity,
suggesting that this integrin may specifically be excluded from
TF-containing microparticles or be present at concentrations too
low to be precipitated. All antibodies to integrins were used at
concentrations known to immunoprecipitate their respective antigens
from cell lysates.42
Active TF has been found in whole blood and plasma.17 18 19 20 Recent data suggest that circulating TF may serve as more than a marker for TF produced at sites of vascular injury and that it may play a primary role in the initiation or propagation of arterial thrombosis.19 The sources of extracellular and plasma TF remain to be determined, as do the structures in which they are contained. Some of the plasma TF may derive from vesicles in the arterial wall that are exposed by injury and dislodged into the circulation. We have recently measured TF activity on the surface of injured rat aorta in a flow chamber.16 A surprising finding was that all measurable TF activity on the luminal surface was released into the perfusate, suggesting that active intimal TF might be rapidly washed away by circulating blood. This clearance of active TF might be important in preventing occlusive thrombosis at sites of arterial injury while simultaneously rendering circulating blood more thrombogenic. The present study provides a potential source for the extracellular TF activity found in the arterial wall. We hypothesize that active intimal TF derives mainly from the release of TF-containing vesicles from the surface of activated SMCs. This provides a reservoir of active TF that persists even after intimal SMCs return to a quiescent state. A similar mechanism involving macrophages and SMCs may account for a substantial portion of the extracellular TF seen in atherosclerotic plaques.
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Acknowledgments |
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This research was supported by National Institutes of Health grants HL54469, HL29019, and HL03801. Lynn Schnapp was a recipient of a Grant-in-Aid from the American Heart Association, Heritage Affiliate.
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Footnotes |
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1 Both authors contributed equally to this study.
Received March 9, 2000; accepted May 23, 2000.
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O. Morel, F. Toti, B. Hugel, B. Bakouboula, L. Camoin-Jau, F. Dignat-George, and J.-M. Freyssinet Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2594 - 2604. [Abstract] [Full Text] [PDF]
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S. Potteaux, C. Combadiere, B. Esposito, C. Lecureuil, H. Ait-Oufella, R. Merval, P. Ardouin, A. Tedgui, and Z. Mallat Role of Bone Marrow-Derived CC-Chemokine Receptor 5 in the Development of Atherosclerosis of Low-Density Lipoprotein Receptor Knockout Mice Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1858 - 1863. [Abstract] [Full Text] [PDF]
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J.-J. Stampfuss, P. Censarek, J. W. Fischer, K. Schror, and A.-A. Weber Rapid Release of Active Tissue Factor From Human Arterial Smooth Muscle Cells Under Flow Conditions Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): e34 - e37. [Abstract] [Full Text] [PDF]
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 J. Suzuki, Z.-G. Jin, D. F. Meoli, T. Matoba, and B. C. Berk Cyclophilin A Is Secreted by a Vesicular Pathway in Vascular Smooth Muscle Cells Circ. Res., March 31, 2006; 98(6): 811 - 817. [Abstract] [Full Text] [PDF]
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 J. Steffel, T. F. Luscher, and F. C. Tanner Tissue Factor in Cardiovascular Diseases: Molecular Mechanisms and Clinical Implications Circulation, February 7, 2006; 113(5): 722 - 731. [Abstract] [Full Text] [PDF]
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 P. Cirillo, P. Golino, P. Calabro, G. Cali, M. Ragni, S. De Rosa, G. Cimmino, M. Pacileo, R. De Palma, L. Forte, et al. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation Cardiovasc Res, October 1, 2005; 68(1): 47 - 55. [Abstract] [Full Text] [PDF]
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J. Steffel, R. A. Latini, A. Akhmedov, D. Zimmermann, P. Zimmerling, T. F. Luscher, and F. C. Tanner Rapamycin, but Not FK-506, Increases Endothelial Tissue Factor Expression: Implications for Drug-Eluting Stent Design Circulation, September 27, 2005; 112(13): 2002 - 2011. [Abstract] [Full Text] [PDF]
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J. Steffel, A. Akhmedov, H. Greutert, T. F. Luscher, and F. C. Tanner Histamine Induces Tissue Factor Expression: Implications for Acute Coronary Syndromes Circulation, July 19, 2005; 112(3): 341 - 349. [Abstract] [Full Text] [PDF]
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C. M. Boulanger and A. Tedgui Dying for attention: Microparticles and angiogenesis Cardiovasc Res, July 1, 2005; 67(1): 1 - 3. [Full Text] [PDF]
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B. Szotowski, S. Antoniak, W. Poller, H.-P. Schultheiss, and U. Rauch Procoagulant Soluble Tissue Factor Is Released From Endothelial Cells in Response to Inflammatory Cytokines Circ. Res., June 24, 2005; 96(12): 1233 - 1239. [Abstract] [Full Text] [PDF]
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J. Steffel, M. Hermann, H. Greutert, S. Gay, T. F. Luscher, F. Ruschitzka, and F. C. Tanner Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation Circulation, April 5, 2005; 111(13): 1685 - 1689. [Abstract] [Full Text] [PDF]
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 M. C. Martinez, A. Tesse, F. Zobairi, and R. Andriantsitohaina Shed membrane microparticles from circulating and vascular cells in regulating vascular function Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1004 - H1009. [Abstract] [Full Text] [PDF]
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 S. Ravassa, A. Bennaghmouch, H. Kenis, T. Lindhout, T. Hackeng, J. Narula, L. Hofstra, and C. Reutelingsperger Annexin A5 Down-regulates Surface Expression of Tissue Factor: A NOVEL MECHANISM OF REGULATING THE MEMBRANE RECEPTOR REPERTOIR J. Biol. Chem., February 18, 2005; 280(7): 6028 - 6035. [Abstract] [Full Text] [PDF]
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 Y. Rong, D. E. Post, R. O. Pieper, D. L. Durden, E. G. Van Meir, and D. J. Brat PTEN and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation by Glioblastoma Cancer Res., February 15, 2005; 65(4): 1406 - 1413. [Abstract] [Full Text] [PDF]
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 S. M. Day, J. L. Reeve, B. Pedersen, D. M Farris, D. D. Myers, M. Im, T. W. Wakefield, N. Mackman, and W. P. Fay Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall Blood, January 1, 2005; 105(1): 192 - 198. [Abstract] [Full Text] [PDF]
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J. Chou, N. Mackman, G. Merrill-Skoloff, B. Pedersen, B. C. Furie, and B. Furie Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation Blood, November 15, 2004; 104(10): 3190 - 3197. [Abstract] [Full Text] [PDF]
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V. Llorente-Cortes, M. Otero-Vinas, S. Camino-Lopez, O. Llampayas, and L. Badimon Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells Circulation, July 27, 2004; 110(4): 452 - 459. [Abstract] [Full Text] [PDF]
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O. Aras, A. Shet, R. R. Bach, J. L. Hysjulien, A. Slungaard, R. P. Hebbel, G. Escolar, B. Jilma, and N. S. Key Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia Blood, June 15, 2004; 103(12): 4545 - 4553. [Abstract] [Full Text] [PDF]
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M. J. VanWijk, E. VanBavel, A. Sturk, and R. Nieuwland Microparticles in cardiovascular diseases Cardiovasc Res, August 1, 2003; 59(2): 277 - 287. [Abstract] [Full Text] [PDF]
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 S. Falati, Q. Liu, P. Gross, G. Merrill-Skoloff, J. Chou, E. Vandendries, A. Celi, K. Croce, B. C. Furie, and B. Furie Accumulation of Tissue Factor into Developing Thrombi In Vivo Is Dependent upon Microparticle P-Selectin Glycoprotein Ligand 1 and Platelet P-Selectin J. Exp. Med., June 2, 2003; 197(11): 1585 - 1598. [Abstract] [Full Text] [PDF]
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V. Balasubramanian, E. Grabowski, A. Bini, and Y. Nemerson Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: real-time fluorescence images of thrombus formation and propagation under defined flow conditions Blood, September 26, 2002; 100(8): 2787 - 2792. [Abstract] [Full Text] [PDF]
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Z. Mallat and A. Tedgui Current Perspective on the Role of Apoptosis in Atherothrombotic Disease Circ. Res., May 25, 2001; 88(10): 998 - 1003. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Smooth Muscle Cells : Another Source of Tissue Factor-Containing Microparticles in Atherothrombosis? Circ. Res., July 21, 2000; 87(2): 81 - 82. [Full Text] [PDF]
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O. Herkert, I. Diebold, R. P. Brandes, J. Hess, R. Busse, and A. Gorlach NADPH Oxidase Mediates Tissue Factor-Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells Circulation, April 30, 2002; 105(17): 2030 - 2036. [Abstract] [Full Text] [PDF]
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