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Mackman and Grover 2018- Review
Mackman and Grover 2018- Review
Tissue Factor
An Essential Mediator of Hemostasis and Trigger of Thrombosis
Steven P. Grover, Nigel Mackman
Abstract—Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa. The TF-FVIIa complex is the
primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular cells and
epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection
to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous
thrombosis. For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles
that drives thrombus formation after plaque rupture. In sepsis, inducible TF expression on monocytes leads to disseminated
intravascular coagulation. In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute
to venous thrombosis. TF also has nonhemostatic roles. For instance, TF-dependent activation of the coagulation cascade
generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of
protease-activated receptors. This review will focus on the roles of TF in protective hemostasis and pathological thrombosis.
Visual Overview—An online visual overview is available for this article. (Arterioscler Thromb Vasc Biol. 2018;38:
709-725. DOI: 10.1161/ATVBAHA.117.309846.)
Key Words: blood coagulation ◼ factor VII ◼ hemostasis ◼ thromboplastin ◼ thrombosis
lize the catalytic site of FVIIa on a plasma membrane (PM) 2 cytokine receptor family. In 1996, 3 groups reported that
to allow optimal interaction with its substrates FIX and FX. deletion of the TF gene in mice leads to universal death during
There are many excellent reviews on TF.1–6 The goal of this embryonic development or shortly after birth, indicating that
review is to summarize our current knowledge on the roles of TF is essential for survival.19–21
TF in hemostasis and thrombosis.
Coagulation Protease Cascade
Brief History of the Major Advances Hoffman and Monroe proposed a new cell-based model of
in TF Research coagulation with a TF-positive cell and activated platelets
The original extrinsic coagulation system consisted of 4 fac- that involves initiation, amplification, and propagation.22 We
tors: fibrinogen (FI), prothrombin (FII), thromboplastin (FIII, have adapted this model and have divided the phases of blood
TF), and Ca++ (FIV). This basic blood coagulation system is coagulation into TF-FVIIa-dependent initiation, inhibition of
present in jawless fish that diverged over 450 million years the TF-FVIIa complex by TF pathway inhibitor (TFPI) and
ago.7 Morawitz was the first to show that conversion of pro- amplification of thrombin generation.
thrombin to thrombin in plasma was induced by tissue throm- After vessel injury or tissue trauma the TF-FVIIa complex
boplastin.8 Indeed, TF was originally simply a laboratory is the spark that triggers blood coagulation by activating both
reagent derived from tissues, such as the placenta, that was FX and FIX. FVII bound to TF is rapidly activated by a vari-
added to plasma to measure the prothrombin time. Early stud- ety of coagulation proteases, although autoactivation by trace
ies showed that TF was a protein that required phospholipid amounts of FVIIa may be the primary pathway.23 Several stud-
for its activity.9,10 It was subsequently purified by 2 groups ies have shown that the TF-FVIIa complex can activate FIX in
in the 1970s.11,12 In 1987, the TF cDNA was cloned by 4 vitro.24–26 One study analyzed the activation of FIX and FX in
groups,13–16 which led to an explosion of research on TF. The an in vitro system and found that FIXa was the major substrate
Received on: December 13, 2017; final version accepted on: January 25, 2018.
From the Thrombosis and Hemostasis Program, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at
Chapel Hill.
Correspondence to Nigel Mackman, PhD, Division of Hematology and Oncology, Department of Medicine, 111 Mason Farm Rd, 2312C Medical
Biomolecular Research Bldg, CB No. 7126 University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail nmackman@med.unc.edu
© 2018 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.117.309846
709
710 Arterioscler Thromb Vasc Biol April 2018
important source of FVa that may contribute to the initiation TF expression by platelets, neutrophils, and eosinophils is
phase of blood coagulation.30 The final part of the initiation controversial (Table 1). We found that unstimulated platelets
phase is thrombin activation of the cofactors FV and FVIII contain TF pre-mRNA that is spliced to TF mRNA after acti-
and platelets via protease-activated receptors (PARs). The vation of the platelets, although this process is relatively slow
TF-FVIIa complex is then rapidly inhibited by TFPI in a FXa- (≈30 minutes).42 Other studies have reported variable levels
dependent manner. of TF mRNA and protein in unstimulated platelets but an
In the amplification phase the tenase complex (FVIIIa- increase of TF mRNA and protein in activated platelets.43–45,67
FIXa) is assembled on the surface of activated platelets and Other groups failed to detect TF expression in platelets.49–51
generates additional FXa. The prothrombinase complex is A recent study convincingly showed that a megakaryocyte
also assembled on the surface of activated platelets. Thrombin line expressed TF pre-mRNA, TF mRNA and TF protein and
activation of FXI also allows additional activation of FIX.31 released a subset of TF-positive platelets.46 Interestingly, the
The net result is the generation of large amounts of throm- megakaryocyte cell line contained higher levels of TF mRNA
bin. Thrombin cleaves fibrinogen to fibrin monomers that are versus TF pre-mRNA whereas platelets derived from the
cross-linked by the transglutaminase FXIIIa, which is acti- cells had more TF pre-mRNA. Similar results were observed
vated by thrombin. In addition, thrombin activates additional with megakaryocytes derived from CD34+ cells. It should be
platelets. noted that the megakaryocyte cell line expresses very low
levels of TF (90±15 pg/mL), which is <0.1% of the level of
Blood-Borne TF TF observed in a human pancreatic cell line.68 Several studies
Blood was not thought to contain functional TF because of its have found TF-positive platelets in patients with acute coro-
high procoagulant activity (PCA). However, in 1999, Giesen nary syndromes and diabetes mellitus.47,48 Because of the time
et al32 reported the presence of blood-borne TF that contributed needed to splice TF pre-mRNA and express TF is seems more
to thrombus formation when native blood was flowed over likely that platelet TF contributes to thrombosis rather than
collagen-coated slides. In contrast, Butenas et al33,34 could not hemostasis.69
detect active TF in whole blood. One difference between these TF has been reported to be expressed by neutro-
studies is flow, which may be required to reveal the functional phils, eosinophils, and T-cells in vitro and in vivo
activity of encrypted or intracellular TF. To date, the accumu- (Table 1).52,53,55,56,58 However, the Osterud group failed
lated evidence suggests that there are very low levels of TF in to detect TF expression in human neutrophils or eosino-
blood but this TF is either encrypted or inhibited and must be phils.54,57 We could not detect any functional TF in acti-
activated in some way to activate coagulation. Interestingly, vated human neutrophils (Alexander W and Mackman N,
Grover and Mackman Tissue Factor in Hemostasis and Thrombosis 711
Table 1. Cell Type-Specific Tissue Factor Expression In Vitro increase in TF PCA would enhance the activation of coagula-
and In Vivo tion at sites of vessel injury and cell damage.
Cell Type In Vitro In Vivo
Several mechanisms have been proposed for the post-
translational control of TF PCA.6 The most popular mecha-
Monocyte Yes 37 39,40 nism is that phosphatidylserine interacts with TF resulting in a
Endothelium Yes 41 40 conformational change and enhanced PCA on cell surfaces.88
Platelets Yes 42–46 47,48 In support of this mechanism, TF PCA is enhanced by the
addition of phosphatidylserine to reconstituted phospholipid
No 49–51 …
vesicles.86,89 Additionally, the pseudosubstrate TFPI-FXa
Neutrophils Yes 52 53 bound to the TF-FVIIa complex on perturbed cells exposing
No 54 … phosphatidylserine but not to the complex on unperturbed
cells, which suggested that activation of the cells leads to a
Eosinophils Yes 55,56 …
change in conformation of TF that enables engagement with
No 57 … substrate.88 Figure 1A shows a summary of the proposed phos-
T-cells Yes 58 58 phatidylserine-dependent model of TF de-encryption. Briefly,
the PM of eukaryotic cells has an asymmetrical distribution
of phospholipids with negatively-charged phospholipids, such
as phosphatidylserine and phosphatidylethanolamine, seques-
unpublished data, 2013). However, there is stronger evi- tered in the inner leaflet and neutrally charged phospholipids,
dence for TF expression by neutrophils in monkeys, rabbits, such as phosphatidylcholine and sphingomyelin, present in the
and mice compared with humans70–73 (Erlich J and Mackman outer leaflet. Cellular damage leads to loss of the PM asym-
N, unpublished data, 2000). In addition, we found that dele- metry and exposure of negatively-charged phospholipid, such
tion of TF in neutrophils reduces LPS-induced activation as phosphatidylserine, on the cell surface. In a recent study,
of coagulation in mice (Grover and Mackman, unpublished molecular dynamic simulations were used to generate a model
data, 2018). of membrane-bound TF-FVIIa complex using soluble TF,
TF expression by ECs is readily demonstrably in vitro but which lacks the transmembrane domain.90 It was found that
it is more difficult to demonstrate TF expression by ECs in “the direct interaction of the phosphatidylserine headgroups
vivo in part because of the very low levels of expression.74–76 with specific residues on soluble TF most likely also affect the
Typically, studies are performed with cultured ECs, such as conformation of these residues.” Further, they concluded that
human umbilical vein ECs. It is often assumed that these cells
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Figure 1. Mechanisms of tissue factor (TF) de-encryption. A, The distribution of phospholipids in the plasma membrane of resting cells
is asymmetrical and contains phosphatidylcholine (PC) and sphingomyelin (SM) primarily in the outer leaflet and phosphatidylinositol (PI),
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phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet. The presence of SM and PC in the outer leaflet maintains
TF in an encrypted state. Upon cell activation phospholipid scramblase mediates transfer of PS to the outer leaflet. Cellular activation also
leads to release of acid sphingomyelinase (ASM) that catalyzes the conversion of SM to ceramide (Cer). These 2 processes lead to de-
encryption of TF increasing its cofactor activity and enabling efficient activation of FX by the TF-FVIIa complex. B, Encrypted TF contains
2 free thiols at Cys186 and Cys209. It is proposed that protein disulfide isomerase (PDI) catalyzes the formation of an allosteric disulfide
bond (Cys186-Cys209) that de-encrypts TF and enhances its procoagulant activity.
vitro.97,99 However, there are several unresolved issues with bind to the TF-FVIIa complex, recombinant TFPI, active site-
the allosteric disulfide bond hypothesis. First, the disul- inhibited FVIIa (FVIIai), nematode anticoagulant protein C2
fide bond must be formed before binding of FVII/FVIIa (NAPc2), and Ixolaris. NAPc2 is an 85-amino acid protein
to TF because this region of TF is buried at the interface isolated from the hematophagous hookworm.103 It acts in a
between TF and FVII/FVIIa.100 Second, as noted by Bach similar manner to TFPI by first binding to FXa and then the
and Monroe100 “there is no direct quantitative evidence for NAPc2-FXa complex binds to TF-FVIIa. Ixolaris was isolated
free thiols in TF.” Finally, protein disulfide isomerase may from a tick salivary gland and contains 2 Kunitz domains.104
also indirectly affect TF PCA by promoting exposure of Unlike TFPI, it binds to zymogen FX and then the complex
phosphatidylserine.101 It should be noted that studies of de- inhibits the TF-FVIIa complex.
encryption of TF PCA have largely used cultured cells and These inhibitors have been used in preclinical and
it is difficult to know what mechanism(s) occur in vivo. clinical studies of acute coronary syndromes, sepsis, HIV
infection, and acute lung injury/acute respiratory distress
TF Inhibitors syndrome. The effect of NAPc2 was examined in patients
After the cloning of the TF cDNA in the late 1980s there was with non–ST-segment–elevation acute coronary syndromes
a lot of excitement about the prospect of using TF inhibitors and seems to be safe because it did not significantly affect
as new antithrombotics.102 This is summarized by a com- major or minor bleeding (3.7% versus 2.5%).105 However, no
ment by Dr Golino in 2002 “many experimental studies have further studies have been performed using NAPc2. A recent
demonstrated that inhibitors of TF:FVIIa PCA are powerful study showed that Ixolaris reduced levels of plasma D-dimer
inhibitors of in vivo thrombosis and that this approach usually in monkeys infected with simian immunodeficiency virus.106
results in less pronounced bleeding tendency, as compared Recombinant TFPI reduced lethality in a baboon model of
with other more classical antithrombotic interventions.”102 sepsis.107 However, there was no effect on all-cause mortal-
There are 5 main classes of human TF (hTF) inhibitors: anti- ity in patients with severe sepsis and there was an increased
TF antibodies that either compete with FVII/VIIa binding or risk of bleeding.108 Early administration of a monoclonal
Grover and Mackman Tissue Factor in Hemostasis and Thrombosis 713
TF-FVIIa-Dependent Signaling
The TF-FVIIa complex has both PCA and signaling activity.
The localization of TF on the cell surface seems to regulate
these functions with the signaling form of TF being located
in lipid rafts.112 The signaling form of the TF-FVIIa complex
also interacts with β1 integrins.113 A recent study identified the
binding motif in the FVIIa protease domain that mediates the
interaction with β1.114
The TF-FVIIa complex and downstream coagulation
proteases, such as thrombin, activate cells by cleavage of G Figure 2. Role of different coagulation proteins in hemostasis
protein-coupled PARs. This family consists of 4 members, and thrombosis. Based on the hemostatic defects of mice with
complete deficiencies in the different coagulation factors, we can
PAR1–4.115 PAR2 can be activated by the TF-FVIIa and divide the coagulation factors into 4 groups. Group 1 consists of
TF-FVIIa-FXa complexes as well as FXa, whereas PAR1 is factors in the extrinsic pathway (tissue factor [TF], factor [F] VII,
activated by thrombin and FXa.116 TF-FVIIa-dependent sig- FV, FX, FII). Group 2 consists of FIX and FVIII. Group 3 consists
of FXI. Group 4 consists of FXII. Pathological TF expression and
naling has been mainly studied in cancer.117 Studies have FXII can trigger thrombosis.
shown that PAR2 activation by TF-FVIIa induces proangio-
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genic and immune modulating cytokines, whereas PAR1 acti- model.131–135 Group 3 contains FXI. A complete deficiency of
vation by thrombin or the TF-FVIIa-FXa complex contributes this protein in mice is not lethal but these mice have a mild
to the metastatic tumor environment.117 hemostatic defect in a saphenous vein injury model.135,136
Group 4 contains FXII. In contrast to the hemostatic defects
Alternatively Spliced TF in mice with deficiencies in proteins in the other groups, mice
A soluble form of TF can be generated by alternative splicing with a complete deficiency in FXII have no hemostatic defects
of the TF gene where exon 5 is skipped.118,119 This alternatively (Figure 2).137 However, FXII-deficient mice are protected in
spliced TF lacks residues required for interaction with FX, the thrombosis models.138,139
allosteric disulfide in the C-module and the transmembrane Unlike mouse studies where gene inactivation leads to a
domain that dramatically reduce its PCA.120–122 However, complete deficiency of a given protein, humans with deficien-
alternatively spliced TF has PCA in the presence of phospho- cies in different coagulation proteins usually have residual
lipids.123 Moreover, alternatively spliced TF plays a role in amounts of functional protein. To date, there are no reports
cancer biology by promoting angiogenesis and proliferation of humans with a deficiency of TF. In contrast, rare inherited
of tumor cells via interacting with integrins containing β1 and bleeding disorders occur because of deficiencies in FII, FVII,
β3.124,125 FX, FXI, and FXIII,140 although the estimated prevalence of
these disorders is very low (between 1 and 2 per 106 individu-
als).140 Individuals with deficiencies in FII, FX, or FV most
Hemostasis
often bleed in the skin and mucus membranes and those with
Hemostatic Defects in Mice and Humans the lowest levels of the different coagulation factors have intra-
Deficient in Different Coagulation Proteins cranial bleeds.140 In terms of the coagulation cascade, the most
Factors of the coagulation cascade can be divided into 4 groups frequent congenital bleeding disorders in the general human
based on the phenotype of mice deficient in each of the factors population are caused by deficiencies in FVIII (hemophilia A)
(Figure 2). Group 1 contains factors of the extrinsic pathway and FIX (hemophilia B). The prevalence rates of these bleed-
(TF, FVII, FV, FX, and FII). Complete deficiencies of any of ing disorders is 1/5000 male births.140 Hemophilia A and B
these proteins in mice leads to universal death during embry- patients are prone to spontaneous bleeding in the joints and
onic development or shortly after birth.19–21,126–130 Group 2 con- skeletal muscle.141 FXI deficiency is rare (1 per 100 000) and
tains FVIII and FIX. Complete deficiencies of these proteins individuals with FXI deficiency rarely exhibit spontaneous
in mice is not lethal but is associated with impaired hemo- bleeding but have an elevated risk of bleeding after surgery
stasis in a tail transection model and a saphenous vein injury such as tooth extraction.142–144
714 Arterioscler Thromb Vasc Biol April 2018
TF as a Hemostatic Envelope Around Blood Table 2. Hemostatic Defects in Low Tissue Factor Mice
Vessels and Body Surfaces Phenotype References
The TF-FVII complex plays an essential role in hemostasis.
Spontaneous
TF is expressed by perivascular cells, such as adventitial fibro-
blasts and pericytes, and at body surfaces, such as keratino- Lung Fatal hemorrhage and 154,155
cytes in the skin.79,84,145 Drake et al79 proposed that TF formed a hemosiderin
hemostatic envelope around blood vessels and body surfaces. Brain Fatal hemorrhage 152,154
Initially, it was thought that the physical separation of TF from Uterus Fatal postpartum hemorrhage 156
blood meant that the TF-FVIIa complex was only formed after
Placenta Blood pools in the placenta 156
vascular injury. However, a recent study reported that perivas-
cular TF was prebound to FVII/FVIIa in the dermal vascu- Testis Hemorrhage and calcification 2,154
lature.146 Indeed, coagulation factors, such as FVII, leak into Heart Hemorrhage and fibrosis 157,158
the extravascular space at levels roughly proportional to their
Intestine Hemorrhage 152,154
size.147,148 The presence of a preformed TF-FVIIa complex
would allow rapid activation of clotting after vessel injury. In Induced
contrast to dermal vessels, there is a high proportion of free TF Intratracheal Increased hemorrhage 159
(non-FVII bound) present in the brain parenchyma and cere- lipopolysaccharide
bral vessels.149 This difference is likely because of the lower Influenza A infection Increased hemorrhage 160
permeability of the blood–brain barrier. The high levels of TF
Collagenase-induced Increased hemorrhage 73
in the brain may compensate for this the lower level of pre-
intracerebral hemorrhage
formed TF-FVIIa complex around the cerebral vasculature.
Tail vein transection Prolonged bleeding 152
Use of Transgenic Mice to Study Saphenous vein laser Prolonged bleeding 161
injury model
the Role of TF in Hemostasis
As noted above, TF−/− and FVII−/− mice die during embryonic Saphenous vein Prolonged bleeding Unpublished
development or shortly after birth, which means that they mechanical injury model
cannot be used to study the roles of the TF-FVIIa complex Skin punch Delayed wound healing 162
in hemostasis in different organs in adult mice.19–21,126 To cir-
cumvent the lethal phenotype of these mice, we and others
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have generated mice that express low levels of either TF or FXI−/− mice survive to wean (Grover and Mackman, unpub-
FVII.150,151 We rescued mTF−/− embryos by expressing hTF lished data, 2018).
from a hTF minigene.150 These mice (mTF−/−, hTF+ minigene) Mice with low levels of TF but lacking PAR4 survive to
are referred to as low TF mice and express ≈1% to 2% of wild- wean but exhibit reduced survival because of fatal bleeds in
type TF levels. Rosen et al151 generated transgenic mice with the lung and brain compared with low TF, PAR4+/+ controls.154
low levels of FVII by targeted replacement of the FVII gene Interestingly, the bleeding phenotype observed in low TF mice
with a FVII cDNA. Remarkably, the phenotypes of low TF in the laser injury model was increased after administration
and low FVII mice are similar supporting the notion for a cen- of the P2Y12 inhibitor clopidogrel at a dose that had a mini-
tral role for the TF-FVIIa complex in hemostasis.152,153 mal effect on bleeding time in wild-type mice.161 These data
Consistent with a role for TF in hemostasis, low TF mice suggest that TF-dependent thrombin generation leads to both
exhibit prolonged bleeding after various hemostatic chal- fibrin deposition and platelet activation that act co-operatively
lenges. For instance, low TF mice have increased bleed- to form and stabilize the hemostatic plug.
ing after tail transection (Table 2).152 In addition, low TF Two other transgenic mouse lines have been made that
mice had prolonged bleeding times in the saphenous vein express hTF in place of mouse TF. Chromosomal vector hTF
mechanical injury model and after repeated vessel injury in mice (mTF−/−, hTF+ chromosomal vector) express hTF from
the saphenous vein laser injury model161 (Table 2; unpub- a vector consisting of the majority of chromosome 1, whereas
lished data, 2018). Interestingly, the hemorrhage observed in hTF knockin mice were generated by gene targeting that
low TF mice in these models is not as severe as FIX−/− mice. replaced the mouse TF gene with the hTF gene.157,164 Mouse
Low TF mice also have excess bleeding after a full thickness FVIIa binds with high affinity to both mouse and hTF but the
skin punch.162 association of human FVIIa with mouse TF is significantly
We determined the effect of combining low levels of TF lower than with hTF.165 Indeed, we found a 6-fold reduction
with a complete deficiency of other procoagulant factors or in FXa generation when we used human FVIIa with mouse TF
PAR4, which is the main thrombin receptor on mouse plate- compared with hTF.166 These studies indicate that hTF can be
lets. Consistent with the importance of FIX in hemostasis, used to replace mouse TF but not vice versa, although we do
mice with a combination of low levels of TF and an absence not know about interactions of hTF with mouse β1 integrins.
of FIX do not survive to wean.163 Our recent studies indicate Finally, we generated mice with a floxed TF gene (TFfl/fl) that
that low TF, FIX−/− mice survive embryonic development but when crossed with mice expressing Cre recombinase under the
die shortly after birth (Grover and Mackman, unpublished control of a specific promoter leads to cell type-specific dele-
data, 2018). In contrast, we found that the majority of low TF, tion of the TF gene (Table 3).157
Grover and Mackman Tissue Factor in Hemostasis and Thrombosis 715
These mice express a very low level of TF (≈1%) in their Table 4. Cellular Sources of Tissue Factor That Drive
brains compared with a slightly higher level of TF (≈2%) in Thrombosis and Disseminated Intravascular Coagulation
the brains of low TF mice. A model of collagenase-induced Cellular Source
intracerebral hemorrhage was used to determine the role of Disease Model of Tissue Factor References
TF in brain hemostasis. Both low TF and TFfl/fl, nestin-cre
Atherosclerosis Macrophage foam cells and 191–193
mice exhibited increased intracerebral hemorrhage com- macrophage-derived microvesicles
pared with controls.172 However, more hemorrhage was
Sepsis/endotoxemia Monocytes 39,40,168
observed in TFfl/fl, nestin-cre compared with low TF mice
and this was associated with death of some of these mice. Surgery Peripheral blood mononuclear cells 194
These studies suggest that the high levels of TF in the brain Cancer Tumor cell-derived microvesicles 195–197
are required to limit intracerebral hemorrhage after trau- Antiphospholipid Monocytes 198–200
matic brain injury. syndrome
Liver injury Hepatocytes 169,170
Heart Sickle cell disease Monocytes 73,201
TF is expressed by both cardiac fibroblasts and cardiac myo-
Viral infection Peripheral blood mononuclear 202,203
cytes in the heart.184 Administration of an inhibitory anti-
cells/monocytes
human TF antibody to TF knockin mice expressing HTF
resulted in cardiac hemorrhage.164 We have observed occa-
sional spontaneous hemorrhages in the heart of low TF mice
and hearts of older low TF mice are fibrotic.158 Mice with Atherosclerosis
only ≈20% expression of hTF in the heart and those with In humans, rupture of advanced atherosclerotic lesions trig-
TF deleted in cardiac myocytes (TFfl/fl, Mlc2v; Table 3) also gers arterial thrombosis leading to myocardial infarction
exhibit cardiac fibrosis.157 Importantly, a similar pattern of and stroke. Atheroma contain high levels of TF that likely
cardiac fibrosis has been observed in low FVII, low FX, and plays a central role in atherothrombosis (Figure 3A).191,204–210
low FII expressing mice but not FIX deficient mice.133,153,188,189 Macrophage foam cells are the main source of TF in plaques
Spontaneous hemorrhage was also observed in the heart with apoptotic macrophages releasing TF-positive microves-
after genetic elimination of prothrombin in adult mice.186 icles into the necrotic core.192,193,211 In addition, patients with
These results indicate that the extrinsic pathway, but not the acute coronary syndromes have increased levels of TF expres-
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intrinsic pathway, mediates cardiac hemostasis.153,158,186,188,189 sion in monocytes, platelets, and leukocyte-platelet aggre-
gates that may also contribute to thrombosis after plaque
rupture.48,212 Many studies have reported increased levels of
Uterus, Placenta, and Testis
TF antigen in the plasma of cardiovascular disease patients.213
Female low TF mice exhibit excess bleeding after delivery and
However, we could not detect increased levels of microvesicle
14% of the mice die, which indicates that TF is required for
TF activity in these patients.214
uterine epithelium hemostasis postpartum (Table 2).156Low
In mice a 50% reduction of TFPI increased thrombo-
TF placentas contain blood pools in the labyrinth (Table 2).156
sis after photochemical disruption of carotid artery plaques
At present, it is unclear whether this is because of a hemo-
in ApoE−/− mice, presumably because of an increase in TF
static defect or a structural defect in the placental labyrinth.
PCA.215 Importantly, inhibition of TF with FVIIai markedly
Interestingly, FVIII−/− and FIX−/− mice have no hemostatic reduced thrombosis after ultrasonic disruption of carotid
defects in the uterus or placenta.132,133 plaques in ApoE−/− mice.216 Similarly, FVIIai or recombinant
We observed that male low TF mice lost fecundity at a TFPI reduced thrombosis after balloon-mediated disrup-
relatively young age and had shrunken and fibrotic testes. tion of carotid plaques in hypercholesterolemic rabbits.217,218
We also observed spontaneous hemorrhage in the testes of These studies indicate that TF within atherosclerotic plaques
low TF mice that may have been induced by trauma or dur- plays a major role in the formation of occlusive thrombi after
ing retraction of the testes into the abdomen. We think that rupture.219
hemorrhage leads to fibrosis of the testes and the loss of
fertility. Sepsis/Endotoxemia
Disseminated intravascular coagulation is a life-threatening
Thrombosis disorder caused by diffuse activation of coagulation that
Thrombosis is a pathological process that occludes blood flow can result in microvascular occlusion and organ dysfunc-
in vessels. TF is involved in the pathogenesis of both arte- tion.220 Disseminated intravascular coagulation is frequently
rial and venous thrombosis.190 Sources of TF that activate observed in patients with bacterial sepsis. TF has been shown
coagulation in different diseases include macrophages and to play a central role in disseminated intravascular coagulation
microvesicles in atherosclerotic plaques, activated cells within (Figure 3B).221 In a human model of LPS-induced endotoxemia
the vasculature and perivascular cells that are exposed because TF mRNA and TF protein expression were induced in blood
of an increase in vascular permeability. cells (presumably monocytes) and this was associated with
There is strong evidence that monocyte TF contributes to increased levels of thrombin-antithrombin complex, a marker
thrombosis in many diseases (Table 4). of activation of coagulation.39 TF expression is also observed
Grover and Mackman Tissue Factor in Hemostasis and Thrombosis 717
Figure 3. Cellular sources of tissue factor (TF) that trigger thrombosis and disseminated intravascular coagulation. A, TF within athero-
sclerotic plaques triggers thrombosis after plaque rupture. Other sources of TF in patients with cardiovascular disease include circulating
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activated monocytes and activated platelets. B, In endotoxemia and sepsis, pathogens induce TF expression in monocytes and endothe-
lial cells and the release of TF-positive microvesicles (MVs). In addition, increased vascular permeability exposes TF on perivascular cells
to blood. All these sources of TF may contribute to disseminated intravascular coagulation. C, Pancreatic tumors express high levels of
TF and release TF-positive MVs that circulate in the blood and trigger venous thrombosis. D, Antiphospholipid antibodies (aPLA) induce
TF expression in monocytes and the release of TF-positive MVs that trigger thrombosis. TF expression by endothelial cells may also con-
tribute to local thrombosis. Administration of the antioxidant ubiquinol reduced Coenyzme Q10 (CoQ10) reduces monocyte TF expression.
in monocytes isolated from septic baboons.40 As noted earlier, of the anticoagulant proteins EC protein C receptor and
immunohistochemistry studies demonstrated TF staining on thrombomodulin.83 Taken together, we propose that activated
ECs in the spleen and aorta of septic baboons and ECs in the monocytes are the major source of TF that activates coagula-
glomerulus of endotoxemic mice.38,80,83 Therefore, EC TF may tion during endotoxemia and sepsis. However, we speculate
also play a role the activation of coagulation during sepsis and that TF expressed on perivascular cells exposed by increased
endotoxemia. Importantly, early inhibition of TF reduced the vascular permeability and possibly TF induced on ECs also
activation of coagulation and mortality in septic baboons.107,222 contribute to the activation of coagulation in sepsis.
We analyzed the role of TF in the activation of coagulation
in a mouse model of endotoxemia. As expected, LPS activa- Surgery
tion of coagulation was lower in low TF mice compared with Surgery is associated with an increased risk of venous throm-
controls.223 Similarly, wild-type mice containing bone marrow bosis. Three studies have reported an increase in monocyte
from low TF mice or mice with TF deleted in myeloid cells TF expression 1 day after surgery to remove tumors as well
(TFfl/fl, LysMCre; Table 2) had lower levels of activation of as after coronary artery bypass surgery and total knee arthro-
coagulation compared with controls.168 However, bone mar- plasty.194,224,225 This suggests that surgery triggers an inflamma-
row cells only account for ≈50% of TF that activates coagula- tory response surgery that induces monocyte TF expression.
tion in endotoxemic mice. We found that deleting TF on ECs Importantly, the increase in monocyte TF occurs before the
did not affect activation of coagulation in a mouse endotox- peak of clinical venous thrombosis, which is 7 days after sur-
emia model.168 Another study found that inducible expression gery.226 These studies suggest that induction of TF expression
of a degradation resistant form of IκBα in ECs blocked the on monocytes contributes to postsurgery venous thrombosis.
induction of TF expression in ECs in the glomerulus of endo-
toxemic mice.83 However, the specific impact of this blockade Cancer
of EC TF expression could not be evaluated because expres- Thromboembolism represents a leading cause of death in
sion of the mutant IκBα also prevented the downregulation patients with cancer and is associated with poor prognosis.227
718 Arterioscler Thromb Vasc Biol April 2018
Venous thrombosis, in particular, is frequently observed The exact mechanism by which aPLA induce a hyperco-
in cancer patients with reported annual incidences ranging aguable state remains unclear. However, results from differ-
between 1.5% to 20% per annum depending on the site of can- ent studies suggest that aPLA induction of TF expression in
cer and treatment.228 In vitro, cancer cell lines shed TF-positive monocytes may underpin the pathogenesis of APS-associated
microvesicles.68,229–231 Moreover, increased levels of circulat- thrombosis. Importantly, human monocytes isolated from
ing TF-positive microvesicles are observed in patient with dif- patients with APS express TF.198–200 Moreover, incubation
ferent types of cancer, including pancreatic, brain, colorectal, of primary human monocytes from healthy individuals with
lung, breast, and prostate.195,232–235 Importantly, elevated levels anti-β2-glycoprotein I IgG leads to increased monocyte TF
of MV TF activity are associated with venous thromboembo- gene expression, PCA and release of TF-positive microves-
lism in pancreatic cancer patients but not in brain, gastric, or icles.243–246 In vitro studies showed that aPLA induces oxi-
colorectal cancer patients.195–197,228 dative stress in monocytes, and levels of cell surface TF
Preclinical studies of cancer-associated thrombosis have exposure correlate with intracellular peroxide generation.247
largely focused on pancreatic cancer, given the high rates of Furthermore, pretreatment of the monocytes with the antioxi-
thrombosis observed in patients with this type of malignancy. dant ubiquinol, reduced Coenzyme Q10, decreased oxidative
Immunocompetent and immunodeficient mouse models have stress and TF expression.248 In a follow-up study, adminis-
been used to study the role of tumor-derived, TF-positive tration of Coenzyme Q10 to APS patients reduced oxidative
microvesicles in thrombosis (Figure 3C). Studies have stress and TF exposure on monocytes.248,249 Further clinical
used the mouse pancreatic cell line Panc02 that expresses studies are required to determine if antioxidant therapies can
TF. Injection of mice with Panc02-derived, TF-positive effectively prevent thrombotic events in patients with APS by
microvesicles enhanced thrombosis in a laser injury model reducing monocyte TF expression.
and an infrarenal vena cava (IVC) stenosis model, whereas Animal models have been used to gain insights into
microvesicles from Panc02 cells with reduced TF expres- the involvement of TF in APS-associated thrombosis
sion were less thrombotic.236,237 Moreover, immunocompetent (Figure 3D).250,251 For instance, low TF mice were protected
mice bearing Panc02 tumors had enhanced thrombus forma- from the thrombotic microangiopathy induced by the pas-
tion in a mesenteric ferric chloride model and an IVC stenosis sive transfer of a murine monoclonal aPLA or purified
model.236,237 patient aPLA.252 Interestingly, aPLA were shown to induce
Immunodeficient mice are required for studies with TF expression in monocytes and ECs via a pathway involv-
human pancreatic cancer cell lines. We and others have ing endosomal NADPH oxidase and TLR7/8.253 Importantly
used several TF-expressing human pancreatic cells lines, induction of TF was absent in aPLA-treated monocytes from
Downloaded from http://ahajournals.org by on December 29, 2021
including L3.6pl, HPAF-II, and BxPc-3.68,238,239 Injection NOX2−/− mice. A follow-up study with mice showed that
of TF-positive microvesicles derived from these cell lines aPLA enhanced thrombosis in an IVC stenosis model.254
activated coagulation and increased thrombus formation Enhanced thrombosis in this study required NOX2 and leu-
in the IVC stenosis model.68,238,239 In addition, inhibition of kocytes but not TLR4 or platelets.250 These 2 studies sug-
TF on BxPc-3 microvesicles with an antihuman TF anti- gest a role for monocyte TF in aPLA induced thrombosis.254
body abolished the enhanced thrombosis. Mice bearing Further studies are needed to understand how TF contributes
HPAF-II tumors also demonstrated markedly shortened to thrombosis in patients with APS.
time to occlusion in a saphenous vein ferric chloride injury
model but there was no increase in thrombosis in the IVC Acute Liver Injury and Cirrhosis
stenosis model.68 However, mice bearing BxPc-3 tumors Acute liver injury and cirrhosis are associated with a pro-
had an increase in thrombosis in the IVC stenosis model.238 thrombotic state. One study found very high levels of circulat-
Recently, we evaluated the contribution of tumor derived, ing MV TF activity in patients with acute liver injury.255 We
TF-positive microvesicles to venous thrombus in tumor found that MV TF activity was increased with cirrhosis and
bearing mice.240 Mice with orthotopic BxPc-3 tumors had levels were associated with the Child–Pugh score and markers
larger thrombi in an IVC stasis model compared with con- of activation of coagulation and fibrin degradation.256
trols and administration of an antihuman TF antibody sig- The liver expresses low levels of TF compared with other
nificantly reduced the size of the thrombi.240 Taken together, organs, such as the brain and lung. The Luyendyk group deter-
these studies suggest that tumors release TF-positive mined the contribution of hepatocytes to basal TF expression
microvesicles into the circulation and that these microvesi- in the liver by comparing levels in mice with TF deleted in
cles enhance venous thrombosis. hepatocytes (TFfl/fl, Albcre) to controls (Table 3). Importantly,
we found a dramatic reduction of TF in TFfl/fl, Albcre mice
Antiphospholipid Syndrome indicating that hepatocytes are the major source of TF in
Antiphospholipid syndrome (APS) is an autoimmune disorder the liver.169 Furthermore, administration of acetaminophen
caused by the development of antibodies against many phos- to wild-type but not TFfl/fl, Albcre mice led to a rapid activa-
pholipids, such as cardiolipin, phospholipid-associated pro- tion of coagulation as measured by increased levels of plasma
teins, including β2-glycoprotein I, and plasma proteins, such thrombin-antithrombin complexes.169 In a second study, we
as prothrombin.241 Collectively, these antibodies are called used a mouse model of bile duct ligation to determine the cel-
antiphospholipid antibodies (aPLA). APS patients with per- lular source of TF responsible for activation of coagulation in
sistently high titers of aPLA are at significant risk of arterial chronic liver injury. As expected, activation of coagulation was
and venous thromboembolic events and fetal loss.242 lower in low TF mice compared with controls.170 Interestingly,
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