REVI EW ARTI CLE

Tissue factor and tissue factor pathway inhibitor

G. C. Price,
1
S. A. Thompson
2
and P. C. A. Kam
3
1 Senior Registrar, Intensive Care Unit, 2 Fellow in Anaesthesia, Department of Anaesthesia, 3 Professor of Anaesthesia,
Dept of Anaesthesia, University of New South Wales at St George Hospital, Kogarah, NSW 2217, Australia
Summary
The classical cascade waterfall hypothesis formulated to explain in vitro coagulation organised
the amplication processes into the intrinsic and extrinsic pathways. Recent molecular biology
and clinical data indicate that tissue factor factor-VII interaction is the primary cellular initiator
of coagulation in vivo. The process of blood coagulation is divided into an initiation phase
followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports
the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence
has shown that blood-borne tissue factor has an important procoagulant function in sepsis,
atherosclerosis and cancer, and other functions beyond haemostasis such as immune function
and metastases.
Keywords Blood coagulation. Tissue factor pathway inhibitor. Tissue factor.
........................................................................................................
Correspondence to: P. C. A. Kam
E-mail: p.kam@unsw.edu.au
Accepted: 16 December 2003
Tissue factor (TF) has been considered an important
initiator of coagulation in vivo since its discovery in the
19th century [1]. Traditionally, TF is believed to be
responsible only for the initiation of the extrinsic pathway
of coagulation. However, an understanding of the exact
role of TF and its regulator, tissue factor pathway
inhibitor (TFPI), has increased signicantly. In addition
to the complex role in coagulation, TF acts as a signalling
receptor [2] and has several non-haemostatic actions. TF
is involved in the pathophysiology of systemic inamma-
tory disorders, coagulopathies, atherosclerotic disease,
tumour angiogenesis and metastasis.
In this article we review the physiology of tissue factor
and tissue factor pathway inhibitor, and potential therap-
ies arising from the modication of these pathways.
Tissue factor and coagulation
Tissue factor, a class 2 cytokine receptor, is a transmem-
brane glycoprotein that consists of three sections: a large
extracellular domain, a transmembrane segment, and a
cytoplasmic tail [3, 4]. The extracellular domain is import-
ant for its haemostatic activity [5]. The transmembrane
portion is necessary for stabilization of the molecule and
its complex in a favourable position for proteolytic action.
The function of the cytoplasmic domain is not yet fully
determined.
Traditionally, TF is thought to initiate the extrinsic
pathway of coagulation, with collagen playing the same
role in the intrinsic pathway. The cascade waterfall
theories of coagulation organised the sequence of bio-
chemical events into extrinsic, intrinsic and common
pathways [6, 7]. The extrinsic pathway is initiated by TF
(tissue thromboplastin or Factor III) interacting with
Factor VII to activate Factor X. The intrinsic pathway,
which is initiated when Factor XII (Hageman Factor)
comes into contact with the negative charges underlying
the endothelium, also generates Factor Xa. Factor Xa
catalyses the conversion of prothrombin to thrombin.
Thrombin combines with Factor XIII and generates a
brin plug from brinogen (Fig. 1).
Deciencies of Factors VIII and IX in the intrinsic
pathway cause severe clinical bleeding disorders, indica-
ting that the extrinsic pathway has only an ancillary role.
This cascade explains the interpretation of abnormal
coagulation screening tests such as prothrombin time and
partial thromboplastin time, but there are several appar-
ent inconsistencies in clinical practice. Deciency of
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2004 Blackwell Publishing Ltd 483
prekallikrein, high molecular weight kininogen or factor
XII prolongs the partial thromboplastin time but such
states are not associated with excessive bleeding. The
cascade theory focusses on procoagulant proteins without
consideration of the cells involved in coagulation,
whose surfaces are essential for various proteinprotein
interactions.
Several clinical and experimental observations suggest
that the cascade waterfall hypothesis does not accurately
reect the events of in vivo haemostasis. Patients
decient in the contact factors (e.g. Factor XII) do
not suffer bleeding problems. John Hageman, the rst
patient identied with Factor XII deciency, suffered
recurrent infections and died from a pulmonary
embolus, not from bleeding problems. When Biggs
repeated an experiment she had originally performed in
1951 she discovered that when prothrombin time was
measured on Factor VIII- or IX-decient plasma using a
physiological concentration of tissue thromboplastin, the
result was abnormal [8]. She postulated that Factor
VII Ca
2+
tissue factor complex was of greater signi-
cance than the cascade hypothesis had suggested [9, 10].
Other clinical observations raised further questions of
the validity of the cascade hypothesis explaining the
events of in vivo haemostasis. Haemophilia C (Factor XI-
decient) patients have a milder clinical picture than
patients with Factor IX (haemophilia B) deciency.
Patients with isolated Factor VII deciency bleed
excessively [11, 12].
Ostend & Rapaport provided experimental evidence
that Factor VII tissue factor complex activates both
Factor X and IX, indicating a central role for tissue factor-
initiated coagulation [13]. If in vivo coagulation is initiated
by tissue factor Factor VIIa-mediated activation of Xa,
why do patients decient in Factor IX or VIII bleed
severely? Biggs & MacFarlane observed that if small
amounts of tissue factor are added to plasma when
performing the prothrombin time assay (which measures
Factor VII activity in the extrinsic pathway) Factors VIII
and IX are necessary for optimal clot formation. The
discovery of a circulating inhibitor of the Factor
VIIa tissue factor complex, called tissue factor pathway
inhibitor (TFPI), suggested an alternative pathway of
events in blood coagulation [14, 15].
Revised hypothesis of blood coagulation
The concept of two separate pathways to clot formation
is replaced by a network model, involving linkage
between the two pathways, which is regulated by a series
of positive and negative feedback loops [5]. The modern
concept of coagulation incorporates the cell surfaces into
the coagulation process. TF has a central role in this new
concept of coagulation (Fig. 2).
The process of clot formation is considered to be a
two-stage process: 1) initiation of coagulation and 2)
propagation of the resultant thrombus. The initiation
phase begins when disruption of vessel walls exposes TF
to circulating Factor VII. Coagulation is therefore
initiated by the exposure of tissue factor to circulating
blood following vascular injury, which then forms a
complex with small amounts of the normally circulating
activated factor VII. Factor VII exists in both active and
inactive states in equilibrium, with approximately 1%
occupying the active state in normal individuals [16].
However, in the absence of TF as its cofactor, FVIIa has
little proteolytic activity [17]. The formation of the Tissue
Factor Factor VII complex (TFFVIIa) induces a con-
formational change in the protease domain of Factor VII,
which causes it to become active [18]. TFFVIIa is
located on the cell surface, in close proximity to
negatively charged phospholipids and this allows optimal
positioning for substrates of the complex [5].
The TFFVIIa complex activates Factor IX as well as
Factor X [1921] on the subendothelial surfaces, but the
amount of FXa generated during this phase is extremely
low. The combination of low levels of FXa and the
absence of its cofactor, FVa, precludes direct brin plug
formation. Trace amounts of thrombin are generated and
this causes back-activation of Factors V, VIII and
possibly XI. Factor VIIIa then complexes with the
activated Factor IXa to generate a sufcient amount of
Factor Xa that will sustain clot formation (propagation
phase). The factor Xa generated by the TF factor VIIa
complex interacts with factor Va and converts pro-
thrombin to thrombin. The prothrombinase complex
activates nearby platelets, leading to the expression of
stores of factor V on their surface, and activate factors V,
VIII, and XI on the surface of the activated platelet. The
factor IXa generated by the TF VIIa complex on the TF
Figure 1 Outline of the waterfall cascade theory of coagula-
tion.
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484 2004 Blackwell Publishing Ltd
cell diffuses through the circulating blood to the surface
of the activated paltelet. Activated factor IX then forms a
tenase complex with factor VIIIa on the platelet surface
and is able to activate factor X. Factor Xa forms the
prothrombinase complex with factor Va, resulting in a
large thrombin generation especially on the platelet
surface to form a brin clot.
Deciency of Factors VIII or IX produces severe
coagulopathy in the form of Haemophilia A or B,
respectively. The activation of Factor XI by thrombin
further increases activation of Factor IX, although this
probably plays only a minor part in clot propagation. The
additional thrombin generated by such back-activation
of factors directly and indirectly increases the amount
of brin present by activation of a brinolysis inhibitor
[22, 23]. Factor XII is no longer considered to have any
signicant role in normal coagulation [24].
It was believed that TF was expressed only in
extravascular tissues by macrophages, monocytes and
broblasts [2527]. However, it is also found in the
adventitia of blood vessels, organ capsules, and the
epithelium of skin and internal mucosae. TF is unable
to interact with coagulation factors, and thereby initiates
thrombosis at these sites, until vessel wall damage occurs.
Circulating TF is present in both the whole blood and
serum of healthy individuals [28, 29]. Eukaryotic cells
shed membrane fragments that form circulating micro-
particles that contain TF [30].
Circulating tissue factor is necessary for the propagation
of thrombus [31]. During thrombogenesis, tissue factor in
the vessel wall is rapidly enveloped by clot and cannot
have signicant effects within the lumen of the blood
vessel. Normally, circulating tissue factor is present at
levels too low to activate the clotting cascade. It is in an
inactive or encrypted form, and therefore cannot initiate
coagulation. TF inactivity may be caused by asymmetrical
distribution of negatively charged phospholipids across
the cell membrane [32]. These phospholipids are required
for the binding of coagulation factors to the cell
membrane and TFFVIIa complex. Disruption of the
membrane allows this to occur. Encryption of TF into
vesicles or caveolae in the cell membrane prevents the
initiation of coagulation. A rise in intracellular calcium
activates encrypted TF [33].
Figure 2 The role of tissue factor in the
revised theory of coagulation. In vivo,
coagulation is initiated by tissue factor,
present on the perivascular tissue
surfaces, binding to factor VII. The
TFFVIIa complex activates X and XI.
VIIIaIXa complex amplies Xa pro-
duction from X. Thrombin is formed
from prothrombin by the action of
XaVa (prothrombinase) complex.
Thrombin activates XI, V and XIII,
and cleaves VIII from its carrier von
Willebrand factor (vWF), increasing
VIIIaIXa and hence XaVa. TFPI
Tissue factor pathway inhibitor.
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In this revised hypothesis, tissue factor rather than
contact factors is responsible for initiating coagulation.
Factors IX and VII are necessary for enhanced Factor Xa
generation and sustained coagulation. A corollary to this
hypothesis is that excessive bleeding in haemophiliacs
(especially those with Factor VIII or IX inhibitors) can be
alleviated by inhibiting the function of TFPI.
Tissue factor pathway inhibitor and the
regulation of coagulation
TFPI is an inhibitor of the Factor VIIa tissue factor
complex. It occurs in two forms in man, TFPI-1 and
TFPI-2. TFPI-1 is the main regulator of the tissue factor
pathway. TFPI-1, a Kunitz-type protease inhibitor, is a
modular protein comprising three tandem units [34]; the
rst and second units inhibit TFFVIIa and FXa,
respectively. The third Kunitz domain and the
C-terminal basic region of the molecule have heparin-
binding sites [35]. TFPI is predominantly produced by the
microvascular endothelium [36]. There are three pools of
TFPI in vivo: the majority of TFPI bound to the vascular
endothelium, approximately 10% associated with lipo-
proteins in the plasma and a smaller portion present in
platelets. The normal concentration of TFPI in the plasma
is approximately 100 ng.ml
)1
[37]. Stored TFPI is
released into the plasma from the endothelial cells by
the action of heparin, and by platelet activation [38, 39].
The anticoagulant action of TFPI is a two-stage
process. The second Kunitz domain binds rst to a
molecule of FXa and deactivates it. The rst domain then
rapidly binds to an adjacent TFFVIIa complex, pre-
venting further activation of Factor X [4042]. The
formation of this quaternary compound is necessary for
the inhibitory action of TFPI on the TF-FVIIa complex.
This process does not occur in the absence of FXa,
indicating that coagulation must be initiated before TFPI
can function.
TFPI inhibits the FxaTFFVIIa complex. It presents
itself as a substrate for the complex and occupies its active
sites. TFPI does not cleave readily, and prevents the
complex from engaging other molecules [5]. TFPI also
causes monocytes to internalise and degrade TFFVIIa
complexes on the cell surface [43]. Circulating TFPI
FxaTFFVIIa complexes are metabolised by the liver
[35].
Heparin may exert its antithrombotic effect through
the TFPI pathway. Heparin induces TFPI synthesis and
secretion by endothelial cells [44, 45], and causes the
displacement of TFPI bound to cell membranes. The
inhibitory effects of TFPI on the FxaTFFVIIa com-
plex are enhanced signicantly in the presence of
heparin [46].
Tissue factor as a signalling receptor
Intracellular signalling by the TFFVIIa complex medi-
ates the non-haemostatic functions of tissue factor.
Structural similarities between TF and the family of
cytokine receptors were rst identied in 1990 [47], but it
was sometime before intracellular signalling by the TF
FVIIa complex was demonstrated.
Binding of activated factor VII to membrane-bound
tissue factor causes several intracellular effects [2], such as
mobilization of intracellular calcium stores [48] and
transient phosphorylation of intracellular proteins [49].
One such protein which is activated by TFFVIIa
signalling is mitogen-activated protein kinase (MAPK)
[50]. Phosphorylated MAPK enters the cell nucleus and
activates several transcription factors. The actions of
MAPK are implicated in tumour metastasis [51]. Alter-
ations in cellular activity induced by this mechanism
include the up-regulation of poly(A)polymerase activity
in broblasts [52], which may increase the stability of
cytokines. Cellular migration in both vascular smooth
muscle cells [53] and some tumour lines [54] is enhanced
by the activity of the TFFVIIa complex, suggesting a
role for the complex in tumour angiogenesis and
metastasis.
The precise pathway of intracellular signalling activated
by the TFFVIIa complex, and the effect of this on
specic changes in the target cell, is not fully understood.
It is likely that members of the family of protease-
activated receptors (PARS) are involved in this signal
transduction [55]. PAR2 is susceptible to activation by
the TFFVIIa complex, and the TFFVIIa-FXa complex
can activate both PAR1 and PAR2.
Tissue factor and tissue factor pathway
inhibitor clinical implications
The role of TF as a major player in the coagulation
cascade is well known [56] but its role as a pro-
inammatory agent is not widely appreciated [57]. The
pathophysiological roles of tissue factor and of its
physiological antithesis, tissue factor pathway inhibitor
(TFPI), are discussed below.
The role of TF and TFPI in sepsis
TF is a procoagulant glycoprotein and a signalling
receptor and is implicated in a wide variety of diseases
that are not directly related to haemostatic disorders [58].
The pathological conditions of interest to anaesthetists
and intensivists in which TF may play an important role
are sepsis and thrombosis.
Coagulation disorders are common in septic patients
and it is perhaps not surprising that the role of TF has
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486 2004 Blackwell Publishing Ltd
been extensively studied in various models of sepsis [59].
Laboratory evidence suggests that TF is one of a number
of secondary inammatory mediators that are involved in
the propagation of sepsis, sepsis syndrome and septic
shock [24]. Randolph and colleagues demonstrated that
mononuclear phagocytes reverse migrate across lymphatic
endothelium [60]. For this migration to occur it is
essential that TF is expressed on the surface of these cells.
The tissue factor activated factor VII complex enables the
macrophages to produce reactive oxygen species that are
essential for bacterial killing. These reactive oxygen
species are not formed if anti TF antibody is administered
around these macrophages [61].
Various substances, such as endotoxin, tumour nec-
rosis factor (TNF)-a, interleukin-1 and activated com-
plement, induce TF expression [62, 63]. An infusion of
endotoxin in healthy human volunteers activates tissue
factor-dependent clotting. This cross talk between the
coagulation and inammatory systems is increasingly
recognised. The central role of tissue factor as the sole
activator of coagulation in sepsis has been conrmed by
laboratory studies [59, 64]. Animal models of sepsis are
broadly divided into those where a septic insult is
administered systemically (intravenous injection of endo-
toxin) or as a local phenomenon (caecal ligation and
puncture). The response in animal models depends on
whether the initiating septic event is systemic or a local
phenomenon. A primate model showed that the coag-
ulopathy associated with sepsis is signicantly attenuated
when the animal is pretreated with antitissue factor
antibodies [6567], giving further evidence of the
important role of tissue factor in inammation. In a
study comparing the effects of infusion of anti TNF
antibodies on systemic vs. local sepsis it was found that
inhibition of TNF activity attenuated the septic episode
in systemic sepsis model, whereas it worsened outcome
in the local sepsis model [68]. This suggested that local
area activation of primary (such as TNF) and secondary
mediators (such as TF) of inammation are important to
prevent spread of local infectious stimuli. In systemic
sepsis, activation of primary and secondary mediators of
inammation caused transient increases in TNF-a,
causing severe systemic disturbances associated with
septic shock. There is increasing experimental evidence
that TF is expressed on the cell membranes of mono-
cytes [69]. These TF-expressing monocytes initiate
coagulation, and this explains the link between the
coagulation and immune systems. The procoagulant
effect of the cytokine-induced expression of TF is
complex. Both thrombin production and brinolytic
pathways are stimulated. However, brinolysis is short-
lived compared with thrombin production, and this
results in a procoagulant tendency [70]. The TF pathway
has an important dual role in sepsis, inammation as well
as its primary function in coagulation. The production
of microvascular thrombi causes end organ damage that
is observed in severe sepsis [71]. Its role as a pro-
inammatory agent is equally important.
TFPI is as essential for survival as TF. Mouse embryos
bred to be devoid of TFPI do not survive the
intrauterine period [72]. Furthermore, to date no human
mutants with a congenital absence of TFPI have been
described. Given the role of tissue factor in sepsis, its
physiological antagonist TFPI can potentially have a
therapeutic role. This has been studied in both animal
models and human trials. The role of TFPI in sepsis and
disseminated intravascular coagulation is shown in rabbits
immunodepleted of TFPI. In this rabbit model, infusion
of TF at a level that would not induce coagulation in
normal rabbits caused marked intravascular coagulation.
This intravascular coagulation also occurred when these
rabbits were infused with endotoxin, adding to the
evidence that endotoxin is a trigger for intravascular
coagulation [73, 74]. The administration of human
recombinant TFPI in a rabbit model of sepsis also
reduced the mortality in rabbits with gram-negative
peritonitis [75]. Other animal models of sepsis also show
the benet of TFPI. TFPI administered shortly after
baboons received a lethal dose of Escherichia coli preven-
ted mortality in baboons. This positive result was
reduced by 60% when the TFPI was administered 4 h
after the lethal dose of E. coli. The effects on coagulation
and inammation were reduced, as indicated by the
lower levels of circulating interleukin 6 [76]. However,
the infusion of TFPI did not cause haemodynamic
instability. This is intriguing as the mechanism of
increased survival following TFPI infusion is not known.
Other animal studies showed an improvement from
lipopolysaccharide-induced lung injury. A study in
Wistar rats showed that infusion of rTFPI reduced lung
injury probably by inhibiting leucocyte activation [77].
On the basis of these and other encouraging animal
studies, human trials of recombinant tissue factor path-
way inhibitor were conducted. Initial encouraging
results from small phase I and phase II studies indicated
that rTFPI is safe in humans with no increase in bleeding
[78]. Unfortunately, these earlier encouraging results
have not been achieved in a recently completed phase
III trial, the OPTIMIST trial. There was no survival
benet with the administration of recombinant TFPI in
humans with severe sepsis [79].
The role of TF and TFPI in thrombosis
Thrombosis occurs commonly in patients with coronary
artery disease and malignancy. Experimental data show
that atheromatous plaques contain a high concentration of
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TF relative to surrounding tissue [80]. In coronary artery
disease, disruption of the coronary arterial wall by
atheromatous plaque formation, along with its rupture,
exposes tissue factor to circulating factor VII. This causes
initiation of clot and may lead to a myocardial infarction.
In deep venous thrombosis the cause is less well dened,
but circulating inammatory mediators may be involved.
The reason why deep venous thrombosis occurs at sites
distant to surgical injury, where the vasculature has not
been damaged, is not known. Indeed, the initial thrombin
plug is rapidly covered by platelets and brin, thus
covering the exposed tissue factor and preventing its
continued activation.
Abundant TF is found in atheromatous lesions as foamy
macrophages in macrovascular disease in humans such as
aortic aneurysms, carotid arteries and coronary arteries
[81]. TF in these plaques is active and can induce
coagulation and clot formation [82]. Examination of
specimens obtained from patients with acute coronary
syndromes demonstrated that higher levels of TF are
present in these lesions, providing additional evidence for
the role of TF in these conditions [83].
Thrombosis is common in malignant disease and is
the second most common cause of death in cancer
patients [84]. It has been known for many years that
malignant cells express TF on their surface [85] and also
induce TF expression on non-malignant cells such as
endothelial cells and monocytes [86]. The expressed TF
can cause thrombosis in cancer patients, leading to
pulmonary thrombo-embolism, migratory thrombo-
phlebitis and arterial thrombo-embolism as well as
disseminated intravascular coagulation. Lung, breast,
stomach, colon and pancreas tumours contain large
amounts of TF [87]. Membrane fragments containing
tissue factor are shed into the circulation and this can
explain the hypercoagulable state so often seen in
malignancy [88].
Tissue factor pathway inhibitor has been extensively
studied as an agent to treat thrombotic disorders. Mural
thrombus formed on ruptured plaque is resistant to
heparinization and aspirin [89]. Animal and laboratory
studies using TFPI to prevent thrombosis have been
encouraging. TFPI that is concentrated from plasma
inhibits brin formation in a ow model on endothelial
cell matrix [90]. In a dog model (where dog femoral
artery was injured leading to thrombosis) treatment
with tissue plasminogen activator and TFPI prevented
reocclusion of the femoral artery [91]. As re-stenosis is
a major problem after coronary artery thrombosis with
or without balloon angioplasty or stenting, and aspirin
and heparin only partially prevent re-stenosis, the
potential benets of TFPI in these patients may be
envisaged.
Recombinant TFPI has been studied in spinal cord
injury. In a rabbit model of ischaemic spinal cord injury,
neurological recovery was achieved in 88% of the rabbits
that received an infusion of rTFPI as compared to 20% in
the heparinization group [92].
In a study comparing rTFPI to low molecular weight
heparin (LMWH) in a venous thrombosis model using
rabbit jugular veins, rTFPI was as effective as LMWH in
decreasing the size of the thrombus. In addition rTFPI did
not cause bleeding [93]. It is now clear that low molecular
weight heparin increases the levels of TFPI in vivo [94],
and this may be one of the mechanisms by which these
agents are effective in the prevention of deep vein
thrombosis. The role of tissue factor pathway inhibitor in
post surgical deep venous thrombosis in patients treated
with LMWH has been studied. In a group of postoper-
ative orthopaedic patients, plasma levels of TFPI were
signicantly raised for up to 7 days in the patients treated
with LMWH compared to controls [95]. A study of
patients who received enoxaparin for deep vein throm-
bosis prophylaxis and underwent either hip knee
arthroplasty or colectomy reported a linear relationship
between an increase in total free TFPI ratio levels and
postoperative bleeding. Therefore measuring TFPI levels
in patients undergoing major surgery may be useful to
allow stratication of their bleeding risk, and possibly
reduction in LMWH dose [96].
In a study of venous thrombosis in a rabbit model in
which brin deposition was quantied on collagen-
coated threads within either the jugular vein or a silicon-
coated vein shunt, an inhibitory monoclonal antibody to
tissue factor was as effective as a specic thrombin
inhibitor (napsagatran) in blocking thrombus formation
[97]. The fact that inhibiting tissue factor activity had such
an impact on thrombus growth in the silicon vein shunt is
signicant and indicates the transfer of active tissue factor
from some active component of blood to the surface of
the growing thrombus [98].
Recent developments in the physiology of coagulation
indicate that exposure of the vessel wall-derived TF at the
site of vascular injury is not always required [99]. Systemic
inammation results in activation of coagulation due to
tissue factor mediated thrombin generation [100]. Leuco-
cytes are a source of TF microparticles present in
circulating blood. These TF microparticles are transferred
to platelets during thrombus formation, thereby propa-
gating further thrombus formation growth. The inhibi-
tion of TF-transfer and TF-activity is an attractive target
for antithrombotic therapy [1012]. More studies are
required to determine the extent to which TF and TFPI
contribute to the pathophysiology of sepsis and other
conditions so that new therapeutic approaches can be
exploited.
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