Anaesthesia, 2004, 59, pages 483–492

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REVIEW ARTICLE
Tissue factor and tissue factor pathway inhibitor
G. C. Price,1 S. A. Thompson2 and P. C. A. Kam3
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 amplification 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.

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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 its complex in a favourable position for proteolytic action.
initiator of coagulation in vivo since its discovery in the The function of the cytoplasmic domain is not yet fully
19th century [1]. Traditionally, TF is believed to be determined.
responsible only for the initiation of the extrinsic pathway Traditionally, TF is thought to initiate the extrinsic
of coagulation. However, an understanding of the exact pathway of coagulation, with collagen playing the same
role of TF and its regulator, tissue factor pathway role in the intrinsic pathway. The cascade ⁄ waterfall
inhibitor (TFPI), has increased significantly. In addition theories of coagulation organised the sequence of bio-
to the complex role in coagulation, TF acts as a signalling chemical events into extrinsic, intrinsic and common
receptor [2] and has several non-haemostatic actions. TF pathways [6, 7]. The extrinsic pathway is initiated by TF
is involved in the pathophysiology of systemic inflamma- (tissue thromboplastin or Factor III) interacting with
tory disorders, coagulopathies, atherosclerotic disease, Factor VII to activate Factor X. The intrinsic pathway,
tumour angiogenesis and metastasis. which is initiated when Factor XII (Hageman Factor)
In this article we review the physiology of tissue factor comes into contact with the negative charges underlying
and tissue factor pathway inhibitor, and potential therap- the endothelium, also generates Factor Xa. Factor Xa
ies arising from the modification of these pathways. catalyses the conversion of prothrombin to thrombin.
Thrombin combines with Factor XIII and generates a
fibrin plug from fibrinogen (Fig. 1).
Tissue factor and coagulation
Deficiencies of Factors VIII and IX in the intrinsic
Tissue factor, a class 2 cytokine receptor, is a transmem- pathway cause severe clinical bleeding disorders, indica-
brane glycoprotein that consists of three sections: a large ting that the extrinsic pathway has only an ancillary role.
extracellular domain, a transmembrane segment, and a This cascade explains the interpretation of abnormal
cytoplasmic tail [3, 4]. The extracellular domain is import- coagulation screening tests such as prothrombin time and
ant for its haemostatic activity [5]. The transmembrane partial thromboplastin time, but there are several appar-
portion is necessary for stabilization of the molecule and ent inconsistencies in clinical practice. Deficiency of

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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
Figure 1 Outline of the waterfall ⁄ cascade theory of coagula-
tion. 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
prekallikrein, high molecular weight kininogen or factor concept of coagulation (Fig. 2).
XII prolongs the partial thromboplastin time but such The process of clot formation is considered to be a
states are not associated with excessive bleeding. The two-stage process: 1) initiation of coagulation and 2)
cascade theory focusses on procoagulant proteins without propagation of the resultant thrombus. The initiation
consideration of the cells involved in coagulation, phase begins when disruption of vessel walls exposes TF
whose surfaces are essential for various protein–protein to circulating Factor VII. Coagulation is therefore
interactions. initiated by the exposure of tissue factor to circulating
Several clinical and experimental observations suggest blood following vascular injury, which then forms a
that the cascade ⁄ waterfall hypothesis does not accurately complex with small amounts of the normally circulating
reflect the events of in vivo haemostasis. Patients activated factor VII. Factor VII exists in both active and
deficient in the contact factors (e.g. Factor XII) do inactive states in equilibrium, with approximately 1%
not suffer bleeding problems. John Hageman, the first occupying the active state in normal individuals [16].
patient identified with Factor XII deficiency, suffered However, in the absence of TF as its cofactor, FVIIa has
recurrent infections and died from a pulmonary little proteolytic activity [17]. The formation of the Tissue
embolus, not from bleeding problems. When Biggs Factor ⁄ Factor VII complex (TF–FVIIa) induces a con-
repeated an experiment she had originally performed in formational change in the protease domain of Factor VII,
1951 she discovered that when prothrombin time was which causes it to become active [18]. TF–FVIIa is
measured on Factor VIII- or IX-deficient plasma using a located on the cell surface, in close proximity to
physiological concentration of tissue thromboplastin, the negatively charged phospholipids and this allows optimal
result was abnormal [8]. She postulated that Factor positioning for substrates of the complex [5].
VII ⁄ Ca2+ ⁄ tissue factor complex was of greater signifi- The TF–FVIIa complex activates Factor IX as well as
cance than the cascade hypothesis had suggested [9, 10]. Factor X [19–21] on the subendothelial surfaces, but the
Other clinical observations raised further questions of amount of FXa generated during this phase is extremely
the validity of the cascade hypothesis explaining the low. The combination of low levels of FXa and the
events of in vivo haemostasis. Haemophilia C (Factor XI- absence of its cofactor, FVa, precludes direct fibrin plug
deficient) patients have a milder clinical picture than formation. Trace amounts of thrombin are generated and
patients with Factor IX (haemophilia B) deficiency. this causes back-activation of Factors V, VIII and
Patients with isolated Factor VII deficiency bleed possibly XI. Factor VIIIa then complexes with the
excessively [11, 12]. activated Factor IXa to generate a sufficient amount of
Ostend & Rapaport provided experimental evidence Factor Xa that will sustain clot formation (propagation
that Factor VII ⁄ tissue factor complex activates both phase). The factor Xa generated by the TF ⁄ factor VIIa
Factor X and IX, indicating a central role for tissue factor- complex interacts with factor Va and converts pro-
initiated coagulation [13]. If in vivo coagulation is initiated thrombin to thrombin. The prothrombinase complex
by tissue factor ⁄ Factor VIIa-mediated activation of Xa, activates nearby platelets, leading to the expression of
why do patients deficient in Factor IX or VIII bleed stores of factor V on their surface, and activate factors V,
severely? Biggs & MacFarlane observed that if small VIII, and XI on the surface of the activated platelet. The
amounts of tissue factor are added to plasma when factor IXa generated by the TF ⁄ VIIa complex on the TF

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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
TF–FVIIa complex activates X and XI.
VIIIa–IXa complex amplifies Xa pro-
duction from X. Thrombin is formed
from prothrombin by the action of
Xa–Va (prothrombinase) complex.
Thrombin activates XI, V and XIII,
and cleaves VIII from its carrier von
Willebrand factor (vWF), increasing
VIIIa–IXa and hence Xa–Va. TFPI ¼
Tissue factor pathway inhibitor.

cell diffuses through the circulating blood to the surface to interact with coagulation factors, and thereby initiates
of the activated paltelet. Activated factor IX then forms a thrombosis at these sites, until vessel wall damage occurs.
tenase complex with factor VIIIa on the platelet surface Circulating TF is present in both the whole blood and
and is able to activate factor X. Factor Xa forms the serum of healthy individuals [28, 29]. Eukaryotic cells
prothrombinase complex with factor Va, resulting in a shed membrane fragments that form circulating micro-
large thrombin generation especially on the platelet particles that contain TF [30].
surface to form a fibrin clot. Circulating tissue factor is necessary for the propagation
Deficiency of Factors VIII or IX produces severe of thrombus [31]. During thrombogenesis, tissue factor in
coagulopathy in the form of Haemophilia A or B, the vessel wall is rapidly enveloped by clot and cannot
respectively. The activation of Factor XI by thrombin have significant effects within the lumen of the blood
further increases activation of Factor IX, although this vessel. Normally, circulating tissue factor is present at
probably plays only a minor part in clot propagation. The levels too low to activate the clotting cascade. It is in an
additional thrombin generated by such back-activation inactive or encrypted form, and therefore cannot initiate
of factors directly and indirectly increases the amount coagulation. TF inactivity may be caused by asymmetrical
of fibrin present by activation of a fibrinolysis inhibitor distribution of negatively charged phospholipids across
[22, 23]. Factor XII is no longer considered to have any the cell membrane [32]. These phospholipids are required
significant role in normal coagulation [24]. for the binding of coagulation factors to the cell
It was believed that TF was expressed only in membrane and TF–FVIIa complex. Disruption of the
extravascular tissues by macrophages, monocytes and membrane allows this to occur. Encryption of TF into
fibroblasts [25–27]. However, it is also found in the vesicles or caveolae in the cell membrane prevents the
adventitia of blood vessels, organ capsules, and the initiation of coagulation. A rise in intracellular calcium
epithelium of skin and internal mucosae. TF is unable activates encrypted TF [33].

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In this revised hypothesis, tissue factor rather than

Tissue factor as a signalling receptor
‘contact’ factors is responsible for initiating coagulation.
Factors IX and VII are necessary for enhanced Factor Xa Intracellular signalling by the TF–FVIIa complex medi-
generation and sustained coagulation. A corollary to this ates the non-haemostatic functions of tissue factor.
hypothesis is that excessive bleeding in haemophiliacs Structural similarities between TF and the family of
(especially those with Factor VIII or IX inhibitors) can be cytokine receptors were first identified in 1990 [47], but it
alleviated by inhibiting the function of TFPI. was sometime before intracellular signalling by the TF–
FVIIa complex was demonstrated.
Binding of activated factor VII to membrane-bound
Tissue factor pathway inhibitor and the
tissue factor causes several intracellular effects [2], such as
regulation of coagulation
mobilization of intracellular calcium stores [48] and
TFPI is an inhibitor of the Factor VIIa ⁄ tissue factor transient phosphorylation of intracellular proteins [49].
complex. It occurs in two forms in man, TFPI-1 and One such protein which is activated by TF–FVIIa
TFPI-2. TFPI-1 is the main regulator of the tissue factor signalling is mitogen-activated protein kinase (MAPK)
pathway. TFPI-1, a Kunitz-type protease inhibitor, is a [50]. Phosphorylated MAPK enters the cell nucleus and
modular protein comprising three tandem units [34]; the activates several transcription factors. The actions of
first and second units inhibit TF–FVIIa and FXa, MAPK are implicated in tumour metastasis [51]. Alter-
respectively. The third Kunitz domain and the ations in cellular activity induced by this mechanism
C-terminal basic region of the molecule have heparin- include the up-regulation of poly(A)polymerase activity
binding sites [35]. TFPI is predominantly produced by the in fibroblasts [52], which may increase the stability of
microvascular endothelium [36]. There are three pools of cytokines. Cellular migration in both vascular smooth
TFPI in vivo: the majority of TFPI bound to the vascular muscle cells [53] and some tumour lines [54] is enhanced
endothelium, approximately 10% associated with lipo- by the activity of the TF–FVIIa complex, suggesting a
proteins in the plasma and a smaller portion present in role for the complex in tumour angiogenesis and
platelets. The normal concentration of TFPI in the plasma metastasis.
is approximately 100 ng.ml)1 [37]. Stored TFPI is The precise pathway of intracellular signalling activated
released into the plasma from the endothelial cells by by the TF–FVIIa complex, and the effect of this on
the action of heparin, and by platelet activation [38, 39]. specific changes in the target cell, is not fully understood.
The anticoagulant action of TFPI is a two-stage It is likely that members of the family of protease-
process. The second Kunitz domain binds first to a activated receptors (PARS) are involved in this signal
molecule of FXa and deactivates it. The first domain then transduction [55]. PAR2 is susceptible to activation by
rapidly binds to an adjacent TF–FVIIa complex, pre- the TF–FVIIa complex, and the TF–FVIIa-FXa complex
venting further activation of Factor X [40–42]. The can activate both PAR1 and PAR2.
formation of this quaternary compound is necessary for
the inhibitory action of TFPI on the TF-FVIIa complex.
Tissue factor and tissue factor pathway
This process does not occur in the absence of FXa,
inhibitor – clinical implications
indicating that coagulation must be initiated before TFPI
can function. The role of TF as a major player in the coagulation
TFPI inhibits the Fxa–TF–FVIIa complex. It presents cascade is well known [56] but its role as a pro-
itself as a substrate for the complex and occupies its active inflammatory agent is not widely appreciated [57]. The
sites. TFPI does not cleave readily, and prevents the pathophysiological roles of tissue factor and of its
complex from engaging other molecules [5]. TFPI also physiological antithesis, tissue factor pathway inhibitor
causes monocytes to internalise and degrade TF–FVIIa (TFPI), are discussed below.
complexes on the cell surface [43]. Circulating TFPI–
Fxa–TF–FVIIa complexes are metabolised by the liver The role of TF and TFPI in sepsis
[35]. TF is a procoagulant glycoprotein and a signalling
Heparin may exert its antithrombotic effect through receptor and is implicated in a wide variety of diseases
the TFPI pathway. Heparin induces TFPI synthesis and that are not directly related to haemostatic disorders [58].
secretion by endothelial cells [44, 45], and causes the The pathological conditions of interest to anaesthetists
displacement of TFPI bound to cell membranes. The and intensivists in which TF may play an important role
inhibitory effects of TFPI on the Fxa–TF–FVIIa com- are sepsis and thrombosis.
plex are enhanced significantly in the presence of Coagulation disorders are common in septic patients
heparin [46]. and it is perhaps not surprising that the role of TF has

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been extensively studied in various models of sepsis [59]. has an important dual role in sepsis, inflammation as well
Laboratory evidence suggests that TF is one of a number as its primary function in coagulation. The production
of secondary inflammatory mediators that are involved in of microvascular thrombi causes end organ damage that
the propagation of sepsis, sepsis syndrome and septic is observed in severe sepsis [71]. Its role as a pro-
shock [24]. Randolph and colleagues demonstrated that inflammatory agent is equally important.
mononuclear phagocytes reverse migrate across lymphatic TFPI is as essential for survival as TF. Mouse embryos
endothelium [60]. For this migration to occur it is bred to be devoid of TFPI do not survive the
essential that TF is expressed on the surface of these cells. intrauterine period [72]. Furthermore, to date no human
The tissue factor ⁄ activated factor VII complex enables the mutants with a congenital absence of TFPI have been
macrophages to produce reactive oxygen species that are described. Given the role of tissue factor in sepsis, its
essential for bacterial killing. These reactive oxygen physiological antagonist TFPI can potentially have a
species are not formed if anti TF antibody is administered therapeutic role. This has been studied in both animal
around these macrophages [61]. models and human trials. The role of TFPI in sepsis and
Various substances, such as endotoxin, tumour nec- disseminated intravascular coagulation is shown in rabbits
rosis factor (TNF)-a, interleukin-1 and activated com- immunodepleted of TFPI. In this rabbit model, infusion
plement, induce TF expression [62, 63]. An infusion of of TF at a level that would not induce coagulation in
endotoxin in healthy human volunteers activates tissue normal rabbits caused marked intravascular coagulation.
factor-dependent clotting. This ‘cross talk’ between the This intravascular coagulation also occurred when these
coagulation and inflammatory systems is increasingly rabbits were infused with endotoxin, adding to the
recognised. The central role of tissue factor as the sole evidence that endotoxin is a trigger for intravascular
activator of coagulation in sepsis has been confirmed by coagulation [73, 74]. The administration of human
laboratory studies [59, 64]. Animal models of sepsis are recombinant TFPI in a rabbit model of sepsis also
broadly divided into those where a septic insult is reduced the mortality in rabbits with gram-negative
administered systemically (intravenous injection of endo- peritonitis [75]. Other animal models of sepsis also show
toxin) or as a local phenomenon (caecal ligation and the benefit of TFPI. TFPI administered shortly after
puncture). The response in animal models depends on baboons received a lethal dose of Escherichia coli preven-
whether the initiating septic event is systemic or a local ted mortality in baboons. This positive result was
phenomenon. A primate model showed that the coag- reduced by 60% when the TFPI was administered 4 h
ulopathy associated with sepsis is significantly attenuated after the lethal dose of E. coli. The effects on coagulation
when the animal is pretreated with antitissue factor and inflammation were reduced, as indicated by the
antibodies [65–67], giving further evidence of the lower levels of circulating interleukin 6 [76]. However,
important role of tissue factor in inflammation. In a the infusion of TFPI did not cause haemodynamic
study comparing the effects of infusion of anti TNF instability. This is intriguing as the mechanism of
antibodies on systemic vs. local sepsis it was found that increased survival following TFPI infusion is not known.
inhibition of TNF activity attenuated the septic episode Other animal studies showed an improvement from
in systemic sepsis model, whereas it worsened outcome lipopolysaccharide-induced lung injury. A study in
in the local sepsis model [68]. This suggested that local Wistar rats showed that infusion of rTFPI reduced lung
area activation of primary (such as TNF) and secondary injury probably by inhibiting leucocyte activation [77].
mediators (such as TF) of inflammation are important to On the basis of these and other encouraging animal
prevent spread of local infectious stimuli. In systemic studies, human trials of recombinant tissue factor path-
sepsis, activation of primary and secondary mediators of way inhibitor were conducted. Initial encouraging
inflammation caused transient increases in TNF-a, results from small phase I and phase II studies indicated
causing severe systemic disturbances associated with that rTFPI is safe in humans with no increase in bleeding
septic shock. There is increasing experimental evidence [78]. Unfortunately, these earlier encouraging results
that TF is expressed on the cell membranes of mono- have not been achieved in a recently completed phase
cytes [69]. These TF-expressing monocytes initiate III trial, the OPTIMIST trial. There was no survival
coagulation, and this explains the link between the benefit with the administration of recombinant TFPI in
coagulation and immune systems. The procoagulant humans with severe sepsis [79].
effect of the cytokine-induced expression of TF is
complex. Both thrombin production and fibrinolytic The role of TF and TFPI in thrombosis
pathways are stimulated. However, fibrinolysis is short- Thrombosis occurs commonly in patients with coronary
lived compared with thrombin production, and this artery disease and malignancy. Experimental data show
results in a procoagulant tendency [70]. The TF pathway that atheromatous plaques contain a high concentration of

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TF relative to surrounding tissue [80]. In coronary artery Recombinant TFPI has been studied in spinal cord
disease, disruption of the coronary arterial wall by injury. In a rabbit model of ischaemic spinal cord injury,
atheromatous plaque formation, along with its rupture, neurological recovery was achieved in 88% of the rabbits
exposes tissue factor to circulating factor VII. This causes that received an infusion of rTFPI as compared to 20% in
initiation of clot and may lead to a myocardial infarction. the heparinization group [92].
In deep venous thrombosis the cause is less well defined, In a study comparing rTFPI to low molecular weight
but circulating inflammatory mediators may be involved. heparin (LMWH) in a venous thrombosis model using
The reason why deep venous thrombosis occurs at sites rabbit jugular veins, rTFPI was as effective as LMWH in
distant to surgical injury, where the vasculature has not decreasing the size of the thrombus. In addition rTFPI did
been damaged, is not known. Indeed, the initial thrombin not cause bleeding [93]. It is now clear that low molecular
plug is rapidly covered by platelets and fibrin, thus weight heparin increases the levels of TFPI in vivo [94],
covering the exposed tissue factor and preventing its and this may be one of the mechanisms by which these
continued activation. agents are effective in the prevention of deep vein
Abundant TF is found in atheromatous lesions as foamy thrombosis. The role of tissue factor pathway inhibitor in
macrophages in macrovascular disease in humans such as post surgical deep venous thrombosis in patients treated
aortic aneurysms, carotid arteries and coronary arteries with LMWH has been studied. In a group of postoper-
[81]. TF in these plaques is active and can induce ative orthopaedic patients, plasma levels of TFPI were
coagulation and clot formation [82]. Examination of significantly raised for up to 7 days in the patients treated
specimens obtained from patients with acute coronary with LMWH compared to controls [95]. A study of
syndromes demonstrated that higher levels of TF are patients who received enoxaparin for deep vein throm-
present in these lesions, providing additional evidence for bosis prophylaxis and underwent either hip ⁄ knee
the role of TF in these conditions [83]. arthroplasty or colectomy reported a linear relationship
Thrombosis is common in malignant disease and is between an increase in total ⁄ free TFPI ratio levels and
the second most common cause of death in cancer postoperative bleeding. Therefore measuring TFPI levels
patients [84]. It has been known for many years that in patients undergoing major surgery may be useful to
malignant cells express TF on their surface [85] and also allow stratification of their bleeding risk, and possibly
induce TF expression on non-malignant cells such as reduction in LMWH dose [96].
endothelial cells and monocytes [86]. The expressed TF In a study of venous thrombosis in a rabbit model in
can cause thrombosis in cancer patients, leading to which fibrin deposition was quantified on collagen-
pulmonary thrombo-embolism, migratory thrombo- coated threads within either the jugular vein or a silicon-
phlebitis and arterial thrombo-embolism as well as coated vein shunt, an inhibitory monoclonal antibody to
disseminated intravascular coagulation. Lung, breast, tissue factor was as effective as a specific thrombin
stomach, colon and pancreas tumours contain large inhibitor (napsagatran) in blocking thrombus formation
amounts of TF [87]. Membrane fragments containing [97]. The fact that inhibiting tissue factor activity had such
tissue factor are shed into the circulation and this can an impact on thrombus growth in the silicon vein shunt is
explain the hypercoagulable state so often seen in significant and indicates the transfer of active tissue factor
malignancy [88]. from some active component of blood to the surface of
Tissue factor pathway inhibitor has been extensively the growing thrombus [98].
studied as an agent to treat thrombotic disorders. Mural Recent developments in the physiology of coagulation
thrombus formed on ruptured plaque is resistant to indicate that exposure of the vessel wall-derived TF at the
heparinization and aspirin [89]. Animal and laboratory site of vascular injury is not always required [99]. Systemic
studies using TFPI to prevent thrombosis have been inflammation results in activation of coagulation due to
encouraging. TFPI that is concentrated from plasma tissue factor mediated thrombin generation [100]. Leuco-
inhibits fibrin formation in a flow model on endothelial cytes are a source of TF microparticles present in
cell matrix [90]. In a dog model (where dog femoral circulating blood. These TF microparticles are transferred
artery was injured leading to thrombosis) treatment to platelets during thrombus formation, thereby propa-
with tissue plasminogen activator and TFPI prevented gating further thrombus formation ⁄ growth. The inhibi-
reocclusion of the femoral artery [91]. As re-stenosis is tion of TF-transfer and TF-activity is an attractive target
a major problem after coronary artery thrombosis with for antithrombotic therapy [101–2]. More studies are
or without balloon angioplasty or stenting, and aspirin required to determine the extent to which TF and TFPI
and heparin only partially prevent re-stenosis, the contribute to the pathophysiology of sepsis and other
potential benefits of TFPI in these patients may be conditions so that new therapeutic approaches can be
envisaged. exploited.

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