Tissue Factor and Tissue Factor Pathway Inhibitor

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.

........................................................................................................

Correspondence to: P. C. A. Kam

E-mail: [email protected]

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 significantly. 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 inflamma-

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 modification 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

fibrin plug from fibrinogen (Fig. 1).

Deficiencies 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. Deficiency of

Anaesthesia, 2004, 59, pages 483–492.....................................................................................................................................................................................................................

� 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 protein–protein

interactions.

Several clinical and experimental observations suggest

that the cascade ⁄waterfall hypothesis does not accurately

reflect the events of in vivo haemostasis. Patients

deficient in the contact factors (e.g. Factor XII) do

not suffer bleeding problems. John Hageman, the first

patient identified with Factor XII deficiency, 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-deficient plasma using a

physiological concentration of tissue thromboplastin, the

result was abnormal [8]. She postulated that Factor

VII ⁄Ca2+ ⁄ tissue factor complex was of greater signifi-

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-

deficient) patients have a milder clinical picture than

patients with Factor IX (haemophilia B) deficiency.

Patients with isolated Factor VII deficiency 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 deficient 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 (TF–FVIIa) induces a con-

formational change in the protease domain of Factor VII,

which causes it to become active [18]. TF–FVIIa 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 TF–FVIIa complex activates Factor IX as well as

Factor X [19–21] 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 fibrin 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 sufficient 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.

G. C. Price et al. Æ Tissue factor and tissue factor pathway inhibitor Anaesthesia, 2004, 59, pages 483–492......................................................................................................................................................................................................................

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 fibrin clot.

Deficiency 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 fibrin present by activation of a fibrinolysis inhibitor

[22, 23]. Factor XII is no longer considered to have any

significant role in normal coagulation [24].

It was believed that TF was expressed only in

extravascular tissues by macrophages, monocytes and

fibroblasts [25–27]. 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 significant 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 TF–FVIIa 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 therevised theory of coagulation. In vivo,coagulation is initiated by tissue factor,present on the perivascular tissuesurfaces, binding to factor VII. TheTF–FVIIa complex activates X and XI.VIIIa–IXa complex amplifies Xa pro-duction from X. Thrombin is formedfrom prothrombin by the action ofXa–Va (prothrombinase) complex.Thrombin activates XI, V and XIII,and cleaves VIII from its carrier vonWillebrand factor (vWF), increasingVIIIa–IXa and hence Xa–Va. TFPI ¼Tissue factor pathway inhibitor.

Anaesthesia, 2004, 59, pages 483–492 G. C. Price et al. Æ Tissue factor and tissue factor pathway inhibitor......................................................................................................................................................................................................................


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

first and second units inhibit TF–FVIIa 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 first to a

molecule of FXa and deactivates it. The first domain then

rapidly binds to an adjacent TF–FVIIa complex, pre-

venting further activation of Factor X [40–42]. 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 Fxa–TF–FVIIa 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 TF–FVIIa

complexes on the cell surface [43]. Circulating TFPI–

Fxa–TF–FVIIa 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 Fxa–TF–FVIIa com-

plex are enhanced significantly in the presence of

heparin [46].

Tissue factor as a signalling receptor

Intracellular signalling by the TF–FVIIa complex medi-

ates the non-haemostatic functions of tissue factor.

Structural similarities between TF and the family of

cytokine receptors were first identified 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 TF–FVIIa

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 fibroblasts [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 TF–FVIIa complex, suggesting a

role for the complex in tumour angiogenesis and

metastasis.

The precise pathway of intracellular signalling activated

by the TF–FVIIa complex, and the effect of this on

specific 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 TF–FVIIa complex, and the TF–FVIIa-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-

inflammatory 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



been extensively studied in various models of sepsis [59].

Laboratory evidence suggests that TF is one of a number

of secondary inflammatory 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 inflammatory systems is increasingly

recognised. The central role of tissue factor as the sole

activator of coagulation in sepsis has been confirmed 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 significantly attenuated

when the animal is pretreated with antitissue factor

antibodies [65–67], giving further evidence of the

important role of tissue factor in inflammation. 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 inflammation are important to

prevent spread of local infectious stimuli. In systemic

sepsis, activation of primary and secondary mediators of

inflammation 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 fibrinolytic

pathways are stimulated. However, fibrinolysis 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, inflammation 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-

inflammatory 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 benefit 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 inflammation 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

benefit 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



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 defined,

but circulating inflammatory 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 fibrin, 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 fibrin formation in a flow 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 benefits 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

significantly 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 stratification of their bleeding risk, and possibly

reduction in LMWH dose [96].

In a study of venous thrombosis in a rabbit model in

which fibrin deposition was quantified 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 specific 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

significant 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

inflammation 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 [101–2]. 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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Tissue Factor and Tissue Factor Pathway Inhibitor

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