Tissue Factor And Tissue Factor Pathway Inhibitor

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

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: [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 inflammatory 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 therapies arising from the modification of these pathways. Tissue factor and coagulation

Tissue factor, a class 2 cytokine receptor, is a transmembrane glycoprotein that consists of three sections: a large extracellular domain, a transmembrane segment, and a cytoplasmic tail [3, 4]. The extracellular domain is important for its haemostatic activity [5]. The transmembrane portion is necessary for stabilization of the molecule and  2004 Blackwell Publishing Ltd

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 biochemical 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, indicating 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 apparent inconsistencies in clinical practice. Deficiency of 483

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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

Figure 1 Outline of the waterfall ⁄ cascade theory of coagula-

tion.

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 significance 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 XIdeficient) 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 factorinitiated 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 484

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 conformational 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 prothrombin 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  2004 Blackwell Publishing Ltd

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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 production 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 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  2004 Blackwell Publishing Ltd

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 microparticles 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]. 485

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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 first and second units inhibit TF–FVIIa and FXa, respectively. The third Kunitz domain and the C-terminal basic region of the molecule have heparinbinding 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 lipoproteins 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, preventing 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 complex are enhanced significantly in the presence of heparin [46]. 486

Tissue factor as a signalling receptor

Intracellular signalling by the TF–FVIIa complex mediates 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]. Alterations 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 proteaseactivated 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 proinflammatory 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  2004 Blackwell Publishing Ltd

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

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 necrosis factor (TNF)-a, interleukin-1 and activated complement, 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 endotoxin) 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 coagulopathy 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 monocytes [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 shortlived compared with thrombin production, and this results in a procoagulant tendency [70]. The TF pathway  2004 Blackwell Publishing Ltd

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 proinflammatory 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 prevented 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 pathway 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 487

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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 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 thrombophlebitis 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. 488

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 postoperative 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 thrombosis 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 collagencoated threads within either the jugular vein or a siliconcoated 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]. Leucocytes are a source of TF microparticles present in circulating blood. These TF microparticles are transferred to platelets during thrombus formation, thereby propagating further thrombus formation ⁄ growth. The inhibition 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.  2004 Blackwell Publishing Ltd

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