Morawitz was the first to describe the clot-promoting substance found in tissues (tissue factor) and introduced it into his clotting theory. He proposed a clotting theory which influenced research in this field over the next 50 years.
Until 1962 12 main clotting factors were described, but their interrelationship was unknown. In 1964, Davie and Macfarlane independently formulated the “cascade theory” of in vivo clotting. Only 30 years later, in 1995, Rapaport and Rao were able to write “Thus little reason exists today to doubt that the binding of factor VII to TF and the subsequent reactions so triggered play a ‘prima ballerina’ role in the initiation of coagulation process.”
In 1987, the efficiency of purification of human tissue factor (TF) from brain and placenta was greatly improved by using a monoclonal antibody against human tissue factor on immunoadsorbent columns. Monoclonal antibodies against human tissue factor allowed immunohistochemical localization of tissue factor in different organs and tissues for the first time. The next step was to isolate the tissue factor gene. Four different groups published the cDNA sequence of the tissue factor gene and its 50 and 30 flanking sequences concurrently in 1987 (Fisher et al. 1987; Morrissey et al. 1987; Scarpati et al. 1987; Spicer et al. 1987).
Cellular and molecular mechanisms underlying tissue factor function are pluripotential. But there is no doubt that tissue factor is the key element of initiation of external coagulation pathway and seems to be the leading factor of trombogenicity of atherosclerotic plaque.
Tissue factor is also unique in that no congenital deficiency of this factor has been established. In the mouse embryo, tissue factor deficiency led to fetal death signifying its importance in maintaining life.
Tissue Factor Structure
Extracellular domain is presented by NH2-terminal molecular part (amino acid residues from 1 to 219) and is made up of two fibronectin molecules of type III. There are three potential N-terminal binding areas with carbohydrates (Muller et al. 1994).
Transmembrane hydrophobic domain by which tissue factor is fixed to the membrane (amino acid residues from 220 to 242).
Cytoplasmic COOH-terminal domain.
Amino acid sequences transcribed from nucleotide sequences of human placental DNA code have shown that tissue factor derives from a larger precursor molecule. The latter has an additional sequence of 32 amino acids (Spicer et al. 1987).
Extracellular and transmembrane domains of tissue factor play an essential role in hemocoagulation (Muller et al. 1994; Edgington 1991). Cytoplasmic domain is significant in signal transduction. It is considered that tissue factor without cytoplasmic domain is functionally totally identical to the initiating thrombin generation protein. In addition, recombinant tissue factor deprived of both transmembrane and cytoplasmic domains is unable to fix to the cell membrane. It cannot activate factor VII and has decreased catalytic efficiency in relation to factor IX and factor X, although it can form a complex with factor VIIa (Fiore et al. 1994).
Regulation Mechanisms of Tissue Factor Expression
Tissue factor expression is principally regulated at the translation level (Mackman 1997). Promotor element of human tissue factor contains five binding sites with the specific protein-1 (Sp1), three binding sites with epidermal growth factor-1 (Egr-1), two binding sites with activator protein 1 (AP-1), and one binding site with nuclear factor kappa B (NF-κB). It is considered that Sp1 sites are mainly responsible for stable expression of tissue factor basal level. Sites Egr-1, AP-1, and NF-κB are primarily responsible for induced expression of tissue factor (Ruf et al. 1991; Mackman 1997). Many cells can produce TF when they are stimulated in vitro by various agents. It is known that tissue factor expression in endothelial cells and in monocytes/macrophages can be induced by tumor necrosis factor-alpha (TNFa), interleukin-1β, ligand CD40, bacterial lipopolysaccharide (LPS), vascular endothelial growth factor, oxidated and acetylated low-density lipoproteins (oxLDL), hypoxia, and hemodynamic stress (Mackman 2004). Aberrant expression of tissue factor can lead to fatal consequences as seen with sepsis, malignancy, and atherosclerosis.
It has been proposed that encryption is the posttranslational suppression of TF procoagulant activity (PCA) on the cell surface. Encrypted TF in normal blood is associated with monocytes and platelets. Tissue factor (TF) procoagulant activity (PCA) is not fully expressed in an otherwise normal unperturbed cell. Lipid raft association may also contribute to TF encryption.
An increase in cytosolic calcium can lead to the decryption of TF PCA. The final step in the decryption of TF PCA is the activation of zymogen factor VII.
Tissue factor differs from other cofactors of hemocoagulation cascade which circulate in inactive state. Tissue factor expressed on the cell surface is functionally active. Tissue factor is present in subendothelial tissue, in thrombocytes and leukocytes, in vascular adventitia, in astrogliocytes and in visceral capsules and is found in relatively high concentration in central nervous system, in lungs, in myocardium (Mackman and Parker 2014) and in placenta (Eddleston et al. 1993; Butenas et al. 2009).
It has been established that tissue factor plays the leading role in pathogenesis of vascular diseases, systemic inflammation, and hemocoagulation. It is significant in cross inflammation processes and coagulation (Mackman 2004; Piazza and Ridker 2015). Tissue factor can bind with cell receptors, where, in its turn, it contributes to the production and release of inflammatory mediators. It has been shown that monocytes and macrophages express tissue factor after cytokine stimulation (Bouchard et al. 2003).
The Role of Tissue Factor in Hemocoagulation
Tissue factor is necessary for the conversion of prothrombin into thrombin (Mackman 2004). In extrinsic coagulation pathway tissue factor activates factor VII (Mariani et al. 1999). Activated factor VII, in its turn, activates coagulation factors IX and X. Activated factor X in the presence of factor V, calcium ions, and thrombocyte phospholipids converts prothrombin into thrombin. In intrinsic coagulation pathway FVIIIa/FIXa complex initiates blood coagulation by means of factor Xа generation. Activated factor Xа forms prothrombinase complex which provides the transformation of prothrombin into thrombin [Demetz and Ott 2012).
Thrombin carries out several functions. It contributes to the conversion of fibrinogen into soluble fibrin monomers. Thrombin transforms factor FXIII into factor FXIIIa, which binds fibrin monomers together. Thrombin activates factor XI which contributes to the generation of factor IXa active form by the alternative pathway (Butenas et al. 2003; Walsh 2003).
Recent studies demonstrated a role of tissue factor apart from hemostasis. Tissue factor plays a role in generation of coagulation proteases, and subsequent activation of protease activated receptors on vascular cells. This TF-mediated signaling leads to a number of biological processes like inflammation, angiogenesis, metastasis, and cell migration (Mackman 2009).
Tissue factor was incorrectly called thromboplastin. Thromboplastin was a lab reagent used to assay prothrombin time. Thromboplastin is the combination of both phospholipids and tissue factor, both needed in the activation of the extrinsic pathway of coagulation.
TF is expressed mainly on subendothelial tissues, but TF expression may be induced on endothelial cells by inflammatory mediators such as tumor necrosis factor (TNF-alpha). TF may also be found circulating on monocytes, on microparticles derived from various cellular sources, and in a soluble form arising from alternate processing of the TF gene. Subendothelial TF is responsible for initiating fibrin formation at sites of vascular injury; blood-borne TF may be an important contributor to propagation of the developing thrombus. Procoagulant activity of TF is regulated by tissue factor pathway inhibitor (TFPI) (Bajaj et al. 2001; Dennis et al. 2004).
In 1999, Giesen PL and colleagues examined thrombus formation on pig arterial media (which contained no stainable TF) and on collagen-coated glass slides (which were devoid of TF) by exposing them to flowing native human blood. In both the conditions, the thrombi stained intensely for TF, much of which was not associated with cells. Again antibodies against TF caused reduction in the amount of thrombus formed on both. A potent inhibitor of TF, factor VIIai, abolished fibrin production and markedly reduced the mass of the thrombi. They also revealed TF-positive membrane vesicles by immunoelectron microscopy. They measured TF by factor Xa formation from whole blood and plasma of healthy subjects. Immunostaining demonstrated TF-containing neutrophils and monocytes in peripheral blood. They concluded that leukocytes are the main source of blood-borne TF which is inherently thrombogenic and may be involved in thrombus propagation at the site of vascular injury (Giezen a, b).
The Role of Tissue Factor in Inflammation and Angiogenesis
Recent studies have shown that tissue factor takes part not only in hemostasis. Tissue factor is required for the formation of coagulation proteases and activation of their receptors on the vascular wall, which provokes intravascular thrombosis (Mackman 2004). Tissue factor modulates signal pathways for a number of biological processes, such as inflammation, angiogenesis, metastasis, and cell migration (Rickles et al. 2003; Mackman 2004; Steffel et al. 2006; Demetz and Ott 2012; Caterina 2015; Chu 2005, 2006, 2011). Tissue factor expression on the cells outside the vascular wall plays an essential role in hemostasis; on the other hand, its expression on endothelium induces intravascular thrombosis (Rickles et al. 2003; Borisoff et al. 2011).
Thrombocyte stimulation through protease receptors accelerates coagulation cascade. Most of these receptors are in the lipid anchors of stimulated thrombocytes. Lipid anchors are microdomains rich in cholesterol and sphingolipids, where membrane ligands localize and stimulation of cell signal pathways occurs (Baglia et al. 2003).
Thrombocytes accelerate coagulation cascade both by means of binding with factor XI through its glycoprotein receptor Ib-IX-V and by producing thrombogenic surface for prothrombinase complex.
There are four groups of receptors activated by thrombocytes (PAR). They are called PAR1, PAR2, PAR3, and PAR4. Each group of these receptors is activated by different proteases. Complex TF/FVIIa activates PAR2 (Camerer et al. 2000). Factor Xa activates both PAR1 and PAR2. Thrombin activates PAR1, PAR3, and PAR4. The study of keratinocytes and endothelial cells activated by cytokines has shown that PAR2 is directly influenced by complex TF/FVIIa and indirectly by factor X, whose active form is also generated by the complex described above (Mackman 2004). Basing on this evidence, it is suggested that PAR2 which are not activated by thrombin can act as sensors for coagulation proteases. This function contributes to endothelial activation in cases of damage or inflammation (Zhu et al. 2011). PAR represent a perfect mechanism providing the transfer of information about vascular wall mechanical injury to the cells (Zhu et al. 2011). Thus PAR participate in hemostasis, thrombosis, inflammation, and even in vascular wall formation.
PAR1, PAR2, and PAR4 are expressed in different cells of the vascular wall including endotheliocytes. The mediators of thrombin-mediated thrombocyte activation in a human are PAR1 and PAR4 (Coughlin 2000).
There are contradictory data about the integration into the cell membrane and release of tissue factor (Butenas et al. 2005). It was demonstrated that the integration was accompanied by posttranslational suppression of tissue factor procoagulant activity on the surface of the cell membrane (Butenas et al. 2004). In the bloodstream tissue factor is usually integrated into the cell membrane of thrombocytes and monocytes (Walsh 2003). In an undamaged cell tissue factor, procoagulant activity does not manifest itself anyway (Mackman 2004). The increase in ionized calcium content in cytosol can lead to the development of tissue factor procoagulant activity followed by activation of factor VII (Maly et al. 2003).
In 2006 C.E. Henriksson and co-workers established that ionized calcium increased intracellular activity of tissue factor but not of the tissue factor antigen on the surface of the cell membrane. This discrepancy between the activity of tissue factor itself and its antigen correlated with the increase in the number of cells containing phosphatidylserine, with most of them in necrotizing state and expressing tissue factor. The authors suggested that the dying cells containing tissue factor contributed to the discrepancy between the activity of tissue factor and its expression (Henriksson et al. 2007).
In 2008 J.J. Stampfuss and co-workers proposed that monocyte apoptosis resulted in significant increase of their procoagulant functions due to the tissue factor hyperexpression in cytoplasm and on the cell membrane.
Tissue factor is predominantly presented in subendothelium, but its expression on endothelial cells can be induced by such proinflammatory mediator as tumor necrosis factor-alpha (Kambas et al. 2008). Tissue factor can also be found on circulating monocytes, in microparticles produced by different cell surfaces, as well as in a soluble form resulting from the alternative way of genetic synthesis (Dietzen et al. 2004; Freeburn 1998). Subendothelial fraction of tissue factor is responsible for fibrin formation in damaged regions of vascular wall; the fraction circulating in blood significantly contributes to the thrombus formation (Bode and Mackman 2014). Procoagulant tissue factor activity is regulated by tissue factor inhibitor (Dietzen et al. 2004).
It has not been clear so far how tissue factor circulates; it can also be present in procoagulant microparticles.
In 2003 V.Y. Bogdanov and co-workers identified a tissue factor form synthesized by the alternative way. They found out that tissue factor synthesized by the alternative way predominantly contained extracellular domain but lacked transmembrane domain. Attachment of that tissue factor fraction to the thrombus surface provoked its further growth.
However the studies of P. Censarek and co-workers (2007) revealed that tissue factor synthesized by the alternative way did not have procoagulant activity. That tissue factor fraction was found to be associated with tumor cell proliferation and angiogenesis (Hobbs et al. 2007).
The contradiction in the assessment of tissue factor level in circulating blood results from the absence of reliable standards for its definition. Physiologically active tissue factor circulates in blood in concentrations over 30 pmoles both as corpuscle component and in the form of microparticles and as plasma protein as well (Butenas et al. 2005). However there has never been a description of a blood clot which would lack exogenous tissue factor. The addition of tissue factor to the whole blood in the amount of 16–20 fmoles was followed by the acceleration of blood clot formation. According to S. Butenas and colleagues, the concentration of physiologically active tissue factor not stimulated by cytokines does not exceed 20 fmoles in healthy people. The authors did not reveal any tissue factor or its antigen activity on native and ionophore-stimulated thrombocytes as well as on blood plasma mononuclear cells in the absence of stimulation, while the whole blood stimulated by lipopolysaccharide contained an essential fraction of monocytes expressing tissue factor. P.L. Giesen and colleagues in 1999 came to the conclusion that leukocytes were the main source of circulating in blood tissue factor involved into thrombus formation in vascular wall damaged regions.
In addition, tumor cells also express TF. It is now evident that tumor angiogenesis, metastasis, and invasiveness are highly dependent on components of the blood coagulation cascade. TF is known as a mediator of intracellular signaling events which can alter gene expression and cell behavior (Buzby et al. 2014). TF significantly participates in tumor-associated angiogenesis. Its expression has been correlated with the metastatic potential of many types of hematological malignancies (López-Pedrera et al. 2006).
Tissue Factor Involvement in Atherogenesis
Tissue factor plays an essential role in atherogenesis (Tremoli et al. 1999; Mackman 2004; Smith et al. 2005). Tissue factor is found in vascular adventitia and in lipid core of atherosclerotic plaque (Mackman 2004). Atherosclerotic plaque damage initiates coagulation due to the tissue factor flow from the lipid core to circulating blood (Wilcox et al. 1989). Tissue factor’s biologically active form is detected both in the vascular wall and circulating blood. It has been reported that TF intravascular fraction is increased in such prothrombotic syndromes as myocardial infarction, sepsis, and antiphospholipid syndrome (Tremoli et al. 1999; Moons et al. 2002; Rickles et al. 2003; Mackman 2004). Tissue factor expression increases in endothelial damage.
The term “vulnerable plaque” refers to the atherosclerotic plaque prone to rupture. At the site of plaque rupture, there is an accelerated entrance of its nucleus components, including tissue factor, into the circulating blood. This leads to the activation of coagulation cascade with the following thrombosis and vascular occlusion.
The term “vulnerable blood” refers to the blood predisposed to hypercoagulation. There are two different fractions of circulating tissue factor described. One of them is associated with the microparticles produced by cells in apoptosis, such as macrophages, smooth muscle cells, and endothelium. The other tissue factor fraction circulates in inactive form and, when activated, additionally reinforces thrombogenic potential (Mackman 2004).
Blood microparticles are vesicular structures with a diameter of 100–1,000 nm. They are present in the blood of normal subjects and in patients with various diseases. Microparticle membranes retain the protein receptors of their parent cells and may retain RNAs and other cytosolic content. On the basis of surface protein expression, microparticles are known to be derived from platelets, granulocytes, monocytes, endothelial cells, smooth muscle cells, and tumor cells. A subpopulation of these microparticles expresses tissue factor (Zwicker et al. 2011).
Human atherosclerotic plaques contain microparticles which are released during cell activation or apoptosis. Large amounts of microparticles are found in plaques but not in healthy vessels. Studies by Leroyer AS et al. have shown that microparticles are more abundant about 200 times and more thrombogenic in human atherosclerotic plaques than in plasma.
It has been established that TF initiates thrombogenic stimulus leading to the formation of a more stable thrombus. Tissue factor pool of plasma comprises TF associated with microparticles, its degradation products, and TF synthesized by the alternative way (Nieuland et al. 1997; Mackman 2004). Microparticles are lipid vesicles produced by thrombocytes, leukocytes, and endothelial cells (Ramacciotti et al. 2009; Zwiker et al. 2011).
Human atherosclerotic plaque contains microparticles which are produced during cell activation or their apoptosis (Stampfuss et al. 2008). A large number of microparticles was revealed in atherosclerotic plaques, but they were absent in healthy vessels (Drake et al. 1989). A.S. Leroyer and colleagues in 2007 reported that microparticles from atherosclerotic plaque were much more thrombogenic than microparticles of plasma. The microparticles in atherosclerotic plaque were mainly produced from leukocytes. In that study it was shown that microparticles both from atherosclerotic plaque and plasma contained tissue factor and generated thrombin, though that activity was twice higher in microparticles isolated from atherosclerotic plaques (Leroyer et al. 2007; Stojkovic 2014).
There was a study of tissue factor expression in smooth muscle cells of human coronary arteries. Tissue factor expression on the surface of smooth muscle cells was short-living, which limited thrombogenic potential of intact smooth muscle cells. On the other hand, intracellular pool is an additional source of TF. This may be meaningful in cases of smooth muscle cell damage, for instance, in atherosclerotic plaque erosion or in carrying out balloon angioplasty.
In myocardial infarction thrombocyte activation and endothelial apoptosis occur in response to the release of procoagulant microparticles from cell membranes into the blood stream (Morel et al. 2009). In patients with myocardial infarction and ST segment elevation, the levels of microparticles produced by leukocytes, endotheliocytes, and microparticles containing tissue factor were significantly higher in coronary artery occlusion zone, than in peripheral blood specimens (Morel et al. 2009). After coronary angioplasty and reestablished coronary blood flow, there was a significant reduction of procoagulant microparticles of leukocyte and endothelial origin (by 30% and 42%, correspondingly). Thus the increase of procoagulant microparticles in occluded coronary artery in patients with myocardial infarction associated with ST segment elevation seems to have a pathophysiologic role in coronary atherothrombosis (Morel et al. 2009).
It was determined that in patients who had undergone fibrinolysis for myocardial infarction with ST segment elevation, arterial recanalization in the infarct zone occurred in approximately 60% of cases (Huisse et al. 2009). There was an investigation of different hemostasis biomarkers in patient groups with myocardial infarction, who had not had recanalization after fibrinolysis. Unsuccessful fibrinolysis in myocardial infarction was characterized by a high procoagulant status due to the microparticles with tissue factor and low plasmin generation (Huisse et al. 2009).
In experimental trials it was reported that rapamycin intensified the activity of tissue factor and provoked arterial thrombosis in vivo in concentrations adequate to its content in drug-coated stents (Camici et al. 2010). The effect of second-generation drugs for drug-coated stents – everolimus and zotarolimus – was studied on the model of carotid artery photochemical damage of a mouse. Rapamycin, everolimus, and zotarolimus appeared to increase tissue factor expression, TNF alpha induced, by 2.2, 1.7, and 2.4 times, correspondingly, along with the increase of tissue factor superficial activity. These data should be taken into account in the construction of second-generation drug eluting stents (Camici et al. 2010).
B. Ray and colleagues in 2007 determined that in patients with intermittent claudication, tissue factor plasma concentration was significantly higher than in control group. The highest TF concentration was found in blood plasma of patients, who developed restenosis after iliofemoral angioplasty (Ray et al. 2007).
It is evident that proinflammatory mechanisms involved in atherosclerosis development can be accelerated under the influence of different factors, such as low-density lipoproteins, peroxidation products, activated blood cells, interleukins, interferon gamma, and CRP (Mallat et al. 1999; Ross 1999; von der Thüsen et al. 2003). It was found out that adipose tissue was functionally active and obesity predisposed to proinflammatory status (Libby 2002; Wang et al. 2010). The in vitro studies with resistin, recently described cytokine produced by adipose tissue, demonstrated that it induced proliferation of human coronary artery smooth muscle cells in dose-dependent degree by extracellular signal kinase and phosphatidylinositol kinase-3 activation (Calabroa et al. 2011). It was revealed that incubation with resistin induced tissue factor microRNA transcription and de novo functionally active TF synthesis. It was established that resistin-induced tissue factor activity in human endotheliocytes was enhanced by peroxidation products, and nuclear factor kappa B transcription potentially modulated that phenomenon (Calabroa et al. 2011).
J. Kim and colleagues in 2010 studied the pathogenetic role of receptor activator for nuclear factor ligand (RANKL) in advanced atherosclerosis (particularly, in atherosclerotic plaque rupture and destabilization). Polymerase chain reaction with reverse transcription and chromosomal analysis showed that RANKL elevated tissue factor microRNA level and procoagulant activity of macrophages (Kim et al. 2010).
One study demonstrated that interleukin-10 (IL-10) expression resulted in the suppression of tissue factor, IL-6, and TNF alpha synthesis (Baker et al. 2009).
Medicinal Correction of Tissue Factor Expression
Statins are the first-line drugs in carrying out secondary prevention of atherosclerosis in CAD patients (ГрацианскийН 1997). Simvastatin and ezetimibe effects on different parameters, including CRP and tissue factor level, were studied (Bruni et al. 2003). Both drugs improved lipid profile values and reduced CRP concentration; however they did not affect tissue factor and Willebrand factor levels (Kostakoua et al. 2010).
However another study investigated the effect of atorvastatin on tissue factor activity in thrombin-stimulated endotheliocytes, as well as the regulation of that activity by mevalonate and its derivatives (Martinez-Sales 2011). Tissue factor activity was assessed through its ability to induce factor Xa production. It was established that atorvastatin prevented thrombin-induced TF activation. Mevalonate and geranylgeranyl pyrophosphate reduced that inhibiting effect of atorvastatin on tissue factor activity, while farnesyl pyrophosphate did not produce such an effect (Martinez-Sales 2011).
Therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists contributed to the decrease of tissue factor level in patients with arterial hypertension (Soejima et al. 1999; Koh et al. 2004).
A new tendency in therapeutic strategy is the production of antibodies to tissue factor (Steffel et al. 2006).
Tissue Factor and the Risk of Coronary Artery Disease
In a number of clinical trials, it was revealed that tissue factor level in blood plasma was associated with the risk of acute coronary syndrome (Annex 1995; Suefuji et al. 1997; Misumi 1998; Falciani 1998) and myocardial infarction (Habis et al. 2000; Seljeflot et al. 2003; Campo et al. 2006; Morange et al. 2007; He et al. 2008). The increased level of tissue factor is the predictor of restenosis in CAD patients after angioplasty (Tutar et al. 2003).
There are several polymorphous variants of tissue factor gene (Arnaud et al. 2000; Opstad et al. 2010). A. Malarstig and colleagues in 2005 established that A5466G polymorphism of tissue factor gene was associated with the risk of cardiovascular death in patients with acute coronary syndrome (Malarstig 2005). In A allele carriers, there was revealed a threefold increase in the risk of fatal outcome. A. Evangelista and colleagues in 2015 did not find an association of TF A5466G polymorphism with venous and arterial thrombosis.
In G allele carriers of A603G polymorphism of tissue factor gene, there was an increased risk of myocardial infarction (Ott et al. 2004). It was in patients – G allele carriers – that a high concentration of tissue factor in blood plasma was found (Ott et al. 2004). In literature there are almost no clinical trials concerning the study of the abovementioned genotype association with the CAD onset age, myocardium, and vascular wall remodeling (Reny et al. 2004).
Thus tissue factor is not only the key element of atherothrombosis but also correlates with immunoinflammatory process and endothelium dysfunctions and has a prognostic value in patients with coronary artery disease.
Tissue Factor, Angiogenesis, and Myocardium Remodeling
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