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TF titrations in contact pathway inhibited whole blood a and plasma b from healthy individuals. Black and white bars represent two healthy donors. This figure was originally published in Blood [ 11 ]. Figure 6. Factor Xa generation was monitored in a chromogenic assay. This figure was originally published in J Biol Chem [ 12 ]. References J. Lawson, S. Butenas, and K. View at: Google Scholar N. Butenas and K. View at: Google Scholar J.
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Bodian, E. Jones, K. Harlos, D. Stuart, and S. Martin, D. O'Brien et al. Baron, A. Main, P. Driscoll, H. Mardon, J. Boyd, and L. Dean, C. Bowlus, and S. Main, T. Harvey, M. Baron, J. Boyd, and I. Muller, M. Peppelenbosch and H. Bouchard, M. Shatos, and P. Schecter, B. Spirn, M. Rossikhina et al. Flossel, T. Luther, M. Muller, S. Albrecht, and M. Drake, J. Morissey, and T. Fleck, L. Rao, S. Rapaport, and N. Eddleston, J. Oldstone, D. Loskutoff, T. Edgington, and N. Bloem, L. Chen, W.
Konigsberg, and R. Levi, T. Bouchard and P. Nijziel, R. Van Oerle, C. Van't Veer, E. Van Pampus, T. Lindhout, and K. Broussas, P. Potron, and P. Ando, S. Kase, T. Ohashi et al. Edwards, F. Rickles, and M. Ruf and B. However, TF-mediated cell signaling can thereby occurs through mechanisms related or not related to its intracellular part. For example, PAR-2 cleavage and certain proximal signaling responses of TF-FVIIa do not require the TF cytoplasmic domain 74 , while it seems essential for signaling complexes and protein trafficking i.
Moreover, Pin1 increases both the protein half-life and pro-coagulant activity of TF in vascular cells. However, TF cytoplasmatic and intracellular domains seem not essential for some biological functions. These conclusions come from the studies performed on the variant of TF generated by an alternative splicing of its mRNA that creates a soluble isoform asTF lacking of the transmembrane and cytoplasmic domain Despite of its procoagulant activity is still matter of debate 11 , 56 , asTF retains the ability to ligate integrins 24 which might be considered as the main asTF signaling, independently of PAR2 pathway.
TF integrin signaling and its implications in angiogenesis and migration has been recently further clarified. Transactivation of matriptase may connect coagulation cascade to epithelial defense and repair programs and contribute to pathogenic effects of extrinsic pathway activation in cancer and inflammation Based on these data and on those described in other reports 71 , TF cytoplasmatic domain and PAR2-signaling seems to cooperate for a regulatory role in angiogenesis and tumor growth in breast cancer 86 as well as in hepatocellular carcinoma It has been also shown that in intestine TF cytoplasmic domain participates in TF trafficking and surface localization and in cooperation with PAR1 signaling in adaptive angiogenesis following colonization of the small intestine with microbiota TF is upregulated in the obese visceral adipose tissue and expressed by adipose tissue macrophages This novel cooperative role of TF signaling in innate immune response is regulated by the anticoagulant PC pathway The role of TF in inflammation is, at least in part, mediated by endothelial cell, predominantly through intracellular signaling rather than coagulation activation In experimental animal models, TF signaling is linked to upregulation of IL-6 without changing markers of intravascular coagulation A recent report indicates that TF is regulated in endothelial cell by the anti-oxidative protein PON2, a cell-associated protein with anti-atherogenic properties In experimental model of PON2 deficiency, a post-transcriptional upregulation of endothelial cell TF activity and a proinflammatory state, via expression of IL-6 and CCL22, is observed 97 , 98 , thus linking the loss of PON2 antioxidant functions to vascular inflammation and dysfunction.
The evidences that TF, besides activating coagulation cascade, has a role as a true receptor on surface of several cells have opened a new scenario in the pathophysiology of cardiovascular disease. Acute cardiovascular events occur when atherosclerosis, a chronic disease that progresses silently and often without any clinical manifestation, evolves toward acute thrombotic complications The thrombogenic role of TF in these events has been well characterized over the past years 3 , 8 , On the contrary, although it has been shown that TF is expressed in several human tissues , including healthy vascular vessel wall and atherosclerotic lesions it is still under investigation whether this glycoprotein might play a role in atherosclerotic plaque development and progression.
It is known that proliferation and migration of smooth muscle cells is an important step in atherosclerotic plaque grow and stability It is known that plaque neovascularization may have a crucial role in plaque instability , and this phenomenon angiogenesis is a crucial mechanism for oxygen supply of the growing plaque contents The role of TF as trigger for several intracellular pathways involving these chemical mediators has been well documented Atherosclerosis is considered an inflammatory disease - Accordingly, TF suppression, anticoagulation, PAR blockade, or general anti-inflammation offers an array of therapeutical benefits for easing diverse pathological conditions.
Tissue factor TF , also known as factor III, essentially provides additional protection to vital organs prone to mechanical injury; its strategic location is considered as a hemostatic envelope for arresting bleeding from vascular beds. High TF expression is found in highly vascularized organs cells such as the brain e. The low expression is detected in the spleen, thymus, and liver [ 1 ]. Circulating blood-borne TF is mainly derived from its expression in blood cells e.
Extracellular soluble form sTF could be released from EC [ 5 ] in response to proinflammatory cytokines. TF initiates the extrinsic coagulation that plays an integral role in blood coagulation, thrombin FIIa generation, and thrombi formation in close relation to thrombosis and cardiovascular dysfunctions [ 9 , 10 ]. Such extracellular TF signaling proceeds with the sequential generation of coagulant mediators FVIIa, FXa, and FIIa: active serine proteases and fibrin production, all of which are proinflammatory [ 4 ].
TF extends its roles to diverse biological phenomena related to either ro both of these two major thrombotic and inflammatory events. TF usually in its latent cryptic form is often upregulated decrypted upon vascular injury by protein disulfide isomerase with phosphatidylserine PS exposure [ 10 — 12 ], inflammation e. Enhanced TF expression has also been reported due to SirT1 inhibition [ 13 ], homocysteine [ 14 ], oral contraceptives [ 15 ], shear stress [ 16 ], amyloid protein A [ 17 ], histamine [ 18 ], smoking [ 19 ], nicotine [ 20 ], estrogen [ 21 ], asbestos [ 22 ], serotonin [ 23 ], dexamethasone [ 24 ], arachidonic acid AA [ 25 ], bFGF [ 26 ], VEGF [ 27 ], EGF [ 28 ], aggregated LDL [ 29 ], leptin [ 30 ], urokinase [ 31 ], shingosinephosphate [ 32 ], or many others.
In general, TF expression is mediated by activations of intracellular signaling kinases e. Exposure to calcium ionophores such as A drastically sustains cellular TF PCA without increased TF expression in cultures, which could either have or not have any pathological implications, and the mechanism of action remains unclear [ 4 ]. The extrinsic pathway plays an integral role in blood coagulation complemented by the intrinsic pathway that ensures FIIa regeneration and clot production Figure 2 , left panel for review, see [ 3 , 4 , 10 , 67 ].
The intrinsic pathway merging with TF-initiated extrinsic coagulation at FX activation is beyond the focus of this paper. FVII readily undergoes proteolytic activation of peptide bond cleavage between Arg and Ilu by either TF dependence or other serine proteases e. FXa acts as a molecular switch not only receiving the upstream extrinsic and intrinsic signals but also dictating the downstream coagulation. Strategically, FXa is an active enzyme component coupled with FVa in prothrombinase complex located at the center of the blood coagulation cascade, which converges the clotting signals derived from both the extrinsic FVII activation and intrinsic FIX activation pathways.
Finally, FIIa derived from FII cleavage by FXa assumes the main coagulant function at the termination stage; it directly catalyzes FBG cleavage releasing fibrinopeptides for fibrin clot production upon cross-linking.
As a consequence of TF hypercoagulation, thrombosis featuring fibrin overproduction is a direct outcome Figure 3 1 in addition to proinflammatory environment for thrombogenesis i.
Alternatively, FIIa-induced platelet activation could result from polymerizing fibrin, which involves the recognition sites in the cross-linking of polymerizing fibrin and surface integrins via GP Ib. Upregulated plasminogen activator inhibitor-1 PAI-1 expression by FIIa via a PKC-dependent mechanism [ 76 ] could further contribute to antifibrinolytic process and fibrin accumulation. Several lines of evidence reveal in vivo coagulation-dependent inflammation.
PARs generally mediate inflammation derived from coagulant mediators e. Moreover, deficiencies in natural anticoagulants e. Consistent with such notion of coagulation-dependent inflammation, anticoagulation readily results in anti-inflammatory effects in vivo and in vitro discussed in Section Conversely, TF deficiency reduces inflammation [ 82 ].
The ability of anti-TF Ab to prevent septic shock [ 83 ] and depress macrophage expression of adhesion molecule CD18 [ 84 ] is consistent with the proinflammatory function of TF.
FIIa activates platelets releasing proinflammatory serotonin, histamine, and eicosanoid precursors as well as adhesion molecules [ 97 ]. Fibrin clot per se is proinflammatory. Fibrin fragment E enhances IL-6 production [ ]. PARs functioning as molecular switches dictate cross-talks of hypercoagulable states with inflammatory outcomes Figure 2. PAR activation by their corresponding activating peptides triggers inflammation [ 4 , — ]. The ability of PAR per se to mediate inflammatory responses [ 4 , — ] is readily in line with coagulation-dependent inflammation.
It is now clear that PARs transmit clotting signals for proinflammation Figures 2 and 3 2. Taken together, it is evident that coagulant mediator e. CRP drastically activates TF expression [ ].
Long pentraxin-3, an acute inflammatory molecule, upregulates TF expression in lung injury [ ]. Conversely, guggulsterone an anti-inflammatory phytosterol inhibits TF expression and arterial thrombosis [ ], which is also in favor of such inflammation-triggered coagulation Figure 3 3.
PAR-2 agonists e. Conversely, TF expression is diminished by anticoagulants e. In addition, Wakefield and his associates have demonstrated that selectin-deficient mice lacking the activation of the extrinsic pathway are defective in fibrin production [ ]. Thus, it is clear that TF initiates cross-talks of hypercoagulable states with inflammatory outcomes Figure 2.
Thrombosis and inflammation are two major consequences of blood coagulation, both of which cross-talk and promote each other. Clinical association of thrombosis with inflammation has been reported in many cases [ ]. Such inflammation-thrombosis connection Figure 3 4 provides an alternative pathway that blood coagulation via its inflammatory consequence indirectly contributes to thrombosis.
P -selectin as a C3b-binding protein sufficiently leads to C3a generation and C5b-C9 formation, which supports a novel mechanism of local inflammation in vascular injury sites [ 69 , ]. Conversely, in vivo inflammation-dependent thrombogenesis also exists. IL-8 enhances fibrosis in rats [ ]. In support of this notion, activation and antagonism of proinflammatory PARs, respectively, trigger and reduce thrombogenesis for review, see [ 69 ]. An earlier study has shown that P -selectin causes leukocyte accumulation to facilitate fibrin deposition [ ], complementing thrombotic episodes.
In parallel, selectin-deficient mice lacking the activation of the extrinsic pathway are defective in fibrin production [ ]. Antibodies to cytokines and adhesion molecules attenuate venous thrombosis [ ]. LYP20, an antibody against P -selectin, blocks leukocyte adhesion to EC and platelets [ ] and modifies thrombosis [ ], and P -selectin inhibition decreases vein wall fibrosis [ ].
In addition, there is a general perception of inflammation-dependent thrombogenesis, which is supported by the observations that anti-inflammatory agents are of antithrombotic benefits. For instance, nonsteroid anti-inflammatory drugs readily block thrombosis.
COX-1 inhibitor such as low doses of aspirin suppresses platelet aggregation [ ]. Thrombosis-inflammation connection Figure 3 4 is integrated into the coagulation-inflammation vicious cycle Figure 3 2 and 3 , thus rounting a complete circuit to link among coagulation, inflammation, and thrombosis. Concomitant with suppressed TF expression by COX inhibitors [ 35 — 37 ], the anti-inflammatory and antithrombotic properties of COX-2 inhibitors [ , ] seem likely to be in agreement with the involvement of TF hypercoagulability in driving the coagulation-inflammation-thrombosis circuit.
Further, activated platelets stimulate TF expression [ ], while antiplatelet agent dilazep inhibits TF expression [ ]. Both observations are in favor of the thrombosis-inflammation connection Figure 3 4 being part of the operative blood coagulation-inflammation-thrombosis circuit.
The paradigm has also been observed in lung [ ] and inflammatory bowel syndrome [ ] while closely relating to cardiovascular risks [ 9 , 69 ]. Mounting evidence reveals that TF hypercoagulability plays pathogenic roles closely relating to its not only inflammatory but also thrombotic actions. By driving the circuit Figure 3 , TF hypercoagulability is readily involved in an array of metabolic syndromes e. Hypercoagulation is often observed in septic shock including endotoxemia or systemic inflammatory responses after trauma, which mainly results from TF overexpression [ — ].
The ability of TF blockade to ease septic shock [ 83 ] or organ injury [ ] points to a fundamental pathogenic role of TF in sepsis. A common manifestation presents DIC, an acquired disorder with hemostatic imbalance; excessive FIIa formation leads to fibrin deposition in microcirculation and consequent ischemic organ damage. Thus, such autocrine or paracrine TF signaling could lead to substantial tissue damages or multiple organ failure. TF overexpression has been reported in ovarian cancer [ ], endometriosis [ ], breast cancer [ ], nonsmall cell lung carcinoma [ ], prostate cancer [ ], pancreatic cancer [ ], melanoma [ ], colorectal cancer [ ], gastric cancer [ ], esophageal cancer [ ], hepatocellular carcinoma [ ], brain tumor glioblastoma [ ], leukemia [ ], and lymphoma [ ].
Accordingly, TF overexpression could be considered a biomarker for solid tumors [ ]. The roles of TF in cancer have been demonstrated with severalfold relevance in relation to thrombotic condition, tumorigenesis per se and TF signaling i. Cancer linked with hypercoagulability and thrombotic risk has long been recognized by Armand Trousseau since Cancer certainly could be recognized as a prothrombotic risk factor, leading to, for instance, venous thromboembolism and its complication of pulmonary embolism and mortality.
Namely, cancers readily induce thrombosis [ ]. Not only tumor cellular membrane-bound TF, but also microparticle-associated TF [ ] links cancer to thrombosis. In addition, the similar hypercoagulable state exists in cancer stem cells [ ].
The critical role of TF in tumorigenesis is supported by the observations that inhibited TF expression blocks tumor growth, metastasis [ ], angiogenesis [ ], cell invasion [ ], and many other cancer characteristics.
It is of particular interest to note that the serine phosphorylated cytoplasmic domain inhibits cellular cytotoxicity [ ], thereby leading to increased tumor survival and metastatic rate. In addition, increased TF cytoplasmic domain phosphorylation and PAR-2 activation significantly correlate to cancer relapse [ ]. Thus, a cooperation of the phosphorylated TF cytoplasmic domain with protease signaling could account for diverse contributions of TF to metastasis and angiogenesis [ 81 , ].
As the proceeding of TF-initiated extrinsic pathway, the resulting FIIa generation and fibrin production are of proangiogenesis.
FIIa could be recognized as a tumor growth factor [ , ], which is accompanied by the enhanced tumor cell cycle mediated by downregulation of p27Kip1 and upregulation of Skp2 and MiR [ ].
FIIa is also able to upregulate cathepsin D which enhances angiogenesis, growth, and metastasis [ ]. FIIa activates fibrinolysis inhibitors e. TF gene overexpression in obese has been reported for more than a decade [ , ] accompanied by upregulated PAI-1, angiogenesis, cell adhesion, and so forth, all of which could stem from TF hypercoagulability.
Inflammation has been proposed to engage in obesity development [ ], while less is clear about the precise role of thrombosis per se in obesity. With the functional coagulation-inflammation-thrombosis circuit Figure 3 , triggered inflammation constitutes the pathogenesis of obesity with manifestation including diabetes and cardiovascular risks e. Based upon high leptin and low adiponectin levels in obesity, the ability of leptin [ 30 ] or adiponectin [ 47 ], respectively, to augment or suppress TF synthesis could imply a mechanistic role of TF in developing inflammatory obesity.
Under hyperglycemia, excessive plasma glucose nonenzymatically conjugates with plasma proteins e. AGEs through their receptors exhibit biological damage in various tissues such as renal failure and vascular complications. Increased circulating AGEs enhance TF expression [ ], making diabetes a hypercoagulable and thrombotic condition [ , , ].
TF overexpression essentially promotes diabetes progression as well as its manifestation. As a consequence of diabetic TF hypercoagulability, elevated inflammatory mediators elicit cardiovascular complications including atherosclerosis. Diabetic complications are more threatening than hyperglycemia per se; accordingly, relief of hypercoagulability could become far more important than glycemic control. Furthermore, rosiglitazone substantially lowering glycemia surprisingly increases the risk of myocardial infarction and death from cardiovascular causes [ ].
For diabetic cardiovascular events, one could not expect that glycemic control per se significantly and promptly reverses the downstream damages done by AGEs. Apparently, nonglycemic factors e. Apart from thrombotic natures, TF could assume a pathogenic role in diabetic progression in a close relation to inflammatory process [ , ]. It is likely that TF signaling Figure 2 through the coagulation-inflammation-thrombosis circuit Figure 3 operating in diabetes could well be responsible for insulin resistance.
Notably, anti-inflammatory adiponectin suppresses TF expression [ 47 ], which could be in support of the role of TF in diabetes pathology. In summary, TF function has twofold significance in diabetes. TF not only dictates diabetic hypercoagulable nature and thrombotic outcomes [ ], but also overlays its signaling in proinflammation Figure 2 for insulin resistance.
The ability of insulin [ 40 ] or an antidiabetic agent metformin [ 59 ] to attenuate TF expression seemingly reinforces a key pathogenic role of TF in diabetes. Cardiovascular complications are a group of disorders closely associated with either inflammation or thrombosis or both.
In these regards, it is not surprising that TF plays a major role in their pathogeneses [ 9 ]. TF overexpression, often correlated to gain-of-function of TF promoter polymorphism AG , promotes the development of cardiovascular diseases [ ].
It has long been established that TF participates in the phase III of plaque rupture [ ] during atherogenesis. TF expression is upregulated in atherosclerotic plaques of patients with unstable angina and myocardial infarction [ ]. TF hypercoagulability driving the coagulation-inflammation-thrombosis circuit Figure 3 readily extends its diverse consequences to cardiovascular complications and vascular diseases [ ] including arrhythmias [ 58 ], arterial hypertension [ ], hypertrophy [ ], ACS [ , ], andatrial fibrillation AF [ ], TF hypercoagulability with elevated proinflammatory cytokines Figure 2 could in part well contribute to atherosclerosis known as chronic inflammatory disease [ ].
As a consequence of accelerated cardiomyocyte turnover, TF could contribute to the induction and progression of cardiac hypertrophy. Angiotensin II stimulates TF synthesis [ ], mediating hypertensive action. In contrast, TF deficiency in mice shows cardiac fibrosis [ , ] largely based upon TF functions in normal extracellular cardiac homeostasis, extracellular matrix regulation, and vascular maintenance [ ].
It awaits further confirmation in human conditions. This autoimmune thrombophilic condition is largely due to enhanced coagulation e. Increased microparticles and TF expression are found in APS with prothrombotic conditions of various manifestations, most commonly venous and arterial thromboembolism and recurrent pregnancy loss.
It is not surprising if APS of TF overexpression also presents a hyperinflammatory condition in view of the paradigm of coagulation-inflammation-thrombosis circuit Figure 3. Miscarriage including fetal death, preeclampsia, and intrauterine growth restriction often closely links to APS involving complement and angiogenic actions.
During trophoblast differentiation, aPL activates complement via the classical pathway. Complement activation C3 and C5a directly mediates placental injury and causes fetal loss and growth restriction, resulting from an imbalance of angiogenic factors e.
In fact, TF on neutrophils and monocytes is a critical mediator in trophoblast injury and embryo damage in aPL-dependent or independent pregnancy loss [ ]. Anti-TF mAb prevents aPL-induced pregnancy loss [ ], while statins [ , ] may be a good treatment for women with recurrent miscarriages and intrauterine growth restriction. Wound, including diabetic foot, healing process generally consists of three phases inflammatory, proliferative, and remodeling phases that continuously overlap one another during the process.
Hemostasis initiates angiogenesis-dependent wound healing. TF overexpression often occurring after wounding, trauma, or surgeries in part accounts for hypercoagulability encouraging wounding healing [ — ]. Limited evidence reveals that TF extracellular domain is essential for embryogenesis [ — ], which is believed to be mediated by TF-dependent FIIa generation and PAR-1 activation.
Thus, TF serves as an important morphogenic factor during embryogenesis. Consistently, inactivation of TF gene results in embryonic lethality in a murine model [ ]. In heparin-induced thrombocytopenia, PF4 also impairs APC activity, making a pronounced hypercoagulable and prothrombotic condition. TF overexpression in adult onset asthma significantly correlates to the gain-of-function of TF promoter polymorphism AG [ ].
Concerning innate immunity and acute inflammation, complement activation is of TF relevance. Complement activation, especially C5a, upregulates TF expression, thereby extending to a broad spectrum of immune consequences [ ]. Similarly, TF overexpression is observed in bacterial pneumonia [ ], Helicobacter pylori [ ] , viral HIV [ ], or parasite malaria [ ] infection. In response to surgical procedures, enhanced TF synthesis is reported in major surgeries such as hip replacement, cardiopulmonary bypass CPB [ ] or transplantation [ — ].
Upon tissue injury, exposure to protein disulfide isomerase and PS readily activates TF [ 10 — 12 ] and its signaling. It is plausible that TF hypercoagulability in part accounts for postsurgical inflammatory responses. With regard to lifestyles, smoking upregulating TF expression apart from its apparent free radical inhalation elicits diverse health problems including cardiovascular and cancer risks.
In addition, TF overexpression is associated with other pathological conditions such as liver cirrhosis [ ], synovial inflammation [ ], sickle cell anemia [ ], or hepatic necrosis during cholestasis [ ]. These pathological conditions likely result from the coagulation-inflammation-thrombosis circuit Figure 3 ; the precise mechanisms of action however remain to be defined. The signaling function of TF cytoplasmic domain has been demonstrated although its biochemical mechanism remains unclear.
The cytoplasmic domain contributes to renal albumin retention, and its renal expression protects against proteinuria. It is proposed that the cytoplasmic domain per se is critical for VEFG expression [ ], an important angiogenic component in tumorigenesis. In view of the paradigm of coagulation-inflammation-thrombosis circuit Figure 3 , any interruption of the circuit is accordingly expected to exert broad antagonism against hypercoagulation, inflammation, thrombosis, and their complications.
Table 1 lists some typical examples of targeting TF hypercoagulation for fighting diverse pathological conditions in cell cultures, ex vivo , animal studies, or clinical trials.
Inhibited TF synthesis readily leads to many clinical applications for easing pathological conditions including inflammation, thrombosis, and cardiovascular dysfunctions.
For instance, vitamin D3 deficiency often exists in APS; consistently, vitamin D3 inhibits transcription factors e. Indobufen, through a thromboxane-mediated mechanism, exhibits antagonisms against atherothrombosis [ 57 ].
Amiodarone inhibiting TF translation attenuates arterial thrombosis including coronary artery thrombosis as much as ventricular arrhythmias [ 58 ]. Nicotinamide inhibits coagulation and inflammation, resulting in anti-inflammation with reduced IL-6 and CD11a in sepsis or DIC [ 41 ].
ACE inhibitors offsetting ATII-induced TF overexpression reduce the risk of recurrent myocardial infarction in patients with left ventricular dysfunction [ 46 ]. Ethyl pyruvate inhibiting TF mRNA expression shows combined anti-inflammatory and anticoagulant effect [ 44 ]. DMSO inhibiting thrombus formation and vascular smooth muscle cell activation could improve acute coronary syndromes [ 45 ].
Liver X receptor agonists attenuate atherothrombosis [ 54 ]. Hydroxyurea has antithrombotic activity [ 43 ], while pentoxifylline attenuates DIC [ 55 ]. Adiponectin could prevent endothelial dysfunction and atherogenesis in acute coronary syndrome [ 47 ]. Antisense oligonucleotide blocking TF expression prevents leukocyte adhesion following renal ischemic reperfusion injury [ 66 , ].
COX inhibitors readily show anti-inflammation [ , ] as well as antithrombosis. Red wine phenolics and quercetin improve cardiovascular health and prevent CHD [ 56 ].
Guggulsterone suppresses TF expression together with anti-inflammation and antagonism against arterial thrombosis [ ]. HMG-CoA reductase inhibitors e. Interestingly, paclitaxel exhibits anticancer activity [ 38 ]. COX-2 inhibitors show the prevention of colorectal cancer [ ], while all-trans retinoic acid inhibiting cancer procoagulation could of benefit to leukemia [ 49 ]. FVIIa inhibition readily shows antagonism against inflammation. Hemextin AB complex, a snake venom protein complex, directly inhibits FVIIa catalytic activity for anticoagulation [ ].
PHA diminishes thrombus formation in primates [ ]. It remains to be determined concerning the antithombotic application of rNAPc2. Remarkably, it has also been documented that FVIIa inhibition exhibits anticancer actions. SamOrg A has recently been evaluated for its antithrombotic application with reduced platelet adhesion and thrombus formation in pigs [ ]. DXa depresses platelet aggregation [ ] and leukocyte adhesion to EC [ ] while providing effective protection against tumor-induced DIC [ ].
Newly developed TAKA shows antithrombotic and anticoagulant activities against venous thrombosis [ ]. Orally active amidinoaryl propanoic acid reduces platelet deposition and fibrin accumulation in venous-type thrombus in baboons [ ]. ZK inhibits arterial thrombosis [ ] as well as venous thrombosis in vascular injury rabbits [ ] and electrolytic injury canines [ ].
SF and inhibit A-V shunt-induced thrombus formation in rabbits [ ]. Orally active YM inhibits thrombosis in mice [ ]. FXV inhibits thrombus formation in canines [ ]. Orally active pyrazole DPC attenuates electrically induced carotid artery thrombosis in rabbits [ ]. Isoxazolines and isoxazoles prevent A-V shunt thrombosis [ ], while RPR reduces venous thrombosis in rabbits [ ].
Rivaroxaban prevents and treats venous thromboembolism and is used for stroke prevention in AF [ ]. GW is of antithrombotic therapeutic benefits [ ]. Apixaban inhibits platelet aggregation [ ].
DUb is considered a new anticoagulant for the prophylaxis and treatment of thromboembolic diseases [ ]. Oral BAY is for the prevention of venous thromboembolism [ ].
Many more direct FXa inhibitors await clinical studies for their anti-inflammatory and antithrombotic applications. Anticancer activity through direct FXa inhibition is also reported.
LMWH Tinzaparin shows antimetastatic effect [ ]. Ixolaris is able to block primary tumor growth and angiogenesis [ ]. DXa inhibits cell proliferation [ ], and MCM09 shows anticancer action by significantly lowering lung metastasis [ ]. Heparin shows a variety of anti-inflammatory potentials for review, see [ ].
Heparin-bonded circuit prevents the increases in IL-6 and IL-8 in CPB patients [ ], while heparin bolus reduces neutrophil activation without affecting platelet aggregation [ ]. Heparin is also considered a treatment for pregnancy loss [ ]. Hirudin suppresses sTFinduced inflammation [ 80 ].
A hirudin analog lepirudin alleviates LPS-induced platelet activation [ ]. Lepirudin, desirudin, and bivalirudin [ ] exhibit antagonism to DVT, VTE, and arterial thrombosis in clinical studies. FIIa active site inhibitor melagatran diminishes P -selectin expression [ ], ximelagatran [ ] shows various antithrombotic actions, and argatroban attenuates DVT and VTE [ ].
Org is a direct anti-FIIa agent with anti-FXa activity, seemingly being superior to argatroban and fondaparinux in animal models of thrombosis [ ].
A new direct FIIa inhibitor FM shows platelet inhibition in vitro and in vivo with an application for fighting ACS [ ]; this oral anticoagulant also inhibits prostate tumor growth in vivo [ ]. Several other direct FIIa inhibitors e. Heparin also reduces lung metastasis [ ]. The second domain directly binds and inhibits FXa.
TFPI plays a significant role in protecting against septic shock induced by E. TFPI in place of antibiotics could be a treatment for pneumonia [ ]. Gene therapy with rTFPI could attenuate pulmonary fibrosis [ ]. It has long been established that APC protects from sepsis, DIC, and endotoxemia [ , ]; APC is recognized as one of the effective anti-inflammatory agents in clinical applications. However, a discrepancy exists concerning improved survival rate in baboons [ ] but not severe human sepsis treated with the high dose of ATIII [ ].
Further research warrants verifying its anti-inflammatory action s. APC antithrombotic potential is implied by increased APC resistance [ ] and the deficiency [ ] or low plasma level [ ] of APC observed in thrombosis.
However, APC antithrombotic potential remains in the experimental stage of animal studies. For instance, a recombinant human APC LY inhibits arterial thrombosis in a canine model [ ]. Infusion of bovine APC suppresses thrombus formation in rats [ ] and rabbit microarterial thrombosis [ ]. A rabbit APC-loaded stent reduces thrombus and platelet deposition in vitro and in vivo [ ].
TFPI-2 expression in tumor tissue could inhibit invasion, tumor growth, and metastasis [ ]. ATIII demonstrates antimetastatic [ ] and antiangiogenic potentials [ ].
It remains unclear whether APC could exhibit consistent anticancer benefits [ ] regardless of limited evidence showing inhibited tumor metastasis [ ]. PARs transmitting blood coagulation signals to cellular activation for proinflammation Figure 2 are apparent therapeutical targets for interrupting the circuit Figure 3. A growing list of PAR antagonists readily shows clinical applications concerning inflammation and thrombosis. For instance, RWJ [ ] selectively blocks PAR-1, resulting in the attenuation in CD61 expression, platelet aggregation, thrombus formation, and restenosis.
RWJ protects from FIIa-induced human platelet activation and platelet-mediated thrombosis [ ]. Orally active himbacine-based SCH shows potent antiplatelet activity [ ]. Refludan suppresses macrophage adhesion [ ]. BMS [ ] and [ ] abolish platelet aggregation. SR and reduce contractile [ ]. PAR4 antagonist P4pal is used for treatment of thrombocytopenia and DIC [ ] protecting from systemic inflammation accompanied by stabilized liver, kidney, and lung function.
P4pal also protects from platelet-mediated thrombosis [ ]. Similarly, general PAR downregulation could also achieve such anti-inflammatory and antithrombotic effects. By increasing GTPase activity of G q? Concerning anticancer potentials, recent research advances reveal that PARs play roles in cancer metastasis [ ] and angiogenesis [ ].
Downregulation of TF function shows antithrombotic effects. TF blocking antibody also reduces allograft rejection [ ]. Blood coagulation, a primitive biological phenomenon in the animal kingdom, has historically been recognized as a host defense to prevent one from bleeding to death.
TF-initiated extrinsic pathway, known as being inducible compared to constitutive intrinsic pathway, plays an integral role in blood coagulation, FIIa generation, and thrombus formation for review, see [ 3 , 10 , 67 ].
Accumulating evidence demonstrates TF diverse biological effects in local or systemic inflammation [ 4 ]. Not only does the extrinsic pathway but also intrinsic pathway results in inflammation [ ]. Such extracellular TF signaling activates cells, and its pronounced effects include proinflammatory cytokine production Figure 2.
It has been elucidated that inflammasomal activation [ ] in response to innate pathogens [ ], viral [ ], fungus [ ], influenza [ ], microbes [ ], and chemicals e.
It, however, remains elusive if inflammasomal activation is involved in such inflammatory process triggered by TF signaling. Thus far, there is no indication whether coagulant mediators e. Could PAR activation directly turn on inflammasomal activation, an interesting question seemingly further addressing the similar issues if inflammasomal activation is critical for coagulation-dependent inflammation?
Among diverse clinical conditions associated with TF overexpression and its signaling mentioned herein, the close link between TF hypercoagulability and neurological disorders is however seldom reported. Although high TF expression in the brain could in part account for thrombotic stroke consequences, it certainly warrants investigation to explore if TF and its signaling participate in other neuronal dysfunctions or CNS disorders.
In view of the paradigm of coagulation-inflammation-thrombosis circuit eliciting diverse pathological events Figure 3 , targeting TF hypercoagulation is of therapeutical relevance. Apparently, the development of anticoagulants is of broad pharmaceutical interests; anticoagulation could turn into strategic approaches for intervention and cure not limiting to thromboprophylaxis. It is highly promising that anticoagulants available arresting different stages of blood coagulation cascade [ ] exhibit benefits other than hemostasis.
In these regards, TF posttranslational downregulation including encryption could deserve attention for interventional therapeutical relevance in prospective of such upstream downregulation of the extrinsic pathway Figure 2 , left panel with broad suppression of downstream proinflammatory coagulant mediators e.
The observations of anticoagulation exhibiting anticancer properties clearly demonstrate the new frontiers of the emerging therapeutical era. Direct PAR blockade could be part of therapeutically targeting coagulation-dependent inflammation and the circuit Figure 3. Further research is needed to study if PAR antagonisms could widely exhibit an array of clinical benefits to relieve diseases including cancer, obesity, diabetes, APS, and others in addition to inflammation and thrombotic related cardiovascular complications.
Like any other therapies, anticoagulation bears certain limitations and cautions for its applications. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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