scholarly journals Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway.

1996 ◽  
Vol 133 (2) ◽  
pp. 293-304 ◽  
Author(s):  
J R Sevinsky ◽  
L V Rao ◽  
W Ruf
Keyword(s):  
Cell Surface ◽  
Tissue Factor ◽  
Cell Biology ◽  
Feedback Inhibition ◽  
Factor Viia ◽  
Coagulation Cascade ◽  
Low Density ◽  
Factor X ◽  
Quaternary Complex ◽  
Enzymatic Complex

The ability to regulate proteolytic functions is critical to cell biology. We describe events that regulate the initiation of the coagulation cascade on endothelial cell surfaces. The transmembrane protease receptor tissue factor (TF) triggers coagulation by forming an enzymatic complex with the serine protease factor VIIa (VIIa) that activates substrate factor X to the protease factor Xa (Xa). Feedback inhibition of the TF-VIIa enzymatic complex is achieved by the formation of a quaternary complex of TF-VIIa, Xa, and the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI). Concomitant with the downregulation of TF-VIIa function on endothelial cells, we demonstrate by immunogold EM that TF redistributes to caveolae. Consistently, TF translocates from the Triton X-100-soluble membrane fractions to low-density, detergent-insoluble microdomains that inefficiently support TF-VIIa proteolytic function. Downregulation of TF-VIIa function is dependent on quaternary complex formation with TFPI that is detected predominantly in detergent-insoluble microdomains. Partitioning of TFPI into low-density fractions results from the association of the inhibitor with glycosyl phosphatidylinositol anchored binding sites on external membranes. Free Xa is not efficiently bound by cell-associated TFPI; hence, we propose that the transient ternary complex of TF-VIIa with Xa supports translocation and assembly with TFPI in glycosphingolipid-rich microdomains. The redistribution of TF provides evidence for an assembly-dependent translocation of the inhibited TF initiation complex into caveolae, thus implicating caveolae in the regulation of cell surface proteolytic activity.

Studies of the Mechanism for Enhanced Cell Surface Factor VIIa/Tissue Factor Activation of Factor X on Fibroblast Monolayers after Their Exposure to N-Ethylmaleimide

1994 ◽  
Vol 72 (06) ◽  
pp. 848-855 ◽  
Author(s):  
Dzung The Le ◽  
Samuel I Rapaport ◽  
L Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Tissue Factor ◽  
Factor Viia ◽  
Cell Damage ◽  
Specific Binding ◽  
Surface Membrane ◽  
Annexin V ◽  
Factor X ◽  
Binding Studies ◽  
Anionic Phospholipid

SummaryFibroblast monolayers constitutively expressing surface membrane tissue factor (TF) were treated with 0.1 mM N-ethylmaleimide (NEM) for 1 min to inhibit aminophospholipid translocase activity without inducing general cell damage. This resulted in increased anionic phospholipid in the outer leaflet of the cell surface membrane as measured by the binding of 125I-annexin V and by the ability of the monolayers to support the generation of prothrombinase. Specific binding of 125I-rVIIa to TF on NEM-treated monolayers was increased 3- to 4-fold over control monolayers after only brief exposure to 125I-rVIIa, but this difference progressively diminished with longer exposure times. A brief exposure of NEM-treated monolayers to rVIIa led to a maximum 3- to 4-fold enhancement of VIIa/TF catalytic activity towards factor X over control monolayers, but, in contrast to the binding studies, this 3- to 4-fold difference persisted despite increasing time of exposure to rVIIa. Adding prothrombin fragment 1 failed to diminish the enhanced VIIa/TF activation of factor X of NEM-treated monolayers. Moreover, adding annexin V, which was shown to abolish the ability of NEM to enhance factor X binding to the fibroblast monolayers, also failed to diminish the enhanced VIIa/TF activation of factor X. These data provide new evidence for a possible mechanism by which availability of anionic phospholipid in the outer layer of the cell membrane limits formation of functional VIIa/TF complexes on cell surfaces.

scholarly journals Cellular localization and trafficking of tissue factor

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4746-4753 ◽  
Author(s):  
Samir K. Mandal ◽  
Usha R. Pendurthi ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Tissue Factor ◽  
Cellular Localization ◽  
Factor Viia ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Cell Surfaces ◽  
Caveolin 1 ◽  
Intracellular Compartments ◽  
Resultant Increase

AbstractTissue factor (TF) is the cellular receptor for clotting factor VIIa (FVIIa). The formation of TF-FVIIa complexes on cell surfaces triggers the activation of coagulation cascade and cell signaling. In the present study, we characterized the subcellular distribution of TF and its transport in fibroblasts by dual immunofluorescence confocal microscopy and biochemical methods. Our data show that a majority of TF resides in various intracellular compartments, predominantly in the Golgi. Tissue factor at the cell surface is localized in cholesterol-rich lipid rafts and extensively colocalized with caveolin-1. FVIIa binding to TF induces the internalization of TF. Of interest, we found that TF-FVIIa complex formation at the cell surface leads to TF mobilization from the Golgi with a resultant increase in TF expression at the cell surface. This process is dependent on FVIIa protease activity. Overall, the present data suggest a novel mechanism for TF expression at the cell surface by FVIIa. This mechanism could play an important role in hemostasis in response to vascular injury by increasing TF activity where and when it is needed.

scholarly journals A Soluble Tissue Factor Mutant Is a Selective Anticoagulant and Antithrombotic Agent

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3219-3227 ◽  
Author(s):  
Robert F. Kelley ◽  
Canio J. Refino ◽  
Mark P. O'Connell ◽  
Nishit Modi ◽  
Pat Sehl ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Arterial Thrombosis ◽  
Factor Viia ◽  
Rabbit Model ◽  
Coagulation Cascade ◽  
Factor X ◽  
Rabbit Plasma ◽  
Extrinsic Pathway ◽  
Antithrombotic Agent ◽  
Thrombotic Disease

Abstract One approach to developing safer and more efficacious agents for the treatment of thrombotic disease involves the design and testing of inhibitors that block specific steps in the coagulation cascade. We describe here the development of a mutant of human tissue factor (TF ) as a specific antagonist of the extrinsic pathway of blood coagulation and the testing of this mutant in a rabbit model of arterial thrombosis. Alanine substitutions of Lys residues 165 and 166 in human TF have been shown previously to diminish the cofactor function of TF in support of factor X (FX) activation catalyzed by factor VIIa (FVIIa). The K165A:K166A mutations have been incorporated into soluble TF (sTF; residues 1-219) to generate the molecule “hTFAA.” hTFAA binds FVIIa with kinetics and affinity equivalent to wild-type sTF, but the hTFAA⋅FVIIa complex shows a 34-fold reduction in catalytic efficiency for FX activation relative to the activity measured for sTF⋅FVIIa. hTFAA inhibits the activation of FX catalyzed by the complex formed between FVIIa and relipidated TF(1-243). hTFAA prolongs prothrombin time (PT) determined with human plasma and relipidated TF(1-243) or membrane bound TF, and has no effect on activated partial thromboplastin time, but is 70-fold less potent as an inhibitor of PT with rabbit plasma. The rabbit homologue of this mutant (“rTFAA”) was produced and shown to have greater potency with rabbit plasma. Both hTFAA and rTFAA display an antithrombotic effect in a rabbit model of arterial thrombosis with rTFAA giving full efficacy at a lower dose than hTFAA. Compared to heparin doses of equal antithrombotic potential, hTFAA and rTFAA cause less bleeding as judged by measurements of the cuticle bleeding time. These results indicate that TF⋅FVIIa is a good target for the development of new anticoagulant drugs for the treatment of thrombotic disease.

scholarly journals Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3815-3823 ◽  
Author(s):  
GJ Jr Broze ◽  
DA Higuchi
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Feedback Inhibition ◽  
Factor Viia ◽  
Factor Xa ◽  
Factor Ix ◽  
Factor X ◽  
Dependent Inhibition ◽  
Fibrinolysis Inhibitor ◽  
Normal Hemostasis

Coagulation is initiated by the binding of factor VIIa to tissue factor, with resultant limited factor IX and X activation and thrombin production. Owing to the feedback inhibition of the factor VIIa/tissue factor complex by tissue factor pathway inhibitor (TFPI), additional factor X activation and thrombin generation must proceed through a pathway involving factors VIII, IX, and XI. Experiments designed to elucidate the requirement for amplified factor Xa and thrombin generation in normal hemostasis show that the resistance of plasma clots to tissue plasminogen activator (tPA)- and urokinase-induced fibrinolysis is related to the extent of thrombin generation. Inhibition of fibrinolysis is mediated in part by plasma carboxypeptidase-U ([CPU] carboxypeptidase-R, procarboxypeptidase-B, thrombin-activatable fibrinolysis inhibitor), a proenzyme that is proteolytically activated by thrombin in a process enhanced dramatically by the cofactor thrombomodulin. A clot induced in factor IX-deficient plasma with limited amounts of tissue factor in the presence of urokinase (100 U/mL) lyses prematurely, and this defect is corrected by supplementation of the deficient plasma with factor IX (5 micrograms/mL) or thrombomodulin (20 ng/mL). These additions enhance the rate and extent of CPU activation: in the case of factor IX, presumably by permitting amplified generation of factor Xa and thrombin, and in the case of thrombomodulin, presumably by increasing the degree of CPU activation produced by the low levels of thrombin generated in the absence of factor IX. Pretreatment of the factor IX-deficient plasma with specific anti-CPU antibodies prevents the increased resistance to fibrinolysis produced by addition of factor IX and thrombomodulin. Likewise, when coagulation is induced by thrombin (2 U/mL) in the presence of tPA (60 U/mL), clots formed from plasmas deficient in factors VIII, IX, X, or XI lyse prematurely unless the missing factor is replaced or thrombomodulin (20 ng/mL) is added.

Factor VIII-Factor IX Interactions: Molecular Sites Involved in Enzyme-Cofactor Complex Assembly

1999 ◽  
Vol 82 (08) ◽  
pp. 209-217 ◽  
Author(s):  
Patrick Celie ◽  
Joost Kolkman ◽  
Peter Lenting ◽  
Koen Mertens
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Factor Viia ◽  
Three Dimensional ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor X ◽  
Factor Ixa ◽  
Factor Viiia ◽  
Factor X Activation

IntroductionThe activation of factor X is one of the steps in the coagulation cascade that is driven by the assembly of an activated serine protease with a membrane-bound cofactor. In the initial phase of coagulation, factor X is activated by the complex of activated factor VII (factor VIIa) and tissue factor. Subsequently, during the so-called propagation phase, factor X activation is catalyzed by the complex of activated factor IX (factor IXa) and activated factor VIII (factor VIIIa). In these complexes, factor VIIa and factor IXa are the factor X-activating enzymes, whereas tissue factor and factor VIIIa serve as non-enzymatic cofactors.1 Factors VIIa and IXa are highly homologous to other cofactor-dependent enzymes, such as activated factor X (factor Xa) and activated protein C, both in amino acid sequence, domain organization, and three-dimensional structure.2 Factor VIIa and IXa further share low or negligible activity towards their natural substrate factor X, unless in complex with their physiological cofactors.Although tissue factor and factor VIIIa serve similar roles as biological amplifiers, they are structurally different. Tissue factor is a small, transmembrane protein with an extracellular part comprising 219 amino acids. Factor VIII is much larger (2,332 amino acids), circulates in plasma, and requires proteolytic processing to exert its biological activity.3 When cofactors are assembled with their respective enzymes, a dramatic increase in enzymatic activity occurs. The underlying molecular mechanism, however, remains poorly understood.During the past few years, remarkable progress has been made in understanding the molecular details of enzyme-cofactor assembly within the coagulation cascade. Crystallography has provided high-resolution structures of tissue factor4 and the various cofactor-dependent coagulation enzymes.2 Moreover, the crystal structure of the factor VIIa—tissue factor complex has been resolved and has allowed the identification of the molecular sites involved in enzyme-cofactor interaction.5,6 Such details are still lacking, however, for the factor IXa—factor VIIIa complex. Current views are derived from three-dimensional models generated by homology modeling based on structurally-related proteins, such as nitrite reductase,7 ceruloplasmin,8 and galactose oxidase.9 Despite their inherent limitations, these models greatly facilitate the interpretation of previous functional studies on factor X activation. As such, the availability of molecular models may be considered an important step toward resolving the structure of the factor IXa—factor VIIIa complex and understanding the role of complex assembly and defects thereof. This chapter provides an overview of the current developments in this field.

Tissue Factor Activation: Is Disulfide Switching a General Regulatory Mechanism?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1747-1747 ◽  
Author(s):  
Usha Pendurthi ◽  
Samit Ghosh ◽  
Samir Mandal ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Cell Signaling ◽  
Tissue Factor ◽  
Factor Viia ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Permeabilized Cells ◽  
Anionic Phospholipids ◽  
Cellular Expression ◽  
Coagulant Activity

Abstract Tissue factor (TF) is the cellular receptor for plasma clotting factor VIIa, and the formation of TF-VIIa complexes on cell surfaces trigger the coagulation cascade and cell signaling. It is a well-known fact that only a small fraction of TF at the cell surface is coagulantly active whereas a majority of TF on the cell surface is non-functional (cryptic). However, it is unclear, at present, how the coagulant active TF differs from the cryptic form, and mechanisms involved in TF activation. Recent studies show that a thiol oxidizing agent, HgCl2, increases TF coagulant activity on the surface of HL-60 cells by several fold (Chen et al., Blood vol 106, abstract #684, 2005). Further, TF is shown to associate with protein disulfide isomerase (PDI) in HaCaT cells (Ahamed et al., Blood vol 106, abstract #685, 2005). Based on these and other observations, it has been proposed that switching between cryptic and coagulant TF involves cleavage and formation of allosteric disulfide bond (Cys186-Cys209) and PDI has been implicated in controlling the conversion of cryptic TF to the coagulant form and to act as a switch between TF-mediated signaling and coagulation. Although these data are interesting and novel, there is no fail-proof evidence that disulfide switching alone and not other potential changes, such as exposure of anionic phospholipids, at the cell surface is responsible for the TF activation associated with various treatments. Therefore we have examined the effect of HgCl2 and other treatments on TF activation in MDA 231 cells in relation to anionic phospholipids and also characterized the cellular expression of PDI in this and other cell types. As reported earlier, the HgCl2 treatment increased the cell surface TF coagulant activity (5-fold or higher). However, the HgCl2 treatment also increased the prothombinase activity by 3-fold. More importantly, annexin V, which binds to anionic phospholipids, markedly reduced the increased TF coagulant activity associated with the HgCl2 treatment whereas it had only minimal and insignificant effect on TF activity of the control cells. Further, pretreatment of cells with 5,5′-dithio-bis(2-nitronezoic acid) (DTNB), a sulfhydryl reagent that reacts with thiol groups and thus can block disulfide switching, failed to prevent the increase in TF activity associated with the HgCl2 treatment. Interestingly, we found that treatment of MDA 231 cells with glutathione (5 to 100 mM), a cell impermeable reducing agent, also increased the surface TF activity by about 2- to 3-fold. In additional studies, we found that PDI antibodies had no effect on either the TF coagulant activity or TF-mediated cell signaling. Further, we found no evidence for the expression of PDI at the cell surface in immunofluorescence confocal microscopy as both monoclonal and polyclonal PDI antibodies failed to stain nonpermeabilized cells whereas they brightly stained intracellular PDI in permeabilized cells. In contrast, TF antibodies stained intensely the surface of both nonpermeabilized and permeabilized cells. Exposure of tumor cells to various proteases failed to transport the intracellular PDI to the cell surface. The present data raise a valid question whether disulfide switching by PDI plays the predominant and general regulatory role in controlling the TF coagulant activity and signaling functions. Our data also suggest that other cellular changes, including increase in anionic phospholipids, may be responsible for increased TF coagulant activity associated with the thiol oxidizers and other treatments.

Glycosylphosphatidylinositol Anchored TFPI As Main Regulator of Factor X Activation On the Surface of Endothelial Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2210-2210
Author(s):  
Michael Dockal ◽  
Robert Pachlinger ◽  
Angelina Baldin-Stoyanova ◽  
Fabian Knofl ◽  
Nadja Ullrich ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Tissue Factor ◽  
Conflicts Of Interest ◽  
Factor Viia ◽  
Umbilical Vein ◽  
Surface Proteins ◽  
Enzyme Linked Immunosorbent Assay ◽  
Factor X ◽  
Extrinsic Pathway

Abstract Abstract 2210 Tissue factor pathway inhibitor (TFPI) is a key regulator of factor X (FX) activation in the extrinsic pathway of blood coagulation. TFPI inhibits FXa generation by formation of a quaternary complex consisting of factor VIIa (FVIIa), tissue factor (TF), FXa and TFPI. The main portion (∼80%) of TFPI in humans is reportedly associated with endothelial cells. We used human umbilical vein endothelial cells (HUVECs) as a model to obtain further insight into the function of TFPIα and the glycosylphosphatidylinositol (GPI) anchored TFPI form, which represents TFPIα bound to GPI-anchored surface proteins and/or TFPIβ. In contrast to TFPIα, which consists of 3 Kunitz domains (KD) and a basic C-terminal part, GPI-anchored TFPIβ lacks the third Kunitz domain (KD3) and the basic C–terminal region due to alternative splicing. In TFPIβ these two domains are replaced by a sequence that adds a GPI anchor to the protein linking it to the cell membrane. Treatment of HUVECs with phosphatidylinositol phospholipase C (PI-PLC) that cleaves GPI-anchors and subsequent fluorescence activated cell sorting (FACS) on living cells showed that GPI-anchored TFPI represents about 70–80% of cell surface TFPI. Staining of TFPI on and in fixed and permeabilized cells (total TFPI) demonstrated that GPI-anchored cell surface TFPI contributes to ∼20% of total cellular TFPI. Enzyme-linked immunosorbent assay (ELISA) showed that PI-PLC treatment released a TFPI protein lacking the KD3 and basic C-terminus. These findings strongly suggest that TFPIβ is the predominant GPI-anchored form of TFPI on HUVECs. FX activation assays performed on the cell surface of PI-PLC treated living HUVECs showed the importance of GPI-anchored TFPI on extrinsic Xase complex activity. PI-PLC treatment resulted in increased FX activation. Although GPI-anchored TFPI displays ∼70–80% of cell surface TFPI, overall FXa generation was increased only by ∼50%. In conclusion, HUVEC surface TFPI is predominantly TFPIβ, and GPI-anchored TFPI is the main but not sole regulator of FX activation on the surface of HUVECs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tissue factor trafficking in fibroblasts: involvement of protease-activated receptor–mediated cell signaling

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 161-170 ◽  
Author(s):  
Samir K. Mandal ◽  
Usha R. Pendurthi ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Cell Signaling ◽  
Tissue Factor ◽  
Neutralizing Antibodies ◽  
Factor Viia ◽  
Surface Expression ◽  
Coagulation Cascade ◽  
Cell Surface Expression ◽  
Clotting Factor ◽  
Intracellular Compartments

Tissue factor (TF) is the cellular receptor for clotting factor VIIa (FVIIa), and the formation of TF-FVIIa complexes on cell surfaces triggers the activation of the coagulation cascade and the cell signaling. Our recent studies have shown that a majority of TF resides in various intracellular compartments, predominantly in the Golgi, and that FVIIa binding to cell surface TF induces TF endocytosis and mobilizes the Golgi TF pool to translocate it to the cell surface. This present study is aimed to elucidate the mechanisms involved in TF endocytosis and its mobilization from the Golgi. Activation of protease-activated receptor 1 (PAR1) and PAR2 by specific peptide agonists and proteases, independent of FVIIa, mobilized TF from the Golgi store and increased the cell surface expression of TF. Blocking PAR2 activation, but not PAR1, with neutralizing antibodies fully attenuated the FVIIa-induced TF mobilization. Consistent with these data, silencing the PAR2 receptor, and not PAR1, abrogated the FVIIa-mediated TF mobilization. In contrast to their effect on TF mobilization, PAR1 and PAR2 activation, in the absence of FVIIa, had no effect on TF endocytosis. However, PAR2 activation is found to be critical for the FVIIa-induced TF endocytosis. Overall the data herein provide novel insights into the role of PARs in regulating cell surface TF expression.

Tissue factor: beyond coagulation in the cardiovascular system

2009 ◽  
Vol 118 (3) ◽  
pp. 159-172 ◽  
Author(s):  
Alexander Breitenstein ◽  
Giovanni G. Camici ◽  
Felix C. Tanner
Keyword(s):  
Tissue Factor ◽  
Factor Viia ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor X ◽  
Signalling Molecules ◽  
Smooth Muscle Cell Migration ◽  
Mitogen Activated Protein ◽  
Coronary Syndromes ◽  
Phosphoinositide 3 Kinase

TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).

scholarly journals Multiple roles of the coagulation protease cascade during virus infection

Blood ◽  
2014 ◽  
Vol 123 (17) ◽  
pp. 2605-2613 ◽  
Author(s):  
Silvio Antoniak ◽  
Nigel Mackman
Keyword(s):  
Immune Response ◽  
Tissue Factor ◽  
Viral Infections ◽  
Factor Viia ◽  
Hemorrhagic Fever ◽  
Multiple Roles ◽  
Coagulation Cascade ◽  
Factor X ◽  
Antiviral Protein ◽  
Monkey Model

Abstract The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

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