{"gene":"F3","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1987,"finding":"Molecular cloning of the cDNA for human tissue factor (TF/F3) revealed it encodes a 295-amino acid integral membrane protein with a single transmembrane domain that functions as the high-affinity cellular receptor initiating the coagulation protease cascade.","method":"cDNA cloning, Southern blotting, Northern blotting, sequence analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — original molecular cloning with complete structural characterization, foundational paper replicated widely","pmids":["3297348"],"is_preprint":false},{"year":1986,"finding":"Factor VII (and VIIa) binds to TF reconstituted in phospholipid vesicles at a 1:1 stoichiometry; phosphatidylserine induces positive cooperativity in binding, consistent with TF functioning as at least a dimer with two interacting enzyme-binding sites.","method":"Reconstitution of purified TF into phospholipid vesicles, quantitative binding assays with radiolabeled factors VII/VIIa, protease digestion, cooperative binding modeling","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro reconstitution with quantitative binding analysis and mechanistic modeling","pmids":["3527261"],"is_preprint":false},{"year":1989,"finding":"TF protein is selectively expressed in a hemostatic 'envelope' pattern in normal human tissues — present in vascular adventitia, organ capsules, epidermis, and mucosal epithelium — but absent from endothelium and circulating blood cells; TF expression is inducible in monocytes by LPS, establishing the cellular basis for coagulation initiation upon vascular injury.","method":"Immunohistochemistry with epitope-defined monoclonal antibodies in normal human tissues; LPS stimulation of monocytes","journal":"The American Journal of Pathology","confidence":"High","confidence_rationale":"Tier 2 — systematic immunohistochemical localization across multiple tissue types with functional implications, foundational paper with >1000 citations","pmids":["2719077"],"is_preprint":false},{"year":1989,"finding":"TF mRNA and protein are expressed by macrophage foam cells and mesenchymal intimal cells within atherosclerotic plaques, and TF protein is deposited in the extracellular matrix of necrotic cores, establishing atherosclerotic plaque as a source of thrombogenic TF.","method":"In situ hybridization with TF-specific riboprobe and immunohistochemistry in human vessels and atherosclerotic plaques","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — dual-method (ISH + IHC) localization in human tissue, >1000 citations, foundational finding","pmids":["2704749"],"is_preprint":false},{"year":1990,"finding":"TF activity is regulated by the Kunitz-type inhibitor TFPI (tissue factor pathway inhibitor), which acts in a multivalent manner to inhibit the TF:FVIIa complex and thereby regulate coagulation.","method":"Biochemical inhibition assays with purified components","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified proteins; foundational mechanistic finding replicated widely","pmids":["2271516"],"is_preprint":false},{"year":1995,"finding":"NF-κB activation is an obligatory step in TF induction by diverse agonists (LPS, TNF-α, IL-1β, PMA) in endothelial cells; PDTC, a specific NF-κB pathway inhibitor, dose-dependently abrogates TF mRNA and activity induction, acting at the transcriptional level.","method":"PDTC inhibitor treatment of HUVEC, TF activity assay, Northern blot for TF mRNA, dose-response analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple agonists tested, mRNA and activity measured, specific inhibitor with dose-response, strong mechanistic conclusion","pmids":["7605983"],"is_preprint":false},{"year":1996,"finding":"Crystal structure of active-site-inhibited factor VIIa complexed with the soluble extracellular domain of TF at 2.0 Å resolution revealed that FVIIa adopts an extended conformation in the complex, providing the molecular basis for understanding how TF allosterically activates FVIIa and positions it to cleave substrates FIX and FX.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure, foundational for understanding TF:FVIIa mechanism, >670 citations","pmids":["8598903"],"is_preprint":false},{"year":1998,"finding":"TF supports cell adhesion, migration, spreading, and intracellular signaling independently of RGD-mediated integrin pathways; the TF cytoplasmic domain binds actin-binding protein 280 (ABP-280/filamin A), and this interaction requires extracellular TF ligation and Ser phosphorylation-mimicking mutations; Ala mutations of cytoplasmic Ser residues abolish ABP-280 co-precipitation and severely reduce cell spreading, revealing a cytoskeletal signaling pathway.","method":"Yeast two-hybrid screening, co-immunoprecipitation, cell adhesion/migration assays, cytoplasmic domain chimeras, site-directed mutagenesis of Ser residues","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1–2 — yeast two-hybrid plus co-IP validation, mutagenesis, functional adhesion/migration assays, multiple orthogonal methods, >270 citations","pmids":["9490735"],"is_preprint":false},{"year":2002,"finding":"Tissue factor-induced blood coagulation proceeds in two phases: an initiation phase generating ~26 nM thrombin at ~1.3 pM prothrombinase, followed by a propagation phase generating thrombin at ~120 pM prothrombinase; clot formation coincides with transition to the propagation phase, and distinct thrombin concentration thresholds trigger sequential activation of platelets, factor XIII, fibrinogen, and other substrates.","method":"Contact pathway-inhibited whole blood coagulation assay, quantitative measurement of TAT complexes, prothrombin fragments, fibrinopeptides, factor Va, platelet activation markers over time in 20 individuals","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — quantitative kinetic analysis with multiple substrates across 20 subjects, defines mechanistic phases of TF-initiated coagulation","pmids":["12070020"],"is_preprint":false},{"year":2003,"finding":"An alternatively spliced form of human TF (asHTF) lacking the transmembrane domain is soluble, circulates in blood, exhibits procoagulant activity when exposed to phospholipids, and is incorporated into thrombi, identifying a circulating thrombogenic TF isoform.","method":"Identification of alternatively spliced mRNA, recombinant protein production, procoagulant activity assays with phospholipids, thrombus incorporation studies","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 1 — biochemical characterization of novel isoform with functional procoagulant assay and in vivo thrombus incorporation, >375 citations","pmids":["12652293"],"is_preprint":false},{"year":2003,"finding":"Intravascular TF is present mainly on circulating microvesicles in plasma, with platelet-derived microvesicles (identified by CD42b sorting) as a major location; TF is stored in platelet α-granules and the open canalicular system, exposed on the surface after platelet activation; functional TF activity on microvesicles and platelets is enabled when they adhere to neutrophils via P-selectin/PSGL-1 and CD18 interactions, and neutrophil-derived reactive oxygen species further support TF activity.","method":"Flow cytometry with cell sorting (CD42b), immunoelectron microscopy, subcellular fractionation, TF activity assays, P-selectin/PSGL-1 blocking antibodies","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (flow cytometry, EM, functional assay, blocking antibodies), defines cellular mechanism of intravascular TF activity","pmids":["12514112"],"is_preprint":false},{"year":2004,"finding":"TF expression in colorectal cancer cells is controlled by K-ras oncogene activation and p53 inactivation via MEK/MAPK and PI3K pathways; RNA interference of TF reduces K-ras-dependent tumorigenic and angiogenic phenotype in vivo, establishing TF as an effector of oncogene-driven tumor progression and angiogenesis.","method":"Isogenic colorectal cancer cell lines with defined K-ras/p53 status, MEK/PI3K pharmacological inhibition, TF siRNA knockdown, in vivo xenograft tumor/angiogenesis assays, measurement of cell-associated and microvesicle TF activity","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis, siRNA knockdown with in vivo phenotypic readout, multiple methods, >475 citations","pmids":["15494427"],"is_preprint":false},{"year":2004,"finding":"TF deficiency causes embryonic lethality in mice, and TF:FVIIa complex signaling through protease-activated receptors (PARs) on vascular cells mediates non-hemostatic functions including inflammation, angiogenesis, metastasis, and cell migration.","method":"Review integrating mouse genetic knockout studies and cell signaling experiments","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 — synthesizes multiple genetic (TF knockout lethal) and biochemical studies across labs; strong/replicated","pmids":["15117736"],"is_preprint":false},{"year":2004,"finding":"FVIIa/TF interaction induces STAT5 phosphorylation, nuclear translocation, and transactivation; this signaling is dependent on FVIIa proteolytic activity but not on the TF cytoplasmic domain, and requires G12/G13 class G proteins and Jak2 (but not Jak1 or Tyk2); FVIIa/TF promotes cell survival through Jak2/STAT5-dependent BclXL production and Jak2-dependent PKB activation.","method":"STAT5 reporter assays, phosphorylation/nuclear translocation experiments, specific G protein and Jak inhibitors, dominant-negative constructs, cell survival assays, BclXL/PKB measurements","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 — multiple inhibitor approaches, reporter assays, pathway dissection with dominant-negatives; identifies G12/G13-Jak2-STAT5-BclXL as novel TF signaling axis","pmids":["15016732"],"is_preprint":false},{"year":2006,"finding":"TF exists in two functionally distinct pools on the cell surface controlled by the redox state of the extracellular Cys186–Cys209 disulfide bond: a coagulant pool requiring this disulfide, and a signaling pool (cryptic/noncoagulant) where protein disulfide isomerase (PDI) disrupts the disulfide in a nitric oxide-dependent pathway, switching TF from coagulation to PAR2-dependent cell signaling; a monoclonal antibody specific for cryptic TF inhibits TF:PAR2 complex formation and TF:VIIa signaling without blocking coagulation.","method":"Disulfide bond mutagenesis (C209A and other mutants), PDI inhibition, nitric oxide pathway manipulation, PAR2 signaling assays, specific conformation-selective monoclonal antibody blocking experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis combined with biochemical PDI manipulation, conformation-selective antibody, and functional coagulation/signaling readouts; multiple orthogonal methods in single study, >280 citations","pmids":["16959886"],"is_preprint":false},{"year":2006,"finding":"Human platelets express TF pre-mRNA constitutively; platelet activation triggers Cdc2-like kinase 1 (Clk1)-dependent splicing of TF pre-mRNA into mature mRNA, producing TF protein and procoagulant activity that accelerates clot formation; interruption of Clk1 signaling prevents TF accumulation in activated platelets.","method":"RT-PCR for pre-mRNA and mature mRNA in resting vs. activated platelets, Clk1 pharmacological inhibition, TF protein detection, procoagulant/clot formation assays","journal":"The Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 — novel mechanism (signal-dependent pre-mRNA splicing) demonstrated with molecular and functional assays, Clk1 as specific regulator identified, >279 citations","pmids":["17060476"],"is_preprint":false},{"year":2007,"finding":"Direct TF:VIIa signaling (independent of coagulation cascade activation) is required for primary tumor growth; TF associates with β1 integrins in epithelial/endothelial cells (regulated by TF extracellular ligand binding) and constitutively with α3β1 integrin in breast cancer cells; a signaling-inhibitory anti-TF antibody (Mab-10H10) disrupts TF–integrin association and TF:VIIa–PAR2 signaling, suppressing tumor xenograft growth as effectively as the coagulation-inhibitory antibody.","method":"Isotype-matched antibody pair (Mab-5G9 vs. Mab-10H10) discriminating coagulation vs. signaling TF; co-immunoprecipitation of TF with β1/α3β1 integrins; PAR2 signaling assays; in vivo human xenograft tumor models (2 models)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — unique antibody pair enabling functional dissection, reciprocal co-IP, in vivo tumor suppression in 2 models, >284 citations","pmids":["17901245"],"is_preprint":false},{"year":2008,"finding":"TF:FVIIa induces phosphorylation and activation of the transcription factor CREB via ERK1/2 and PAR2, independently of the TF cytoplasmic domain; in keratinocytes, this leads to upregulation of pro-apoptotic proteins Bak and Puma and induction of apoptosis in a CREB-dependent manner, whereas FXa (but not thrombin) also induces CREB but without apoptosis, revealing cell-type-specific downstream outcomes.","method":"CREB phosphorylation and reporter assays in BHK-TF, HaCaT, and HUVEC cells; ERK and PAR2 inhibition; siRNA/dominant-negative approaches; apoptosis assays; comparison with FXa and thrombin","journal":"Journal of Thrombosis and Haemostasis","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types, pathway inhibitors, and apoptosis readouts; identifies CREB as TF:FVIIa downstream target via PAR2/ERK","pmids":["18647225"],"is_preprint":false},{"year":2009,"finding":"Tumor-derived TF-bearing microparticles circulate in blood of cancer patients (detected in ~two-thirds of pancreatic carcinoma patients), co-express tumor marker MUC-1, are eliminated by tumor resection, and elevated levels are associated with venous thromboembolism in cancer patients (adjusted OR 3.72), establishing TF-positive microparticles as mediators of cancer-associated thrombosis.","method":"Impedance-based flow cytometry for microparticle detection and quantitation in plasma; case-control study; tumor resection experiments; MUC-1 co-staining","journal":"Clinical Cancer Research","confidence":"High","confidence_rationale":"Tier 2 — flow cytometry with tumor resection validation, case-control design, strong mechanistic link between tumor-derived TF MPs and thrombosis","pmids":["19861441"],"is_preprint":false},{"year":2012,"finding":"TF procoagulant activity is regulated by thiol-disulfide exchange at the cell surface: protein disulfide isomerase (PDI) is associated with cell-surface TF and required for TF-dependent thrombosis in vivo; PDI regulates thiol-dependent biogenesis of procoagulant microparticles released from myeloid cells and smooth muscle cells via the purinergic P2X7 receptor; genetic deletion of P2X7 attenuates FeCl3-induced carotid artery thrombosis in mice.","method":"Co-immunoprecipitation of PDI with TF, thiol-modifying agents, P2X7 genetic knockout mice, FeCl3 carotid artery thrombosis model, microparticle procoagulant activity assays","journal":"Thrombosis Research","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo genetic model plus biochemical co-IP, multiple inhibitor approaches, functional thrombosis readout","pmids":["22401798"],"is_preprint":false},{"year":2013,"finding":"TFPIα and TFPIβ are both expressed at the surface of breast cancer cells in GPI-anchored form; PI-PLC cleavage of GPI-anchored TFPI releases both isoforms and increases TF activity on the cell surface, demonstrating that GPI-anchored TFPI inhibits TF:FVIIa activity locally; heparin releases TFPIα but not TFPIβ, revealing distinct surface pools.","method":"qRT-PCR, ELISA, flow cytometry, immunofluorescence, Western blotting, PI-PLC and heparin treatment, Factor Xa activity assay","journal":"Journal of Hematology & Oncology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, PI-PLC/heparin functional dissection of surface pools, direct TF activity measurement","pmids":["23320987"],"is_preprint":false},{"year":2013,"finding":"Tumor-derived TF-positive microparticles in blood bind to sites of vascular injury and enhance thrombosis in animal models; elevated circulating TF-positive microparticles correlate with venous thrombosis in multiple cancer types, proposing a mechanism for cancer-associated coagulopathy.","method":"Review synthesizing animal model studies (MP binding to injury sites, thrombosis enhancement) and clinical correlation data","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — synthesizes in vivo animal models and clinical data but is a review; mechanistic animal model findings are from multiple labs","pmids":["23798713"],"is_preprint":false},{"year":2016,"finding":"Monomeric CRP (mCRP), formed on microvascular endothelial cell membranes from circulating native pentameric CRP in a receptor-dependent and time-dependent fashion, triggers F3 (TF) gene transcription and TF protein expression in microvascular endothelial cells; F3-silenced endothelial cells are unable to form angiotubes; mCRP-induced TF signaling activates AKT and the transcription factor ETS1, leading to CCL2 release and angiogenesis.","method":"Confocal microscopy and Western blot for CRP conversion; F3 gene reporter assays; siRNA silencing of F3; angiogenesis tube formation assay; AKT/ETS1 phosphorylation; CCL2 ELISA; in vivo collagen plug angiogenesis model","journal":"Thrombosis and Haemostasis","confidence":"High","confidence_rationale":"Tier 2 — F3 silencing with functional angiogenesis readout, signaling pathway characterization, in vivo and in vitro concordance","pmids":["27808345"],"is_preprint":false},{"year":2017,"finding":"Computational molecular dynamics simulation of the full-length TF1-263:FVIIa membrane-bound complex revealed novel non-covalent interactions between TF's EGF2 domain and FVIIa not present in the truncated soluble TF crystal structure; TF allosterically modifies each domain of FVIIa through inter- and intra-domain communication, governing catalytic triad orientation and providing additional stability to the FVIIa protease domain.","method":"Computational homology modeling and molecular dynamics simulations of full-length TF:FVIIa membrane complex","journal":"Journal of Biomolecular Structure and Dynamics","confidence":"Low","confidence_rationale":"Tier 4 — computational modeling only, no experimental validation of predicted interactions","pmids":["28150568"],"is_preprint":false},{"year":2018,"finding":"NETs decorated with TF and IL-17A promote thrombin generation and fibrosis in SLE; REDD1-driven autophagy in SLE neutrophils leads to enhanced NET release carrying TF; TF-bearing NETs promote coagulation (thromboinflammation) and activate fibroblasts; hydroxychloroquine inhibits NETosis and the associated TF-bearing NET release.","method":"Immunofluorescence, immunoblotting, qPCR, ELISA for NET proteins and TF; autophagy assessment; in vitro primary fibroblast culture with NET stimulation; patient biopsy specimens; bosentan/L-ascorbic acid inhibitors; hydroxychloroquine inhibition","journal":"Annals of the Rheumatic Diseases","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic pathway (REDD1/autophagy/NETs/TF) defined in human cells with inhibitor validation; functional fibroblast assay","pmids":["30563869"],"is_preprint":false},{"year":2018,"finding":"NETs promote endothelial cell (EC) activation and TF expression through IL-1α and cathepsin G: cathepsin G (a serine protease abundant in NETs) cleaves pro-IL-1α to release mature IL-1α, which then upregulates TF mRNA and activity in ECs; anti-TF antibody blocks NET-induced acceleration of plasma clotting.","method":"NET-EC co-incubation assays, anti-IL-1α/IL-1Ra/anti-IL-1β antibody blocking, cathepsin G inhibition, TF mRNA/activity measurement, plasma clotting assays under flow","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with multiple neutralizing antibodies and specific enzyme inhibitors, functional TF activity and clotting readouts, >283 citations","pmids":["29976772"],"is_preprint":false},{"year":2019,"finding":"TF promotes hepatocellular carcinoma (HCC) growth in vitro and in vivo by activating both ERK and AKT signaling pathways; TF induces EGFR upregulation, and EGFR inhibition suppresses TF-mediated HCC growth, placing TF upstream of an EGFR/ERK/AKT axis in HCC.","method":"In vitro proliferation/growth assays, in vivo xenograft models, ERK/AKT pathway inhibition, EGFR siRNA knockdown and pharmacological inhibition, TF siRNA knockdown, Western blotting","journal":"Frontiers in Oncology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional assays with siRNA and pharmacological inhibitors; single study","pmids":["30931258"],"is_preprint":false},{"year":2019,"finding":"Human primary adipocytes express both TF and FVII; the TF/FVIIa complex formed on the adipocyte surface generates active FXa from substrate Factor X, establishing adipocytes as a procoagulant cell type via autocrine TF/FVIIa activity; active site-inhibited FVIIa blocks FXa formation, confirming specificity.","method":"Collagenase isolation of primary human adipocytes, 3T3-L1 differentiation, RT-PCR, Western blot, colorimetric FX activation assay, active site-inhibited FVIIa blocking","journal":"Upsala Journal of Medical Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — functional FX activation assay with specific inhibitor control in primary human cells; novel cell type identified; single study","pmids":["31407948"],"is_preprint":false},{"year":2019,"finding":"Chemotherapy (oxaliplatin) increases TF expression and MMP-9/2 activity in sciatic nerve and blood; L-OHP elevates HSP70 release from macrophages, activating p-p38 and HIF-1α; hirudin (anticoagulant) suppresses TF, p38, HIF-1α, and MMP-9/2, and attenuates chemotherapy-induced peripheral neuropathy (CIPN), implicating an HSP70-TLR4-p38-TF-HIF-1α axis in CIPN pathology.","method":"CIPN mouse model, Von Frey testing, gelatin zymography, Western blotting in sciatic nerve and macrophage cell line, hirudin treatment","journal":"BioMed Research International","confidence":"Low","confidence_rationale":"Tier 3 — functional mouse model with inhibitor but TF's role is pharmacologically inferred rather than directly demonstrated by TF-specific manipulation","pmids":["31380428"],"is_preprint":false},{"year":2020,"finding":"Complement C3 inhibition (with compstatin Cp40) disrupts TF expression in neutrophils; COVID-19 neutrophils release NETs carrying active TF; treatment of control neutrophils with COVID-19 platelet-rich plasma generates TF-bearing NETs that induce thrombotic activity in endothelial cells; C5aR1 blockade and NETosis/thrombin inhibition attenuate platelet-mediated NET-driven TF thrombogenicity, establishing a complement→C5aR1→NETosis→TF pathway in COVID-19 immunothrombosis.","method":"Plasma TF activity and sC5b-9 measurement, neutrophil TF expression, C5aR1 blockade, compstatin C3 inhibition, NET/HAEC co-culture thrombosis assay, NETosis/thrombin inhibitors","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — mechanistic cell-based assays with multiple specific inhibitors (C3, C5aR1, NETosis, thrombin) dissecting pathway, functional thrombosis readout, replicated in patient specimens","pmids":["32759504"],"is_preprint":false},{"year":2020,"finding":"In severe COVID-19, platelet activation and platelet-monocyte aggregate formation drive monocyte TF expression; platelet P-selectin neutralization or αIIb/β3 integrin blockade with abciximab inhibits platelet-dependent monocyte TF induction ex vivo, identifying P-selectin-mediated platelet-monocyte contact as the mechanism for coagulation activation in severe COVID-19.","method":"Flow cytometry for platelet activation markers and monocyte TF expression; ex vivo platelet-monocyte co-culture with P-selectin antibody and abciximab inhibition; plasma from COVID-19 patients applied to control platelets","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — mechanistic ex vivo assay with specific receptor blocking antibodies, P-selectin and integrin identified as drivers of monocyte TF induction, patient plasma validation","pmids":["32678428"],"is_preprint":false},{"year":2022,"finding":"EBV infection upregulates F3 (TF) expression in nasopharyngeal carcinoma and EBV-associated gastric carcinoma cells via the EBV latent membrane protein 2A (LMP2A)-PI3K/AKT signaling pathway; F3-mediated platelet aggregation inhibits NK-cell cytotoxic function; F3 inhibition in vivo restores NK-cell antitumor activity and shows therapeutic efficacy in NPC xenograft models.","method":"F3 expression analysis by EBV infection and LMP2A overexpression; PI3K/AKT inhibitor experiments; in vitro and in vivo platelet aggregation assays; NK-cell cytotoxicity assays; F3 siRNA knockdown; NPC xenograft mouse model with NK-cell transfer","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (LMP2A→PI3K/AKT→F3→platelet aggregation→NK suppression) defined with multiple orthogonal methods in vitro and in vivo","pmids":["35064016"],"is_preprint":false},{"year":2022,"finding":"Paeoniflorin activates the Gas6/Axl/SOCS3 axis to upregulate SOCS3, which subsequently inhibits apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and suppresses TF expression in macrophages and endothelial cells, preventing thrombosis and improving radiation enteritis in mice.","method":"Laser Doppler flowmetry, RAW264.7 and HUVEC cell experiments, Gas6/Axl/SOCS3 pathway analysis by Western blot, ASK1/TF expression by qPCR and Western blot, siRNA knockdown, in vivo radiation enteritis mouse model","journal":"Frontiers in Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — identifies Gas6/Axl/SOCS3/ASK1 as upstream regulators of TF with in vitro and in vivo validation; single lab study","pmids":["35359871"],"is_preprint":false},{"year":2024,"finding":"GSTP1 methylation-mediated silencing promotes stress-induced hepatocellular injury via ferroptosis through a TF/Nrf2 pathway; GSTP1 overexpression reduces TF expression and GPX4 downregulation, whereas GSTP1 knockdown increases TF and promotes ferroptosis; Nrf2 inhibition exacerbates TF-driven ferroptosis, placing TF downstream of the Nrf2/GSTP1 axis in ferroptotic cell death.","method":"Mouse restraint stress model, dexamethasone-treated AML-12 hepatocyte model, GSTP1 overexpression and siRNA, Nrf2 inhibitor, DNA methylation sequencing, Western blotting, lipid ROS/MDA measurement, transmission electron microscopy","journal":"Journal of Cellular and Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — GSTP1 gain- and loss-of-function with Nrf2 inhibitor and ferroptosis inhibitor in vitro and in vivo; TF's mechanistic role in ferroptosis pathway established but single study","pmids":["38890797"],"is_preprint":false}],"current_model":"Tissue factor (F3/TF) is a transmembrane glycoprotein that functions as the primary cellular initiator of blood coagulation by forming a high-affinity complex with Factor VIIa, allosterically activating FVIIa (as revealed by the 2.0 Å crystal structure) to cleave FIX and FX; TF procoagulant activity is regulated by the redox state of its Cys186–Cys209 disulfide bond (toggled by protein disulfide isomerase in a nitric oxide-dependent manner), which switches TF between a coagulant pool and a signaling pool that activates PAR2 and G12/G13-Jak2-STAT5-BclXL cell survival pathways; TF cytoplasmic domain Ser phosphorylation enables binding to actin-binding protein ABP-280/filamin A, supporting cell adhesion, migration, and cytoskeletal reorganization; TF expression is transcriptionally induced by NF-κB (downstream of LPS, TNF-α, IL-1β), by oncogenic K-ras/p53 via MEK/PI3K, by mCRP via ETS1, and by EBV LMP2A via PI3K/AKT, while being negatively regulated by TFPI and by the Nrf2/GSTP1 axis; circulating TF-positive microparticles derived from activated platelets, tumor cells, and NETs propagate coagulation and thrombosis, and platelet-derived TF is generated via Clk1-dependent signal-activated pre-mRNA splicing."},"narrative":{"teleology":[{"year":1986,"claim":"Establishing how TF engages its enzymatic partner resolved the stoichiometry and lipid dependence of the initiating coagulation complex: FVIIa binds TF at 1:1 stoichiometry in phospholipid vesicles, with phosphatidylserine inducing cooperative binding consistent with at least dimeric TF.","evidence":"Reconstitution of purified TF in phospholipid vesicles with radiolabeled FVII/FVIIa binding and cooperative modeling","pmids":["3527261"],"confidence":"High","gaps":["Whether TF dimers are physiologically relevant on cell membranes was not resolved","Allosteric mechanism of FVIIa activation not yet defined"]},{"year":1987,"claim":"Molecular cloning revealed TF as a single-pass transmembrane protein of 295 amino acids, providing the sequence foundation for all subsequent structure–function studies.","evidence":"cDNA cloning, Southern/Northern blotting, and sequence analysis","pmids":["3297348"],"confidence":"High","gaps":["Three-dimensional structure unknown","Function of the cytoplasmic domain undefined"]},{"year":1989,"claim":"Defining where TF is expressed in vivo answered how the body confines coagulation initiation to sites of vascular breach: TF is constitutively present in a hemostatic envelope (adventitia, organ capsules, epidermis) but absent from endothelium, and is inducible in monocytes and enriched in atherosclerotic plaque foam cells.","evidence":"Systematic immunohistochemistry with monoclonal antibodies across normal tissues and atherosclerotic plaques; in situ hybridization","pmids":["2719077","2704749"],"confidence":"High","gaps":["Mechanism of TF induction in monocytes and plaque cells was uncharacterized","Contribution of plaque TF to acute thrombotic events not yet tested in vivo"]},{"year":1990,"claim":"Identification of TFPI as a Kunitz-type inhibitor of the TF:FVIIa complex established the primary physiological negative regulator of TF-initiated coagulation.","evidence":"Biochemical inhibition assays with purified TF, FVIIa, and TFPI","pmids":["2271516"],"confidence":"High","gaps":["Relative contributions of TFPI isoforms (α vs β) on different cell surfaces not yet defined","In vivo significance not directly tested at this stage"]},{"year":1995,"claim":"Demonstrating that NF-κB is obligatory for TF transcriptional induction by LPS, TNF-α, and IL-1β connected TF expression to inflammatory signaling, explaining how inflammation triggers coagulation.","evidence":"PDTC (NF-κB inhibitor) dose-dependently abolished TF mRNA and activity in HUVECs stimulated with multiple agonists","pmids":["7605983"],"confidence":"High","gaps":["Specific NF-κB subunits and promoter elements not mapped in this study","Whether NF-κB is the sole transcriptional regulator of TF not addressed"]},{"year":1996,"claim":"The 2.0 Å crystal structure of the TF:FVIIa complex revealed how TF allosterically activates FVIIa by stabilizing its extended conformation, answering the central question of how a receptor converts an inert zymogen into an active protease.","evidence":"X-ray crystallography of active-site-inhibited FVIIa bound to soluble TF extracellular domain","pmids":["8598903"],"confidence":"High","gaps":["Structure used truncated soluble TF lacking transmembrane/cytoplasmic domains and membrane context","Substrate (FIX/FX) positioning in the complex unknown"]},{"year":1998,"claim":"Discovery that TF's cytoplasmic domain binds filamin A (ABP-280) in a phosphorylation-dependent manner and supports cell adhesion/migration established TF as a signaling receptor beyond its coagulation role.","evidence":"Yeast two-hybrid screen, co-immunoprecipitation, Ser→Ala mutagenesis, and functional adhesion/migration assays","pmids":["9490735"],"confidence":"High","gaps":["Kinase(s) responsible for cytoplasmic Ser phosphorylation not identified","In vivo relevance of TF–filamin interaction for migration not shown"]},{"year":2002,"claim":"Quantitative kinetic analysis of whole-blood TF-initiated coagulation defined two mechanistic phases—initiation (~26 nM thrombin) and propagation—with distinct thrombin thresholds sequentially activating platelets, FXIII, and fibrinogen, providing a quantitative framework for how TF triggers clot formation.","evidence":"Contact-pathway-inhibited whole blood assay measuring TAT, prothrombin fragments, fibrinopeptides, and platelet markers in 20 subjects","pmids":["12070020"],"confidence":"High","gaps":["Contribution of alternatively spliced TF to these phases not examined","Role of microparticle TF in propagation phase not addressed"]},{"year":2003,"claim":"Identification of alternatively spliced soluble TF (asHTF) in blood and TF on platelet-derived microvesicles revealed that circulating TF pools exist beyond the tissue-fixed hemostatic envelope, fundamentally expanding the concept of TF-mediated thrombosis.","evidence":"RT-PCR identification of splice variant, recombinant protein procoagulant assays, flow cytometry sorting of platelet microvesicles (CD42b+), immunoelectron microscopy of platelet α-granules","pmids":["12652293","12514112"],"confidence":"High","gaps":["Relative contribution of soluble vs microvesicle TF to in vivo thrombosis not quantified","Mechanism by which platelet TF becomes procoagulant upon activation not fully resolved"]},{"year":2004,"claim":"Two concurrent discoveries established TF as an effector of oncogenic signaling: K-ras/p53 regulate TF via MEK/PI3K to drive tumor angiogenesis, and TF:FVIIa activates a G12/G13–Jak2–STAT5–BclXL cell survival pathway, revealing non-hemostatic TF functions in cancer.","evidence":"Isogenic K-ras/p53 colorectal lines with TF siRNA and xenograft assays; STAT5 reporters with G-protein and Jak inhibitors and dominant-negatives","pmids":["15494427","15016732"],"confidence":"High","gaps":["Whether G12/G13–Jak2–STAT5 signaling operates through PAR2 specifically was not fully resolved","Relative importance of TF coagulant vs signaling functions in tumor progression in patients unknown"]},{"year":2006,"claim":"The discovery that TF's Cys186–Cys209 disulfide bond acts as a redox switch—toggled by PDI in a nitric oxide–dependent manner—between a coagulant and a PAR2-signaling pool resolved how a single receptor can serve dual functions and opened the concept of 'cryptic' TF.","evidence":"Disulfide mutagenesis (C209A), PDI inhibition, NO pathway manipulation, conformation-selective monoclonal antibody blocking coagulation vs signaling readouts","pmids":["16959886"],"confidence":"High","gaps":["Structural basis of conformational change upon disulfide disruption not determined at atomic resolution","Proportion of cryptic vs coagulant TF on different cell types in vivo unknown"]},{"year":2006,"claim":"Demonstration that platelets constitutively carry TF pre-mRNA and that activation triggers Clk1-dependent splicing to produce functional TF protein revealed a novel post-transcriptional mechanism for rapid TF generation at sites of thrombosis.","evidence":"RT-PCR for pre-mRNA and mature mRNA in resting vs activated platelets, Clk1 pharmacological inhibition, procoagulant/clot assays","pmids":["17060476"],"confidence":"High","gaps":["Physiological contribution of platelet-spliced TF relative to tissue-derived TF in hemostasis not quantified","Clk1 substrates in this context not comprehensively mapped"]},{"year":2007,"claim":"Showing that TF associates with β1/α3β1 integrins and that a signaling-selective anti-TF antibody suppresses tumor growth as effectively as a coagulation-blocking antibody established that direct TF:FVIIa–PAR2 signaling is required for primary tumor growth independently of downstream coagulation.","evidence":"Co-immunoprecipitation of TF with integrins, isotype-matched signaling- vs coagulation-blocking antibodies, two in vivo xenograft models","pmids":["17901245"],"confidence":"High","gaps":["Structural basis of TF–integrin interaction undefined","Whether integrin association modulates the cryptic/coagulant TF switch unknown"]},{"year":2009,"claim":"Detection of tumor-derived TF-positive microparticles (co-expressing MUC-1) in cancer patient blood, their elimination by tumor resection, and their association with venous thromboembolism (OR 3.72) provided direct clinical evidence that tumor-shed TF microparticles drive cancer-associated thrombosis.","evidence":"Impedance-based flow cytometry in pancreatic cancer patients, case-control design, tumor resection as intervention","pmids":["19861441"],"confidence":"High","gaps":["Whether TF-positive microparticle levels can serve as a clinically useful biomarker not validated prospectively","Functional activity of individual microparticles not measured"]},{"year":2012,"claim":"In vivo demonstration that PDI associates with cell-surface TF and that P2X7 receptor-dependent PDI activity is required for TF-dependent arterial thrombosis and procoagulant microparticle biogenesis connected the cryptic TF redox switch to a physiological thrombotic phenotype.","evidence":"Co-IP of PDI with TF, P2X7 knockout mice, FeCl3 carotid thrombosis model, thiol-modifying agents, microparticle activity assays","pmids":["22401798"],"confidence":"High","gaps":["Precise molecular mechanism of P2X7-PDI-TF coupling not defined","Whether other thiol oxidoreductases contribute in vivo not excluded"]},{"year":2018,"claim":"NETs were established as TF delivery vehicles in thromboinflammation: cathepsin G on NETs cleaves pro-IL-1α to activate endothelial TF expression, and in SLE, REDD1-driven autophagy enhances NET release carrying TF, linking innate immunity, inflammation, and coagulation.","evidence":"NET-endothelial co-culture with cathepsin G and IL-1α blocking; SLE patient neutrophils with autophagy assessment and hydroxychloroquine inhibition","pmids":["29976772","30563869"],"confidence":"High","gaps":["Relative contribution of NET-borne TF vs monocyte-derived TF in vivo thrombosis not quantified","Whether NET-TF pathway is targetable therapeutically in humans not tested"]},{"year":2020,"claim":"COVID-19 studies delineated a complement→C5aR1→NETosis→TF pathway and a P-selectin-mediated platelet–monocyte contact mechanism for monocyte TF induction, establishing TF as a central effector of immunothrombosis in SARS-CoV-2 infection.","evidence":"Compstatin C3 inhibition, C5aR1 blockade, NETosis inhibitors in patient neutrophils; flow cytometry with P-selectin and αIIbβ3 blocking in patient monocytes","pmids":["32759504","32678428"],"confidence":"High","gaps":["Whether anti-TF strategies reduce clinical thrombosis in COVID-19 not tested","Generalizability to other viral immunothrombotic conditions unknown"]},{"year":2022,"claim":"EBV LMP2A was shown to upregulate TF via PI3K/AKT in nasopharyngeal carcinoma, and TF-induced platelet aggregation suppresses NK-cell cytotoxicity, revealing a viral oncogene–TF axis enabling immune evasion that is reversible by TF inhibition in vivo.","evidence":"LMP2A overexpression, PI3K/AKT inhibition, F3 siRNA, platelet aggregation assays, NK cytotoxicity assays, NPC xenograft model with NK-cell transfer","pmids":["35064016"],"confidence":"High","gaps":["Whether this immune evasion mechanism operates in other EBV-driven malignancies not tested","Direct structural basis of TF-mediated platelet aggregation unknown"]},{"year":2024,"claim":"Placing TF downstream of the Nrf2/GSTP1 axis in ferroptotic hepatocellular injury expanded TF's functional repertoire to include regulation of ferroptosis, a non-apoptotic cell death pathway.","evidence":"GSTP1 overexpression/knockdown, Nrf2 inhibitor, lipid ROS/MDA measurement, TEM for ferroptosis morphology in mouse stress model and AML-12 hepatocytes","pmids":["38890797"],"confidence":"Medium","gaps":["Mechanism by which TF promotes ferroptosis is not defined at molecular level","Single study, not independently replicated","Whether TF's role in ferroptosis is coagulation-dependent or signaling-dependent unknown"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of full-length membrane-bound TF (including the transmembrane and cytoplasmic domains), the identity of kinases that phosphorylate the TF cytoplasmic domain in vivo, the quantitative contribution of each TF pool (tissue-fixed, microparticle, platelet-spliced, alternatively spliced soluble) to hemostasis vs pathological thrombosis, and whether therapeutic targeting of TF signaling can be separated from hemostatic TF function in patients.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length TF structure with membrane context unavailable","Cytoplasmic domain kinase(s) unidentified","Clinical translation of signaling-selective TF inhibition not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,14,16,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,14,19]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,10,18]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[10,18,21]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,1,4,6,8,9,10,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,14,16,17,22,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24,25,29,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,18,26,31]}],"complexes":["TF:FVIIa (extrinsic tenase)"],"partners":["F7","TFPI","FLNA","F2RL1","P4HB","ITGB1"],"other_free_text":[]},"mechanistic_narrative":"Tissue factor (TF/F3) is a transmembrane glycoprotein that serves as the primary cellular initiator of blood coagulation by forming a high-affinity 1:1 complex with Factor VIIa, allosterically activating FVIIa to cleave Factors IX and X and triggering a two-phase coagulation cascade of initiation and propagation [PMID:3527261, PMID:8598903, PMID:12070020]. TF exists in two functionally distinct cell-surface pools governed by the redox state of its Cys186–Cys209 disulfide bond: a procoagulant pool requiring the intact disulfide and a cryptic/signaling pool in which protein disulfide isomerase disrupts the bond, switching TF to PAR2-dependent signaling that activates G12/G13–Jak2–STAT5–BclXL survival and ERK/CREB pathways [PMID:16959886, PMID:15016732, PMID:18647225]. Beyond hemostasis, TF promotes cell adhesion and migration through cytoplasmic-domain phosphorylation-dependent binding to filamin A, drives oncogene (K-ras/p53)-regulated tumor growth and angiogenesis, and mediates immune evasion by inducing platelet aggregation that suppresses NK-cell cytotoxicity [PMID:9490735, PMID:15494427, PMID:35064016]. TF-bearing microparticles released from activated platelets, tumor cells, and neutrophil extracellular traps propagate thrombosis in cancer and inflammatory settings including COVID-19, where complement-driven NETosis and P-selectin-mediated platelet–monocyte interactions induce monocyte TF expression [PMID:19861441, PMID:32759504, PMID:32678428]."},"prefetch_data":{"uniprot":{"accession":"P13726","full_name":"Tissue factor","aliases":["Coagulation factor III","Thromboplastin"],"length_aa":295,"mass_kda":33.1,"function":"Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited proteolysis. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P13726/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F3","classification":"Not Classified","n_dependent_lines":74,"n_total_lines":1208,"dependency_fraction":0.061258278145695365},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/F3","total_profiled":1310},"omim":[{"mim_id":"621535","title":"SPINOCEREBELLAR ATAXIA 52; SCA52","url":"https://www.omim.org/entry/621535"},{"mim_id":"621424","title":"LEUKOENCEPHALOPATHY WITHOUT LACUNAE, ADULT-ONSET; LUCAO","url":"https://www.omim.org/entry/621424"},{"mim_id":"621102","title":"NEURODEVELOPMENTAL DISORDER WITH PROGRESSIVE SPASTICITY AND BRAIN ABNORMALITIES; NEDPSB","url":"https://www.omim.org/entry/621102"},{"mim_id":"620887","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 9B; MMDS9B","url":"https://www.omim.org/entry/620887"},{"mim_id":"620873","title":"ADHESION G PROTEIN-COUPLED RECEPTOR F3; ADGRF3","url":"https://www.omim.org/entry/620873"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/F3"},"hgnc":{"alias_symbol":["CD142","TF"],"prev_symbol":[]},"alphafold":{"accession":"P13726","domains":[{"cath_id":"2.60.40.10","chopping":"43-137","consensus_level":"high","plddt":95.8014,"start":43,"end":137},{"cath_id":"2.60.40.10","chopping":"146-242","consensus_level":"high","plddt":94.9757,"start":146,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13726","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13726-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13726-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=F3","jax_strain_url":"https://www.jax.org/strain/search?query=F3"},"sequence":{"accession":"P13726","fasta_url":"https://rest.uniprot.org/uniprotkb/P13726.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13726/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13726"}},"corpus_meta":[{"pmid":"1311101","id":"PMC_1311101","title":"Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1311101","citation_count":400,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24335146","id":"PMC_24335146","title":"Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24335146","citation_count":345,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17949945","id":"PMC_17949945","title":"What is an epigenetic transgenerational phenotype? 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COVID-19.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32678428","citation_count":604,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15117736","id":"PMC_15117736","title":"Role of tissue factor in hemostasis, thrombosis, and vascular development.","date":"2004","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15117736","citation_count":505,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15494427","id":"PMC_15494427","title":"Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15494427","citation_count":476,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19861441","id":"PMC_19861441","title":"Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy.","date":"2009","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19861441","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2271516","id":"PMC_2271516","title":"Regulation of coagulation by a multivalent Kunitz-type inhibitor.","date":"1990","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2271516","citation_count":381,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12652293","id":"PMC_12652293","title":"Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12652293","citation_count":377,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26018600","id":"PMC_26018600","title":"How it all starts: Initiation of the clotting cascade.","date":"2015","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26018600","citation_count":323,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12070020","id":"PMC_12070020","title":"Thrombin functions during tissue factor-induced blood coagulation.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12070020","citation_count":316,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12514112","id":"PMC_12514112","title":"Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets.","date":"2003","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/12514112","citation_count":314,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3297348","id":"PMC_3297348","title":"Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade.","date":"1987","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3297348","citation_count":309,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3527261","id":"PMC_3527261","title":"Factor VII binding to tissue factor in reconstituted phospholipid vesicles: induction of cooperativity by phosphatidylserine.","date":"1986","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3527261","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16959886","id":"PMC_16959886","title":"Disulfide isomerization switches tissue factor from coagulation to cell signaling.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16959886","citation_count":284,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17901245","id":"PMC_17901245","title":"Inhibition of tissue factor signaling suppresses tumor growth.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17901245","citation_count":284,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29976772","id":"PMC_29976772","title":"Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1α and Cathepsin G.","date":"2018","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29976772","citation_count":283,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17060476","id":"PMC_17060476","title":"Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.","date":"2006","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17060476","citation_count":279,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23798713","id":"PMC_23798713","title":"Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23798713","citation_count":277,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9490735","id":"PMC_9490735","title":"A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9490735","citation_count":272,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48802,"output_tokens":4651,"usd":0.108086},"stage2":{"model":"claude-opus-4-6","input_tokens":7760,"output_tokens":3644,"usd":0.19485},"total_usd":0.759206,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":61750,"output_tokens":10119,"usd":0.168517},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":13427,"output_tokens":4988,"usd":0.287753}},"stage1_raw":"Looking at the corpus, I need to identify what gene \"F3\" refers to in the context of human/mammalian biology. The corpus contains papers about:\n\n1. **F3/Contactin (CNTN1)** - a neuronal cell adhesion molecule (GPI-anchored Ig superfamily member) - this appears to be the primary mammalian gene being queried based on multiple dedicated papers (PMIDs 12500940, 9063727, etc.)\n2. **Tissue Factor (F3/TF, coagulation factor III)** - also appears extensively\n3. **COUP-TF** - orphan nuclear receptors (different gene family)\n4. **Alphavirus TF protein** - viral protein (skip)\n5. **Ba/F3 cells** - cell line (skip)\n6. **Transgenerational F3 generation** - epidemiology concept (skip)\n7. Plant F3'H genes - symbol collision (skip)\n\nGiven the gene symbol \"F3\" in the human genome context, this most likely refers to **Coagulation Factor III / Tissue Factor (F3/TF)**, which is the official HGNC symbol. However, the corpus also heavily features F3/Contactin (CNTN1). I'll include mechanistic findings for both F3 (tissue factor) and F3/contactin as the corpus clearly covers both, but focus on those where \"F3\" is the actual gene designation.\n\nGiven that F3 is the official gene symbol for **Tissue Factor (Coagulation Factor III)**, I'll prioritize those mechanistic findings, while also including F3/Contactin findings since multiple papers use \"F3\" to refer to it.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"NF-κB activation is required for tissue factor (TF/F3) induction on endothelial cells by diverse agonists (LPS, TNF-α, IL-1β, PMA); PDTC, a specific NF-κB inhibitor, abolished TF mRNA and surface activity, establishing NF-κB as an obligatory step in TF transcriptional induction.\",\n      \"method\": \"PDTC inhibitor treatment of HUVEC, TF activity assay, TF mRNA measurement by Northern blot\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean pharmacological inhibition with mRNA and activity readouts, single lab\",\n      \"pmids\": [\"7605983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The FVIIa/TF complex induces cell survival through G12/G13-dependent JAK2/STAT5 activation and downstream BclXL production, as well as JAK2-dependent PKB activation; this signaling requires FVIIa proteolytic activity but not the TF cytoplasmic domain.\",\n      \"method\": \"STAT5 reporter assay, pharmacological inhibition of JAK2/G12/G13, cell survival assays in TF-expressing cells\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter, inhibitor, survival assay), single lab\",\n      \"pmids\": [\"15016732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The TF:FVIIa complex induces CREB phosphorylation via the ERK1/2 pathway and PAR2 in a TF cytoplasmic domain-independent manner; in keratinocytes this leads to upregulation of pro-apoptotic proteins Bak and Puma in a CREB-dependent manner.\",\n      \"method\": \"Phosphorylation assays, PAR2 blockade, ERK inhibition, apoptosis protein expression, multiple cell types (BHK-TF, HaCaT, HUVEC)\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types and orthogonal inhibitor approaches, single lab\",\n      \"pmids\": [\"18647225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TF (F3) contains a surface-exposed allosteric disulfide bond in its carboxyl-terminal domain that regulates procoagulant activity; protein disulfide isomerase (PDI) associates with cell-surface TF and is required for TF-dependent thrombosis in vivo, and PDI regulates thiol-dependent biogenesis of procoagulant TF-bearing microparticles.\",\n      \"method\": \"Thiol-modifying agents, genetic deletion of P2X7 signaling, in vivo carotid artery thrombosis model, cell surface PDI association\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic deletion plus biochemical characterization, single lab review/summary\",\n      \"pmids\": [\"22401798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Molecular dynamics simulations of full-length TF1-263 bound to FVIIa revealed novel non-covalent interactions between the TF EGF2 domain and FVIIa not seen in the truncated crystal structure; TF allosterically modifies FVIIa through inter- and intra-domain communication affecting the catalytic triad orientation.\",\n      \"method\": \"Computational modeling and molecular dynamics simulation of full-length TF-FVIIa membrane complex\",\n      \"journal\": \"Journal of biomolecular structure & dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation in this paper\",\n      \"pmids\": [\"28150568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"monomeric CRP (mCRP) triggers F3 (tissue factor) gene transcription and TF protein expression in microvascular endothelial cells, driving angiogenesis; F3-silenced mECs are unable to form angiotubes, and downstream signaling involves AKT phosphorylation and ETS1 activation leading to CCL2 release.\",\n      \"method\": \"F3 siRNA knockdown, in vivo collagen plug angiogenesis assay, Western blot, confocal microscopy, tube formation assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (F3 siRNA) with specific angiogenic phenotype plus in vivo validation\",\n      \"pmids\": [\"27808345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TF (F3) promotes hepatocellular carcinoma growth by activating ERK and AKT signaling pathways and inducing EGFR upregulation; EGFR inhibition suppressed TF-mediated HCC growth, placing TF upstream of EGFR in a TF-AKT/ERK-EGFR pathway.\",\n      \"method\": \"In vitro and in vivo functional experiments, Western blot, pharmacological inhibition of EGFR\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with pathway inhibition, single lab\",\n      \"pmids\": [\"30931258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Adipocytes express both TF (F3) and FVII and form a functional TF/FVIIa complex on the cell surface that can activate substrate FX, demonstrating adipocytes as procoagulant cells in a TF/FVIIa-dependent manner.\",\n      \"method\": \"RT-PCR, Western blot, colorimetric FX activity assay, active site-inhibited FVIIa blockade\",\n      \"journal\": \"Upsala journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional coagulation activity assay with specific inhibitor, primary human cells\",\n      \"pmids\": [\"31407948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EBV infection upregulates F3 (tissue factor) expression in nasopharyngeal carcinoma and EBV-associated gastric carcinoma cells via LMP2A-mediated PI3K/AKT signaling; F3-mediated platelet aggregation inhibits NK-cell antitumor function, and F3 inhibition restored NK-cell activity and showed therapeutic efficacy in xenograft models.\",\n      \"method\": \"In vitro platelet aggregation assay, in vivo NPC xenograft model, NK-cell cytotoxicity assay, PI3K/AKT pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway identification (LMP2A→PI3K/AKT→F3→platelet aggregation→NK inhibition) with in vivo validation\",\n      \"pmids\": [\"35064016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"F3/contactin (the neural cell adhesion molecule) was shown to interact with L1 family Ig-CAMs (L1, NrCAM, neurofascin) via its Ig domains; F3/contactin binds caspr/paranodin at paranodes and voltage-gated sodium channels at nodes of Ranvier; F3-deficient mice display severe ataxia with defects in axonal/dendritic projections and disrupted axo-glial contacts at paranodes.\",\n      \"method\": \"F3/contactin knockout mouse phenotype, binding studies, immunolocalization\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout phenotype plus multiple binding partner identifications, replicated across studies\",\n      \"pmids\": [\"12500940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"F3/contactin, previously thought to be exclusively neuronal, is expressed as a GPI-anchored protein by oligodendrocyte-lineage cells and is present in myelin; oligodendroglial F3 is susceptible to PI-PLC cleavage, similar to neuronal F3.\",\n      \"method\": \"Biosynthetic labeling, 2D gel electrophoresis, microsequencing, Western blotting, immunoprecipitation, double immunostaining, PI-PLC cleavage assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods confirming expression and GPI anchoring in oligodendrocytes\",\n      \"pmids\": [\"9063727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tenascin-R (TN-R) and its neuronal receptor F3/contactin promote neurite defasciculation in cerebellar explant cultures; the N-terminal cysteine-rich/EGF-like repeats of TN-R interact with Ig-like domains of F3; perturbation of this interaction with antibodies or antisense oligonucleotides increased fasciculation, and PKC activation reversed this effect.\",\n      \"method\": \"Cerebellar explant culture, antibody perturbation, antisense oligonucleotides, PKC activator/inhibitor pharmacology\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple perturbation approaches (antibody, antisense, pharmacological) with defined morphological phenotype\",\n      \"pmids\": [\"9589384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"F3/contactin is localized in secretory granules in all neuronal compartments of hypothalamic magnocellular neurons; physiological stimulation (lactation, osmotic challenge) upregulates F3 expression >3-fold and reverses its distribution, mobilizing it to axon terminal surfaces via the regulated secretory pathway.\",\n      \"method\": \"Immunocytochemistry, immunoblot, in situ hybridization, sucrose density gradient fractionation, confocal and electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing granule localization and activity-dependent surface mobilization\",\n      \"pmids\": [\"9651216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"F3/contactin surface expression on hypothalamic neurons is polarized to axons and occurs in GPI-linked form; re-expression after GPI-PLC removal is accelerated by neuronal activity (K+ depolarization, bicuculline) and inhibited by Ca2+ channel blockers, Na+ channel blockers (TTX), or glutamate antagonists, establishing that F3/contactin mobilization to the axonal surface is Ca2+-entry and activity-dependent.\",\n      \"method\": \"GPI-PLC treatment, live cell antibody labeling, K+ depolarization, pharmacological activity manipulation, immunocytochemistry, immunoblot\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological approaches with quantitative immunoblot and imaging, clear functional linkage\",\n      \"pmids\": [\"11556889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"F3/contactin (GPI-anchored) binds to glial-expressed molecules including tenascin-R, tenascin-C, and RPTPβ/phosphacan via its Ig domains; preclustered F3IgFc chimera modifies phosphotyrosine distribution in C6 glia, and PTPζ/RPTPβ stimulates neurite outgrowth, establishing F3 as a mediator of bidirectional neuron-glia signaling.\",\n      \"method\": \"Fc-chimeric molecule binding assay, fluorosphere binding, brain extract pulldown, phosphotyrosine immunostaining, neurite outgrowth assay\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pulldown and functional assays, single study with multiple approaches\",\n      \"pmids\": [\"10635039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"F3/contactin interacts with Notch receptors and promotes oligodendrocyte development via a Deltex1-dependent signaling cascade; this F3/Notch signaling pathway promotes oligodendrocyte precursor generation while its downstream effects on differentiation depend on Deltex1 as an intermediate.\",\n      \"method\": \"Animal models, binding studies, genetic epistasis with Deltex1\",\n      \"journal\": \"Developmental neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established with Deltex1, multiple animal models, single lab\",\n      \"pmids\": [\"16508301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"F3/contactin overexpression in transgenic mice promotes adult hippocampal neurogenesis (increased precursor proliferation, NeuN expression), enhances CA1 long-term potentiation, and improves spatial and object recognition memory; increased phospho-CREB was identified as a molecular correlate.\",\n      \"method\": \"Transgenic mouse overexpression, BrdU labeling, LTP electrophysiology, behavioral memory tasks, Western blot for p-CREB\",\n      \"journal\": \"Hippocampus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function transgenic with multiple orthogonal functional readouts\",\n      \"pmids\": [\"23939883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Contactin-1/F3 (Cntn1) knockdown in neural stem cells via in utero electroporation delays neuronal migration in the developing neocortex; Cntn1 KD upregulates RhoA, and expression of dominant-negative RhoAN19 partially rescues the migration defect, placing Cntn1 upstream of RhoA in neuronal migration.\",\n      \"method\": \"In utero electroporation with shRNA knockdown, immunohistochemistry, dominant-negative RhoA rescue experiment\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with genetic epistasis (dominant-negative rescue) establishing pathway position\",\n      \"pmids\": [\"30515076\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"F3 (Tissue Factor/Coagulation Factor III) functions as a transmembrane glycoprotein receptor that binds FVIIa to initiate the extrinsic coagulation cascade via an allosteric disulfide bond mechanism regulated by PDI-mediated thiol exchange, and also signals intracellularly through G12/G13-JAK2/STAT5-BclXL, ERK1/2-CREB-PAR2, and PI3K/AKT-EGFR pathways to promote cell survival, angiogenesis, and tumor progression; in the nervous system, the F3/contactin (CNTN1) neural cell adhesion molecule—a GPI-anchored Ig superfamily protein stored in secretory granules and mobilized to axonal surfaces in an activity- and Ca2+-dependent manner—mediates axonal growth and defasciculation via interactions with L1-family CAMs, tenascin-R, and RPTPβ, organizes paranodal domains through caspr binding, and regulates neuronal migration and oligodendrocyte development by modulating RhoA signaling and Notch/Deltex1 pathways.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**F3 gene context**: The human F3 gene encodes Tissue Factor (TF), the transmembrane glycoprotein that initiates blood coagulation by binding Factor VIIa. Papers about F3/contactin (a neuronal cell adhesion molecule, gene CNTN1) are EXCLUDE (alias collision). Papers about COUP-TF transcription factors are EXCLUDE (alias collision). Papers about Ba/F3 cells, TF-1 cells, F3 generation (transgenerational), alphavirus TF protein, Thomsen-Friedenreich antigen, pyocin F3, Asp f3, etc. are EXCLUDE (alias/symbol collision).\n\n**Classification:**\n- Papers about canonical human TF (F3/tissue factor coagulation protein): KEEP\n- F3/contactin neuronal CAM (CNTN1): EXCLUDE\n- COUP-TF nuclear receptors: EXCLUDE\n- Ba/F3 cells: EXCLUDE\n- Alphavirus TF protein: EXCLUDE\n- TF-1 hematopoietic cell line: EXCLUDE\n- Thomsen-Friedenreich antigen: EXCLUDE\n- Transgenerational F3 generation: EXCLUDE\n- Pyocin F3: EXCLUDE\n- Asp f3 (Aspergillus): EXCLUDE\n- Histone f3: EXCLUDE\n- Plant F3'H: EXCLUDE\n- Generic TF=transcription factor papers: EXCLUDE\n\n**KEPT papers** (canonical tissue factor / F3 coagulation protein):\n- PMID:2719077, 2704749, 3297348, 3527261, 8598903, 7605983, 15117736, 15494427, 12070020, 12514112, 16959886, 17901245, 17060476, 12477932, 15489334, 16344560, 26186194, 28514442, 33961781, 32296183, 2271516, 12652293, 19861441, 23798713, 9490735, 30563869 (NETs/TF), 32759504 (COVID NETs/TF), 32678428 (COVID platelets/TF), 29976772 (NETs/TF), 15016732 (FVIIa:TF signaling), 18647225 (TF:FVIIa/CREB), 22401798 (TF thiol), 23320987 (TFPI/TF), 20723970 (TFPI/TF monocytes), 26178021 (TF microparticles), 27052787 (TF microparticles), 30931258 (TF/AKT/ERK HCC), 27808345 (mCRP/F3/TF angiogenesis), 35064016 (EBV/F3/NK cells), 28150568 (TF-FVIIa structure MD), 35359871 (paeoniflorin/TF), 38890797 (TF/Nrf2/GSTP1), 31380428 (p38/TF/HIF), 31407948 (adipocytes TF/FVII), 17982314 (monocyte TF), 14649881 — EXCLUDE (transferrin receptor, not TF/F3).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1987,\n      \"finding\": \"Molecular cloning of the cDNA for human tissue factor (TF/F3) revealed it encodes a 295-amino acid integral membrane protein with a single transmembrane domain that functions as the high-affinity cellular receptor initiating the coagulation protease cascade.\",\n      \"method\": \"cDNA cloning, Southern blotting, Northern blotting, sequence analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular cloning with complete structural characterization, foundational paper replicated widely\",\n      \"pmids\": [\"3297348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Factor VII (and VIIa) binds to TF reconstituted in phospholipid vesicles at a 1:1 stoichiometry; phosphatidylserine induces positive cooperativity in binding, consistent with TF functioning as at least a dimer with two interacting enzyme-binding sites.\",\n      \"method\": \"Reconstitution of purified TF into phospholipid vesicles, quantitative binding assays with radiolabeled factors VII/VIIa, protease digestion, cooperative binding modeling\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro reconstitution with quantitative binding analysis and mechanistic modeling\",\n      \"pmids\": [\"3527261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"TF protein is selectively expressed in a hemostatic 'envelope' pattern in normal human tissues — present in vascular adventitia, organ capsules, epidermis, and mucosal epithelium — but absent from endothelium and circulating blood cells; TF expression is inducible in monocytes by LPS, establishing the cellular basis for coagulation initiation upon vascular injury.\",\n      \"method\": \"Immunohistochemistry with epitope-defined monoclonal antibodies in normal human tissues; LPS stimulation of monocytes\",\n      \"journal\": \"The American Journal of Pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic immunohistochemical localization across multiple tissue types with functional implications, foundational paper with >1000 citations\",\n      \"pmids\": [\"2719077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"TF mRNA and protein are expressed by macrophage foam cells and mesenchymal intimal cells within atherosclerotic plaques, and TF protein is deposited in the extracellular matrix of necrotic cores, establishing atherosclerotic plaque as a source of thrombogenic TF.\",\n      \"method\": \"In situ hybridization with TF-specific riboprobe and immunohistochemistry in human vessels and atherosclerotic plaques\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual-method (ISH + IHC) localization in human tissue, >1000 citations, foundational finding\",\n      \"pmids\": [\"2704749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"TF activity is regulated by the Kunitz-type inhibitor TFPI (tissue factor pathway inhibitor), which acts in a multivalent manner to inhibit the TF:FVIIa complex and thereby regulate coagulation.\",\n      \"method\": \"Biochemical inhibition assays with purified components\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified proteins; foundational mechanistic finding replicated widely\",\n      \"pmids\": [\"2271516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NF-κB activation is an obligatory step in TF induction by diverse agonists (LPS, TNF-α, IL-1β, PMA) in endothelial cells; PDTC, a specific NF-κB pathway inhibitor, dose-dependently abrogates TF mRNA and activity induction, acting at the transcriptional level.\",\n      \"method\": \"PDTC inhibitor treatment of HUVEC, TF activity assay, Northern blot for TF mRNA, dose-response analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple agonists tested, mRNA and activity measured, specific inhibitor with dose-response, strong mechanistic conclusion\",\n      \"pmids\": [\"7605983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Crystal structure of active-site-inhibited factor VIIa complexed with the soluble extracellular domain of TF at 2.0 Å resolution revealed that FVIIa adopts an extended conformation in the complex, providing the molecular basis for understanding how TF allosterically activates FVIIa and positions it to cleave substrates FIX and FX.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure, foundational for understanding TF:FVIIa mechanism, >670 citations\",\n      \"pmids\": [\"8598903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TF supports cell adhesion, migration, spreading, and intracellular signaling independently of RGD-mediated integrin pathways; the TF cytoplasmic domain binds actin-binding protein 280 (ABP-280/filamin A), and this interaction requires extracellular TF ligation and Ser phosphorylation-mimicking mutations; Ala mutations of cytoplasmic Ser residues abolish ABP-280 co-precipitation and severely reduce cell spreading, revealing a cytoskeletal signaling pathway.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, cell adhesion/migration assays, cytoplasmic domain chimeras, site-directed mutagenesis of Ser residues\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — yeast two-hybrid plus co-IP validation, mutagenesis, functional adhesion/migration assays, multiple orthogonal methods, >270 citations\",\n      \"pmids\": [\"9490735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tissue factor-induced blood coagulation proceeds in two phases: an initiation phase generating ~26 nM thrombin at ~1.3 pM prothrombinase, followed by a propagation phase generating thrombin at ~120 pM prothrombinase; clot formation coincides with transition to the propagation phase, and distinct thrombin concentration thresholds trigger sequential activation of platelets, factor XIII, fibrinogen, and other substrates.\",\n      \"method\": \"Contact pathway-inhibited whole blood coagulation assay, quantitative measurement of TAT complexes, prothrombin fragments, fibrinopeptides, factor Va, platelet activation markers over time in 20 individuals\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative kinetic analysis with multiple substrates across 20 subjects, defines mechanistic phases of TF-initiated coagulation\",\n      \"pmids\": [\"12070020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"An alternatively spliced form of human TF (asHTF) lacking the transmembrane domain is soluble, circulates in blood, exhibits procoagulant activity when exposed to phospholipids, and is incorporated into thrombi, identifying a circulating thrombogenic TF isoform.\",\n      \"method\": \"Identification of alternatively spliced mRNA, recombinant protein production, procoagulant activity assays with phospholipids, thrombus incorporation studies\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical characterization of novel isoform with functional procoagulant assay and in vivo thrombus incorporation, >375 citations\",\n      \"pmids\": [\"12652293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Intravascular TF is present mainly on circulating microvesicles in plasma, with platelet-derived microvesicles (identified by CD42b sorting) as a major location; TF is stored in platelet α-granules and the open canalicular system, exposed on the surface after platelet activation; functional TF activity on microvesicles and platelets is enabled when they adhere to neutrophils via P-selectin/PSGL-1 and CD18 interactions, and neutrophil-derived reactive oxygen species further support TF activity.\",\n      \"method\": \"Flow cytometry with cell sorting (CD42b), immunoelectron microscopy, subcellular fractionation, TF activity assays, P-selectin/PSGL-1 blocking antibodies\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (flow cytometry, EM, functional assay, blocking antibodies), defines cellular mechanism of intravascular TF activity\",\n      \"pmids\": [\"12514112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TF expression in colorectal cancer cells is controlled by K-ras oncogene activation and p53 inactivation via MEK/MAPK and PI3K pathways; RNA interference of TF reduces K-ras-dependent tumorigenic and angiogenic phenotype in vivo, establishing TF as an effector of oncogene-driven tumor progression and angiogenesis.\",\n      \"method\": \"Isogenic colorectal cancer cell lines with defined K-ras/p53 status, MEK/PI3K pharmacological inhibition, TF siRNA knockdown, in vivo xenograft tumor/angiogenesis assays, measurement of cell-associated and microvesicle TF activity\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis, siRNA knockdown with in vivo phenotypic readout, multiple methods, >475 citations\",\n      \"pmids\": [\"15494427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TF deficiency causes embryonic lethality in mice, and TF:FVIIa complex signaling through protease-activated receptors (PARs) on vascular cells mediates non-hemostatic functions including inflammation, angiogenesis, metastasis, and cell migration.\",\n      \"method\": \"Review integrating mouse genetic knockout studies and cell signaling experiments\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — synthesizes multiple genetic (TF knockout lethal) and biochemical studies across labs; strong/replicated\",\n      \"pmids\": [\"15117736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FVIIa/TF interaction induces STAT5 phosphorylation, nuclear translocation, and transactivation; this signaling is dependent on FVIIa proteolytic activity but not on the TF cytoplasmic domain, and requires G12/G13 class G proteins and Jak2 (but not Jak1 or Tyk2); FVIIa/TF promotes cell survival through Jak2/STAT5-dependent BclXL production and Jak2-dependent PKB activation.\",\n      \"method\": \"STAT5 reporter assays, phosphorylation/nuclear translocation experiments, specific G protein and Jak inhibitors, dominant-negative constructs, cell survival assays, BclXL/PKB measurements\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple inhibitor approaches, reporter assays, pathway dissection with dominant-negatives; identifies G12/G13-Jak2-STAT5-BclXL as novel TF signaling axis\",\n      \"pmids\": [\"15016732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TF exists in two functionally distinct pools on the cell surface controlled by the redox state of the extracellular Cys186–Cys209 disulfide bond: a coagulant pool requiring this disulfide, and a signaling pool (cryptic/noncoagulant) where protein disulfide isomerase (PDI) disrupts the disulfide in a nitric oxide-dependent pathway, switching TF from coagulation to PAR2-dependent cell signaling; a monoclonal antibody specific for cryptic TF inhibits TF:PAR2 complex formation and TF:VIIa signaling without blocking coagulation.\",\n      \"method\": \"Disulfide bond mutagenesis (C209A and other mutants), PDI inhibition, nitric oxide pathway manipulation, PAR2 signaling assays, specific conformation-selective monoclonal antibody blocking experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis combined with biochemical PDI manipulation, conformation-selective antibody, and functional coagulation/signaling readouts; multiple orthogonal methods in single study, >280 citations\",\n      \"pmids\": [\"16959886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human platelets express TF pre-mRNA constitutively; platelet activation triggers Cdc2-like kinase 1 (Clk1)-dependent splicing of TF pre-mRNA into mature mRNA, producing TF protein and procoagulant activity that accelerates clot formation; interruption of Clk1 signaling prevents TF accumulation in activated platelets.\",\n      \"method\": \"RT-PCR for pre-mRNA and mature mRNA in resting vs. activated platelets, Clk1 pharmacological inhibition, TF protein detection, procoagulant/clot formation assays\",\n      \"journal\": \"The Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel mechanism (signal-dependent pre-mRNA splicing) demonstrated with molecular and functional assays, Clk1 as specific regulator identified, >279 citations\",\n      \"pmids\": [\"17060476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Direct TF:VIIa signaling (independent of coagulation cascade activation) is required for primary tumor growth; TF associates with β1 integrins in epithelial/endothelial cells (regulated by TF extracellular ligand binding) and constitutively with α3β1 integrin in breast cancer cells; a signaling-inhibitory anti-TF antibody (Mab-10H10) disrupts TF–integrin association and TF:VIIa–PAR2 signaling, suppressing tumor xenograft growth as effectively as the coagulation-inhibitory antibody.\",\n      \"method\": \"Isotype-matched antibody pair (Mab-5G9 vs. Mab-10H10) discriminating coagulation vs. signaling TF; co-immunoprecipitation of TF with β1/α3β1 integrins; PAR2 signaling assays; in vivo human xenograft tumor models (2 models)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unique antibody pair enabling functional dissection, reciprocal co-IP, in vivo tumor suppression in 2 models, >284 citations\",\n      \"pmids\": [\"17901245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TF:FVIIa induces phosphorylation and activation of the transcription factor CREB via ERK1/2 and PAR2, independently of the TF cytoplasmic domain; in keratinocytes, this leads to upregulation of pro-apoptotic proteins Bak and Puma and induction of apoptosis in a CREB-dependent manner, whereas FXa (but not thrombin) also induces CREB but without apoptosis, revealing cell-type-specific downstream outcomes.\",\n      \"method\": \"CREB phosphorylation and reporter assays in BHK-TF, HaCaT, and HUVEC cells; ERK and PAR2 inhibition; siRNA/dominant-negative approaches; apoptosis assays; comparison with FXa and thrombin\",\n      \"journal\": \"Journal of Thrombosis and Haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types, pathway inhibitors, and apoptosis readouts; identifies CREB as TF:FVIIa downstream target via PAR2/ERK\",\n      \"pmids\": [\"18647225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tumor-derived TF-bearing microparticles circulate in blood of cancer patients (detected in ~two-thirds of pancreatic carcinoma patients), co-express tumor marker MUC-1, are eliminated by tumor resection, and elevated levels are associated with venous thromboembolism in cancer patients (adjusted OR 3.72), establishing TF-positive microparticles as mediators of cancer-associated thrombosis.\",\n      \"method\": \"Impedance-based flow cytometry for microparticle detection and quantitation in plasma; case-control study; tumor resection experiments; MUC-1 co-staining\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — flow cytometry with tumor resection validation, case-control design, strong mechanistic link between tumor-derived TF MPs and thrombosis\",\n      \"pmids\": [\"19861441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TF procoagulant activity is regulated by thiol-disulfide exchange at the cell surface: protein disulfide isomerase (PDI) is associated with cell-surface TF and required for TF-dependent thrombosis in vivo; PDI regulates thiol-dependent biogenesis of procoagulant microparticles released from myeloid cells and smooth muscle cells via the purinergic P2X7 receptor; genetic deletion of P2X7 attenuates FeCl3-induced carotid artery thrombosis in mice.\",\n      \"method\": \"Co-immunoprecipitation of PDI with TF, thiol-modifying agents, P2X7 genetic knockout mice, FeCl3 carotid artery thrombosis model, microparticle procoagulant activity assays\",\n      \"journal\": \"Thrombosis Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo genetic model plus biochemical co-IP, multiple inhibitor approaches, functional thrombosis readout\",\n      \"pmids\": [\"22401798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TFPIα and TFPIβ are both expressed at the surface of breast cancer cells in GPI-anchored form; PI-PLC cleavage of GPI-anchored TFPI releases both isoforms and increases TF activity on the cell surface, demonstrating that GPI-anchored TFPI inhibits TF:FVIIa activity locally; heparin releases TFPIα but not TFPIβ, revealing distinct surface pools.\",\n      \"method\": \"qRT-PCR, ELISA, flow cytometry, immunofluorescence, Western blotting, PI-PLC and heparin treatment, Factor Xa activity assay\",\n      \"journal\": \"Journal of Hematology & Oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, PI-PLC/heparin functional dissection of surface pools, direct TF activity measurement\",\n      \"pmids\": [\"23320987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tumor-derived TF-positive microparticles in blood bind to sites of vascular injury and enhance thrombosis in animal models; elevated circulating TF-positive microparticles correlate with venous thrombosis in multiple cancer types, proposing a mechanism for cancer-associated coagulopathy.\",\n      \"method\": \"Review synthesizing animal model studies (MP binding to injury sites, thrombosis enhancement) and clinical correlation data\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — synthesizes in vivo animal models and clinical data but is a review; mechanistic animal model findings are from multiple labs\",\n      \"pmids\": [\"23798713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Monomeric CRP (mCRP), formed on microvascular endothelial cell membranes from circulating native pentameric CRP in a receptor-dependent and time-dependent fashion, triggers F3 (TF) gene transcription and TF protein expression in microvascular endothelial cells; F3-silenced endothelial cells are unable to form angiotubes; mCRP-induced TF signaling activates AKT and the transcription factor ETS1, leading to CCL2 release and angiogenesis.\",\n      \"method\": \"Confocal microscopy and Western blot for CRP conversion; F3 gene reporter assays; siRNA silencing of F3; angiogenesis tube formation assay; AKT/ETS1 phosphorylation; CCL2 ELISA; in vivo collagen plug angiogenesis model\",\n      \"journal\": \"Thrombosis and Haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — F3 silencing with functional angiogenesis readout, signaling pathway characterization, in vivo and in vitro concordance\",\n      \"pmids\": [\"27808345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Computational molecular dynamics simulation of the full-length TF1-263:FVIIa membrane-bound complex revealed novel non-covalent interactions between TF's EGF2 domain and FVIIa not present in the truncated soluble TF crystal structure; TF allosterically modifies each domain of FVIIa through inter- and intra-domain communication, governing catalytic triad orientation and providing additional stability to the FVIIa protease domain.\",\n      \"method\": \"Computational homology modeling and molecular dynamics simulations of full-length TF:FVIIa membrane complex\",\n      \"journal\": \"Journal of Biomolecular Structure and Dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational modeling only, no experimental validation of predicted interactions\",\n      \"pmids\": [\"28150568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NETs decorated with TF and IL-17A promote thrombin generation and fibrosis in SLE; REDD1-driven autophagy in SLE neutrophils leads to enhanced NET release carrying TF; TF-bearing NETs promote coagulation (thromboinflammation) and activate fibroblasts; hydroxychloroquine inhibits NETosis and the associated TF-bearing NET release.\",\n      \"method\": \"Immunofluorescence, immunoblotting, qPCR, ELISA for NET proteins and TF; autophagy assessment; in vitro primary fibroblast culture with NET stimulation; patient biopsy specimens; bosentan/L-ascorbic acid inhibitors; hydroxychloroquine inhibition\",\n      \"journal\": \"Annals of the Rheumatic Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic pathway (REDD1/autophagy/NETs/TF) defined in human cells with inhibitor validation; functional fibroblast assay\",\n      \"pmids\": [\"30563869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NETs promote endothelial cell (EC) activation and TF expression through IL-1α and cathepsin G: cathepsin G (a serine protease abundant in NETs) cleaves pro-IL-1α to release mature IL-1α, which then upregulates TF mRNA and activity in ECs; anti-TF antibody blocks NET-induced acceleration of plasma clotting.\",\n      \"method\": \"NET-EC co-incubation assays, anti-IL-1α/IL-1Ra/anti-IL-1β antibody blocking, cathepsin G inhibition, TF mRNA/activity measurement, plasma clotting assays under flow\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple neutralizing antibodies and specific enzyme inhibitors, functional TF activity and clotting readouts, >283 citations\",\n      \"pmids\": [\"29976772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TF promotes hepatocellular carcinoma (HCC) growth in vitro and in vivo by activating both ERK and AKT signaling pathways; TF induces EGFR upregulation, and EGFR inhibition suppresses TF-mediated HCC growth, placing TF upstream of an EGFR/ERK/AKT axis in HCC.\",\n      \"method\": \"In vitro proliferation/growth assays, in vivo xenograft models, ERK/AKT pathway inhibition, EGFR siRNA knockdown and pharmacological inhibition, TF siRNA knockdown, Western blotting\",\n      \"journal\": \"Frontiers in Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional assays with siRNA and pharmacological inhibitors; single study\",\n      \"pmids\": [\"30931258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human primary adipocytes express both TF and FVII; the TF/FVIIa complex formed on the adipocyte surface generates active FXa from substrate Factor X, establishing adipocytes as a procoagulant cell type via autocrine TF/FVIIa activity; active site-inhibited FVIIa blocks FXa formation, confirming specificity.\",\n      \"method\": \"Collagenase isolation of primary human adipocytes, 3T3-L1 differentiation, RT-PCR, Western blot, colorimetric FX activation assay, active site-inhibited FVIIa blocking\",\n      \"journal\": \"Upsala Journal of Medical Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional FX activation assay with specific inhibitor control in primary human cells; novel cell type identified; single study\",\n      \"pmids\": [\"31407948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chemotherapy (oxaliplatin) increases TF expression and MMP-9/2 activity in sciatic nerve and blood; L-OHP elevates HSP70 release from macrophages, activating p-p38 and HIF-1α; hirudin (anticoagulant) suppresses TF, p38, HIF-1α, and MMP-9/2, and attenuates chemotherapy-induced peripheral neuropathy (CIPN), implicating an HSP70-TLR4-p38-TF-HIF-1α axis in CIPN pathology.\",\n      \"method\": \"CIPN mouse model, Von Frey testing, gelatin zymography, Western blotting in sciatic nerve and macrophage cell line, hirudin treatment\",\n      \"journal\": \"BioMed Research International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional mouse model with inhibitor but TF's role is pharmacologically inferred rather than directly demonstrated by TF-specific manipulation\",\n      \"pmids\": [\"31380428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Complement C3 inhibition (with compstatin Cp40) disrupts TF expression in neutrophils; COVID-19 neutrophils release NETs carrying active TF; treatment of control neutrophils with COVID-19 platelet-rich plasma generates TF-bearing NETs that induce thrombotic activity in endothelial cells; C5aR1 blockade and NETosis/thrombin inhibition attenuate platelet-mediated NET-driven TF thrombogenicity, establishing a complement→C5aR1→NETosis→TF pathway in COVID-19 immunothrombosis.\",\n      \"method\": \"Plasma TF activity and sC5b-9 measurement, neutrophil TF expression, C5aR1 blockade, compstatin C3 inhibition, NET/HAEC co-culture thrombosis assay, NETosis/thrombin inhibitors\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic cell-based assays with multiple specific inhibitors (C3, C5aR1, NETosis, thrombin) dissecting pathway, functional thrombosis readout, replicated in patient specimens\",\n      \"pmids\": [\"32759504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In severe COVID-19, platelet activation and platelet-monocyte aggregate formation drive monocyte TF expression; platelet P-selectin neutralization or αIIb/β3 integrin blockade with abciximab inhibits platelet-dependent monocyte TF induction ex vivo, identifying P-selectin-mediated platelet-monocyte contact as the mechanism for coagulation activation in severe COVID-19.\",\n      \"method\": \"Flow cytometry for platelet activation markers and monocyte TF expression; ex vivo platelet-monocyte co-culture with P-selectin antibody and abciximab inhibition; plasma from COVID-19 patients applied to control platelets\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic ex vivo assay with specific receptor blocking antibodies, P-selectin and integrin identified as drivers of monocyte TF induction, patient plasma validation\",\n      \"pmids\": [\"32678428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EBV infection upregulates F3 (TF) expression in nasopharyngeal carcinoma and EBV-associated gastric carcinoma cells via the EBV latent membrane protein 2A (LMP2A)-PI3K/AKT signaling pathway; F3-mediated platelet aggregation inhibits NK-cell cytotoxic function; F3 inhibition in vivo restores NK-cell antitumor activity and shows therapeutic efficacy in NPC xenograft models.\",\n      \"method\": \"F3 expression analysis by EBV infection and LMP2A overexpression; PI3K/AKT inhibitor experiments; in vitro and in vivo platelet aggregation assays; NK-cell cytotoxicity assays; F3 siRNA knockdown; NPC xenograft mouse model with NK-cell transfer\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (LMP2A→PI3K/AKT→F3→platelet aggregation→NK suppression) defined with multiple orthogonal methods in vitro and in vivo\",\n      \"pmids\": [\"35064016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Paeoniflorin activates the Gas6/Axl/SOCS3 axis to upregulate SOCS3, which subsequently inhibits apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and suppresses TF expression in macrophages and endothelial cells, preventing thrombosis and improving radiation enteritis in mice.\",\n      \"method\": \"Laser Doppler flowmetry, RAW264.7 and HUVEC cell experiments, Gas6/Axl/SOCS3 pathway analysis by Western blot, ASK1/TF expression by qPCR and Western blot, siRNA knockdown, in vivo radiation enteritis mouse model\",\n      \"journal\": \"Frontiers in Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identifies Gas6/Axl/SOCS3/ASK1 as upstream regulators of TF with in vitro and in vivo validation; single lab study\",\n      \"pmids\": [\"35359871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GSTP1 methylation-mediated silencing promotes stress-induced hepatocellular injury via ferroptosis through a TF/Nrf2 pathway; GSTP1 overexpression reduces TF expression and GPX4 downregulation, whereas GSTP1 knockdown increases TF and promotes ferroptosis; Nrf2 inhibition exacerbates TF-driven ferroptosis, placing TF downstream of the Nrf2/GSTP1 axis in ferroptotic cell death.\",\n      \"method\": \"Mouse restraint stress model, dexamethasone-treated AML-12 hepatocyte model, GSTP1 overexpression and siRNA, Nrf2 inhibitor, DNA methylation sequencing, Western blotting, lipid ROS/MDA measurement, transmission electron microscopy\",\n      \"journal\": \"Journal of Cellular and Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GSTP1 gain- and loss-of-function with Nrf2 inhibitor and ferroptosis inhibitor in vitro and in vivo; TF's mechanistic role in ferroptosis pathway established but single study\",\n      \"pmids\": [\"38890797\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Tissue factor (F3/TF) is a transmembrane glycoprotein that functions as the primary cellular initiator of blood coagulation by forming a high-affinity complex with Factor VIIa, allosterically activating FVIIa (as revealed by the 2.0 Å crystal structure) to cleave FIX and FX; TF procoagulant activity is regulated by the redox state of its Cys186–Cys209 disulfide bond (toggled by protein disulfide isomerase in a nitric oxide-dependent manner), which switches TF between a coagulant pool and a signaling pool that activates PAR2 and G12/G13-Jak2-STAT5-BclXL cell survival pathways; TF cytoplasmic domain Ser phosphorylation enables binding to actin-binding protein ABP-280/filamin A, supporting cell adhesion, migration, and cytoskeletal reorganization; TF expression is transcriptionally induced by NF-κB (downstream of LPS, TNF-α, IL-1β), by oncogenic K-ras/p53 via MEK/PI3K, by mCRP via ETS1, and by EBV LMP2A via PI3K/AKT, while being negatively regulated by TFPI and by the Nrf2/GSTP1 axis; circulating TF-positive microparticles derived from activated platelets, tumor cells, and NETs propagate coagulation and thrombosis, and platelet-derived TF is generated via Clk1-dependent signal-activated pre-mRNA splicing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"The F3 gene symbol designates two distinct loci: coagulation tissue factor (TF/CD142) and the neural cell adhesion molecule contactin-1 (CNTN1/F3). As tissue factor, F3 is a transmembrane glycoprotein whose transcription is induced by NF-κB in response to inflammatory stimuli and whose procoagulant activity is regulated by a surface-exposed allosteric disulfide bond controlled by protein disulfide isomerase; upon binding FVIIa it initiates the extrinsic coagulation cascade and activates intracellular signaling through G12/G13–JAK2/STAT5, ERK1/2–CREB–PAR2, and PI3K/AKT–EGFR pathways that promote cell survival, angiogenesis, and tumor growth [PMID:7605983, PMID:15016732, PMID:18647225, PMID:22401798, PMID:30931258]. As contactin-1, F3 is a GPI-anchored Ig-superfamily protein expressed on neurons and oligodendrocytes that is stored in secretory granules and mobilized to the axonal surface in a Ca²⁺- and activity-dependent manner; it binds L1-family CAMs, tenascin-R, RPTPβ, and caspr to mediate neurite outgrowth, defasciculation, paranodal organization, and neuronal migration—the latter through RhoA regulation—and promotes oligodendrocyte development via Notch/Deltex1 signaling [PMID:12500940, PMID:9651216, PMID:11556889, PMID:30515076, PMID:16508301].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying the transcriptional switch for TF induction: NF-κB was established as an obligatory transcription factor for TF expression on endothelial cells in response to inflammatory stimuli, resolving how diverse agonists converge on TF upregulation.\",\n      \"evidence\": \"PDTC NF-κB inhibitor abolished TF mRNA and surface activity in HUVEC stimulated with LPS, TNF-α, IL-1β, or PMA\",\n      \"pmids\": [\"7605983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor only; genetic confirmation of NF-κB requirement not shown\", \"Contribution of other transcription factors (e.g., AP-1, Egr-1) not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that neural F3/contactin resides in a regulated secretory pool and reaches the axonal surface in an activity-dependent manner resolved how a GPI-anchored adhesion molecule could be dynamically controlled at synapses and axon terminals.\",\n      \"evidence\": \"Immunocytochemistry, electron microscopy, and sucrose gradient fractionation in hypothalamic neurons; subsequent pharmacology (K⁺ depolarization, Ca²⁺-channel and Na⁺-channel blockers) showed Ca²⁺-entry-dependent surface mobilization\",\n      \"pmids\": [\"9651216\", \"11556889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery linking Ca²⁺ entry to granule exocytosis of F3 not identified\", \"Whether similar regulated secretion occurs outside hypothalamic neurons is untested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that tenascin-R binds F3/contactin Ig domains and promotes neurite defasciculation provided the first defined extracellular ligand–function link for neural F3 in axon guidance.\",\n      \"evidence\": \"Cerebellar explant cultures with antibody perturbation, antisense oligonucleotides, and PKC pharmacology\",\n      \"pmids\": [\"9589384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PKC-dependent signaling downstream of GPI-anchored F3 not mechanistically resolved\", \"In vivo relevance of defasciculation phenotype not demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showing that F3/contactin engages RPTPβ/phosphacan and tenascin-C in addition to tenascin-R, and modifies glial phosphotyrosine signaling, established F3 as a bidirectional neuron–glia signaling hub.\",\n      \"evidence\": \"Fc-chimeric binding assays, brain extract pulldowns, and phosphotyrosine immunostaining in C6 glia\",\n      \"pmids\": [\"10635039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream phosphatase substrates of RPTPβ engaged by F3 not identified\", \"Bidirectional signaling demonstrated only in glioma cell line\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"F3/contactin knockout mice revealed that loss of F3 causes severe ataxia with disrupted paranodal axo-glial junctions and aberrant dendritic/axonal projections, proving F3 is essential for nervous system organization in vivo.\",\n      \"evidence\": \"F3/contactin knockout mouse phenotyping, immunolocalization of paranodal and nodal markers, binding studies with L1, NrCAM, neurofascin, and caspr\",\n      \"pmids\": [\"12500940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of individual binding partners (caspr vs. L1-family) to the knockout phenotype not dissected\", \"Whether oligodendroglial F3 versus neuronal F3 drives the paranodal defect is unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of G12/G13–JAK2/STAT5–BclXL signaling downstream of the TF:FVIIa complex answered how TF promotes cell survival independently of its cytoplasmic domain.\",\n      \"evidence\": \"STAT5 reporter, JAK2/G12/G13 inhibition, cell survival assays in TF-expressing cells\",\n      \"pmids\": [\"15016732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a transmembrane receptor lacking intrinsic kinase activity engages G12/G13 is unclear\", \"Whether this pathway operates in primary cells in vivo is not shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that F3/contactin activates Notch signaling through Deltex1 to promote oligodendrocyte precursor generation established a non-canonical Notch ligand role for a GPI-anchored molecule in gliogenesis.\",\n      \"evidence\": \"Animal models, binding studies, genetic epistasis with Deltex1\",\n      \"pmids\": [\"16508301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether F3 acts in cis or trans on Notch receptors not resolved\", \"Deltex1-independent effects on oligodendrocyte differentiation not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the ERK1/2–CREB–PAR2 axis downstream of TF:FVIIa clarified a second, cytoplasmic-domain-independent signaling arm that leads to pro-apoptotic protein induction in keratinocytes, distinguishing TF signaling outcomes by cell type.\",\n      \"evidence\": \"Phosphorylation assays, PAR2 blockade, ERK inhibition in BHK-TF, HaCaT, and HUVEC\",\n      \"pmids\": [\"18647225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How pro-survival (BclXL) and pro-apoptotic (Bak/Puma) outputs from TF signaling are balanced is unknown\", \"CREB target gene specificity not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of a PDI-regulated allosteric disulfide bond in TF's C-terminal domain that controls procoagulant activity and microparticle biogenesis resolved a longstanding question about how TF transitions between cryptic and active states.\",\n      \"evidence\": \"Thiol-modifying agents, P2X7 genetic deletion, in vivo carotid artery thrombosis model, cell-surface PDI association\",\n      \"pmids\": [\"22401798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crystal structure of the disulfide-switching intermediate not available\", \"Relative contribution of disulfide switching versus phospholipid exposure to TF activation in vivo not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that mCRP-induced F3 expression drives angiogenesis via AKT/ETS1/CCL2 signaling established TF as a necessary effector linking inflammation to new vessel formation in microvascular endothelium.\",\n      \"evidence\": \"F3 siRNA knockdown, in vivo collagen plug angiogenesis assay, tube formation assay in mECs\",\n      \"pmids\": [\"27808345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether angiogenic role is coagulation-dependent or signaling-dependent not dissected\", \"ETS1 activation mechanism downstream of AKT not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In vivo knockdown of contactin-1/F3 in developing neocortex delayed neuronal migration and upregulated RhoA; rescue by dominant-negative RhoA placed F3 upstream of RhoA, providing a signaling mechanism for how a GPI-anchored molecule controls cell motility.\",\n      \"evidence\": \"In utero electroporation with shRNA knockdown and dominant-negative RhoAN19 rescue\",\n      \"pmids\": [\"30515076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transmembrane co-receptor linking GPI-anchored F3 to intracellular RhoA regulation not identified\", \"Whether this pathway operates outside the neocortex is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that TF activates ERK/AKT to upregulate EGFR in hepatocellular carcinoma positioned TF as an upstream driver of EGFR-dependent tumor growth, suggesting a TF–AKT/ERK–EGFR feed-forward loop in cancer.\",\n      \"evidence\": \"In vitro and in vivo HCC models with EGFR pharmacological inhibition and pathway Western blots\",\n      \"pmids\": [\"30931258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of EGFR transcriptional upregulation by TF signaling not identified\", \"Patient-derived validation limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that EBV LMP2A upregulates F3 via PI3K/AKT to induce platelet aggregation that shields tumor cells from NK-cell killing established a coagulation-immune evasion axis exploited by virus-associated cancers.\",\n      \"evidence\": \"Platelet aggregation assay, NK-cell cytotoxicity assay, NPC xenograft model, PI3K/AKT pathway analysis\",\n      \"pmids\": [\"35064016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether F3-mediated immune evasion occurs in non-EBV cancers is untested\", \"Relative contribution of F3-dependent coagulation vs. F3-dependent signaling to immune evasion not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) how GPI-anchored contactin-1/F3 couples to intracellular signaling cascades (RhoA, Notch) without a transmembrane domain—identification of obligate co-receptors is needed; (2) whether the disulfide-switching and signaling functions of coagulation TF are structurally coupled; and (3) the in vivo balance between pro-survival and pro-apoptotic TF signaling outputs across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-receptor linking GPI-anchored F3/contactin to intracellular signaling unidentified\", \"Structural basis of allosteric disulfide switching in TF lacks atomic-resolution data\", \"Tissue-specific determinants of TF pro-survival vs. pro-apoptotic signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 11, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 3, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 6, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 9, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 6, 8, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 15, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 11, 12, 13, 17]}\n    ],\n    \"complexes\": [\n      \"TF:FVIIa coagulation initiation complex\"\n    ],\n    \"partners\": [\n      \"F7\",\n      \"CNTNAP1\",\n      \"TNR\",\n      \"PTPRZ1\",\n      \"L1CAM\",\n      \"NRCAM\",\n      \"NFASC\",\n      \"NOTCH1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Tissue factor (TF/F3) is a transmembrane glycoprotein that serves as the primary cellular initiator of blood coagulation by forming a high-affinity 1:1 complex with Factor VIIa, allosterically activating FVIIa to cleave Factors IX and X and triggering a two-phase coagulation cascade of initiation and propagation [PMID:3527261, PMID:8598903, PMID:12070020]. TF exists in two functionally distinct cell-surface pools governed by the redox state of its Cys186–Cys209 disulfide bond: a procoagulant pool requiring the intact disulfide and a cryptic/signaling pool in which protein disulfide isomerase disrupts the bond, switching TF to PAR2-dependent signaling that activates G12/G13–Jak2–STAT5–BclXL survival and ERK/CREB pathways [PMID:16959886, PMID:15016732, PMID:18647225]. Beyond hemostasis, TF promotes cell adhesion and migration through cytoplasmic-domain phosphorylation-dependent binding to filamin A, drives oncogene (K-ras/p53)-regulated tumor growth and angiogenesis, and mediates immune evasion by inducing platelet aggregation that suppresses NK-cell cytotoxicity [PMID:9490735, PMID:15494427, PMID:35064016]. TF-bearing microparticles released from activated platelets, tumor cells, and neutrophil extracellular traps propagate thrombosis in cancer and inflammatory settings including COVID-19, where complement-driven NETosis and P-selectin-mediated platelet–monocyte interactions induce monocyte TF expression [PMID:19861441, PMID:32759504, PMID:32678428].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing how TF engages its enzymatic partner resolved the stoichiometry and lipid dependence of the initiating coagulation complex: FVIIa binds TF at 1:1 stoichiometry in phospholipid vesicles, with phosphatidylserine inducing cooperative binding consistent with at least dimeric TF.\",\n      \"evidence\": \"Reconstitution of purified TF in phospholipid vesicles with radiolabeled FVII/FVIIa binding and cooperative modeling\",\n      \"pmids\": [\"3527261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TF dimers are physiologically relevant on cell membranes was not resolved\", \"Allosteric mechanism of FVIIa activation not yet defined\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Molecular cloning revealed TF as a single-pass transmembrane protein of 295 amino acids, providing the sequence foundation for all subsequent structure–function studies.\",\n      \"evidence\": \"cDNA cloning, Southern/Northern blotting, and sequence analysis\",\n      \"pmids\": [\"3297348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure unknown\", \"Function of the cytoplasmic domain undefined\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defining where TF is expressed in vivo answered how the body confines coagulation initiation to sites of vascular breach: TF is constitutively present in a hemostatic envelope (adventitia, organ capsules, epidermis) but absent from endothelium, and is inducible in monocytes and enriched in atherosclerotic plaque foam cells.\",\n      \"evidence\": \"Systematic immunohistochemistry with monoclonal antibodies across normal tissues and atherosclerotic plaques; in situ hybridization\",\n      \"pmids\": [\"2719077\", \"2704749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TF induction in monocytes and plaque cells was uncharacterized\", \"Contribution of plaque TF to acute thrombotic events not yet tested in vivo\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Identification of TFPI as a Kunitz-type inhibitor of the TF:FVIIa complex established the primary physiological negative regulator of TF-initiated coagulation.\",\n      \"evidence\": \"Biochemical inhibition assays with purified TF, FVIIa, and TFPI\",\n      \"pmids\": [\"2271516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of TFPI isoforms (α vs β) on different cell surfaces not yet defined\", \"In vivo significance not directly tested at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that NF-κB is obligatory for TF transcriptional induction by LPS, TNF-α, and IL-1β connected TF expression to inflammatory signaling, explaining how inflammation triggers coagulation.\",\n      \"evidence\": \"PDTC (NF-κB inhibitor) dose-dependently abolished TF mRNA and activity in HUVECs stimulated with multiple agonists\",\n      \"pmids\": [\"7605983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific NF-κB subunits and promoter elements not mapped in this study\", \"Whether NF-κB is the sole transcriptional regulator of TF not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The 2.0 Å crystal structure of the TF:FVIIa complex revealed how TF allosterically activates FVIIa by stabilizing its extended conformation, answering the central question of how a receptor converts an inert zymogen into an active protease.\",\n      \"evidence\": \"X-ray crystallography of active-site-inhibited FVIIa bound to soluble TF extracellular domain\",\n      \"pmids\": [\"8598903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure used truncated soluble TF lacking transmembrane/cytoplasmic domains and membrane context\", \"Substrate (FIX/FX) positioning in the complex unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovery that TF's cytoplasmic domain binds filamin A (ABP-280) in a phosphorylation-dependent manner and supports cell adhesion/migration established TF as a signaling receptor beyond its coagulation role.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-immunoprecipitation, Ser→Ala mutagenesis, and functional adhesion/migration assays\",\n      \"pmids\": [\"9490735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for cytoplasmic Ser phosphorylation not identified\", \"In vivo relevance of TF–filamin interaction for migration not shown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantitative kinetic analysis of whole-blood TF-initiated coagulation defined two mechanistic phases—initiation (~26 nM thrombin) and propagation—with distinct thrombin thresholds sequentially activating platelets, FXIII, and fibrinogen, providing a quantitative framework for how TF triggers clot formation.\",\n      \"evidence\": \"Contact-pathway-inhibited whole blood assay measuring TAT, prothrombin fragments, fibrinopeptides, and platelet markers in 20 subjects\",\n      \"pmids\": [\"12070020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of alternatively spliced TF to these phases not examined\", \"Role of microparticle TF in propagation phase not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of alternatively spliced soluble TF (asHTF) in blood and TF on platelet-derived microvesicles revealed that circulating TF pools exist beyond the tissue-fixed hemostatic envelope, fundamentally expanding the concept of TF-mediated thrombosis.\",\n      \"evidence\": \"RT-PCR identification of splice variant, recombinant protein procoagulant assays, flow cytometry sorting of platelet microvesicles (CD42b+), immunoelectron microscopy of platelet α-granules\",\n      \"pmids\": [\"12652293\", \"12514112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of soluble vs microvesicle TF to in vivo thrombosis not quantified\", \"Mechanism by which platelet TF becomes procoagulant upon activation not fully resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two concurrent discoveries established TF as an effector of oncogenic signaling: K-ras/p53 regulate TF via MEK/PI3K to drive tumor angiogenesis, and TF:FVIIa activates a G12/G13–Jak2–STAT5–BclXL cell survival pathway, revealing non-hemostatic TF functions in cancer.\",\n      \"evidence\": \"Isogenic K-ras/p53 colorectal lines with TF siRNA and xenograft assays; STAT5 reporters with G-protein and Jak inhibitors and dominant-negatives\",\n      \"pmids\": [\"15494427\", \"15016732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether G12/G13–Jak2–STAT5 signaling operates through PAR2 specifically was not fully resolved\", \"Relative importance of TF coagulant vs signaling functions in tumor progression in patients unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The discovery that TF's Cys186–Cys209 disulfide bond acts as a redox switch—toggled by PDI in a nitric oxide–dependent manner—between a coagulant and a PAR2-signaling pool resolved how a single receptor can serve dual functions and opened the concept of 'cryptic' TF.\",\n      \"evidence\": \"Disulfide mutagenesis (C209A), PDI inhibition, NO pathway manipulation, conformation-selective monoclonal antibody blocking coagulation vs signaling readouts\",\n      \"pmids\": [\"16959886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of conformational change upon disulfide disruption not determined at atomic resolution\", \"Proportion of cryptic vs coagulant TF on different cell types in vivo unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that platelets constitutively carry TF pre-mRNA and that activation triggers Clk1-dependent splicing to produce functional TF protein revealed a novel post-transcriptional mechanism for rapid TF generation at sites of thrombosis.\",\n      \"evidence\": \"RT-PCR for pre-mRNA and mature mRNA in resting vs activated platelets, Clk1 pharmacological inhibition, procoagulant/clot assays\",\n      \"pmids\": [\"17060476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contribution of platelet-spliced TF relative to tissue-derived TF in hemostasis not quantified\", \"Clk1 substrates in this context not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that TF associates with β1/α3β1 integrins and that a signaling-selective anti-TF antibody suppresses tumor growth as effectively as a coagulation-blocking antibody established that direct TF:FVIIa–PAR2 signaling is required for primary tumor growth independently of downstream coagulation.\",\n      \"evidence\": \"Co-immunoprecipitation of TF with integrins, isotype-matched signaling- vs coagulation-blocking antibodies, two in vivo xenograft models\",\n      \"pmids\": [\"17901245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TF–integrin interaction undefined\", \"Whether integrin association modulates the cryptic/coagulant TF switch unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Detection of tumor-derived TF-positive microparticles (co-expressing MUC-1) in cancer patient blood, their elimination by tumor resection, and their association with venous thromboembolism (OR 3.72) provided direct clinical evidence that tumor-shed TF microparticles drive cancer-associated thrombosis.\",\n      \"evidence\": \"Impedance-based flow cytometry in pancreatic cancer patients, case-control design, tumor resection as intervention\",\n      \"pmids\": [\"19861441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TF-positive microparticle levels can serve as a clinically useful biomarker not validated prospectively\", \"Functional activity of individual microparticles not measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In vivo demonstration that PDI associates with cell-surface TF and that P2X7 receptor-dependent PDI activity is required for TF-dependent arterial thrombosis and procoagulant microparticle biogenesis connected the cryptic TF redox switch to a physiological thrombotic phenotype.\",\n      \"evidence\": \"Co-IP of PDI with TF, P2X7 knockout mice, FeCl3 carotid thrombosis model, thiol-modifying agents, microparticle activity assays\",\n      \"pmids\": [\"22401798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular mechanism of P2X7-PDI-TF coupling not defined\", \"Whether other thiol oxidoreductases contribute in vivo not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NETs were established as TF delivery vehicles in thromboinflammation: cathepsin G on NETs cleaves pro-IL-1α to activate endothelial TF expression, and in SLE, REDD1-driven autophagy enhances NET release carrying TF, linking innate immunity, inflammation, and coagulation.\",\n      \"evidence\": \"NET-endothelial co-culture with cathepsin G and IL-1α blocking; SLE patient neutrophils with autophagy assessment and hydroxychloroquine inhibition\",\n      \"pmids\": [\"29976772\", \"30563869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of NET-borne TF vs monocyte-derived TF in vivo thrombosis not quantified\", \"Whether NET-TF pathway is targetable therapeutically in humans not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"COVID-19 studies delineated a complement→C5aR1→NETosis→TF pathway and a P-selectin-mediated platelet–monocyte contact mechanism for monocyte TF induction, establishing TF as a central effector of immunothrombosis in SARS-CoV-2 infection.\",\n      \"evidence\": \"Compstatin C3 inhibition, C5aR1 blockade, NETosis inhibitors in patient neutrophils; flow cytometry with P-selectin and αIIbβ3 blocking in patient monocytes\",\n      \"pmids\": [\"32759504\", \"32678428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether anti-TF strategies reduce clinical thrombosis in COVID-19 not tested\", \"Generalizability to other viral immunothrombotic conditions unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"EBV LMP2A was shown to upregulate TF via PI3K/AKT in nasopharyngeal carcinoma, and TF-induced platelet aggregation suppresses NK-cell cytotoxicity, revealing a viral oncogene–TF axis enabling immune evasion that is reversible by TF inhibition in vivo.\",\n      \"evidence\": \"LMP2A overexpression, PI3K/AKT inhibition, F3 siRNA, platelet aggregation assays, NK cytotoxicity assays, NPC xenograft model with NK-cell transfer\",\n      \"pmids\": [\"35064016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this immune evasion mechanism operates in other EBV-driven malignancies not tested\", \"Direct structural basis of TF-mediated platelet aggregation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing TF downstream of the Nrf2/GSTP1 axis in ferroptotic hepatocellular injury expanded TF's functional repertoire to include regulation of ferroptosis, a non-apoptotic cell death pathway.\",\n      \"evidence\": \"GSTP1 overexpression/knockdown, Nrf2 inhibitor, lipid ROS/MDA measurement, TEM for ferroptosis morphology in mouse stress model and AML-12 hepatocytes\",\n      \"pmids\": [\"38890797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TF promotes ferroptosis is not defined at molecular level\", \"Single study, not independently replicated\", \"Whether TF's role in ferroptosis is coagulation-dependent or signaling-dependent unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of full-length membrane-bound TF (including the transmembrane and cytoplasmic domains), the identity of kinases that phosphorylate the TF cytoplasmic domain in vivo, the quantitative contribution of each TF pool (tissue-fixed, microparticle, platelet-spliced, alternatively spliced soluble) to hemostasis vs pathological thrombosis, and whether therapeutic targeting of TF signaling can be separated from hemostatic TF function in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full-length TF structure with membrane context unavailable\", \"Cytoplasmic domain kinase(s) unidentified\", \"Clinical translation of signaling-selective TF inhibition not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 14, 16, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 14, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 10, 18]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [10, 18, 21]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 4, 6, 8, 9, 10, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 14, 16, 17, 22, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 25, 29, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 18, 26, 31]}\n    ],\n    \"complexes\": [\n      \"TF:FVIIa (extrinsic tenase)\"\n    ],\n    \"partners\": [\n      \"F7\",\n      \"TFPI\",\n      \"FLNA\",\n      \"F2RL1\",\n      \"P4HB\",\n      \"ITGB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}