{"gene":"F11","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1986,"finding":"The complete amino acid sequence of human coagulation factor XI was determined from a cDNA library. Each of the two identical polypeptide chains of this disulfide-linked homodimer (607 amino acids) contains four tandem repeats of ~90 amino acids (subsequently named apple domains) in the N-terminal heavy chain and a C-terminal serine protease catalytic domain homologous to trypsin-family proteases. Factor XIIa cleaves the Arg369–Ile370 bond in each chain to generate activated FXIa. FXI shares 58% sequence identity with plasma prekallikrein.","method":"cDNA cloning, DNA sequencing, amino acid sequence analysis of purified protein","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — primary sequence determination by cDNA cloning and protein sequencing; foundational study replicated and confirmed by all subsequent structural work","pmids":["3636155"],"is_preprint":false},{"year":1987,"finding":"The human F11 gene spans 23 kb and comprises 15 exons and 14 introns. Exons I–II encode the 5′ UTR and signal peptide; exons III–X encode the four apple-domain tandem repeats (each repeat split by one intron at a conserved position); exons XI–XV encode the serine protease catalytic domain. The intron positions in the catalytic domain exons match those in tissue plasminogen activator and urokinase genes.","method":"Restriction mapping, Southern blotting, selective DNA sequencing of genomic phage clones","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — direct genomic structural determination; foundational gene organization study","pmids":["2827746"],"is_preprint":false},{"year":1989,"finding":"The human F11 gene was localized by in situ hybridization to chromosome 4q35 (distal end of the long arm), using a genomic DNA probe containing exons VIII, IX, and X.","method":"In situ hybridization with genomic DNA probe","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 2 — direct chromosomal mapping by in situ hybridization","pmids":["2612218"],"is_preprint":false},{"year":1989,"finding":"Three point mutations in the F11 gene cause factor XI deficiency in Ashkenazi Jews: a splice-junction mutation disrupting mRNA splicing (Type I), a nonsense mutation Glu117→Stop (Type II), and a missense mutation Phe283→Leu (Type III). Compound heterozygotes for Types II and III were identified, and there was no correlation found between genotype and bleeding tendency in the initial cohort.","method":"PCR amplification and restriction-enzyme digestion of patient DNA; direct sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — molecular characterization of causative mutations; replicated in large subsequent cohort studies","pmids":["2813350"],"is_preprint":false},{"year":1991,"finding":"Factor XI is efficiently activated by thrombin (kcat/Km = 1.6 × 10⁵ M⁻¹s⁻¹) independently of factor XII, cleaving the same Arg–Ile bond as FXIIa. Dextran sulfate enhances thrombin-mediated FXI activation ~2000-fold, partly via FXI autoactivation by FXIa. This established a revised coagulation model in which thrombin feedback activates FXI.","method":"In vitro kinetic assays with purified proteins; plasma clotting assays with factor XII-deficient plasma","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro biochemical assay with purified components; foundational mechanistic study widely replicated","pmids":["1652157"],"is_preprint":false},{"year":1991,"finding":"Human factor XI is activated by thrombin or autoactivation (by FXIa) only in the presence of negatively charged surfaces (dextran sulfate, sulfatide, heparin). The cleavage produces the same 50-kDa heavy chain and 35-kDa light chain as FXIIa-mediated activation, consistent with cleavage at the single Arg–Ile bond. Addition of thrombin plus sulfatide to FXII-deficient plasma shortened clotting time, confirming FXI activation in plasma independent of FXII.","method":"In vitro activation assays with purified proteins; SDS-PAGE analysis of cleavage products; plasma clotting time assays with FXII-deficient plasma","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted biochemical assay with purified proteins; independently corroborates thrombin-feedback mechanism","pmids":["2019570"],"is_preprint":false},{"year":1991,"finding":"The 19 disulfide bonds in each FXI subunit were mapped by amino acid sequencing of peptide fragments. The four apple domains each contain three internal disulfide bonds. The two identical subunits are covalently linked by a single intermolecular disulfide bond at Cys321 (in apple domain 4). Cys11 (apple domain 1) in each subunit forms an intrachain disulfide bond.","method":"Chemical and enzymatic digestion of purified FXI; amino acid sequence analysis of peptide fragments; disulfide bond assignment","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical determination of disulfide bond locations by peptide sequencing","pmids":["1998667"],"is_preprint":false},{"year":1979,"finding":"Factor XI binds directly to high molecular weight kininogen (HMW-kininogen) with an association constant of 4.2 × 10⁸ M⁻¹. Prekallikrein and FXI compete for the same (or overlapping) binding site(s) on HMW-kininogen, and binding is mediated through the isolated light chain of HMW-kininogen. This interaction is essential for HMW-kininogen function as a coagulation cofactor.","method":"Binding assays with purified proteins; competition experiments; direct binding to isolated HMW-kininogen light chain","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding assays with purified components; competition and domain-mapping experiments","pmids":["291905"],"is_preprint":false},{"year":1988,"finding":"Two naturally occurring human antibodies (Baltimore and Winston-Salem) against FXI both bind the heavy chain of FXIa but act on distinct functional domains: the Baltimore antibody (IgG1) blocks FXI binding to HMW-kininogen and thereby inhibits surface-mediated activation by FXIIa, but does not affect FXIa activation of FIX; the Winston-Salem antibody (IgG3) inhibits FXIa-mediated activation of FIX but does not block FXI–HMW-kininogen binding. Both leave the FXIa active site (light chain amidolytic activity) unaffected.","method":"Immunoaffinity purification; Fab′ fragment inhibition assays; FIX activation assay; HMW-kininogen binding assay; amidolytic activity assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — functional domain mapping with purified antibody fragments and multiple orthogonal assays","pmids":["2460161"],"is_preprint":false},{"year":1988,"finding":"Protein C inhibitor (PCI) inhibits factor XIa with a second-order rate constant of 0.94 × 10⁴ M⁻¹s⁻¹, which is enhanced ~10-fold by heparin (to 9.1 × 10⁴ M⁻¹s⁻¹). SDS-PAGE demonstrates covalent 1:1 complex formation of FXIa with PCI. The heavy chain of FXIa plays a minor role in the inhibition, as isolated FXIa light chains are inhibited at similar rates.","method":"Kinetic inhibition assays with purified proteins; SDS-PAGE and immunoblotting of complexes; isolated light chain experiments","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted kinetic assay with purified proteins; covalent complex demonstrated by SDS-PAGE","pmids":["2844223"],"is_preprint":false},{"year":1991,"finding":"Factor XI deficiency in Ashkenazi Jews is caused predominantly by Type II (Glu117Stop) and Type III (Phe283Leu) mutations, each accounting for ~49% and ~47% of alleles, respectively, in 43 probands. Type III homozygotes have residual FXI activity (~9.7% of normal) significantly higher than Type II homozygotes (~1.2%) or Type II/III compound heterozygotes (~3.3%), indicating that the Phe283Leu substitution impairs but does not abolish function.","method":"PCR amplification and restriction enzyme digestion of patient DNA; FXI clotting activity assays; clinical correlation","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 — genotype–phenotype correlation with large patient cohort; replicated in subsequent studies","pmids":["2052060"],"is_preprint":false},{"year":1996,"finding":"TFPI-2/PP5, a Kunitz-type protease inhibitor, potently inhibits FXIa amidolytic activity with a Ki of 15 nM, as well as kallikrein (Ki = 25 nM) and plasmin (Ki = 3 nM). TFPI-2 prolonged coagulation time of plasma initiated by contact activation (which requires FXI), and heparin did not further enhance FXIa inhibition. Inhibition is at the FXIa active site (light chain).","method":"In vitro amidolytic inhibition assays with purified proteins; plasma clotting time assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro enzyme inhibition assay with Ki determination","pmids":["8555184"],"is_preprint":false},{"year":2006,"finding":"Mutation analysis of 116 UK index cases with FXI deficiency identified 140 causative F11 mutations (57 unique variants including 31 novel), confirming extensive molecular heterogeneity outside the Ashkenazi Jewish population. Common mutations E117X (Type II), F283L (Type III), and C128X account for 39.3% of alleles; whole gene deletions were also identified.","method":"Sequencing of F11 gene exons and flanking intronic regions in patient samples","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale mutation survey; no direct mechanistic experiments but establishes mutation landscape","pmids":["16835901"],"is_preprint":false},{"year":2009,"finding":"Structural analysis of 120 missense mutations across the F11 gene (70 in apple domains, 47 in serine protease domain) using a consensus apple-domain structure derived from the FXI dimer crystal structure revealed that the majority of FXI deficiency mutations (Type I: CRM-) cause protein misfolding rather than functional active-site defects (Type II: CRM+). The periphery of the apple-domain β-sheet is particularly sensitive to perturbation, and this β-sheet is critical for FXI dimer formation. Residues at the Ap4:Ap4 dimer interface are less directly involved in causing deficiency.","method":"Structural modeling using FXI dimer crystal structure; analysis of mutation database (183 mutations); homology modeling","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 3 — computational structural analysis; no direct mutagenesis experiments but uses validated crystal structure coordinates","pmids":["19652879"],"is_preprint":false},{"year":2009,"finding":"In plasma systems where FXII is either inhibited or absent, FXI contributes significantly to thrombin generation when coagulation is initiated with low concentrations of tissue factor, FXa, or thrombin. Replacing FXI with a recombinant form that activates FIX poorly, or one that is poorly activated by thrombin, reduced thrombin generation. An antibody blocking FXIa activation of FIX reduced thrombin generation, while an antibody blocking FXI activation by FXIIa did not. This demonstrates a FXII-independent pathway in which thrombin activates FXI, and FXIa sustains thrombin generation via FIX activation.","method":"Thrombin generation assays in FXII-deficient or FXII-inhibited plasma; recombinant FXI variants; function-blocking antibodies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal approaches including recombinant mutants and blocking antibodies; directly establishes pathway position","pmids":["19351955"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of zymogen FXI and the FXIa catalytic domain reveal that FXI contains four apple domains forming a disk structure with extensive interface at the base of the catalytic domain. The apple-disk structure controls FXI activation, FXIa interaction with substrate FIX, and FXI binding to platelets. Structural data localize ligand-binding sites and explain how missense mutations impair FXI function.","method":"X-ray crystallography of FXI zymogen and FXIa catalytic domain; structure-function analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional validation; foundational structural characterization","pmids":["20110423"],"is_preprint":false},{"year":2012,"finding":"FXI contains disulfide bonds (specifically Cys362–Cys482 and Cys118–Cys147) that are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). TRX-1-treated (reduced) FXI is activated significantly more efficiently by thrombin, FXIIa, or FXIa than non-reduced FXI. Patients with antiphospholipid syndrome (APS) thrombosis have higher plasma levels of reduced FXI than healthy controls.","method":"In vitro reduction assays with recombinant TRX-1 and PDI; FXI activation kinetics assays; novel ELISA for reduced FXI in patient plasma; mass spectrometry identification of reduced disulfide bonds","journal":"Journal of autoimmunity","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro biochemical assays with identification of specific disulfide bonds by MS, activation kinetics, and patient samples","pmids":["22704541"],"is_preprint":false},{"year":2017,"finding":"In angiotensin II-induced hypertension in mice, platelet-localized FXI mediates thrombin feedback amplification independently of FXII. The FXI receptor glycoprotein Ibα (GPIbα) on platelets is required for thrombin-dependent FXI feedback activation. Antisense oligonucleotide (ASO) inhibition of FXI synthesis prevented thrombin propagation on platelets, vascular leukocyte infiltration, endothelial dysfunction, and arterial hypertension in mice and rats, and reduced blood pressure in animals with established hypertension.","method":"Genetic and pharmacological (ASO) FXI inhibition in mouse/rat models of hypertension; platelet localization studies; GPIbα receptor identification by genetic and antibody experiments","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function, ASO inhibition, receptor identification with multiple animal models","pmids":["28148841"],"is_preprint":false},{"year":2019,"finding":"MAA868, a fully human antibody targeting the catalytic domain of FXI/FXIa, binds both the zymogen and activated forms with equal high affinity. Structural studies show MAA868 traps FXI/FXIa in an inactive, zymogen-like conformation, inhibiting the enzyme before it enters the coagulation process. MAA868 showed dose-dependent antithrombotic activity in a murine ferric chloride carotid occlusion model and sustained aPTT prolongation and FXI suppression in cynomolgus monkeys and healthy human subjects.","method":"Structural analysis (crystallography/binding studies); in vivo thrombosis model (ferric chloride, mouse); primate pharmacodynamics; phase I human clinical study","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — structural mechanism defined, validated in vitro and in multiple in vivo species including humans","pmids":["30692123"],"is_preprint":false},{"year":2020,"finding":"Using three distinct mouse models of venous thrombosis (IVC stasis, IVC stenosis, and femoral vein electrolytic injury), FXI deficiency reduced thrombus weight and incidence in models with blood flow (stenosis and electrolytic injury) but not in the stasis model. FXI deficiency altered fibrin(ogen) content and neutrophil extracellular trap markers in the stasis model, indicating FXI affects thrombus composition. FXI and FXII deficiency produced equivalent and non-additive effects, consistent with their functioning in the same pathway.","method":"Genetic knockout mice (FXI-deficient, FXII-deficient); three in vivo venous thrombosis models; thrombus weight, fibrin, and NETs quantification","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with multiple models and quantitative endpoint measurements","pmids":["33094904"],"is_preprint":false},{"year":2022,"finding":"Mathematical modeling combined with in vitro thrombin generation assays established that thrombin feedback activation of FXI contributes to thrombin generation propagation, but only when TFPI (tissue factor pathway inhibitor) is active. The extended Hockin-Mann (ext.HM) model predicted that selective elimination of TFPI's inhibitory function abolishes the FXI-positive feedback contribution; this was experimentally validated using anti-TFPI antibodies and FXI-depleted plasma in thrombin generation assays.","method":"Systems biology mathematical modeling; in vitro thrombin generation assays; function-blocking antibodies against TFPI; FXI-depleted plasma","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 1–2 — model-based prediction experimentally validated with function-blocking antibodies and depleted plasma","pmids":["35352494"],"is_preprint":false}],"current_model":"Human coagulation Factor XI (FXI/F11) is a GPI-unlinked, disulfide-linked homodimer (each subunit comprising four N-terminal apple domains and a C-terminal serine protease domain) that circulates as a zymogen bound to high-molecular-weight kininogen; it is activated by FXIIa on negatively charged surfaces in vitro, or—critically in vivo—by thrombin feedback (enhanced by dextran sulfate and negatively charged surfaces), with platelet GPIbα facilitating this feedback; activated FXIa then propagates coagulation by activating factor IX, sustaining thrombin generation; FXI's disulfide bonds (including the inter-subunit Cys321–Cys321 bond) are regulated by oxidoreductases TRX-1 and PDI (reduction enhancing activation), and FXIa is inhibited by protein C inhibitor and TFPI-2; genetic deficiency causes a bleeding disorder with mutations predominantly causing protein misfolding (CRM-), and severe FXI deficiency is protective against ischemic stroke and deep-vein thrombosis without fully impairing hemostasis."},"narrative":{"teleology":[{"year":1979,"claim":"Establishing that FXI circulates bound to high-molecular-weight kininogen (HMWK) via the HMWK light chain resolved how FXI localizes to activating surfaces and placed it within the contact system alongside prekallikrein.","evidence":"Quantitative binding and competition assays with purified FXI, prekallikrein, and HMWK","pmids":["291905"],"confidence":"High","gaps":["Exact apple domain responsible for HMWK binding not mapped in this study","Physiological surface for contact assembly in vivo not identified"]},{"year":1986,"claim":"Determination of the complete primary structure of FXI revealed its unique homodimeric architecture with four apple-domain tandem repeats per subunit and a C-terminal serine protease domain, distinguishing it from other coagulation proteases and establishing its structural framework.","evidence":"cDNA cloning and amino acid sequencing of purified human FXI","pmids":["3636155"],"confidence":"High","gaps":["Three-dimensional structure of apple domains and dimer interface unknown","Functional roles of individual apple domains not yet assigned"]},{"year":1988,"claim":"Identification of two distinct functional epitopes on the FXI heavy chain—one mediating HMWK binding/surface activation and another mediating FIX activation—demonstrated that the apple domains serve separable roles in cofactor engagement and substrate recognition.","evidence":"Domain-mapping with purified human anti-FXI antibodies (Baltimore, Winston-Salem) using Fab′ inhibition and functional assays","pmids":["2460161"],"confidence":"High","gaps":["Precise apple-domain assignments for each function not resolved","Whether additional exosites exist on the heavy chain untested"]},{"year":1988,"claim":"Demonstration that protein C inhibitor forms a covalent 1:1 complex with FXIa, enhanced by heparin, established the first physiological serpin-based inhibitory mechanism for FXIa.","evidence":"Kinetic inhibition assays and SDS-PAGE of purified FXIa–PCI complexes","pmids":["2844223"],"confidence":"High","gaps":["Relative in vivo contribution of PCI versus other serpins (e.g., antithrombin, C1-inhibitor) to FXIa regulation unclear","Effect of platelet surface on PCI inhibition not tested"]},{"year":1989,"claim":"Identification of three founder mutations in Ashkenazi Jewish patients (Type I splice defect, Type II Glu117Stop, Type III Phe283Leu) established the molecular genetic basis of FXI deficiency and linked it to a clinically variable bleeding disorder.","evidence":"PCR-based genotyping and sequencing of patient DNA; genotype–phenotype correlation in a cohort","pmids":["2813350","2052060"],"confidence":"High","gaps":["Poor genotype–bleeding phenotype correlation left modifiers of clinical severity unresolved","Molecular mechanism of Phe283Leu dysfunction (misfolding vs. catalytic defect) not determined"]},{"year":1991,"claim":"The discovery that thrombin directly activates FXI—independently of FXIIa—on negatively charged surfaces overturned the view that FXI activation requires the contact pathway and introduced the thrombin-feedback loop as a central amplification mechanism in coagulation.","evidence":"Reconstituted kinetic assays with purified thrombin/FXI; clotting assays in FXII-deficient plasma with dextran sulfate/sulfatide","pmids":["1652157","2019570"],"confidence":"High","gaps":["The physiological negatively charged surface in vivo was not identified","Relative contribution of thrombin-feedback vs. FXIIa-mediated activation in vivo remained unknown"]},{"year":1991,"claim":"Complete mapping of all 19 intrachain disulfide bonds per subunit and the single Cys321–Cys321 interchain bond defined the covalent architecture of the FXI homodimer and localized the dimerization linkage to apple domain 4.","evidence":"Peptide fragmentation and amino acid sequencing of purified FXI disulfide-linked fragments","pmids":["1998667"],"confidence":"High","gaps":["Functional consequences of individual disulfide bond reduction not tested","Whether disulfide redox status is regulated in vivo was unknown"]},{"year":1996,"claim":"Identification of TFPI-2 as a potent Kunitz-type inhibitor of FXIa (Ki 15 nM) expanded the repertoire of endogenous FXIa regulators beyond serpins.","evidence":"In vitro amidolytic inhibition assays and plasma clotting assays with purified TFPI-2","pmids":["8555184"],"confidence":"High","gaps":["In vivo relevance of TFPI-2 inhibition of FXIa not established","Whether TFPI-2 encounters FXIa at relevant tissue sites unclear"]},{"year":2009,"claim":"Plasma reconstitution experiments with recombinant FXI variants and function-blocking antibodies demonstrated that in FXII-independent coagulation, thrombin activates FXI which then sustains thrombin generation exclusively through FIX activation, placing FXI unambiguously between thrombin feedback and the tenase complex.","evidence":"Thrombin generation assays in FXII-deficient/inhibited plasma; recombinant FXI mutants; anti-FXIa and anti-FXI antibodies","pmids":["19351955"],"confidence":"High","gaps":["Quantitative contribution of this loop in whole blood or under flow conditions not assessed","Role of platelet-bound FXI not explored in this system"]},{"year":2009,"claim":"Structural analysis of >120 missense mutations against the FXI crystal structure revealed that most FXI-deficiency mutations disrupt apple-domain β-sheet folding (CRM− mechanism) rather than active-site catalysis, explaining the predominance of quantitative over qualitative deficiency.","evidence":"Computational structural mapping of mutation database onto FXI dimer crystal structure coordinates","pmids":["19652879"],"confidence":"Medium","gaps":["Predictions not validated by in vitro expression/folding studies for most variants","A minority of mutations lack structural rationalization"]},{"year":2010,"claim":"Crystal structures of zymogen FXI and the FXIa catalytic domain revealed the apple-domain disk architecture, localized ligand-binding sites, and explained how the heavy-chain scaffold controls activation and substrate engagement.","evidence":"X-ray crystallography with structure–function analysis","pmids":["20110423"],"confidence":"High","gaps":["Full-length activated FXIa dimer structure not resolved","Conformational dynamics during activation not captured by static structures"]},{"year":2012,"claim":"Discovery that oxidoreductases TRX-1 and PDI reduce specific FXI disulfide bonds (Cys362–Cys482, Cys118–Cys147), markedly enhancing its activation, introduced redox regulation as a novel layer of FXI control and linked it to thrombotic risk in antiphospholipid syndrome.","evidence":"In vitro reduction and activation kinetics; mass spectrometry identification of reduced bonds; patient plasma ELISA","pmids":["22704541"],"confidence":"High","gaps":["Whether TRX-1/PDI-mediated FXI reduction occurs on platelet surfaces in vivo is unresolved","Causal relationship between elevated reduced FXI and thrombosis in APS not established"]},{"year":2017,"claim":"Identification of platelet GPIbα as the receptor that facilitates thrombin-dependent FXI activation on platelets in vivo resolved a long-standing question about the physiological surface for thrombin-feedback activation, and ASO-mediated FXI depletion prevented thromboinflammation and hypertension in animal models.","evidence":"Genetic knockouts, anti-GPIbα antibodies, and FXI-targeting ASOs in mouse and rat hypertension models","pmids":["28148841"],"confidence":"High","gaps":["Applicability of GPIbα-dependent mechanism to human platelet FXI activation not directly demonstrated","Whether FXI's role in hypertension extends beyond thromboinflammation is unclear"]},{"year":2020,"claim":"Genetic FXI deficiency reduced venous thrombus formation in flow-dependent but not stasis models, and FXI and FXII deficiency were non-additive, confirming they function in the same pathway and that FXI is dispensable for thrombus formation under complete stasis.","evidence":"Three distinct venous thrombosis models (stasis, stenosis, electrolytic) in FXI- and FXII-knockout mice","pmids":["33094904"],"confidence":"High","gaps":["Mechanism by which flow selectively engages FXI/FXII pathway not elucidated","Extrapolation to human deep vein thrombosis contexts requires clinical validation"]},{"year":2022,"claim":"Mathematical modeling and experimental validation demonstrated that thrombin-feedback through FXI contributes to thrombin generation only when TFPI is active, providing a systems-level explanation for why FXI is important for sustained coagulation under physiological regulatory conditions.","evidence":"Extended Hockin-Mann model predictions validated by thrombin generation assays with anti-TFPI antibodies and FXI-depleted plasma","pmids":["35352494"],"confidence":"High","gaps":["Whether additional regulators modulate the FXI–TFPI interplay in vivo is unexplored","Model does not incorporate platelet-surface reactions or flow"]},{"year":null,"claim":"Key unresolved questions include the full structural basis for FXIa engagement with FIX on physiological membranes, the quantitative balance between FXII-dependent and thrombin-dependent FXI activation in different human vascular beds, and the molecular determinants of the variable bleeding phenotype in FXI-deficient patients.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal structure of FXIa bound to FIX","In vivo quantification of FXII-dependent vs. thrombin-dependent FXI activation in humans lacking","Genetic or proteomic modifiers of bleeding severity in FXI deficiency not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,4,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,4,5,14,17,20]}],"complexes":["FXI homodimer","FXI–HMWK complex"],"partners":["F12","F2","F9","KNG1","SERPINA5","TFPI2","GP1BA"],"other_free_text":[]},"mechanistic_narrative":"Coagulation factor XI (FXI) is a disulfide-linked homodimeric zymogen of the contact pathway that, upon activation to FXIa, propagates coagulation by cleaving factor IX and thereby sustaining thrombin generation [PMID:19351955, PMID:1652157]. Each subunit comprises four N-terminal apple domains arranged as a disk and a C-terminal trypsin-family serine protease domain; FXIIa or thrombin activates FXI by cleaving the Arg369–Ile370 bond, with thrombin feedback activation on negatively charged surfaces and platelet GPIbα representing the physiologically dominant activation route [PMID:3636155, PMID:1652157, PMID:28148841]. The thrombin-FXI positive feedback loop sustains thrombin generation specifically when tissue factor pathway inhibitor (TFPI) is active, and FXI disulfide bonds regulated by thioredoxin-1 and protein disulfide isomerase modulate its activation efficiency [PMID:35352494, PMID:22704541]. Genetic deficiency of FXI causes a bleeding disorder of variable severity—predominantly due to protein-misfolding mutations—and confers protection against thrombotic events [PMID:2813350, PMID:19652879, PMID:33094904]."},"prefetch_data":{"uniprot":{"accession":"P03951","full_name":"Coagulation factor XI","aliases":["Plasma thromboplastin antecedent","PTA"],"length_aa":625,"mass_kda":70.1,"function":"Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P03951/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F11","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/F11","total_profiled":1310},"omim":[{"mim_id":"619525","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIw; CDG2W","url":"https://www.omim.org/entry/619525"},{"mim_id":"618372","title":"GASTROINTESTINAL ULCERATION, RECURRENT, WITH DYSFUNCTIONAL PLATELETS; GURDP","url":"https://www.omim.org/entry/618372"},{"mim_id":"617637","title":"DEAFNESS, AUTOSOMAL RECESSIVE 106; DFNB106","url":"https://www.omim.org/entry/617637"},{"mim_id":"617362","title":"DEAH-BOX HELICASE 37; DHX37","url":"https://www.omim.org/entry/617362"},{"mim_id":"615144","title":"PROTEASE, SERINE, 55; PRSS55","url":"https://www.omim.org/entry/615144"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in 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    \"pmids\": [\"2627374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"F11 is anchored to neural plasma membranes via a covalently linked glycosyl-phosphatidylinositol (GPI) lipid, as demonstrated by PI-PLC-mediated release from brain plasma membranes and the presence of ethanolamine in biosynthetic labeling.\",\n      \"method\": \"PI-PLC treatment of brain membranes, biosynthetic labeling with ethanolamine\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical demonstration with PI-PLC and metabolic labeling, replicated across multiple preparations\",\n      \"pmids\": [\"2735929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"F3/F11 functions as a homophilic cell adhesion molecule that promotes self-adhesion and neurite outgrowth; transfection of F3 cDNA into CHO cells conferred enhanced self-aggregation and promoted neurite outgrowth of sensory neurons when used as substrate.\",\n      \"method\": \"Transfection of F3 cDNA into CHO cells, aggregation assays, neurite outgrowth assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function transfection with two distinct functional readouts (aggregation and neurite outgrowth)\",\n      \"pmids\": [\"2015094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Contactin/F11 binds tenascin via its N-terminal immunoglobulin-like domains; a 45 kDa proteolytic fragment beginning at the NH2-terminus retains tenascin binding, while the 190 kDa tenascin isoform (lacking alternatively spliced FNIII domains) is the preferred binding partner.\",\n      \"method\": \"Affinity chromatography on tenascin-Sepharose, NH2-terminal sequencing, solid-phase binding assays with 125I-labeled contactin/F11 and fractionated tenascin isoforms, proteolytic fragment analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution by affinity chromatography, solid-phase binding, and domain mapping by proteolysis with multiple controls\",\n      \"pmids\": [\"1382076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"F11 displays three functionally distinct activities mappable to specific domains: (1) binding to Ng-CAM via the first two Ig-like domains, (2) binding to restrictin (tenascin-R) via the second or third Ig-like domain, and (3) a neurite outgrowth-promoting activity that is independent of Ng-CAM and restrictin binding.\",\n      \"method\": \"Deletion mutants expressed in COS cells, epitope mapping of monoclonal antibodies, neurite outgrowth assays with tectal cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain deletion mutagenesis with functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"7682821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"F11 interacts directly with Nr-CAM/Bravo via a heterophilic binding activity mapped to the second or third Ig-like domain of F11; this interaction mediates neurite extension of tectal cells on immobilized F11.\",\n      \"method\": \"Neurite outgrowth assays, antibody blocking experiments, direct binding studies with deletion mutant proteins on COS cells, domain-specific monoclonal antibodies\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain deletion mutagenesis combined with functional blocking and direct binding assays\",\n      \"pmids\": [\"8274278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The GPI-anchored contactin/F11 physically complexes with the cytoplasmic src-family tyrosine kinase Fyn in detergent-resistant immune complexes; antibody-mediated cross-linking of contactin/F11 increases Fyn activity co-precipitated with the complex and phosphorylates an additional 75/80 kDa component; ligand binding (antibody or tenascin-R) causes co-redistribution of contactin/F11 and Fyn, indicating physical association and Fyn-dependent signaling.\",\n      \"method\": \"Co-immunoprecipitation of detergent-resistant complexes, Fyn kinase activity assay, antibody cross-linking, capping/redistribution experiments in HeLa transfectants\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with functional kinase assay and independent redistribution experiment in transfectants\",\n      \"pmids\": [\"7496631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tenascin-R (restrictin) binds F11 through its second and third fibronectin type III (FNIII)-like domains; a mutant F11 containing only Ig-like domains demonstrates direct interaction between F11 Ig domains and FNIII domains 2-3 of tenascin-R; this interaction enhances F11-mediated neurite outgrowth in vitro.\",\n      \"method\": \"Recombinant TN-R fragment expression in bacteria, domain-specific binding assays, F11 Ig-domain-only mutant, in vitro neurite outgrowth assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding reconstitution with domain mutants and functional neurite outgrowth readout\",\n      \"pmids\": [\"7615642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NrCAM-induced neurite extension requires F11 on the axonal surface as its receptor (not neurofascin), demonstrated by antibody blocking experiments; a direct interaction between neurofascin and NrCAM was confirmed by binding assays with transfected COS7 cells and immunoprecipitation, mapped to the Ig domains within neurofascin.\",\n      \"method\": \"Neurite outgrowth assays, antibody blocking, binding assays with transfected COS7 cells, immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional and binding evidence from multiple assays\",\n      \"pmids\": [\"8922386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Neurofascin binds directly to F11 (as well as axonin-1 and tenascin-R); in the presence of tenascin-R, F11 binds to the neurofascin/TN-R complex via TN-R (not neurofascin directly), shifting cellular receptor usage from NrCAM to F11 and altering neurite outgrowth; alternative splicing of neurofascin modulates F11 binding only slightly.\",\n      \"method\": \"Cellular binding assays, competition binding assays, neurite outgrowth experiments on neurofascin-Fc substrate\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and functional assays with defined molecular complexes\",\n      \"pmids\": [\"9722619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Tenascin-C and tenascin-R differentially modulate F11-mediated cell adhesion and neurite outgrowth: tenascin-R increases both, while tenascin-C increases cell attachment but decreases neurite outgrowth; in the presence of either tenascin, the F11 receptor shifts from NrCAM to β1 integrins; tenascin-C and tenascin-R can form molecular bridges linking F11 polypeptides.\",\n      \"method\": \"Cell adhesion assays, neurite outgrowth assays, antibody perturbation, cellular binding assays, sandwich binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays identifying receptor switching and molecular bridging mechanism\",\n      \"pmids\": [\"10446214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In vivo, proprioceptive sensory axons require F11/F3/contactin interactions for pathfinding to ventral horn motoneurons, while nociceptive fibers require axonin-1; F11 selectively partners with NrCAM (not NgCAM) for proprioceptive axon guidance, despite both NrCAM and NgCAM binding F11 in vitro.\",\n      \"method\": \"In vivo chick spinal cord perturbation experiments, antibody blocking in ovo, in vitro binding assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with specific anatomical phenotype plus in vitro binding validation\",\n      \"pmids\": [\"11430805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human platelet F11 receptor (F11R/JAM-A) is an integral membrane immunoglobulin superfamily member with two extracellular C2-type domains; it mediates platelet aggregation and secretion dependent on FcγRII cross-linking (via mAb F11 IgG Fc domain) and mediates platelet adhesion independently of FcγRII or GPIIb/IIIa; the protein is phosphorylated after thrombin and collagen stimulation.\",\n      \"method\": \"cDNA cloning, Western blot, immunoprecipitation, platelet aggregation/secretion assays, Fab fragment inhibition experiments, N-glycanase treatment, thrombin/collagen phosphorylation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — molecular cloning with multiple functional assays and phosphorylation demonstration\",\n      \"pmids\": [\"10753840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"F11R/JAM-A mediates platelet adhesion to cytokine-inflamed endothelial cells via homophilic interactions between platelet and endothelial F11R; ~40–60% of platelet adhesion force is F11R-dependent, inhibited by soluble recombinant F11R and by peptides from the N-terminal region and first Ig fold of F11R.\",\n      \"method\": \"Platelet adhesion assays to inflamed HUVEC, inhibition by recombinant soluble F11R and domain-specific peptides\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional adhesion assay with peptide inhibitors defining binding domains, single lab\",\n      \"pmids\": [\"12428104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"F11R/JAM-A signaling in platelets involves: phosphoinositide-3 kinase-dependent actin filament assembly, elevation of free intracellular calcium, phosphorylation of 32 and 35 kDa F11R forms, F11R dimerization (concurrent with decrease in monomeric F11R), and physical association of F11R with integrin GPIIIa and CD9.\",\n      \"method\": \"Wortmannin inhibition, calcium measurement, phosphorylation assays, co-immunoprecipitation of F11R with GPIIIa and CD9\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP plus pharmacological inhibition; single lab, multiple readouts\",\n      \"pmids\": [\"15344881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FXI (the F11 gene product coagulation factor XI) is a substrate for oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI); TRX-1 reduces the Cys362-Cys482 and Cys118-Cys147 disulfide bonds in FXI; reduced FXI is activated more efficiently by thrombin, FXIIa, or FXIa than oxidized FXI.\",\n      \"method\": \"In vitro reduction by recombinant TRX-1 and PDI, mass spectrometry identification of reduced disulfide bonds, activation assays comparing reduced vs. oxidized FXI, ELISA for reduced FXI in patient plasma\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with site identification by MS and functional activation assay\",\n      \"pmids\": [\"22704541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Platelet-localized FXI mediates thrombin feedback activation via the FXI receptor glycoprotein Ibα (GPIbα) on platelets in angiotensin II-induced hypertension, independent of factor XII; this drives vascular leukocyte infiltration and endothelial dysfunction.\",\n      \"method\": \"FXI antisense oligonucleotide knockdown in mice and rats, genetic FXI deficiency, angiotensin II infusion model, in vivo thrombin generation assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic and ASO loss-of-function with specific pathway placement (GPIbα-dependent thrombin feedback), replicated across mouse and rat models\",\n      \"pmids\": [\"28148841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAA868, a fully human antibody targeting the catalytic domain of FXI/FXIa, traps both the zymogen and activated forms in an inactive, zymogen-like conformation, explaining equally high binding affinity for both; this prevents FXI from entering the coagulation process before activation.\",\n      \"method\": \"Structural studies (antibody-FXI complex), binding affinity measurements, carotid occlusion thrombosis model in mice, aPTT assay in cynomolgus monkeys, first-in-human study\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination of binding mode plus in vivo functional validation across species\",\n      \"pmids\": [\"30692123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Naturally occurring human antibodies against FXI map to two distinct functional domains in the FXI/FXIa heavy chain: one (Baltimore) blocks binding of FXI to high molecular weight kininogen (HK) required for surface-mediated activation, and the other (Winston-Salem) inhibits FXIa-mediated activation of FIX, without affecting the amidolytic active site on the light chain.\",\n      \"method\": \"Purified patient IgG and Fab' fragments, coagulation activity assays, FXI activation by FXIIa, FIX activation assays, HK binding inhibition assays, immunoaffinity fractionation of reduced/alkylated FXIa chains\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional domain dissection with Fab' fragments and multiple mechanistic assays\",\n      \"pmids\": [\"2460161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Thrombin-dependent feedback activation of FXI contributes to TF pathway thrombin propagation; the contribution of this FXI feedback is modulated by TFPI (which normally suppresses the feedback loop), validated by combining a systems biology model with experimental thrombin generation assays using TFPI-blocking antibodies and FXI-depleted plasma.\",\n      \"method\": \"Mathematical (systems biology) modeling extended from Hockin-Mann model, in vitro thrombin generation assays, function-blocking antibodies against TFPI, FXI-depleted plasma\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — computational model validated by two independent experimental approaches (antibody blocking and FXI-depleted plasma), single lab\",\n      \"pmids\": [\"35352494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FXI and FXII contribute equivalently to venous thrombosis in flow-dependent models (IVC stenosis and femoral vein electrolytic injury), reducing thrombus weight, incidence, fibrin, and platelet accumulation; in the stasis model, their absence altered thrombus composition (fibrin/NETs) but not size.\",\n      \"method\": \"Genetic deficiency (FXI KO and FXII KO mice), three distinct venous thrombosis models, thrombus weight, fibrin/platelet accumulation, citrullinated histone H3 measurement\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined phenotypic readouts across three models\",\n      \"pmids\": [\"33094904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FXI structural analysis: FXI is a disulfide-linked homodimer; the majority of FXI deficiency mutations cause Type I (CRM-) deficiency through protein misfolding, attributed to sensitivity of the apple (Ap) domain beta-sheet structure; the Ap beta-sheet is crucial for FXI dimer formation, and periphery of Ap domains are most sensitive to structural perturbation.\",\n      \"method\": \"Structural analysis using consensus Ap domain structure from FXI dimer crystal structure, mapping of 120 missense mutations, Western blot classification of CRM+/CRM- status\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for structural analysis — crystal structure used for domain mapping; CRM classification from patient plasma by single lab\",\n      \"pmids\": [\"19652879\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human coagulation factor XI (F11 gene product) is a GPI-anchored (for the neural contactin/F11 ortholog) or disulfide-linked homodimeric serine protease (for the coagulation FXI) that: (1) in neural contexts, promotes neurite outgrowth and axon guidance through heterophilic interactions with Ng-CAM/NrCAM (via N-terminal Ig domains), tenascin isoforms (via Ig domains interacting with FNIII repeats 2–3 of tenascin-R), and Nr-CAM, while transducing signals through physical association with the src-family kinase Fyn; and (2) in coagulation, functions as a zymogen activated by thrombin feedback (via GPIbα on platelets) or FXIIa, with its activation efficiency regulated by oxidoreductase-mediated reduction of specific disulfide bonds (Cys362-Cys482, Cys118-Cys147), and two distinct functional heavy-chain domains mediating HK binding and FIX activation respectively, with TFPI modulating the thrombin-FXI positive feedback loop.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries from KEEP papers only.\n\n**Classification Notes:**\n\nThe gene F11 in question is human coagulation **Factor XI** (F11/FXI). I need to distinguish this from:\n- F11 neural cell adhesion molecule (contactin/F11/F3) — EXCLUDE (different protein, alias collision)\n- F-11 cell line (neuroblastoma×DRG hybrid) — EXCLUDE (cell line named F-11, not the gene)\n- Vaccinia virus F11 protein — EXCLUDE (viral protein)\n- Pseudoginsenoside-F11 (PF11) — EXCLUDE (small molecule)\n- F11R/JAM-A — This is a separate gene (F11 Receptor/JAM-A), not coagulation Factor XI — EXCLUDE\n- Bacterial/fungal/plant F11 — EXCLUDE (symbol collision)\n- JAA-F11 antibody — EXCLUDE (anti-TF antigen antibody)\n- PP-F11 peptide — EXCLUDE\n- 9F7-F11 antibody — EXCLUDE (anti-HER3)\n- lncRNA F11-AS1 — EXCLUDE (alt-locus product, case B)\n- S(F11)-RNase — EXCLUDE (plant, symbol collision)\n\n**KEEP papers** (coagulation Factor XI / F11 gene):\n- PMID:2612218 (chromosome localization of F11 gene)\n- PMID:30692123 (MAA868 antibody binding FXI catalytic domain, structural studies)\n- PMID:28148841 (platelet-localized FXI, thrombin feedback, GpIbα)\n- PMID:22704541 (FXI as substrate for oxidoreductases, disulfide bonds)\n- PMID:16835901 (spectrum of F11 mutations)\n- PMID:19652879 (structural analysis of FXI mutations, apple domains)\n- PMID:1652157 (factor XI activation by thrombin, revised coagulation model)\n- PMID:2052060 (FXI deficiency in Ashkenazi Jews, mutations)\n- PMID:18268095 (FXI deficiency protective against ischemic stroke)\n- PMID:21057700 (FXI deficiency protective against DVT)\n- PMID:3636155 (amino acid sequence of FXI, four tandem repeats, cDNA)\n- PMID:20110423 (structure and function of FXI review)\n- PMID:2827746 (gene organization of FXI)\n- PMID:2844223 (inhibition of FXIa by protein C inhibitor)\n- PMID:1998667 (disulfide bonds in FXI, apple domains)\n- PMID:2019570 (FXI activation by thrombin/FXIa on negatively charged surfaces)\n- PMID:8555184 (TFPI-2 inhibits FXIa)\n- PMID:291905 (prekallikrein and FXI binding to HMW-kininogen)\n- PMID:2460161 (naturally occurring antibodies against FXI heavy chain domains)\n- PMID:2813350 (three point mutations in FXI gene in Ashkenazi Jews)\n- PMID:19351955 (FXI contributes to thrombin generation without FXII)\n- PMID:19617576 (elevated FXI associated with VTE risk)\n- PMID:23929304 (FXI deficiency review)\n- PMID:35352494 (revised model, thrombin feedback activation of FXI)\n- PMID:33094904 (FXII and FXI in venous thrombosis mouse models)\n- PMID:35697739 (FXI activity associations in VTE)\n- PMID:34085768 (FXI antisense oligonucleotide PK/PD)\n- PMID:12477932 — generic cDNA paper, no FXI-specific mechanism — EXCLUDE\n- PMID:10391209 — SNP survey, no FXI mechanism — EXCLUDE\n- PMID:28514442 — interactome, no FXI-specific mechanism — EXCLUDE\n- PMID:33961781 — interactome — EXCLUDE\n- PMID:19056867 — proteomics — EXCLUDE\n- PMID:15489334 — MGC — EXCLUDE\n- PMID:16344560 — promoters — EXCLUDE\n- PMID:16335952 — plasma proteomics — EXCLUDE\n- PMID:10962009 — matriptase — EXCLUDE\n- PMID:20339536 — statins GWAS — EXCLUDE\n- PMID:19913121 — lipid genetics — EXCLUDE\n- PMID:17284699 — VT genetics, mentions F11 locus but no mechanism — EXCLUDE\n- PMID:21980494 — GWAS VT, mentions F11 locus — EXCLUDE\n- PMID:23376485 — proteomics — EXCLUDE\n- PMID:12924154 — fish crossbreeding F9-F11 — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1986,\n      \"finding\": \"The complete amino acid sequence of human coagulation factor XI was determined from a cDNA library. Each of the two identical polypeptide chains of this disulfide-linked homodimer (607 amino acids) contains four tandem repeats of ~90 amino acids (subsequently named apple domains) in the N-terminal heavy chain and a C-terminal serine protease catalytic domain homologous to trypsin-family proteases. Factor XIIa cleaves the Arg369–Ile370 bond in each chain to generate activated FXIa. FXI shares 58% sequence identity with plasma prekallikrein.\",\n      \"method\": \"cDNA cloning, DNA sequencing, amino acid sequence analysis of purified protein\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary sequence determination by cDNA cloning and protein sequencing; foundational study replicated and confirmed by all subsequent structural work\",\n      \"pmids\": [\"3636155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The human F11 gene spans 23 kb and comprises 15 exons and 14 introns. Exons I–II encode the 5′ UTR and signal peptide; exons III–X encode the four apple-domain tandem repeats (each repeat split by one intron at a conserved position); exons XI–XV encode the serine protease catalytic domain. The intron positions in the catalytic domain exons match those in tissue plasminogen activator and urokinase genes.\",\n      \"method\": \"Restriction mapping, Southern blotting, selective DNA sequencing of genomic phage clones\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic structural determination; foundational gene organization study\",\n      \"pmids\": [\"2827746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The human F11 gene was localized by in situ hybridization to chromosome 4q35 (distal end of the long arm), using a genomic DNA probe containing exons VIII, IX, and X.\",\n      \"method\": \"In situ hybridization with genomic DNA probe\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping by in situ hybridization\",\n      \"pmids\": [\"2612218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Three point mutations in the F11 gene cause factor XI deficiency in Ashkenazi Jews: a splice-junction mutation disrupting mRNA splicing (Type I), a nonsense mutation Glu117→Stop (Type II), and a missense mutation Phe283→Leu (Type III). Compound heterozygotes for Types II and III were identified, and there was no correlation found between genotype and bleeding tendency in the initial cohort.\",\n      \"method\": \"PCR amplification and restriction-enzyme digestion of patient DNA; direct sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization of causative mutations; replicated in large subsequent cohort studies\",\n      \"pmids\": [\"2813350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Factor XI is efficiently activated by thrombin (kcat/Km = 1.6 × 10⁵ M⁻¹s⁻¹) independently of factor XII, cleaving the same Arg–Ile bond as FXIIa. Dextran sulfate enhances thrombin-mediated FXI activation ~2000-fold, partly via FXI autoactivation by FXIa. This established a revised coagulation model in which thrombin feedback activates FXI.\",\n      \"method\": \"In vitro kinetic assays with purified proteins; plasma clotting assays with factor XII-deficient plasma\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro biochemical assay with purified components; foundational mechanistic study widely replicated\",\n      \"pmids\": [\"1652157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Human factor XI is activated by thrombin or autoactivation (by FXIa) only in the presence of negatively charged surfaces (dextran sulfate, sulfatide, heparin). The cleavage produces the same 50-kDa heavy chain and 35-kDa light chain as FXIIa-mediated activation, consistent with cleavage at the single Arg–Ile bond. Addition of thrombin plus sulfatide to FXII-deficient plasma shortened clotting time, confirming FXI activation in plasma independent of FXII.\",\n      \"method\": \"In vitro activation assays with purified proteins; SDS-PAGE analysis of cleavage products; plasma clotting time assays with FXII-deficient plasma\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted biochemical assay with purified proteins; independently corroborates thrombin-feedback mechanism\",\n      \"pmids\": [\"2019570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The 19 disulfide bonds in each FXI subunit were mapped by amino acid sequencing of peptide fragments. The four apple domains each contain three internal disulfide bonds. The two identical subunits are covalently linked by a single intermolecular disulfide bond at Cys321 (in apple domain 4). Cys11 (apple domain 1) in each subunit forms an intrachain disulfide bond.\",\n      \"method\": \"Chemical and enzymatic digestion of purified FXI; amino acid sequence analysis of peptide fragments; disulfide bond assignment\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical determination of disulfide bond locations by peptide sequencing\",\n      \"pmids\": [\"1998667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"Factor XI binds directly to high molecular weight kininogen (HMW-kininogen) with an association constant of 4.2 × 10⁸ M⁻¹. Prekallikrein and FXI compete for the same (or overlapping) binding site(s) on HMW-kininogen, and binding is mediated through the isolated light chain of HMW-kininogen. This interaction is essential for HMW-kininogen function as a coagulation cofactor.\",\n      \"method\": \"Binding assays with purified proteins; competition experiments; direct binding to isolated HMW-kininogen light chain\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding assays with purified components; competition and domain-mapping experiments\",\n      \"pmids\": [\"291905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Two naturally occurring human antibodies (Baltimore and Winston-Salem) against FXI both bind the heavy chain of FXIa but act on distinct functional domains: the Baltimore antibody (IgG1) blocks FXI binding to HMW-kininogen and thereby inhibits surface-mediated activation by FXIIa, but does not affect FXIa activation of FIX; the Winston-Salem antibody (IgG3) inhibits FXIa-mediated activation of FIX but does not block FXI–HMW-kininogen binding. Both leave the FXIa active site (light chain amidolytic activity) unaffected.\",\n      \"method\": \"Immunoaffinity purification; Fab′ fragment inhibition assays; FIX activation assay; HMW-kininogen binding assay; amidolytic activity assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional domain mapping with purified antibody fragments and multiple orthogonal assays\",\n      \"pmids\": [\"2460161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Protein C inhibitor (PCI) inhibits factor XIa with a second-order rate constant of 0.94 × 10⁴ M⁻¹s⁻¹, which is enhanced ~10-fold by heparin (to 9.1 × 10⁴ M⁻¹s⁻¹). SDS-PAGE demonstrates covalent 1:1 complex formation of FXIa with PCI. The heavy chain of FXIa plays a minor role in the inhibition, as isolated FXIa light chains are inhibited at similar rates.\",\n      \"method\": \"Kinetic inhibition assays with purified proteins; SDS-PAGE and immunoblotting of complexes; isolated light chain experiments\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted kinetic assay with purified proteins; covalent complex demonstrated by SDS-PAGE\",\n      \"pmids\": [\"2844223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Factor XI deficiency in Ashkenazi Jews is caused predominantly by Type II (Glu117Stop) and Type III (Phe283Leu) mutations, each accounting for ~49% and ~47% of alleles, respectively, in 43 probands. Type III homozygotes have residual FXI activity (~9.7% of normal) significantly higher than Type II homozygotes (~1.2%) or Type II/III compound heterozygotes (~3.3%), indicating that the Phe283Leu substitution impairs but does not abolish function.\",\n      \"method\": \"PCR amplification and restriction enzyme digestion of patient DNA; FXI clotting activity assays; clinical correlation\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genotype–phenotype correlation with large patient cohort; replicated in subsequent studies\",\n      \"pmids\": [\"2052060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TFPI-2/PP5, a Kunitz-type protease inhibitor, potently inhibits FXIa amidolytic activity with a Ki of 15 nM, as well as kallikrein (Ki = 25 nM) and plasmin (Ki = 3 nM). TFPI-2 prolonged coagulation time of plasma initiated by contact activation (which requires FXI), and heparin did not further enhance FXIa inhibition. Inhibition is at the FXIa active site (light chain).\",\n      \"method\": \"In vitro amidolytic inhibition assays with purified proteins; plasma clotting time assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro enzyme inhibition assay with Ki determination\",\n      \"pmids\": [\"8555184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutation analysis of 116 UK index cases with FXI deficiency identified 140 causative F11 mutations (57 unique variants including 31 novel), confirming extensive molecular heterogeneity outside the Ashkenazi Jewish population. Common mutations E117X (Type II), F283L (Type III), and C128X account for 39.3% of alleles; whole gene deletions were also identified.\",\n      \"method\": \"Sequencing of F11 gene exons and flanking intronic regions in patient samples\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale mutation survey; no direct mechanistic experiments but establishes mutation landscape\",\n      \"pmids\": [\"16835901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Structural analysis of 120 missense mutations across the F11 gene (70 in apple domains, 47 in serine protease domain) using a consensus apple-domain structure derived from the FXI dimer crystal structure revealed that the majority of FXI deficiency mutations (Type I: CRM-) cause protein misfolding rather than functional active-site defects (Type II: CRM+). The periphery of the apple-domain β-sheet is particularly sensitive to perturbation, and this β-sheet is critical for FXI dimer formation. Residues at the Ap4:Ap4 dimer interface are less directly involved in causing deficiency.\",\n      \"method\": \"Structural modeling using FXI dimer crystal structure; analysis of mutation database (183 mutations); homology modeling\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — computational structural analysis; no direct mutagenesis experiments but uses validated crystal structure coordinates\",\n      \"pmids\": [\"19652879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In plasma systems where FXII is either inhibited or absent, FXI contributes significantly to thrombin generation when coagulation is initiated with low concentrations of tissue factor, FXa, or thrombin. Replacing FXI with a recombinant form that activates FIX poorly, or one that is poorly activated by thrombin, reduced thrombin generation. An antibody blocking FXIa activation of FIX reduced thrombin generation, while an antibody blocking FXI activation by FXIIa did not. This demonstrates a FXII-independent pathway in which thrombin activates FXI, and FXIa sustains thrombin generation via FIX activation.\",\n      \"method\": \"Thrombin generation assays in FXII-deficient or FXII-inhibited plasma; recombinant FXI variants; function-blocking antibodies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal approaches including recombinant mutants and blocking antibodies; directly establishes pathway position\",\n      \"pmids\": [\"19351955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of zymogen FXI and the FXIa catalytic domain reveal that FXI contains four apple domains forming a disk structure with extensive interface at the base of the catalytic domain. The apple-disk structure controls FXI activation, FXIa interaction with substrate FIX, and FXI binding to platelets. Structural data localize ligand-binding sites and explain how missense mutations impair FXI function.\",\n      \"method\": \"X-ray crystallography of FXI zymogen and FXIa catalytic domain; structure-function analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation; foundational structural characterization\",\n      \"pmids\": [\"20110423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FXI contains disulfide bonds (specifically Cys362–Cys482 and Cys118–Cys147) that are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). TRX-1-treated (reduced) FXI is activated significantly more efficiently by thrombin, FXIIa, or FXIa than non-reduced FXI. Patients with antiphospholipid syndrome (APS) thrombosis have higher plasma levels of reduced FXI than healthy controls.\",\n      \"method\": \"In vitro reduction assays with recombinant TRX-1 and PDI; FXI activation kinetics assays; novel ELISA for reduced FXI in patient plasma; mass spectrometry identification of reduced disulfide bonds\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro biochemical assays with identification of specific disulfide bonds by MS, activation kinetics, and patient samples\",\n      \"pmids\": [\"22704541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In angiotensin II-induced hypertension in mice, platelet-localized FXI mediates thrombin feedback amplification independently of FXII. The FXI receptor glycoprotein Ibα (GPIbα) on platelets is required for thrombin-dependent FXI feedback activation. Antisense oligonucleotide (ASO) inhibition of FXI synthesis prevented thrombin propagation on platelets, vascular leukocyte infiltration, endothelial dysfunction, and arterial hypertension in mice and rats, and reduced blood pressure in animals with established hypertension.\",\n      \"method\": \"Genetic and pharmacological (ASO) FXI inhibition in mouse/rat models of hypertension; platelet localization studies; GPIbα receptor identification by genetic and antibody experiments\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function, ASO inhibition, receptor identification with multiple animal models\",\n      \"pmids\": [\"28148841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAA868, a fully human antibody targeting the catalytic domain of FXI/FXIa, binds both the zymogen and activated forms with equal high affinity. Structural studies show MAA868 traps FXI/FXIa in an inactive, zymogen-like conformation, inhibiting the enzyme before it enters the coagulation process. MAA868 showed dose-dependent antithrombotic activity in a murine ferric chloride carotid occlusion model and sustained aPTT prolongation and FXI suppression in cynomolgus monkeys and healthy human subjects.\",\n      \"method\": \"Structural analysis (crystallography/binding studies); in vivo thrombosis model (ferric chloride, mouse); primate pharmacodynamics; phase I human clinical study\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural mechanism defined, validated in vitro and in multiple in vivo species including humans\",\n      \"pmids\": [\"30692123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Using three distinct mouse models of venous thrombosis (IVC stasis, IVC stenosis, and femoral vein electrolytic injury), FXI deficiency reduced thrombus weight and incidence in models with blood flow (stenosis and electrolytic injury) but not in the stasis model. FXI deficiency altered fibrin(ogen) content and neutrophil extracellular trap markers in the stasis model, indicating FXI affects thrombus composition. FXI and FXII deficiency produced equivalent and non-additive effects, consistent with their functioning in the same pathway.\",\n      \"method\": \"Genetic knockout mice (FXI-deficient, FXII-deficient); three in vivo venous thrombosis models; thrombus weight, fibrin, and NETs quantification\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with multiple models and quantitative endpoint measurements\",\n      \"pmids\": [\"33094904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mathematical modeling combined with in vitro thrombin generation assays established that thrombin feedback activation of FXI contributes to thrombin generation propagation, but only when TFPI (tissue factor pathway inhibitor) is active. The extended Hockin-Mann (ext.HM) model predicted that selective elimination of TFPI's inhibitory function abolishes the FXI-positive feedback contribution; this was experimentally validated using anti-TFPI antibodies and FXI-depleted plasma in thrombin generation assays.\",\n      \"method\": \"Systems biology mathematical modeling; in vitro thrombin generation assays; function-blocking antibodies against TFPI; FXI-depleted plasma\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — model-based prediction experimentally validated with function-blocking antibodies and depleted plasma\",\n      \"pmids\": [\"35352494\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human coagulation Factor XI (FXI/F11) is a GPI-unlinked, disulfide-linked homodimer (each subunit comprising four N-terminal apple domains and a C-terminal serine protease domain) that circulates as a zymogen bound to high-molecular-weight kininogen; it is activated by FXIIa on negatively charged surfaces in vitro, or—critically in vivo—by thrombin feedback (enhanced by dextran sulfate and negatively charged surfaces), with platelet GPIbα facilitating this feedback; activated FXIa then propagates coagulation by activating factor IX, sustaining thrombin generation; FXI's disulfide bonds (including the inter-subunit Cys321–Cys321 bond) are regulated by oxidoreductases TRX-1 and PDI (reduction enhancing activation), and FXIa is inhibited by protein C inhibitor and TFPI-2; genetic deficiency causes a bleeding disorder with mutations predominantly causing protein misfolding (CRM-), and severe FXI deficiency is protective against ischemic stroke and deep-vein thrombosis without fully impairing hemostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"F11 encodes two functionally distinct proteins depending on species and context: in neural tissue, the F11/contactin glycoprotein is a GPI-anchored immunoglobulin superfamily member (six Ig-like domains, four FNIII repeats) that promotes neurite outgrowth and proprioceptive axon guidance through heterophilic interactions with NrCAM, Ng-CAM, tenascin-R, and tenascin-C via its N-terminal Ig domains, transducing signals through physical association with the src-family kinase Fyn [PMID:2627374, PMID:7682821, PMID:7496631, PMID:11430805]. In the coagulation system, the F11 gene product is coagulation factor XI, a disulfide-linked homodimeric serine protease zymogen with distinct apple-domain-mediated functions: one heavy-chain domain binds high molecular weight kininogen for surface-mediated activation, while another mediates FIX activation; FXI is activated by thrombin feedback (via platelet GPIbα) or FXIIa, with activation efficiency enhanced by oxidoreductase-mediated reduction of specific disulfide bonds (Cys362-Cys482, Cys118-Cys147) [PMID:2460161, PMID:22704541, PMID:28148841]. FXI and FXII contribute equivalently to venous thrombosis in flow-dependent models, and the thrombin-FXI positive feedback loop is physiologically modulated by TFPI [PMID:33094904, PMID:35352494]. The majority of FXI deficiency mutations cause Type I (CRM-negative) deficiency through misfolding of the apple domain β-sheet structure critical for homodimerization [PMID:19652879].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Patient-derived antibodies revealed that the FXI heavy chain contains two functionally separable domains — one required for HK binding/surface-mediated activation and another for FIX activation — establishing that FXI's substrate recognition and cofactor binding are spatially distinct.\",\n      \"evidence\": \"Purified patient IgG/Fab' fragments tested in coagulation, FIX activation, and HK binding assays\",\n      \"pmids\": [\"2460161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise residues mediating each function not identified\", \"No structural data at this stage\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Molecular cloning and biochemical studies established that neural F11/contactin is a GPI-anchored protein with six Ig-like and four FNIII domains, resolving its membrane attachment mechanism and domain architecture.\",\n      \"evidence\": \"cDNA sequencing, domain analysis, PI-PLC release from brain membranes, metabolic labeling with ethanolamine\",\n      \"pmids\": [\"2627374\", \"2735929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand interactions mapped at this stage\", \"GPI anchor composition not fully characterized\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Gain-of-function experiments demonstrated that F11/contactin can mediate homophilic cell adhesion and promote neurite outgrowth, establishing it as a functional neural adhesion molecule.\",\n      \"evidence\": \"F3 cDNA transfection into CHO cells with aggregation and neurite outgrowth assays\",\n      \"pmids\": [\"2015094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterophilic binding partners not yet identified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Deletion mutagenesis mapped three separable functions of F11 to specific Ig domains — Ng-CAM binding (Ig1-2), tenascin-R/restrictin binding (Ig2-3), and NrCAM-mediated neurite extension (Ig2-3) — revealing that a single molecule integrates multiple guidance cues through discrete domain interactions.\",\n      \"evidence\": \"COS cell expression of deletion mutants, domain-specific mAb blocking, neurite outgrowth assays with tectal cells\",\n      \"pmids\": [\"7682821\", \"8274278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of F11 Ig domains not available\", \"Relative affinities of each interaction not quantified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Two key advances defined the molecular basis of F11 signaling and ligand recognition: (1) the GPI-anchored F11 physically associates with cytoplasmic Fyn kinase, whose activity increases upon F11 cross-linking, providing a signal transduction mechanism for a molecule lacking an intracellular domain; (2) tenascin-R FNIII domains 2-3 were identified as the F11-binding site, with this interaction enhancing neurite outgrowth.\",\n      \"evidence\": \"Co-IP of F11-Fyn complexes with kinase assays and capping experiments in HeLa transfectants; recombinant TN-R fragment binding assays with F11 Ig-domain-only mutants and neurite outgrowth assays\",\n      \"pmids\": [\"7496631\", \"7615642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediary linker between GPI-anchored F11 and cytoplasmic Fyn not identified\", \"Downstream signaling targets beyond 75/80 kDa phosphoprotein unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Tenascin-R was shown to act as a molecular switch that redirects neurofascin signaling from NrCAM to F11, and tenascin-C and tenascin-R differentially modulate F11-mediated adhesion and outgrowth with receptor switching to β1 integrins, revealing combinatorial control of axon guidance by extracellular matrix composition.\",\n      \"evidence\": \"Competition binding assays with neurofascin, TN-R, and F11; neurite outgrowth on defined substrates; sandwich binding assays demonstrating molecular bridging\",\n      \"pmids\": [\"9722619\", \"10446214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of receptor switching not demonstrated\", \"Structural basis of ternary complexes not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"In vivo perturbation in chick spinal cord demonstrated that F11 is selectively required for proprioceptive (not nociceptive) axon pathfinding to ventral horn motoneurons, partnering specifically with NrCAM, providing the first in vivo functional validation of F11's axon guidance role.\",\n      \"evidence\": \"Antibody blocking in ovo with anatomical tracing of proprioceptive and nociceptive axons\",\n      \"pmids\": [\"11430805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic knockout phenotype not available\", \"Whether F11 acts permissively or instructively in vivo unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Crystal structure-based analysis of 120 FXI missense mutations revealed that most FXI deficiency is caused by misfolding of the apple domain β-sheet structure critical for homodimerization, establishing the structural basis of Type I (CRM-negative) deficiency.\",\n      \"evidence\": \"Mapping of mutations onto consensus apple domain structure from FXI dimer crystal structure, CRM classification from patient plasma\",\n      \"pmids\": [\"19652879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation of individual mutations by recombinant expression limited\", \"Mechanism of Type II (CRM-positive) mutations less characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"FXI was identified as a substrate of thioredoxin-1 and PDI, which reduce the Cys362-Cys482 and Cys118-Cys147 disulfides, with reduced FXI being activated more efficiently by thrombin and FXIIa — establishing redox regulation as a novel layer of FXI activation control.\",\n      \"evidence\": \"In vitro reduction by recombinant TRX-1/PDI, mass spectrometry of reduced disulfides, activation assays, ELISA in patient plasma\",\n      \"pmids\": [\"22704541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of redox regulation of FXI not demonstrated in animal models\", \"Whether redox state of FXI changes in thrombotic disease unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The thrombin-FXI positive feedback loop was shown to operate in vivo through platelet GPIbα, independently of FXII, driving vascular inflammation in hypertension — establishing FXI as a link between coagulation and vascular pathology.\",\n      \"evidence\": \"FXI ASO knockdown and genetic deficiency in mouse and rat angiotensin II hypertension models with thrombin generation assays\",\n      \"pmids\": [\"28148841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of FXI-GPIbα interaction site not resolved\", \"Relevance to human hypertensive vascular disease not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural studies of the anti-FXI antibody MAA868 revealed that FXI's catalytic domain can be trapped in a zymogen-like conformation, explaining how both zymogen and enzyme forms can be equally inhibited and validating FXI as a druggable antithrombotic target.\",\n      \"evidence\": \"Structural studies of antibody-FXI complex, carotid occlusion model in mice, aPTT in cynomolgus monkeys, first-in-human study\",\n      \"pmids\": [\"30692123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term clinical safety and efficacy of FXI inhibition not established from this study alone\", \"Whether conformational trapping applies to other FXI inhibitor modalities unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic knockout studies established that FXI and FXII contribute equivalently to venous thrombosis under flow conditions but differentially affect thrombus composition under stasis, clarifying FXI's role in the contact pathway in vivo.\",\n      \"evidence\": \"FXI KO and FXII KO mice in three venous thrombosis models with thrombus weight, fibrin, platelet, and NET quantification\",\n      \"pmids\": [\"33094904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of FXI vs FXII in human venous thrombosis unclear\", \"Whether FXI's thrombin feedback role or contact activation role dominates in each model not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Computational modeling validated experimentally showed that TFPI modulates the thrombin-FXI positive feedback loop, placing TFPI as a physiological brake on FXI-dependent thrombin amplification via the tissue factor pathway.\",\n      \"evidence\": \"Systems biology model validated by thrombin generation assays with anti-TFPI antibodies and FXI-depleted plasma\",\n      \"pmids\": [\"35352494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of TFPI-FXI interplay not performed\", \"Whether TFPI directly inhibits FXI or acts indirectly through TF/FVIIa/FXa not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of FXI interaction with GPIbα, the molecular intermediary linking GPI-anchored neural F11 to Fyn, and the in vivo significance of redox regulation of FXI activation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of FXI-GPIbα complex\", \"GPI-Fyn coupling mechanism for neural F11 unknown\", \"In vivo redox regulation of FXI not tested in thrombosis models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 4, 5, 11, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 17, 18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 12, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 7, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [15, 16, 17, 18, 19, 20, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 8, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"complexes\": [\n      \"FXI homodimer\",\n      \"F11/contactin-Fyn signaling complex\"\n    ],\n    \"partners\": [\n      \"NrCAM\",\n      \"TNR\",\n      \"TNC\",\n      \"NFASC\",\n      \"FYN\",\n      \"GP1BA\",\n      \"CNTN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Coagulation factor XI (FXI) is a disulfide-linked homodimeric zymogen of the contact pathway that, upon activation to FXIa, propagates coagulation by cleaving factor IX and thereby sustaining thrombin generation [PMID:19351955, PMID:1652157]. Each subunit comprises four N-terminal apple domains arranged as a disk and a C-terminal trypsin-family serine protease domain; FXIIa or thrombin activates FXI by cleaving the Arg369–Ile370 bond, with thrombin feedback activation on negatively charged surfaces and platelet GPIbα representing the physiologically dominant activation route [PMID:3636155, PMID:1652157, PMID:28148841]. The thrombin-FXI positive feedback loop sustains thrombin generation specifically when tissue factor pathway inhibitor (TFPI) is active, and FXI disulfide bonds regulated by thioredoxin-1 and protein disulfide isomerase modulate its activation efficiency [PMID:35352494, PMID:22704541]. Genetic deficiency of FXI causes a bleeding disorder of variable severity—predominantly due to protein-misfolding mutations—and confers protection against thrombotic events [PMID:2813350, PMID:19652879, PMID:33094904].\",\n  \"teleology\": [\n    {\n      \"year\": 1979,\n      \"claim\": \"Establishing that FXI circulates bound to high-molecular-weight kininogen (HMWK) via the HMWK light chain resolved how FXI localizes to activating surfaces and placed it within the contact system alongside prekallikrein.\",\n      \"evidence\": \"Quantitative binding and competition assays with purified FXI, prekallikrein, and HMWK\",\n      \"pmids\": [\"291905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact apple domain responsible for HMWK binding not mapped in this study\",\n        \"Physiological surface for contact assembly in vivo not identified\"\n      ]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Determination of the complete primary structure of FXI revealed its unique homodimeric architecture with four apple-domain tandem repeats per subunit and a C-terminal serine protease domain, distinguishing it from other coagulation proteases and establishing its structural framework.\",\n      \"evidence\": \"cDNA cloning and amino acid sequencing of purified human FXI\",\n      \"pmids\": [\"3636155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Three-dimensional structure of apple domains and dimer interface unknown\",\n        \"Functional roles of individual apple domains not yet assigned\"\n      ]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Identification of two distinct functional epitopes on the FXI heavy chain—one mediating HMWK binding/surface activation and another mediating FIX activation—demonstrated that the apple domains serve separable roles in cofactor engagement and substrate recognition.\",\n      \"evidence\": \"Domain-mapping with purified human anti-FXI antibodies (Baltimore, Winston-Salem) using Fab′ inhibition and functional assays\",\n      \"pmids\": [\"2460161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise apple-domain assignments for each function not resolved\",\n        \"Whether additional exosites exist on the heavy chain untested\"\n      ]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstration that protein C inhibitor forms a covalent 1:1 complex with FXIa, enhanced by heparin, established the first physiological serpin-based inhibitory mechanism for FXIa.\",\n      \"evidence\": \"Kinetic inhibition assays and SDS-PAGE of purified FXIa–PCI complexes\",\n      \"pmids\": [\"2844223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative in vivo contribution of PCI versus other serpins (e.g., antithrombin, C1-inhibitor) to FXIa regulation unclear\",\n        \"Effect of platelet surface on PCI inhibition not tested\"\n      ]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of three founder mutations in Ashkenazi Jewish patients (Type I splice defect, Type II Glu117Stop, Type III Phe283Leu) established the molecular genetic basis of FXI deficiency and linked it to a clinically variable bleeding disorder.\",\n      \"evidence\": \"PCR-based genotyping and sequencing of patient DNA; genotype–phenotype correlation in a cohort\",\n      \"pmids\": [\"2813350\", \"2052060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Poor genotype–bleeding phenotype correlation left modifiers of clinical severity unresolved\",\n        \"Molecular mechanism of Phe283Leu dysfunction (misfolding vs. catalytic defect) not determined\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"The discovery that thrombin directly activates FXI—independently of FXIIa—on negatively charged surfaces overturned the view that FXI activation requires the contact pathway and introduced the thrombin-feedback loop as a central amplification mechanism in coagulation.\",\n      \"evidence\": \"Reconstituted kinetic assays with purified thrombin/FXI; clotting assays in FXII-deficient plasma with dextran sulfate/sulfatide\",\n      \"pmids\": [\"1652157\", \"2019570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The physiological negatively charged surface in vivo was not identified\",\n        \"Relative contribution of thrombin-feedback vs. FXIIa-mediated activation in vivo remained unknown\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Complete mapping of all 19 intrachain disulfide bonds per subunit and the single Cys321–Cys321 interchain bond defined the covalent architecture of the FXI homodimer and localized the dimerization linkage to apple domain 4.\",\n      \"evidence\": \"Peptide fragmentation and amino acid sequencing of purified FXI disulfide-linked fragments\",\n      \"pmids\": [\"1998667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of individual disulfide bond reduction not tested\",\n        \"Whether disulfide redox status is regulated in vivo was unknown\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of TFPI-2 as a potent Kunitz-type inhibitor of FXIa (Ki 15 nM) expanded the repertoire of endogenous FXIa regulators beyond serpins.\",\n      \"evidence\": \"In vitro amidolytic inhibition assays and plasma clotting assays with purified TFPI-2\",\n      \"pmids\": [\"8555184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of TFPI-2 inhibition of FXIa not established\",\n        \"Whether TFPI-2 encounters FXIa at relevant tissue sites unclear\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Plasma reconstitution experiments with recombinant FXI variants and function-blocking antibodies demonstrated that in FXII-independent coagulation, thrombin activates FXI which then sustains thrombin generation exclusively through FIX activation, placing FXI unambiguously between thrombin feedback and the tenase complex.\",\n      \"evidence\": \"Thrombin generation assays in FXII-deficient/inhibited plasma; recombinant FXI mutants; anti-FXIa and anti-FXI antibodies\",\n      \"pmids\": [\"19351955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative contribution of this loop in whole blood or under flow conditions not assessed\",\n        \"Role of platelet-bound FXI not explored in this system\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural analysis of >120 missense mutations against the FXI crystal structure revealed that most FXI-deficiency mutations disrupt apple-domain β-sheet folding (CRM− mechanism) rather than active-site catalysis, explaining the predominance of quantitative over qualitative deficiency.\",\n      \"evidence\": \"Computational structural mapping of mutation database onto FXI dimer crystal structure coordinates\",\n      \"pmids\": [\"19652879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Predictions not validated by in vitro expression/folding studies for most variants\",\n        \"A minority of mutations lack structural rationalization\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Crystal structures of zymogen FXI and the FXIa catalytic domain revealed the apple-domain disk architecture, localized ligand-binding sites, and explained how the heavy-chain scaffold controls activation and substrate engagement.\",\n      \"evidence\": \"X-ray crystallography with structure–function analysis\",\n      \"pmids\": [\"20110423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length activated FXIa dimer structure not resolved\",\n        \"Conformational dynamics during activation not captured by static structures\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that oxidoreductases TRX-1 and PDI reduce specific FXI disulfide bonds (Cys362–Cys482, Cys118–Cys147), markedly enhancing its activation, introduced redox regulation as a novel layer of FXI control and linked it to thrombotic risk in antiphospholipid syndrome.\",\n      \"evidence\": \"In vitro reduction and activation kinetics; mass spectrometry identification of reduced bonds; patient plasma ELISA\",\n      \"pmids\": [\"22704541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TRX-1/PDI-mediated FXI reduction occurs on platelet surfaces in vivo is unresolved\",\n        \"Causal relationship between elevated reduced FXI and thrombosis in APS not established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of platelet GPIbα as the receptor that facilitates thrombin-dependent FXI activation on platelets in vivo resolved a long-standing question about the physiological surface for thrombin-feedback activation, and ASO-mediated FXI depletion prevented thromboinflammation and hypertension in animal models.\",\n      \"evidence\": \"Genetic knockouts, anti-GPIbα antibodies, and FXI-targeting ASOs in mouse and rat hypertension models\",\n      \"pmids\": [\"28148841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Applicability of GPIbα-dependent mechanism to human platelet FXI activation not directly demonstrated\",\n        \"Whether FXI's role in hypertension extends beyond thromboinflammation is unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic FXI deficiency reduced venous thrombus formation in flow-dependent but not stasis models, and FXI and FXII deficiency were non-additive, confirming they function in the same pathway and that FXI is dispensable for thrombus formation under complete stasis.\",\n      \"evidence\": \"Three distinct venous thrombosis models (stasis, stenosis, electrolytic) in FXI- and FXII-knockout mice\",\n      \"pmids\": [\"33094904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which flow selectively engages FXI/FXII pathway not elucidated\",\n        \"Extrapolation to human deep vein thrombosis contexts requires clinical validation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mathematical modeling and experimental validation demonstrated that thrombin-feedback through FXI contributes to thrombin generation only when TFPI is active, providing a systems-level explanation for why FXI is important for sustained coagulation under physiological regulatory conditions.\",\n      \"evidence\": \"Extended Hockin-Mann model predictions validated by thrombin generation assays with anti-TFPI antibodies and FXI-depleted plasma\",\n      \"pmids\": [\"35352494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional regulators modulate the FXI–TFPI interplay in vivo is unexplored\",\n        \"Model does not incorporate platelet-surface reactions or flow\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full structural basis for FXIa engagement with FIX on physiological membranes, the quantitative balance between FXII-dependent and thrombin-dependent FXI activation in different human vascular beds, and the molecular determinants of the variable bleeding phenotype in FXI-deficient patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No co-crystal structure of FXIa bound to FIX\",\n        \"In vivo quantification of FXII-dependent vs. thrombin-dependent FXI activation in humans lacking\",\n        \"Genetic or proteomic modifiers of bleeding severity in FXI deficiency not identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 4, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 4, 5, 14, 17, 20]}\n    ],\n    \"complexes\": [\n      \"FXI homodimer\",\n      \"FXI–HMWK complex\"\n    ],\n    \"partners\": [\n      \"F12\",\n      \"F2\",\n      \"F9\",\n      \"KNG1\",\n      \"SERPINA5\",\n      \"TFPI2\",\n      \"GP1BA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}