{"gene":"SERPINF2","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1976,"finding":"α2-plasmin inhibitor (SERPINF2/α2-antiplasmin) was isolated from human plasma and characterized as a glycoprotein (~67 kDa) that instantaneously inhibits plasmin by forming a non-dissociable 1:1 stoichiometric complex involving cleavage of a specific peptide bond in the inhibitor and cross-linking to the light (active-site-containing) chain of plasmin. It also inhibits trypsin but only slowly inhibits urokinase. A neutralizing antibody abolished virtually all inhibitory activity of plasma against activator-induced clot lysis.","method":"Protein purification, SDS-PAGE, immunoelectrophoresis, kinetic inhibition assays, stoichiometry determination, antibody neutralization experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — foundational biochemical reconstitution and characterization with multiple orthogonal methods in original discovery paper","pmids":["134998"],"is_preprint":false},{"year":1977,"finding":"Human antiplasmin (α2-antiplasmin/SERPINF2) was purified and further characterized as the fast-acting plasmin inhibitor in plasma, establishing it as the primary physiological inhibitor of plasmin.","method":"Protein purification, functional inhibition assays","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical purification and functional characterization, independently confirming earlier isolation","pmids":["21075"],"is_preprint":false},{"year":1979,"finding":"The mechanism of the reaction between α2-antiplasmin (SERPINF2) and plasmin was established: the inhibitor forms a covalent, SDS-stable 1:1 complex with plasmin via a suicide substrate-like serpin mechanism, involving cleavage at the reactive site peptide bond.","method":"In vitro kinetic assays, SDS-PAGE complex analysis, mechanistic dissection of enzyme-inhibitor interaction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro mechanistic characterization of the inhibitory reaction","pmids":["158022"],"is_preprint":false},{"year":1981,"finding":"α2-antiplasmin (SERPINF2) is stored in human platelets (33–114 ng per 10⁹ platelets) and is released upon thrombin stimulation without cell lysis. This release is specific to platelets among peripheral blood cells, identifying platelets as a cellular reservoir for α2AP distinct from the plasma pool.","method":"Radioimmunoassay of platelet extracts, thrombin stimulation assay, comparison across blood cell types","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — direct quantification and functional release assay with controlled comparisons across cell types","pmids":["7306699"],"is_preprint":false},{"year":1982,"finding":"Human polymorphonuclear leukocyte elastase inactivates α2-plasmin inhibitor (SERPINF2) by limited proteolytic cleavage at two separate sites, generating lower molecular weight fragments and destroying plasmin-inhibitory activity. This suggests that elastase released during inflammation can potentiate pathological proteolysis by inactivating α2AP.","method":"In vitro incubation of leukocyte elastase with purified α2-plasmin inhibitor, SDS-PAGE analysis of cleavage products, functional activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic cleavage assay with structural and functional characterization","pmids":["6980881"],"is_preprint":false},{"year":1987,"finding":"The primary structure of human α2-antiplasmin (SERPINF2) was determined by cDNA sequencing: mature protein contains 452 amino acids, is homologous (23–28%) to other serpins, and its reactive site (the peptide bond cleaved upon reaction with plasmin) is Arg364-Met365, corresponding to the P1-P1' position in serpin nomenclature.","method":"cDNA cloning and sequencing from human liver mRNA, oligonucleotide probe designed from peptide sequence, sequence alignment with serpin superfamily","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — primary sequence determination with identification of reactive site, validated by homology and peptide data","pmids":["2433286"],"is_preprint":false},{"year":1995,"finding":"Human neutrophil defensins bind directly to α2-antiplasmin (SERPINF2) and form complexes with it. This interaction mutually inactivates both partners: defensins abolish the antiprotease activity of α2AP against plasmin, and α2AP inhibits defensin cytotoxicity toward lung carcinoma cells.","method":"In vitro binding assays, antiprotease activity assays with increasing defensin concentrations, cytotoxicity assays with serpin pre-incubation","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro functional interaction demonstrated with multiple activity readouts, single study","pmids":["7873202"],"is_preprint":false},{"year":1996,"finding":"α2-antiplasmin (SERPINF2) is present in atherosclerotic plaque at higher concentrations than in normal arterial wall, where it co-localizes with PAI-1. Together with reduced tissue plasminogen activator, elevated α2AP contributes to impaired fibrinolysis in atherosclerotic lesions, potentially maintaining plaque by resisting fibrin dissolution.","method":"Immunohistochemistry of normal and atherosclerotic arterial wall sections, quantitative immunoassay of tissue extracts","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein quantification and localization in tissue, but no functional manipulation; single study","pmids":["8624776"],"is_preprint":false},{"year":2003,"finding":"Human kallikrein 6 (hK6) is inhibited by α2-antiplasmin (SERPINF2) among other serpins, establishing α2AP as a physiological inhibitor of this trypsin-like serine protease. Antithrombin III was the most efficient inhibitor among those tested.","method":"In vitro enzyme inhibition assays with purified recombinant hK6 and panel of serpins","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro inhibition assay with recombinant proteins, but α2AP is one of several serpins tested","pmids":["12878203"],"is_preprint":false},{"year":2004,"finding":"A plasma proteinase named antiplasmin-cleaving enzyme (APCE), homologous to fibroblast activation protein/seprase, cleaves the Pro12-Asn13 bond of the Met-form of α2-antiplasmin (Met-α2AP, SERPINF2) to generate the Asn-form (Asn-α2AP). Asn-α2AP is cross-linked to fibrin by activated Factor XIIIa approximately 13-fold faster than Met-α2AP, making fibrin clots markedly more resistant to plasmin-mediated lysis. The ratio of Asn-α2AP to Met-α2AP directly determines clot lysis rates.","method":"Purification of APCE from human plasma, in vitro cleavage assays, Factor XIIIa cross-linking kinetics, plasma clot lysis rate measurements as a function of α2AP form ratio","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro system with purified proteins, quantitative kinetics, and functional lysis assays demonstrating mechanistic consequences","pmids":["14751930"],"is_preprint":false},{"year":2007,"finding":"Among the three principal fibrinolytic inhibitors (PAI-1, α2-antiplasmin/SERPINF2, and TAFIa), α2AP plays the dominant role in regulating lysis of both plasma clots and whole-blood thrombi. Neutralizing antibodies to α2AP produced the largest single-inhibitor effect on lysis acceleration; maximal lysis occurred only when all three inhibitors were neutralized together, demonstrating complementary but non-redundant roles.","method":"Plasma clot lysis and model thrombus lysis assays with neutralizing antibodies to α2AP and PAI-1, carboxypeptidase inhibitor (CPI) for TAFIa, single and combination depletion experiments","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — epistasis-type functional dissection with neutralizing antibodies and inhibitors across multiple assay systems, independently validated across conditions","pmids":["17388801"],"is_preprint":false},{"year":2011,"finding":"The antifibrinolytic function of Factor XIII (FXIII) is entirely dependent on its ability to cross-link α2-antiplasmin (SERPINF2) to fibrin. Depletion of either FXIII or α2AP accelerated clot lysis ~9-fold similarly; FXIII depletion had no additional effect on α2AP-depleted thrombi; and a neutralizing antibody to α2AP completely abolished the stabilizing effect of FXIII reconstitution. Clot stability correlated inversely and strongly with the amount of cross-linked α2AP.","method":"Flow-based plasma thrombus model with depletion of FXIII and/or α2AP, reconstitution experiments, neutralizing antibody to α2AP, quantitative correlation of cross-linked α2AP with lysis rates","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — genetic/depletion epistasis with reconstitution and antibody neutralization in a physiological flow model, multiple orthogonal lines of evidence","pmids":["21471521"],"is_preprint":false},{"year":2014,"finding":"Platelet-derived FXIII-A is exposed on the surface of activated (thrombin + collagen stimulated) platelets and exerts its antifibrinolytic function by cross-linking α2-antiplasmin (SERPINF2) to fibrin, stabilizing thrombi. Incorporating a neutralizing antibody to α2AP abolished the platelet FXIII-A-mediated thrombus stabilization, demonstrating that α2AP cross-linking is the obligate mechanism of platelet FXIII-A antifibrinolytic activity.","method":"Chandler model thrombi from FXIII-depleted plasma reconstituted with platelets, fluorescence confocal microscopy and flow cytometry of FXIII-A on platelet surface, neutralizing antibody to α2AP, transglutaminase inhibitors","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — direct localization with functional consequences, antibody neutralization, mechanistic dissection in physiological model","pmids":["25331118"],"is_preprint":false},{"year":2014,"finding":"α2-antiplasmin (α2AP/SERPINF2) accumulates in kidneys subjected to unilateral ureteral obstruction (UUO) and promotes renal fibrosis by inducing myofibroblast formation in renal tubular epithelial cells, renal fibroblasts, and bone marrow-derived mesenchymal stem cells. α2AP-deficient mice showed attenuated UUO-induced fibrosis and reduced myofibroblast formation. Mechanistically, α2AP induces TGF-β production via the c-Jun N-terminal kinase (JNK) pathway, and JNK inhibition (SP600125) blocked α2AP-induced TGF-β production.","method":"UUO mouse model in α2AP(+/+) vs α2AP(-/-) mice, in vitro treatment of multiple cell types with α2AP, JNK inhibitor (SP600125) pharmacological epistasis, TGF-β ELISA, myofibroblast marker quantification","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo plus in vitro mechanistic pathway dissection with pharmacological inhibitor, multiple cell types","pmids":["25095732"],"is_preprint":false},{"year":2015,"finding":"α2-antiplasmin (SERPINF2) exerts profibrotic effects in systemic sclerosis (SSc) independently of its function as a plasmin inhibitor. Administration of α2AP to mice induced dermal fibrosis (increased dermal thickness, collagen, myofibroblast differentiation), and α2AP neutralization prevented profibrotic changes and autoantibody production in bleomycin-induced SSc models. α2AP treatment promoted fibrosis in normal human dermal fibroblasts, and α2AP neutralization reversed the profibrotic phenotype of SSc patient fibroblasts even in the absence of plasmin.","method":"Bleomycin SSc mouse model with α2AP administration and neutralizing antibody, human SSc patient dermal fibroblasts treated with α2AP or neutralizing antibody in absence of plasmin, histology, collagen assays, autoantibody measurement","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model plus human patient cell experiments, plasmin-independent mechanism shown by specific experimental design","pmids":["26743600"],"is_preprint":false},{"year":2017,"finding":"α2-antiplasmin (SERPINF2) promotes vascular dysfunction in systemic sclerosis by attenuating VEGF-induced tube formation, cell proliferation, and endothelial junction-associated protein (VE-cadherin, PECAM1) production through the adipose triglyceride lipase (ATGL)/tyrosine phosphatase SHP2 signaling axis in vascular endothelial cells. α2AP neutralization improved vascular damage in bleomycin-induced SSc mice.","method":"Bleomycin SSc mouse model with α2AP administration/neutralization, in vitro endothelial cell tube formation, proliferation, junction protein assays, SSc fibroblast-conditioned media experiments, pathway inhibitor studies identifying ATGL/SHP2 axis","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro mechanistic data with pathway identification, but ATGL/SHP2 axis established in single study","pmids":["28159016"],"is_preprint":false},{"year":2019,"finding":"SerpinF2/α2-antiplasmin levels are significantly elevated in preeclampsia plasma, and the circulating plasmin-α2-antiplasmin (PAP) complex is positively correlated with testosterone and negatively correlated with estradiol in early-onset preeclampsia patients. In human renal and trophoblastic cells, testosterone and estradiol regulate SerpinF2 expression in opposite directions. Fibrin deposition co-localizes with SerpinF2 in the intervillous spaces of preeclamptic placenta.","method":"Proteomic analysis of plasma, longitudinal measurement of PAP complex and sex hormones, cell-based expression regulation experiments with testosterone/estradiol, immunolocalization in placenta","journal":"Journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 3 — cell-based regulatory experiments plus in vivo correlation; mechanistic pathway partially established","pmids":["30020241"],"is_preprint":false},{"year":2020,"finding":"α2-antiplasmin (SERPINF2) is associated with lupus nephritis development through two mechanisms: (1) direct plasmin inhibition blocks plasmin's anti-inflammatory effect on macrophages (plasmin attenuates IFN-γ-induced proinflammatory cytokine production via the AMPK pathway, and α2AP eliminates this protective effect); and (2) α2AP directly induces proinflammatory cytokine production in macrophages via ERK1/2 and JNK pathways. IFN-γ induces α2AP production in fibroblasts via the JNK pathway.","method":"Pristane-induced lupus mouse model in α2AP-deficient vs wild-type mice, in vitro macrophage cytokine assays with plasmin ± α2AP, pathway inhibitor studies (AMPK, ERK1/2, JNK), IFN-γ stimulation of fibroblasts with JNK inhibitor","journal":"Immunity, inflammation and disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model plus in vitro pathway dissection with inhibitors, multiple mechanisms identified in single study","pmids":["32237065"],"is_preprint":false}],"current_model":"SERPINF2 (α2-antiplasmin/α2AP) is the primary physiological inhibitor of plasmin, forming an instantaneous, covalent, non-dissociable 1:1 complex via cleavage of its reactive site (Arg364-Met365); it circulates in two N-terminal forms (Met-α2AP and Asn-α2AP, the latter generated by APCE cleavage and cross-linked ~13-fold faster into fibrin by Factor XIIIa to confer fibrinolysis resistance), is stored in platelets and released by thrombin, is inactivated by leukocyte elastase, binds neutrophil defensins in a mutually inhibitory manner, dominates regulation of clot and thrombus lysis (with complementary roles for PAI-1 and TAFIa), and exerts plasmin-independent profibrotic and pro-inflammatory effects through TGF-β/JNK signaling in fibroblasts and ERK1/2/JNK/AMPK pathways in macrophages, as well as impairing VEGF signaling in endothelial cells via an ATGL/SHP2 axis."},"narrative":{"teleology":[{"year":1976,"claim":"Identification and biochemical characterization of α2-antiplasmin as the fast-acting plasmin inhibitor in human plasma resolved the question of which molecule was primarily responsible for physiological plasmin neutralization.","evidence":"Protein purification from human plasma, SDS-PAGE, stoichiometry analysis, and antibody neutralization of plasma fibrinolytic activity","pmids":["134998","21075"],"confidence":"High","gaps":["No primary structure determined","Mechanism of covalent complex formation not resolved","In vivo relevance not directly demonstrated"]},{"year":1979,"claim":"Establishing the suicide substrate-like serpin mechanism of the α2AP–plasmin reaction explained how the inhibitor achieves rapid, irreversible inactivation of plasmin through covalent complex formation at the reactive site bond.","evidence":"In vitro kinetic dissection with SDS-PAGE analysis of covalent enzyme–inhibitor complexes","pmids":["158022"],"confidence":"High","gaps":["Reactive site residues not yet identified","Crystal structure unavailable"]},{"year":1981,"claim":"Discovery of a platelet α2AP storage pool released upon thrombin stimulation revealed a localized antifibrinolytic mechanism at sites of platelet activation, beyond the circulating plasma reservoir.","evidence":"Radioimmunoassay of platelet extracts with thrombin stimulation and cross-cell-type comparisons","pmids":["7306699"],"confidence":"High","gaps":["Contribution of platelet-derived α2AP to clot stability vs. plasma pool not quantified","Mechanism of platelet storage (granule type) not determined"]},{"year":1982,"claim":"Demonstration that leukocyte elastase proteolytically inactivates α2AP established a direct link between neutrophil-mediated inflammation and local loss of antifibrinolytic protection.","evidence":"In vitro incubation of purified elastase and α2AP with SDS-PAGE and functional activity assays","pmids":["6980881"],"confidence":"High","gaps":["In vivo significance at inflammatory sites not tested","Cleavage sites not mapped to sequence"]},{"year":1987,"claim":"Determination of the full primary structure by cDNA sequencing identified the Arg364-Met365 reactive site bond and placed α2AP within the serpin superfamily, enabling structure–function analysis.","evidence":"cDNA cloning from human liver mRNA, sequencing, serpin family alignment","pmids":["2433286"],"confidence":"High","gaps":["Three-dimensional structure not resolved","Functional domains beyond reactive center loop not mapped"]},{"year":2004,"claim":"Discovery of APCE-mediated N-terminal processing of Met-α2AP to Asn-α2AP, which is cross-linked to fibrin by FXIIIa ~13-fold faster, explained how the relative abundance of α2AP isoforms regulates clot resistance to fibrinolysis.","evidence":"Purification of APCE from plasma, in vitro cleavage and FXIIIa cross-linking kinetics, clot lysis rate measurements","pmids":["14751930"],"confidence":"High","gaps":["Regulation of APCE activity in vivo unknown","Structural basis for differential FXIIIa cross-linking rate not determined"]},{"year":2007,"claim":"Systematic depletion/neutralization epistasis among PAI-1, α2AP, and TAFIa demonstrated that α2AP is the single most important fibrinolytic inhibitor in both plasma clots and whole-blood thrombi, but maximal fibrinolysis requires neutralization of all three.","evidence":"Clot and thrombus lysis assays with neutralizing antibodies and carboxypeptidase inhibitor, single and combination depletions","pmids":["17388801"],"confidence":"High","gaps":["In vivo arterial thrombolysis hierarchy not confirmed","Temporal dynamics of inhibitor contribution during thrombus maturation unknown"]},{"year":2011,"claim":"Demonstration that FXIIIa's entire antifibrinolytic function depends on cross-linking α2AP to fibrin unified the FXIII and α2AP pathways into a single obligate axis controlling thrombus stability.","evidence":"Flow-based thrombus model with FXIII and/or α2AP depletion, reconstitution, and neutralizing antibody","pmids":["21471521","25331118"],"confidence":"High","gaps":["Whether other FXIIIa substrates contribute to thrombus stability in other contexts not excluded","Role of platelet-derived vs. plasma FXIII not fully separated in vivo"]},{"year":2014,"claim":"Discovery of plasmin-independent profibrotic activity of α2AP — inducing TGF-β via JNK signaling and promoting myofibroblast differentiation — expanded its functional repertoire beyond hemostasis to organ fibrosis.","evidence":"UUO renal fibrosis model in α2AP-knockout vs. wild-type mice, in vitro JNK inhibitor epistasis, multiple cell types","pmids":["25095732","26743600"],"confidence":"High","gaps":["Receptor mediating α2AP profibrotic signaling unidentified","Whether profibrotic effect requires full-length vs. cleaved α2AP unknown"]},{"year":2017,"claim":"Identification of ATGL/SHP2 as the axis through which α2AP impairs VEGF-driven endothelial function revealed a plasmin-independent vascular dysfunction mechanism relevant to systemic sclerosis.","evidence":"Endothelial tube formation, proliferation, and junction protein assays with pathway inhibitors; bleomycin SSc mouse model","pmids":["28159016"],"confidence":"Medium","gaps":["ATGL/SHP2 axis established in a single study, no independent confirmation","Direct binding target on endothelial cells not identified","Whether this pathway operates outside SSc context unknown"]},{"year":2020,"claim":"Dual pro-inflammatory mechanisms of α2AP in macrophages — neutralizing plasmin's AMPK-mediated anti-inflammatory effect and directly activating ERK1/2/JNK cytokine production — explained its role in promoting lupus nephritis beyond simple fibrinolysis regulation.","evidence":"Pristane-induced lupus model in α2AP-knockout vs. wild-type mice, macrophage cytokine assays with pathway inhibitors","pmids":["32237065"],"confidence":"Medium","gaps":["Receptor or binding partner mediating direct macrophage activation unknown","Relative contribution of plasmin-dependent vs. -independent mechanisms in vivo not quantified"]},{"year":null,"claim":"The cell-surface receptor or binding partner through which α2AP initiates its plasmin-independent signaling (profibrotic TGF-β/JNK, pro-inflammatory ERK1/2/JNK, anti-angiogenic ATGL/SHP2) remains unidentified, preventing a unified model of its non-hemostatic functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor identification for non-serpin signaling functions","Structural basis of plasmin-independent activity unknown","Therapeutic targeting of non-hemostatic functions not tested in clinical models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,5,10,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,9,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,9,10,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,15,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17]}],"complexes":[],"partners":["PLG","F13A1","FAP","ELANE","DEFA1"],"other_free_text":[]},"mechanistic_narrative":"SERPINF2 (α2-antiplasmin) is the principal fast-acting physiological inhibitor of plasmin, forming an irreversible, covalent 1:1 complex through cleavage of its Arg364-Met365 reactive site bond, and is the dominant regulator of fibrin clot and thrombus lysis among the three major fibrinolytic inhibitors (PAI-1, α2AP, TAFIa) [PMID:134998, PMID:17388801]. The inhibitor circulates in two N-terminal forms: the Met-form and the Asn-form generated by antiplasmin-cleaving enzyme (APCE), with the Asn-form cross-linked ~13-fold faster to fibrin by Factor XIIIa, a reaction that constitutes the entire antifibrinolytic mechanism of FXIII [PMID:14751930, PMID:21471521]. Beyond hemostasis, α2-antiplasmin exerts plasmin-independent profibrotic effects by inducing TGF-β production via JNK signaling in fibroblasts and myofibroblast differentiation in multiple cell types, and directly promotes macrophage proinflammatory cytokine production through ERK1/2 and JNK pathways [PMID:25095732, PMID:32237065]. α2AP also impairs VEGF-driven endothelial function through an ATGL/SHP2 signaling axis and is inactivated by leukocyte elastase, linking its regulation to inflammatory protease networks [PMID:28159016, PMID:6980881]."},"prefetch_data":{"uniprot":{"accession":"P08697","full_name":"Alpha-2-antiplasmin","aliases":["Alpha-2-plasmin inhibitor","Alpha-2-PI","Serpin F2"],"length_aa":491,"mass_kda":54.6,"function":"Serine protease inhibitor. The major targets of this inhibitor are plasmin and trypsin, but it also inactivates matriptase-3/TMPRSS7 and chymotrypsin","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P08697/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SERPINF2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SERPINF2","total_profiled":1310},"omim":[{"mim_id":"613168","title":"SERPIN PEPTIDASE INHIBITOR, CLADE F, MEMBER 2; SERPINF2","url":"https://www.omim.org/entry/613168"},{"mim_id":"262850","title":"ALPHA-2-PLASMIN INHIBITOR DEFICIENCY","url":"https://www.omim.org/entry/262850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":1497.5}],"url":"https://www.proteinatlas.org/search/SERPINF2"},"hgnc":{"alias_symbol":["API","ALPHA-2-PI","A2AP","AAP","alpha2AP"],"prev_symbol":["PLI"]},"alphafold":{"accession":"P08697","domains":[{"cath_id":"3.30.497.10","chopping":"77-240_342-387","consensus_level":"medium","plddt":93.7404,"start":77,"end":387},{"cath_id":"2.30.39.10","chopping":"242-338_390-445","consensus_level":"medium","plddt":90.3066,"start":242,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08697","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08697-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08697-F1-predicted_aligned_error_v6.png","plddt_mean":78.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SERPINF2","jax_strain_url":"https://www.jax.org/strain/search?query=SERPINF2"},"sequence":{"accession":"P08697","fasta_url":"https://rest.uniprot.org/uniprotkb/P08697.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08697/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08697"}},"corpus_meta":[{"pmid":"33290554","id":"PMC_33290554","title":"PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33290554","citation_count":973,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23631572","id":"PMC_23631572","title":"Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases.","date":"2013","source":"Journal of periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/23631572","citation_count":364,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23631582","id":"PMC_23631582","title":"Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases.","date":"2013","source":"Journal of 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Staph identification test and with transfer RNA-intergenic spacer PCR combined with capillary electrophoresis.","date":"2012","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/23040022","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20557297","id":"PMC_20557297","title":"Bet v 1 and its homologous food allergen Api g 1 stimulate dendritic cells from birch pollen-allergic individuals to induce different Th-cell polarization.","date":"2010","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/20557297","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32237065","id":"PMC_32237065","title":"α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses.","date":"2020","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/32237065","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29253085","id":"PMC_29253085","title":"JASPAR RESTful API: accessing JASPAR data from any programming language.","date":"2018","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29253085","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11688210","id":"PMC_11688210","title":"Quality control Lactobacillus strains for use with the API 50CH and API ZYM systems at 37 degrees C.","date":"2001","source":"Journal of basic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11688210","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25451974","id":"PMC_25451974","title":"IgE recognition of chimeric isoforms of the honeybee (Apis mellifera) venom allergen Api m 10 evaluated by protein array technology.","date":"2014","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25451974","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1677227","id":"PMC_1677227","title":"Enzyme activities of urinary alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG) in healthy dogs.","date":"1991","source":"Zentralblatt fur Veterinarmedizin. Reihe A","url":"https://pubmed.ncbi.nlm.nih.gov/1677227","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37357285","id":"PMC_37357285","title":"Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program.","date":"2023","source":"The journal of prevention of Alzheimer's disease","url":"https://pubmed.ncbi.nlm.nih.gov/37357285","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32551109","id":"PMC_32551109","title":"A novel apidaecin Api-PR19 synergizes with the gut microbial community to maintain intestinal health and promote growth performance of broilers.","date":"2020","source":"Journal of animal science and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32551109","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32458183","id":"PMC_32458183","title":"Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie.","date":"2020","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32458183","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28159016","id":"PMC_28159016","title":"α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: the roles of α2AP in vascular dysfunction in systemic sclerosis.","date":"2017","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28159016","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17069633","id":"PMC_17069633","title":"Genomic and transcriptional analysis of protein heterogeneity of the honeybee venom allergen Api m 6.","date":"2006","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17069633","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22345097","id":"PMC_22345097","title":"The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition.","date":"2012","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/22345097","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"134998","id":"PMC_134998","title":"Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis.","date":"1976","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/134998","citation_count":465,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16335952","id":"PMC_16335952","title":"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.","date":"2005","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/16335952","citation_count":350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19073825","id":"PMC_19073825","title":"Plasmin in nephrotic urine activates the epithelial sodium channel.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19073825","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21075","id":"PMC_21075","title":"Purification and characterization of human antiplasmin, the fast-acting plasmin inhibitor in plasma.","date":"1977","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21075","citation_count":208,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24172014","id":"PMC_24172014","title":"Update of the human and mouse SERPIN gene superfamily.","date":"2013","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24172014","citation_count":205,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28675934","id":"PMC_28675934","title":"Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.","date":"2017","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/28675934","citation_count":185,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6980881","id":"PMC_6980881","title":"Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase.","date":"1982","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6980881","citation_count":176,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12621583","id":"PMC_12621583","title":"Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12621583","citation_count":173,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"158022","id":"PMC_158022","title":"On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin.","date":"1979","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/158022","citation_count":166,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24068962","id":"PMC_24068962","title":"Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24068962","citation_count":157,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21471521","id":"PMC_21471521","title":"The antifibrinolytic function of factor XIII is exclusively expressed through α₂-antiplasmin cross-linking.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21471521","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12878203","id":"PMC_12878203","title":"Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12878203","citation_count":124,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2433286","id":"PMC_2433286","title":"Primary structure of human alpha 2-antiplasmin, a serine protease inhibitor (serpin).","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2433286","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8624776","id":"PMC_8624776","title":"Inhibitors of fibrinolysis are elevated in atherosclerotic plaque.","date":"1996","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8624776","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7873202","id":"PMC_7873202","title":"Human neutrophil defensin and serpins form complexes and inactivate each other.","date":"1995","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7873202","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14751930","id":"PMC_14751930","title":"A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14751930","citation_count":109,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17388801","id":"PMC_17388801","title":"TAFIa, PAI-1 and alpha-antiplasmin: complementary roles in regulating lysis of thrombi and plasma clots.","date":"2007","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/17388801","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20071328","id":"PMC_20071328","title":"Osteopontin is cleaved at multiple sites close to its integrin-binding motifs in milk and is a novel substrate for plasmin and cathepsin D.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20071328","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25331118","id":"PMC_25331118","title":"Functional factor XIII-A is exposed on the stimulated platelet surface.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/25331118","citation_count":96,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7306699","id":"PMC_7306699","title":"The presence and release of alpha 2-antiplasmin from human platelets.","date":"1981","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7306699","citation_count":96,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49789,"output_tokens":1616,"usd":0.086804},"stage2":{"model":"claude-opus-4-6","input_tokens":4828,"output_tokens":1843,"usd":0.105322},"total_usd":0.498378,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62708,"output_tokens":5793,"usd":0.13751},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8929,"output_tokens":2714,"usd":0.168742}},"stage1_raw":"Looking through the abstracts for mechanistic findings about SERPINF2 (alpha-2-antiplasmin, α2AP), I find relevant papers at PMIDs 77, 83, 84, 90, and 98. The rest of the corpus consists of unrelated genes/proteins (various \"API\" acronyms, allergens, bacterial proteins, bioinformatics tools, etc.).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"α2-antiplasmin (SERPINF2/α2AP) induces myofibroblast formation in renal tubular epithelial cells, renal fibroblasts, and bone marrow-derived mesenchymal stem cells via TGF-β production, and this TGF-β induction is mediated through the c-Jun N-terminal kinase (JNK) pathway. α2AP deficiency attenuated unilateral ureteral obstruction-induced renal fibrosis in mice.\",\n      \"method\": \"α2AP knockout mouse model (UUO), in vitro cell treatment with α2AP, JNK inhibitor (SP600125) rescue experiment, TGF-β measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined phenotype plus in vitro mechanistic follow-up with inhibitor rescue across multiple cell types\",\n      \"pmids\": [\"25095732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"α2-antiplasmin (SERPINF2/α2AP) exerts a profibrotic effect in systemic sclerosis dermal fibroblasts that is independent of its role as a plasmin inhibitor; α2AP treatment promoted collagen production and myofibroblast differentiation in normal human dermal fibroblasts, and α2AP neutralization reversed the profibrotic phenotype of SSc fibroblasts even in the absence of plasmin.\",\n      \"method\": \"Bleomycin-induced SSc mouse model, α2AP neutralizing antibody, in vitro fibroblast treatment with α2AP in plasmin-free conditions, collagen and myofibroblast marker measurement\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model plus in vitro plasmin-free mechanistic experiment demonstrating plasmin-independent profibrotic function\",\n      \"pmids\": [\"26743600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"α2-antiplasmin (SERPINF2/α2AP) inhibits VEGF-induced tube formation, cell proliferation, and endothelial junction-associated protein (VE-cadherin, PECAM1) production in vascular endothelial cells through the adipose triglyceride lipase/tyrosine phosphatase SHP2 axis, thereby promoting vascular dysfunction in systemic sclerosis.\",\n      \"method\": \"Bleomycin-induced SSc mouse model, α2AP neutralizing antibody, in vitro endothelial cell tube formation and proliferation assays, mechanistic pathway analysis (ATGL/SHP2 axis)\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro with pathway identification, but single lab study\",\n      \"pmids\": [\"28159016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"α2-antiplasmin (SERPINF2/α2AP) promotes inflammatory responses in lupus nephritis via two mechanisms: (1) inhibiting plasmin, which otherwise attenuates IFN-γ-induced proinflammatory cytokine production through the AMPK pathway in macrophages; and (2) directly inducing proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages. IFN-γ induces α2AP production in fibroblasts through the JNK pathway.\",\n      \"method\": \"Pristane-induced lupus mouse model, α2AP-deficient mice, in vitro macrophage treatment with plasmin and α2AP, pathway inhibitor experiments (AMPK, ERK1/2, JNK)\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined phenotype and in vitro pathway dissection, single lab\",\n      \"pmids\": [\"32237065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SERPINF2 (α2-antiplasmin/SerpinF2) is significantly elevated in preeclampsia plasma; testosterone upregulates and estradiol downregulates SerpinF2 expression in human renal and trophoblastic cells; fibrin deposition co-localizes with SerpinF2 in early-onset preeclampsia placenta, implicating SerpinF2 as a procoagulation mediator regulated by sex hormones.\",\n      \"method\": \"Proteomics of preeclampsia plasma, PAP complex measurement, hormone treatment of human cell lines (renal and trophoblastic cells), placental immunofluorescence co-localization\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct cell-based hormone regulation experiment combined with proteomics and co-localization, single lab\",\n      \"pmids\": [\"30020241\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINF2 (α2-antiplasmin) functions as the primary physiological inhibitor of plasmin and, beyond this canonical anticoagulant/antifibrinolytic role, directly induces myofibroblast formation and fibrosis via TGF-β/JNK signaling, promotes inflammatory cytokine production in macrophages through ERK1/2 and JNK pathways, inhibits VEGF-driven endothelial function through an ATGL/SHP2 axis, and is transcriptionally regulated by sex hormones (testosterone upregulates; estradiol downregulates), collectively establishing it as a multifunctional profibrotic and proinflammatory mediator independent of its plasmin-inhibitory activity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe gene SERPINF2 encodes α2-antiplasmin (α2AP), also known as alpha-2-plasmin inhibitor, the primary inhibitor of plasmin in human plasma.\n\nFrom the main corpus of 100 papers: Nearly all are about \"API\" meaning Application Programming Interface, allergens (Api g 1, Api m), bacterial identification systems, or other unrelated proteins. None describe SERPINF2/α2-antiplasmin mechanistically.\n\nPaper [77] from main corpus (PMID:30020241) describes SerpinF2/α2-antiplasmin in preeclampsia — this is correlation/biomarker work, not mechanistic. KEEP but no mechanistic discoveries.\nPaper [83] (PMID:25095732) describes α2AP in renal fibrosis — mechanistic (myofibroblast formation, TGF-β, JNK pathway). KEEP.\nPaper [84] (PMID:26743600) describes α2AP in systemic sclerosis fibrosis. KEEP — some mechanism.\nPaper [90] (PMID:32237065) describes α2AP in lupus nephritis via JNK/ERK/AMPK. KEEP — mechanistic.\nPaper [98] (PMID:28159016) describes α2AP in vascular dysfunction via ATGL/SHP2 axis. KEEP — mechanistic.\n\nFrom gene2pubmed curated papers:\n- PMID:134998 — isolation and characterization of α2-plasmin inhibitor. KEEP.\n- PMID:21075 — mechanism of α2-antiplasmin/plasmin reaction. KEEP.\n- PMID:6980881 — leukocyte elastase cleaves α2-plasmin inhibitor. KEEP.\n- PMID:158022 — mechanism of reaction between α2-antiplasmin and plasmin. KEEP.\n- PMID:2433286 — primary structure, reactive site Arg364-Met365. KEEP.\n- PMID:14751930 — APCE cleaves Met-α2AP to Asn-α2AP; cross-linking to fibrin. KEEP.\n- PMID:21471521 — FXIII antifibrinolytic function through α2AP cross-linking. KEEP.\n- PMID:25331118 — platelet FXIII-A cross-links α2AP to fibrin. KEEP.\n- PMID:7306699 — α2AP in platelets, released by thrombin. KEEP.\n- PMID:8624776 — α2AP elevated in atherosclerotic plaque. KEEP but epidemiological.\n- PMID:7873202 — defensins interact with α2AP. KEEP — mechanistic.\n- PMID:17388801 — α2AP dominant role in clot lysis regulation. KEEP — mechanistic.\n- PMID:12878203 — hK6 inhibited by serpins including α2AP. KEEP — mechanistic.\n- PMID:24172014 — SERPIN family overview. Limited mechanistic for SERPINF2 specifically.\n- PMID:19073825 — plasmin activates ENaC; α2AP context. Mostly about plasmin, not α2AP mechanism directly.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1976,\n      \"finding\": \"α2-plasmin inhibitor (SERPINF2/α2-antiplasmin) was isolated from human plasma and characterized as a glycoprotein (~67 kDa) that instantaneously inhibits plasmin by forming a non-dissociable 1:1 stoichiometric complex involving cleavage of a specific peptide bond in the inhibitor and cross-linking to the light (active-site-containing) chain of plasmin. It also inhibits trypsin but only slowly inhibits urokinase. A neutralizing antibody abolished virtually all inhibitory activity of plasma against activator-induced clot lysis.\",\n      \"method\": \"Protein purification, SDS-PAGE, immunoelectrophoresis, kinetic inhibition assays, stoichiometry determination, antibody neutralization experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational biochemical reconstitution and characterization with multiple orthogonal methods in original discovery paper\",\n      \"pmids\": [\"134998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1977,\n      \"finding\": \"Human antiplasmin (α2-antiplasmin/SERPINF2) was purified and further characterized as the fast-acting plasmin inhibitor in plasma, establishing it as the primary physiological inhibitor of plasmin.\",\n      \"method\": \"Protein purification, functional inhibition assays\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical purification and functional characterization, independently confirming earlier isolation\",\n      \"pmids\": [\"21075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"The mechanism of the reaction between α2-antiplasmin (SERPINF2) and plasmin was established: the inhibitor forms a covalent, SDS-stable 1:1 complex with plasmin via a suicide substrate-like serpin mechanism, involving cleavage at the reactive site peptide bond.\",\n      \"method\": \"In vitro kinetic assays, SDS-PAGE complex analysis, mechanistic dissection of enzyme-inhibitor interaction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro mechanistic characterization of the inhibitory reaction\",\n      \"pmids\": [\"158022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1981,\n      \"finding\": \"α2-antiplasmin (SERPINF2) is stored in human platelets (33–114 ng per 10⁹ platelets) and is released upon thrombin stimulation without cell lysis. This release is specific to platelets among peripheral blood cells, identifying platelets as a cellular reservoir for α2AP distinct from the plasma pool.\",\n      \"method\": \"Radioimmunoassay of platelet extracts, thrombin stimulation assay, comparison across blood cell types\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct quantification and functional release assay with controlled comparisons across cell types\",\n      \"pmids\": [\"7306699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"Human polymorphonuclear leukocyte elastase inactivates α2-plasmin inhibitor (SERPINF2) by limited proteolytic cleavage at two separate sites, generating lower molecular weight fragments and destroying plasmin-inhibitory activity. This suggests that elastase released during inflammation can potentiate pathological proteolysis by inactivating α2AP.\",\n      \"method\": \"In vitro incubation of leukocyte elastase with purified α2-plasmin inhibitor, SDS-PAGE analysis of cleavage products, functional activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic cleavage assay with structural and functional characterization\",\n      \"pmids\": [\"6980881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The primary structure of human α2-antiplasmin (SERPINF2) was determined by cDNA sequencing: mature protein contains 452 amino acids, is homologous (23–28%) to other serpins, and its reactive site (the peptide bond cleaved upon reaction with plasmin) is Arg364-Met365, corresponding to the P1-P1' position in serpin nomenclature.\",\n      \"method\": \"cDNA cloning and sequencing from human liver mRNA, oligonucleotide probe designed from peptide sequence, sequence alignment with serpin superfamily\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary sequence determination with identification of reactive site, validated by homology and peptide data\",\n      \"pmids\": [\"2433286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human neutrophil defensins bind directly to α2-antiplasmin (SERPINF2) and form complexes with it. This interaction mutually inactivates both partners: defensins abolish the antiprotease activity of α2AP against plasmin, and α2AP inhibits defensin cytotoxicity toward lung carcinoma cells.\",\n      \"method\": \"In vitro binding assays, antiprotease activity assays with increasing defensin concentrations, cytotoxicity assays with serpin pre-incubation\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro functional interaction demonstrated with multiple activity readouts, single study\",\n      \"pmids\": [\"7873202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"α2-antiplasmin (SERPINF2) is present in atherosclerotic plaque at higher concentrations than in normal arterial wall, where it co-localizes with PAI-1. Together with reduced tissue plasminogen activator, elevated α2AP contributes to impaired fibrinolysis in atherosclerotic lesions, potentially maintaining plaque by resisting fibrin dissolution.\",\n      \"method\": \"Immunohistochemistry of normal and atherosclerotic arterial wall sections, quantitative immunoassay of tissue extracts\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein quantification and localization in tissue, but no functional manipulation; single study\",\n      \"pmids\": [\"8624776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human kallikrein 6 (hK6) is inhibited by α2-antiplasmin (SERPINF2) among other serpins, establishing α2AP as a physiological inhibitor of this trypsin-like serine protease. Antithrombin III was the most efficient inhibitor among those tested.\",\n      \"method\": \"In vitro enzyme inhibition assays with purified recombinant hK6 and panel of serpins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro inhibition assay with recombinant proteins, but α2AP is one of several serpins tested\",\n      \"pmids\": [\"12878203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A plasma proteinase named antiplasmin-cleaving enzyme (APCE), homologous to fibroblast activation protein/seprase, cleaves the Pro12-Asn13 bond of the Met-form of α2-antiplasmin (Met-α2AP, SERPINF2) to generate the Asn-form (Asn-α2AP). Asn-α2AP is cross-linked to fibrin by activated Factor XIIIa approximately 13-fold faster than Met-α2AP, making fibrin clots markedly more resistant to plasmin-mediated lysis. The ratio of Asn-α2AP to Met-α2AP directly determines clot lysis rates.\",\n      \"method\": \"Purification of APCE from human plasma, in vitro cleavage assays, Factor XIIIa cross-linking kinetics, plasma clot lysis rate measurements as a function of α2AP form ratio\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro system with purified proteins, quantitative kinetics, and functional lysis assays demonstrating mechanistic consequences\",\n      \"pmids\": [\"14751930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Among the three principal fibrinolytic inhibitors (PAI-1, α2-antiplasmin/SERPINF2, and TAFIa), α2AP plays the dominant role in regulating lysis of both plasma clots and whole-blood thrombi. Neutralizing antibodies to α2AP produced the largest single-inhibitor effect on lysis acceleration; maximal lysis occurred only when all three inhibitors were neutralized together, demonstrating complementary but non-redundant roles.\",\n      \"method\": \"Plasma clot lysis and model thrombus lysis assays with neutralizing antibodies to α2AP and PAI-1, carboxypeptidase inhibitor (CPI) for TAFIa, single and combination depletion experiments\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-type functional dissection with neutralizing antibodies and inhibitors across multiple assay systems, independently validated across conditions\",\n      \"pmids\": [\"17388801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The antifibrinolytic function of Factor XIII (FXIII) is entirely dependent on its ability to cross-link α2-antiplasmin (SERPINF2) to fibrin. Depletion of either FXIII or α2AP accelerated clot lysis ~9-fold similarly; FXIII depletion had no additional effect on α2AP-depleted thrombi; and a neutralizing antibody to α2AP completely abolished the stabilizing effect of FXIII reconstitution. Clot stability correlated inversely and strongly with the amount of cross-linked α2AP.\",\n      \"method\": \"Flow-based plasma thrombus model with depletion of FXIII and/or α2AP, reconstitution experiments, neutralizing antibody to α2AP, quantitative correlation of cross-linked α2AP with lysis rates\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genetic/depletion epistasis with reconstitution and antibody neutralization in a physiological flow model, multiple orthogonal lines of evidence\",\n      \"pmids\": [\"21471521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Platelet-derived FXIII-A is exposed on the surface of activated (thrombin + collagen stimulated) platelets and exerts its antifibrinolytic function by cross-linking α2-antiplasmin (SERPINF2) to fibrin, stabilizing thrombi. Incorporating a neutralizing antibody to α2AP abolished the platelet FXIII-A-mediated thrombus stabilization, demonstrating that α2AP cross-linking is the obligate mechanism of platelet FXIII-A antifibrinolytic activity.\",\n      \"method\": \"Chandler model thrombi from FXIII-depleted plasma reconstituted with platelets, fluorescence confocal microscopy and flow cytometry of FXIII-A on platelet surface, neutralizing antibody to α2AP, transglutaminase inhibitors\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct localization with functional consequences, antibody neutralization, mechanistic dissection in physiological model\",\n      \"pmids\": [\"25331118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"α2-antiplasmin (α2AP/SERPINF2) accumulates in kidneys subjected to unilateral ureteral obstruction (UUO) and promotes renal fibrosis by inducing myofibroblast formation in renal tubular epithelial cells, renal fibroblasts, and bone marrow-derived mesenchymal stem cells. α2AP-deficient mice showed attenuated UUO-induced fibrosis and reduced myofibroblast formation. Mechanistically, α2AP induces TGF-β production via the c-Jun N-terminal kinase (JNK) pathway, and JNK inhibition (SP600125) blocked α2AP-induced TGF-β production.\",\n      \"method\": \"UUO mouse model in α2AP(+/+) vs α2AP(-/-) mice, in vitro treatment of multiple cell types with α2AP, JNK inhibitor (SP600125) pharmacological epistasis, TGF-β ELISA, myofibroblast marker quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo plus in vitro mechanistic pathway dissection with pharmacological inhibitor, multiple cell types\",\n      \"pmids\": [\"25095732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"α2-antiplasmin (SERPINF2) exerts profibrotic effects in systemic sclerosis (SSc) independently of its function as a plasmin inhibitor. Administration of α2AP to mice induced dermal fibrosis (increased dermal thickness, collagen, myofibroblast differentiation), and α2AP neutralization prevented profibrotic changes and autoantibody production in bleomycin-induced SSc models. α2AP treatment promoted fibrosis in normal human dermal fibroblasts, and α2AP neutralization reversed the profibrotic phenotype of SSc patient fibroblasts even in the absence of plasmin.\",\n      \"method\": \"Bleomycin SSc mouse model with α2AP administration and neutralizing antibody, human SSc patient dermal fibroblasts treated with α2AP or neutralizing antibody in absence of plasmin, histology, collagen assays, autoantibody measurement\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model plus human patient cell experiments, plasmin-independent mechanism shown by specific experimental design\",\n      \"pmids\": [\"26743600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"α2-antiplasmin (SERPINF2) promotes vascular dysfunction in systemic sclerosis by attenuating VEGF-induced tube formation, cell proliferation, and endothelial junction-associated protein (VE-cadherin, PECAM1) production through the adipose triglyceride lipase (ATGL)/tyrosine phosphatase SHP2 signaling axis in vascular endothelial cells. α2AP neutralization improved vascular damage in bleomycin-induced SSc mice.\",\n      \"method\": \"Bleomycin SSc mouse model with α2AP administration/neutralization, in vitro endothelial cell tube formation, proliferation, junction protein assays, SSc fibroblast-conditioned media experiments, pathway inhibitor studies identifying ATGL/SHP2 axis\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro mechanistic data with pathway identification, but ATGL/SHP2 axis established in single study\",\n      \"pmids\": [\"28159016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SerpinF2/α2-antiplasmin levels are significantly elevated in preeclampsia plasma, and the circulating plasmin-α2-antiplasmin (PAP) complex is positively correlated with testosterone and negatively correlated with estradiol in early-onset preeclampsia patients. In human renal and trophoblastic cells, testosterone and estradiol regulate SerpinF2 expression in opposite directions. Fibrin deposition co-localizes with SerpinF2 in the intervillous spaces of preeclamptic placenta.\",\n      \"method\": \"Proteomic analysis of plasma, longitudinal measurement of PAP complex and sex hormones, cell-based expression regulation experiments with testosterone/estradiol, immunolocalization in placenta\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cell-based regulatory experiments plus in vivo correlation; mechanistic pathway partially established\",\n      \"pmids\": [\"30020241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"α2-antiplasmin (SERPINF2) is associated with lupus nephritis development through two mechanisms: (1) direct plasmin inhibition blocks plasmin's anti-inflammatory effect on macrophages (plasmin attenuates IFN-γ-induced proinflammatory cytokine production via the AMPK pathway, and α2AP eliminates this protective effect); and (2) α2AP directly induces proinflammatory cytokine production in macrophages via ERK1/2 and JNK pathways. IFN-γ induces α2AP production in fibroblasts via the JNK pathway.\",\n      \"method\": \"Pristane-induced lupus mouse model in α2AP-deficient vs wild-type mice, in vitro macrophage cytokine assays with plasmin ± α2AP, pathway inhibitor studies (AMPK, ERK1/2, JNK), IFN-γ stimulation of fibroblasts with JNK inhibitor\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model plus in vitro pathway dissection with inhibitors, multiple mechanisms identified in single study\",\n      \"pmids\": [\"32237065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINF2 (α2-antiplasmin/α2AP) is the primary physiological inhibitor of plasmin, forming an instantaneous, covalent, non-dissociable 1:1 complex via cleavage of its reactive site (Arg364-Met365); it circulates in two N-terminal forms (Met-α2AP and Asn-α2AP, the latter generated by APCE cleavage and cross-linked ~13-fold faster into fibrin by Factor XIIIa to confer fibrinolysis resistance), is stored in platelets and released by thrombin, is inactivated by leukocyte elastase, binds neutrophil defensins in a mutually inhibitory manner, dominates regulation of clot and thrombus lysis (with complementary roles for PAI-1 and TAFIa), and exerts plasmin-independent profibrotic and pro-inflammatory effects through TGF-β/JNK signaling in fibroblasts and ERK1/2/JNK/AMPK pathways in macrophages, as well as impairing VEGF signaling in endothelial cells via an ATGL/SHP2 axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SERPINF2 (α2-antiplasmin) is the principal physiological serpin inhibitor of plasmin and additionally functions as a plasmin-independent profibrotic and proinflammatory mediator. SERPINF2 induces myofibroblast differentiation and collagen production in fibroblasts, renal epithelial cells, and mesenchymal stem cells by driving TGF-β production through the JNK pathway, and α2AP deficiency attenuates renal fibrosis in vivo; this profibrotic activity persists in plasmin-free conditions [PMID:25095732, PMID:26743600]. SERPINF2 directly stimulates proinflammatory cytokine production in macrophages via ERK1/2 and JNK signaling and inhibits VEGF-driven endothelial tube formation and junction-protein expression through an ATGL/SHP2 axis [PMID:32237065, PMID:28159016]. SERPINF2 expression is transcriptionally upregulated by testosterone and downregulated by estradiol in renal and trophoblastic cells, and the protein is elevated in preeclampsia plasma where it co-localizes with fibrin in placental tissue [PMID:30020241].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that SERPINF2 is not merely a plasmin inhibitor but an active inducer of fibrosis: α2AP drove myofibroblast formation via TGF-β/JNK, and its genetic absence protected against renal fibrosis, defining a new profibrotic effector role.\",\n      \"evidence\": \"α2AP-knockout mice subjected to UUO plus in vitro cell stimulation with JNK-inhibitor rescue across epithelial, fibroblast, and mesenchymal cell types\",\n      \"pmids\": [\"25095732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Receptor or cell-surface binding partner mediating α2AP signaling to JNK is unknown\",\n        \"Relative contribution of plasmin-dependent versus plasmin-independent mechanisms in vivo not separated in this study\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving whether the profibrotic effect requires plasmin inhibition: α2AP promoted collagen and myofibroblast markers in plasmin-free conditions, and neutralizing α2AP reversed the fibrotic phenotype of SSc fibroblasts, establishing a bona fide plasmin-independent profibrotic function.\",\n      \"evidence\": \"Bleomycin SSc mouse model with neutralizing antibody, in vitro dermal fibroblast treatment under plasmin-free conditions\",\n      \"pmids\": [\"26743600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the cell-surface receptor mediating plasmin-independent signaling remains unidentified\",\n        \"Whether the JNK/TGF-β axis demonstrated in renal cells also operates in dermal fibroblasts was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extending SERPINF2 biology to the vasculature: α2AP inhibited VEGF-driven endothelial proliferation and tube formation through ATGL and SHP2, identifying a mechanism for SSc-associated vasculopathy.\",\n      \"evidence\": \"Bleomycin SSc mouse model with α2AP neutralizing antibody, in vitro endothelial tube formation and proliferation assays with pathway analysis\",\n      \"pmids\": [\"28159016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication in another vascular model is lacking\",\n        \"How α2AP engages ATGL on endothelial cells mechanistically is not resolved\",\n        \"Relationship between the ATGL/SHP2 axis and the JNK pathway used in fibroblasts is unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying hormonal control of SERPINF2: testosterone upregulates and estradiol downregulates SERPINF2 in renal and trophoblastic cells, linking sex-hormone imbalance to elevated α2AP and fibrin deposition in preeclampsia.\",\n      \"evidence\": \"Proteomics of preeclampsia plasma, hormone treatment of human cell lines, placental immunofluorescence co-localization\",\n      \"pmids\": [\"30020241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcriptional mechanism (promoter elements, transcription factors) mediating hormone regulation not defined\",\n        \"Causal relationship between elevated α2AP and preeclampsia pathology not established beyond correlation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating a dual inflammatory mechanism in lupus nephritis: α2AP both blocks plasmin's anti-inflammatory AMPK signaling and directly activates ERK1/2- and JNK-dependent cytokine production in macrophages, broadening its role from fibrosis to inflammation.\",\n      \"evidence\": \"Pristane-induced lupus model in α2AP-deficient mice, in vitro macrophage stimulation with pathway inhibitors\",\n      \"pmids\": [\"32237065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell-surface receptor on macrophages through which α2AP signals to ERK1/2/JNK is unidentified\",\n        \"Whether IFN-γ-driven α2AP production by fibroblasts constitutes a feed-forward loop in vivo remains untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the cell-surface receptor that mediates SERPINF2's plasmin-independent signaling to JNK, ERK1/2, and ATGL/SHP2 pathways remains the central unresolved question, without which the full signal transduction mechanism cannot be mapped.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor or direct binding partner on target cells has been identified for plasmin-independent signaling\",\n        \"No structural or biophysical characterization of α2AP's non-serpin signaling interface exists\",\n        \"Cross-talk among JNK, ERK1/2, and ATGL/SHP2 axes in different cell types has not been integrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TGFB1\",\n      \"SHP2\",\n      \"ATGL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SERPINF2 (α2-antiplasmin) is the principal fast-acting physiological inhibitor of plasmin, forming an irreversible, covalent 1:1 complex through cleavage of its Arg364-Met365 reactive site bond, and is the dominant regulator of fibrin clot and thrombus lysis among the three major fibrinolytic inhibitors (PAI-1, α2AP, TAFIa) [PMID:134998, PMID:17388801]. The inhibitor circulates in two N-terminal forms: the Met-form and the Asn-form generated by antiplasmin-cleaving enzyme (APCE), with the Asn-form cross-linked ~13-fold faster to fibrin by Factor XIIIa, a reaction that constitutes the entire antifibrinolytic mechanism of FXIII [PMID:14751930, PMID:21471521]. Beyond hemostasis, α2-antiplasmin exerts plasmin-independent profibrotic effects by inducing TGF-β production via JNK signaling in fibroblasts and myofibroblast differentiation in multiple cell types, and directly promotes macrophage proinflammatory cytokine production through ERK1/2 and JNK pathways [PMID:25095732, PMID:32237065]. α2AP also impairs VEGF-driven endothelial function through an ATGL/SHP2 signaling axis and is inactivated by leukocyte elastase, linking its regulation to inflammatory protease networks [PMID:28159016, PMID:6980881].\",\n  \"teleology\": [\n    {\n      \"year\": 1976,\n      \"claim\": \"Identification and biochemical characterization of α2-antiplasmin as the fast-acting plasmin inhibitor in human plasma resolved the question of which molecule was primarily responsible for physiological plasmin neutralization.\",\n      \"evidence\": \"Protein purification from human plasma, SDS-PAGE, stoichiometry analysis, and antibody neutralization of plasma fibrinolytic activity\",\n      \"pmids\": [\"134998\", \"21075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No primary structure determined\", \"Mechanism of covalent complex formation not resolved\", \"In vivo relevance not directly demonstrated\"]\n    },\n    {\n      \"year\": 1979,\n      \"claim\": \"Establishing the suicide substrate-like serpin mechanism of the α2AP–plasmin reaction explained how the inhibitor achieves rapid, irreversible inactivation of plasmin through covalent complex formation at the reactive site bond.\",\n      \"evidence\": \"In vitro kinetic dissection with SDS-PAGE analysis of covalent enzyme–inhibitor complexes\",\n      \"pmids\": [\"158022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reactive site residues not yet identified\", \"Crystal structure unavailable\"]\n    },\n    {\n      \"year\": 1981,\n      \"claim\": \"Discovery of a platelet α2AP storage pool released upon thrombin stimulation revealed a localized antifibrinolytic mechanism at sites of platelet activation, beyond the circulating plasma reservoir.\",\n      \"evidence\": \"Radioimmunoassay of platelet extracts with thrombin stimulation and cross-cell-type comparisons\",\n      \"pmids\": [\"7306699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of platelet-derived α2AP to clot stability vs. plasma pool not quantified\", \"Mechanism of platelet storage (granule type) not determined\"]\n    },\n    {\n      \"year\": 1982,\n      \"claim\": \"Demonstration that leukocyte elastase proteolytically inactivates α2AP established a direct link between neutrophil-mediated inflammation and local loss of antifibrinolytic protection.\",\n      \"evidence\": \"In vitro incubation of purified elastase and α2AP with SDS-PAGE and functional activity assays\",\n      \"pmids\": [\"6980881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance at inflammatory sites not tested\", \"Cleavage sites not mapped to sequence\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Determination of the full primary structure by cDNA sequencing identified the Arg364-Met365 reactive site bond and placed α2AP within the serpin superfamily, enabling structure–function analysis.\",\n      \"evidence\": \"cDNA cloning from human liver mRNA, sequencing, serpin family alignment\",\n      \"pmids\": [\"2433286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure not resolved\", \"Functional domains beyond reactive center loop not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery of APCE-mediated N-terminal processing of Met-α2AP to Asn-α2AP, which is cross-linked to fibrin by FXIIIa ~13-fold faster, explained how the relative abundance of α2AP isoforms regulates clot resistance to fibrinolysis.\",\n      \"evidence\": \"Purification of APCE from plasma, in vitro cleavage and FXIIIa cross-linking kinetics, clot lysis rate measurements\",\n      \"pmids\": [\"14751930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of APCE activity in vivo unknown\", \"Structural basis for differential FXIIIa cross-linking rate not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Systematic depletion/neutralization epistasis among PAI-1, α2AP, and TAFIa demonstrated that α2AP is the single most important fibrinolytic inhibitor in both plasma clots and whole-blood thrombi, but maximal fibrinolysis requires neutralization of all three.\",\n      \"evidence\": \"Clot and thrombus lysis assays with neutralizing antibodies and carboxypeptidase inhibitor, single and combination depletions\",\n      \"pmids\": [\"17388801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo arterial thrombolysis hierarchy not confirmed\", \"Temporal dynamics of inhibitor contribution during thrombus maturation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that FXIIIa's entire antifibrinolytic function depends on cross-linking α2AP to fibrin unified the FXIII and α2AP pathways into a single obligate axis controlling thrombus stability.\",\n      \"evidence\": \"Flow-based thrombus model with FXIII and/or α2AP depletion, reconstitution, and neutralizing antibody\",\n      \"pmids\": [\"21471521\", \"25331118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other FXIIIa substrates contribute to thrombus stability in other contexts not excluded\", \"Role of platelet-derived vs. plasma FXIII not fully separated in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of plasmin-independent profibrotic activity of α2AP — inducing TGF-β via JNK signaling and promoting myofibroblast differentiation — expanded its functional repertoire beyond hemostasis to organ fibrosis.\",\n      \"evidence\": \"UUO renal fibrosis model in α2AP-knockout vs. wild-type mice, in vitro JNK inhibitor epistasis, multiple cell types\",\n      \"pmids\": [\"25095732\", \"26743600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating α2AP profibrotic signaling unidentified\", \"Whether profibrotic effect requires full-length vs. cleaved α2AP unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of ATGL/SHP2 as the axis through which α2AP impairs VEGF-driven endothelial function revealed a plasmin-independent vascular dysfunction mechanism relevant to systemic sclerosis.\",\n      \"evidence\": \"Endothelial tube formation, proliferation, and junction protein assays with pathway inhibitors; bleomycin SSc mouse model\",\n      \"pmids\": [\"28159016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ATGL/SHP2 axis established in a single study, no independent confirmation\", \"Direct binding target on endothelial cells not identified\", \"Whether this pathway operates outside SSc context unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dual pro-inflammatory mechanisms of α2AP in macrophages — neutralizing plasmin's AMPK-mediated anti-inflammatory effect and directly activating ERK1/2/JNK cytokine production — explained its role in promoting lupus nephritis beyond simple fibrinolysis regulation.\",\n      \"evidence\": \"Pristane-induced lupus model in α2AP-knockout vs. wild-type mice, macrophage cytokine assays with pathway inhibitors\",\n      \"pmids\": [\"32237065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or binding partner mediating direct macrophage activation unknown\", \"Relative contribution of plasmin-dependent vs. -independent mechanisms in vivo not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cell-surface receptor or binding partner through which α2AP initiates its plasmin-independent signaling (profibrotic TGF-β/JNK, pro-inflammatory ERK1/2/JNK, anti-angiogenic ATGL/SHP2) remains unidentified, preventing a unified model of its non-hemostatic functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No receptor identification for non-serpin signaling functions\", \"Structural basis of plasmin-independent activity unknown\", \"Therapeutic targeting of non-hemostatic functions not tested in clinical models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 9, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 9, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 15, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLG\",\n      \"F13A1\",\n      \"FAP\",\n      \"ELANE\",\n      \"DEFA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}