Affinage

TFPI

Tissue factor pathway inhibitor · UniProt P10646

Round 2 corrected
Length
304 aa
Mass
35.0 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFPI is a multivalent Kunitz-type serine protease inhibitor that serves as the primary physiological regulator of the extrinsic coagulation pathway by directly inhibiting factor Xa through its Kunitz-2 (K2) domain and, in a factor Xa-dependent manner, forming a quaternary TF–FVIIa–FXa–TFPI complex in which K1 engages the FVIIa active site to shut down tissue factor-initiated coagulation (PMID:3422166, PMID:2927510, PMID:2271516). Protein S acts as a cofactor that enhances TFPI-mediated FXa inhibition approximately 10-fold, bringing the Ki into the physiologically relevant range, while the TFPIα isoform additionally inhibits prothrombinase through an exosite interaction between its basic C-terminus and the factor Va B-domain acidic region — an activity lost upon thrombin cleavage of FVa — whereas TFPIβ is GPI-anchored to endothelial surfaces where it directly inhibits TF–FVIIa (PMID:16488980, PMID:24127605, PMID:24620349). Beyond hemostasis, TFPI inhibits MASP-2 of the lectin complement pathway via K2 (PMID:25359215), interacts with angiomotin in vascular smooth muscle cells to modulate YAP/Hippo signaling and suppress atherosclerotic remodeling (PMID:27875740), and functions as the colonic crypt receptor for clade 2 Clostridioides difficile TcdB toxin variants as defined by CRISPR screening and cryo-EM structural analysis (PMID:35303428, PMID:36351897).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1987 High

    Establishing that tissue factor pathway inhibition requires the simultaneous presence of factor VIIa/TF, catalytically active FXa, and the inhibitor resolved the long-standing question of how the extrinsic pathway is downregulated by showing it depends on its own product (FXa) as a cofactor for feedback inhibition.

    Evidence Reconstituted activated peptide release assays using purified/depleted plasma components with 3H-FIX substrate

    PMID:3024756 PMID:3492226

    Open questions at the time
    • Molecular identity of the inhibitor was not yet determined
    • Stoichiometry of the quaternary complex was unknown
  2. 1988 High

    Cloning TFPI (LACI) revealed a three-Kunitz-domain architecture and demonstrated that it directly inhibits FXa and forms a quaternary VIIa–TF–Xa–LACI complex requiring the FXa Gla domain, providing the first molecular framework for its dual inhibitory mechanism.

    Evidence cDNA cloning and sequencing; in vitro chromogenic substrate assays, nondenaturing PAGE complex detection, Gla-domain-deleted FXa competition

    PMID:2452157 PMID:3422166

    Open questions at the time
    • Which Kunitz domain inhibits which protease was unknown
    • Post-translational processing and isoform diversity were uncharacterized
  3. 1988 High

    Demonstrating that heparin releases TFPI from endothelial cells in a dose-dependent manner identified the vascular endothelium as a physiological reservoir and suggested that part of heparin's clinical anticoagulant effect operates through TFPI mobilization.

    Evidence In vivo heparin injection in humans; chromogenic EPI activity assay in plasma; gel filtration of endothelial conditioned medium; polybrene/antibody controls

    PMID:3413731

    Open questions at the time
    • Mechanism of endothelial TFPI storage and release was undefined
    • Relative contributions of heparin-released TFPI vs. antithrombin potentiation were not quantified
  4. 1989 High

    Site-directed mutagenesis mapped K2 as the FXa-inhibitory domain and K1 as the VIIa/TF-inhibitory domain, while K3 had no direct protease-inhibiting function, establishing the domain-function architecture that guided all subsequent TFPI biology.

    Evidence Active-site mutagenesis of each Kunitz domain with quantitative FXa and VIIa/TF inhibition assays

    PMID:2927510

    Open questions at the time
    • Function of K3 and the C-terminal basic region remained unknown
    • Structural basis of the K1–VIIa and K2–Xa interactions was unresolved
  5. 1990 High

    Reconstitution experiments in TFPI-depleted plasma demonstrated that TFPI synergizes with heparin/sulfated polysaccharides to prolong tissue factor-triggered clotting, quantifying TFPI as a physiologically significant modulator of the anticoagulant effect of heparin therapy.

    Evidence APTT and modified PT assays with LACI-depleted plasma reconstituted with purified recombinant LACI; heparin and polysaccharide titrations

    PMID:1346095 PMID:2271516

    Open questions at the time
    • Whether TFPI acts additively or mechanistically synergistically with antithrombin was unclear
    • In vivo quantitative contribution of TFPI to heparin anticoagulation was not yet established
  6. 2006 High

    Identification of protein S as a cofactor that reduces the TFPI–FXa Ki ~10-fold (from 4.4 nM to 0.5 nM) answered the question of how TFPI achieves effective FXa inhibition at its low plasma concentration, revealing a previously unrecognized anticoagulant partnership.

    Evidence Purified protein reconstitution with chromogenic substrate assay; kinetic Ki determination; plasma thrombin generation assays

    PMID:16488980

    Open questions at the time
    • Binding interface between protein S and TFPI was not structurally defined
    • Whether protein S cofactor activity is isoform-specific was unknown
  7. 2009 High

    Demonstration that protein S and TFPI form a stable plasma complex — and that protein S deficiency causes co-depletion of TFPI — established that the hypercoagulable state in protein S deficiency is partly attributable to loss of TFPI function.

    Evidence Protein S immunodepletion with TFPI ELISA quantification; surface plasmon resonance binding; calibrated automated thrombography

    PMID:20002538

    Open questions at the time
    • Stoichiometry and domain requirements for the protein S–TFPI complex were not mapped
    • Clinical impact of co-deficiency versus isolated protein S deficiency was not dissected
  8. 2013 High

    Discovery that TFPIα inhibits prothrombinase through a high-affinity exosite interaction between its basic C-terminus and the FVa B-domain acidic region — lost after thrombin cleaves FVa — revealed an entirely new anticoagulant function beyond TF pathway inhibition, providing a temporal switch that limits early but not propagated coagulation.

    Evidence Purified prothrombinase reconstitution; TFPIα vs. TFPIβ comparison; FVa B-domain deletion mutants; thrombin cleavage experiments

    PMID:24127605

    Open questions at the time
    • Structural basis of the C-terminus–B-domain interaction was not resolved
    • Physiological contribution of prothrombinase inhibition versus TF pathway inhibition in vivo was unmeasured
  9. 2013 High

    Systematic domain-deletion kinetics showed that the K3–C-terminal region enhances FVIIa inhibition 7–10-fold and that phospholipids and the FXa Gla domain are essential for quaternary complex assembly, completing the quantitative model of TFPI's multidomain inhibitory mechanism.

    Evidence Chromogenic FVIIa activity assays with truncated TFPI constructs; relipidated and soluble TF; protein S titrations; quantitative Ki analysis

    PMID:23347185

    Open questions at the time
    • Atomic-resolution structure of the full quaternary complex was not available
    • How membrane composition modulates complex assembly in vivo was unclear
  10. 2014 Medium

    Showing that TFPI selectively inhibits MASP-2 (but not MASP-1, C1s, or C1r) via K2 expanded TFPI's functional repertoire beyond coagulation to regulation of the lectin complement pathway, suggesting a role at the coagulation–innate immunity interface.

    Evidence Lectin pathway C4 deposition assay on mannan-coated plates; fluid-phase MASP-2 chromogenic assay; domain-mapping with anti-K2 monoclonal antibodies

    PMID:25359215

    Open questions at the time
    • In vivo significance of TFPI–MASP-2 inhibition for complement regulation was not demonstrated
    • Whether physiological TFPI concentrations are sufficient to modulate lectin pathway in plasma was untested
  11. 2015 High

    Genetic epistasis showing that PAR4 deficiency partially rescues Tfpi-null embryonic lethality demonstrated that TFPI's physiological role extends to modulating thrombin-dependent platelet activation in vivo, and that loss of TFPI causes lethal disseminated intravascular coagulation through uncontrolled thrombin signaling.

    Evidence Tfpi−/−:Par4−/− double knockout mouse crosses; survival analysis; fibrin immunohistochemistry; thrombin-antithrombin complex measurement; injury models

    PMID:25954015

    Open questions at the time
    • Whether TFPIα prothrombinase inhibition specifically mediates the embryonic rescue was not dissected
    • Human genetic correlates of TFPI deficiency remain poorly defined
  12. 2016 Medium

    Conditional TFPI knockout in vascular smooth muscle cells accelerated atherosclerosis and identified angiomotin (AMOT) as a TFPI-interacting partner that modulates YAP/Hippo signaling, revealing a non-hemostatic function of TFPI in vascular remodeling.

    Evidence Conditional knockout mouse (Tfpi1fl/fl/Sma-Cre+ApoE−/−); mass spectrometry; Co-IP of AMOT; Western blot for YAP phosphorylation; qPCR for SLUG/CTGF

    PMID:27875740

    Open questions at the time
    • Direct binding interface between TFPI and AMOT was not mapped
    • Whether AMOT interaction is isoform-specific was not determined
    • Single lab without independent replication
  13. 2022 High

    Identification of TFPI as the colonic crypt receptor for clade 2 C. difficile TcdB variants — supported by CRISPR screening, cryo-EM structure, and functional protection assays — established an unexpected role for TFPI's extracellular domains in toxin entry and defined a new therapeutic target for hypervirulent C. difficile infection.

    Evidence Genome-wide CRISPR/Cas9 screen; cryo-EM of TcdB4–TFPI complex; recombinant TFPI protection of colonic epithelium; cross-subtype binding and mutagenesis across 206 TcdB variants

    PMID:35303428 PMID:36351897

    Open questions at the time
    • Whether TFPI-mediated toxin entry occurs via endocytosis of the GPI-anchored TFPIβ isoform or free TFPIα was not resolved
    • Species selectivity determinants on TFPI itself were not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the full quaternary TF–FVIIa–FXa–TFPI complex, the structural basis of the TFPIα C-terminus interaction with the FVa B-domain, in vivo quantification of the relative contributions of TFPIα prothrombinase inhibition versus TF pathway inhibition, and the physiological significance of TFPI–MASP-2 inhibition in complement regulation.
  • Full quaternary complex structure unavailable
  • In vivo dissection of isoform-specific anticoagulant contributions incomplete
  • Physiological relevance of complement pathway inhibition by TFPI untested in animal models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0016787 hydrolase activity 2
Localization
GO:0005576 extracellular region 6 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-109582 Hemostasis 12 R-HSA-162582 Signal Transduction 1 R-HSA-168256 Immune System 1
Partners
AMOTF10F3F5F7MASP2PROS1
Complex memberships
FXa-FVa prothrombinase (TFPIα target)TF-FVIIa-FXa-TFPI quaternary complexTFPI-protein S complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 LACI (later renamed TFPI) directly inhibits factor Xa at or near its active site, and in a factor Xa-dependent manner inhibits the factor VIIa/tissue factor (TF) complex, consistent with formation of a quaternary VIIa-TF-Xa-LACI complex. The gamma-carboxyglutamic acid (Gla) domain of factor Xa is required for this quaternary complex formation and for efficient TF/VIIa inhibition. In vitro chromogenic substrate assay, nondenaturing PAGE complex detection, Gla-domain-deleted factor Xa competition experiments, antibody inhibition studies Blood High 3422166
1988 LACI/TFPI is encoded by a cDNA predicting a 276-residue mature protein with three tandem Kunitz-type serine protease inhibitory domains, a negatively charged N-terminus, and a positively charged C-terminus, with multiple molecular weight forms in plasma associated with apolipoprotein A-II via mixed disulfide bonds. cDNA cloning, nucleotide sequencing, Northern blot, 125I-factor Xa binding assay, lambda gt11 library screening with polyclonal antiserum The Journal of biological chemistry High 2452157
1987 Inhibition of TF activity by the extrinsic pathway inhibitor (EPI/TFPI) requires the simultaneous presence of factor VIIa/TF, factor Xa (with active site intact), calcium, and EPI; the inhibition is reversible and factor VIIa/TF activity can be recovered from a dissociated inhibited complex. Preliminary incubation of EPI with factor Xa alone or factor VIIa/TF alone does not substitute for simultaneous presence of all components. Activated peptide release assay using 3H-factor IX substrate, plasma reconstitution experiments with purified/depleted components, EPI supplementation and antibody blocking Blood High 3492226
1987 The TF inhibitory activity present in serum (later identified as TFPI) requires factor VII(a), catalytically active factor Xa, and an additional plasma component present in BaSO4-absorbed serum. HepG2 hepatoma cells secrete this inhibitory activity in vitro, identifying endothelium/liver as a source of TFPI. Clotting assay using crude TF with immunodepleted and BaSO4-absorbed plasma fractions; HepG2 conditioned media assay Blood High 3024756
1989 Site-directed mutagenesis of each of the three Kunitz domains of LACI/TFPI revealed that Kunitz domain 2 (K2) is required for efficient binding and inhibition of factor Xa, and that both K1 and K2 are required for inhibition of VIIa/TF; K3 active-site mutation has no significant effect on either function. This established the domain-function map: K1 binds VIIa/TF active site, K2 binds Xa active site. Site-directed mutagenesis of active-site residues in each Kunitz domain, followed by functional assays for Xa inhibition and VIIa/TF inhibition in vitro Nature High 2927510
1989 Plasma LACI/TFPI was purified and shown to exist in multiple molecular weight forms (40–130 kDa); the 46-kDa and larger forms are associated with apolipoprotein A-II via mixed disulfide linkages. LDL contains primarily the 40-kDa form while HDL contains primarily the LACI/apoA-II complex form, with ~50% of plasma TFPI associated with LDL/VLDL. Sequential hydrophobic, ion-exchange, and affinity chromatography purification; SDS-PAGE; N-terminal sequencing; lipoprotein fractionation; gel filtration The Journal of biological chemistry High 2553722
1988 Heparin induces release of EPI (TFPI) from endothelial cells into the circulation in a dose-dependent manner following intravenous injection, an effect not abolished by polybrene or anti-antithrombin antibodies, suggesting active secretion from endothelial stores rather than antithrombin displacement. Gel filtration of endothelial cell culture supernatant reveals a single inhibitory fraction at ~43 kDa. Chromogenic substrate assay for EPI activity in plasma; in vivo heparin injection in humans; gel filtration of endothelial cell conditioned medium; polybrene neutralization and antibody blocking controls Thrombosis research High 3413731
1990 TFPI (LACI) acts as a cofactor for heparin in inhibiting tissue factor-induced coagulation: in LACI-depleted plasma, heparin causes only moderate linear prolongation of prothrombin time, while normal plasma shows greater and threshold-dependent anticoagulation at the same heparin concentrations, demonstrating synergistic anticoagulant action between LACI and sulfated polysaccharides. APTT and modified prothrombin time assays with LACI-depleted plasma reconstituted with purified recombinant LACI; titration with unfractionated heparin and various sulfated polysaccharides Blood High 1346095
1990 TFPI regulates tissue factor-induced coagulation as a multivalent Kunitz-type inhibitor, directly inhibiting activated factor X and producing feedback inhibition of the factor VIIa/tissue factor catalytic complex in a factor Xa-dependent manner. Biochemical reconstitution, enzyme kinetics, plasma coagulation assays Biochemistry High 2271516
1991 EPI (TFPI) is released into blood during extensive physical exercise (30 km cross-country skiing or long-distance running), with peak plasma EPI levels reached 2 hours post-exercise, suggesting mobilization from endothelial stores and possibly from lipoprotein-associated pools due to exercise-induced lipoprotein lipase activity. EPI plasma activity assay in athletes before and after exercise of various durations; plasma volume-corrected measurements Thrombosis and haemostasis Medium 2274917
1991 EPI (TFPI) released in vivo by heparin significantly contributes to the post-heparin anticoagulant effect (prolonged clotting time and retarded fibrinopeptide A release) as demonstrated by blocking with polyclonal anti-EPI antibodies in post-heparin plasma, including plasma from cancer patients. Polybrene neutralization of heparin followed by TTP/CaCl2-triggered coagulation; polyclonal blocking antibody addition; clotting time and fibrinopeptide A release assay Thrombosis research supplement Medium 1658969
1993 TFPI is a major anticoagulant in normal plasma specifically in the extrinsic (tissue factor) pathway, with its effect particularly pronounced at prolonged clotting times and enhanced by the simultaneous presence of other anticoagulants (heparin/antithrombin); blocking TFPI in warfarin-treated plasma significantly shortens clotting times. The TFPI/antithrombin cooperation is dependent on antithrombin anticoagulant activity. APTT and PT clotting assays with TFPI-depleted plasma, TFPI/heparin/hirudin combinations, ATIII-deficient plasma, warfarin-treated plasma; polyclonal antibody depletion Thrombosis and haemostasis Medium 8259547
2001 TFPI structure comprises three Kunitz domains with defined functions: K1 inhibits factor VIIa complexed to tissue factor, K2 inhibits factor Xa, and K3 has no demonstrated direct protease-inhibiting function. The C-terminal basic region is required for rapid physiological inhibition of coagulation and for inhibition of smooth muscle cell proliferation, and plays an important role in cell surface binding. Structural analysis, domain-deletion studies, cell proliferation assays, binding studies reviewed from multiple primary sources Thrombosis and haemostasis High 11686353
2006 Protein S stimulates inhibition of factor Xa by full-length TFPI approximately 10-fold by reducing the Ki of the FXa/TFPI complex from 4.4 nM to 0.5 nM. This cofactor activity of protein S is specific to full-length TFPI (not truncated forms) and brings TFPI inhibitory concentration into the physiologically relevant plasma range, demonstrating that protein S and TFPI act together to inhibit TF activity. Purified protein reconstitution with chromogenic substrate assay for FXa inhibition; kinetic analysis (Ki determination); thrombin generation assays in plasma Proceedings of the National Academy of Sciences of the United States of America High 16488980
2009 Full-length TFPI and protein S form a complex in plasma as demonstrated by protein S immunodepletion experiments and surface plasmon resonance, which reduces full-length TFPI levels in hereditary and acquired protein S deficiency. The co-deficiency of TFPI substantially contributes to the hypercoagulable state associated with protein S deficiency. Plasma immunodepletion of protein S, TFPI antigen measurement by ELISA, surface plasmon resonance binding analysis, thrombin generation by calibrated automated thrombography Journal of thrombosis and haemostasis High 20002538
2013 Direct inhibition of TF-bound FVIIa by full-length TFPI requires contributions from multiple domains: K2 alone is a poor TF-FVIIa inhibitor (Ki=434 nM); K1-K2 improves this; the K3-C-terminus further enhances FVIIa inhibition (~7–10-fold) though is not essential for quaternary TF-FVIIa-TFPI-FXa complex formation. In the quaternary complex, Ki values drop to <0.15 nM for full-length TFPI. Phospholipids and the Gla-domain of FXa are required for quaternary complex formation. Protein S further stimulates TF-FVIIa inhibition by full-length TFPI. Chromogenic substrate assay for FVIIa activity; truncated TFPI constructs (KD1, KD1-KD2, TFPI1-150, full-length); relipidated and soluble TF; kinetic analysis; protein S and phospholipid titrations Journal of thrombosis and haemostasis High 23347185
2013 TFPIα produces isoform-specific rapid inhibition of prothrombinase (FXa/FVa/phospholipid/Ca2+ complex) during coagulation initiation, mediated through a high-affinity exosite interaction between the basic C-terminus of TFPIα and an acidic region in the factor V/Va B domain retained in FXa-activated and platelet-derived FVa. This inhibitory activity is absent in TFPIβ and is lost after thrombin cleaves the acidic region from FVa. Purified prothrombinase reconstitution assays; TFPIα/TFPIβ isoform comparison; factor Va B-domain acidic region deletion mutants; platelet-derived FVa testing; thrombin cleavage experiments Proceedings of the National Academy of Sciences of the United States of America High 24127605
2014 TFPIα and TFPIβ are alternatively spliced isoforms with distinct expression patterns and anticoagulant activities: TFPIα is the only isoform in platelets, while endothelial cells produce both isoforms (secreting TFPIα and expressing TFPIβ on the cell surface via GPI anchor). TFPIβ is a potent surface inhibitor of TF-FVIIa on endothelial cells; TFPIα contains a unique basic C-terminus that interacts with factor V B domain to inhibit prothrombinase during coagulation initiation. Isoform characterization via alternative splicing analysis; cell-type expression studies; GPI anchor validation; platelet vs. endothelial cell functional comparison; review of primary reconstitution data Blood High 24620349
2015 Physiological concentrations of phospholipids (~10 µM negatively charged) enhance FXa inhibition by full-length TFPI 5–6-fold. Unfractionated heparin at 0.2–1 U/ml enhances FXa inhibition ~8-fold but impairs inhibition at >1 U/ml. Protein S and factor V (but not thrombin-activated FVa) each enhance FXa inhibition 2–3-fold, while FVa impairs TFPI-mediated FXa inhibition. TFPI fails to inhibit FXa-catalyzed prothrombin activation in the presence of FVa (prothrombinase). These modulatory effects are absent for truncated TFPI1-150, identifying the K3-C-terminus as essential for exosite-mediated regulation. Progress curve analysis with chromogenic substrate CS11-(65); systematic titration of phospholipids, heparin, prothrombin, FV, FVa, protein S; full-length vs. truncated TFPI comparison Thrombosis and haemostasis High 26607136
2014 TFPI selectively inhibits MASP-2 of the lectin pathway of complement without affecting MASP-1, C1s, or C1r, thus acting as an inhibitor of complement activation. The Kunitz-2 domain of TFPI is required for MASP-2 inhibition. This was demonstrated using rTFPI, MASP-2 chromogenic assay, C4-deposition assay, and domain-specific blocking monoclonal antibodies. Ex vivo lectin pathway activation on mannan-coated plates (C4 deposition assay); fluid-phase MASP-2 chromogenic assay; domain-specific anti-TFPI monoclonal antibodies to map K2 requirement European journal of immunology Medium 25359215
2010 Surface TFPI on human monocytes acts as an important regulator of monocyte procoagulant reactivity: pre-incubation of LPS-stimulated PBMCs with anti-TFPI IgG significantly enhanced TF activity, shortened lag-time, and increased thrombin generation. LPS stimulation causes parallel upregulation of both TFPIα and TFPIβ mRNA isoforms on monocyte surfaces, where TFPI co-localizes with TF. RT-qPCR for TFPI mRNA isoforms; flow cytometry and confocal microscopy for surface presentation; TF activity assay; calibrated automated thrombogram (CAT); anti-TFPI IgG blocking Thrombosis research Medium 20723970
2015 A balance between TFPI anticoagulant activity and thrombin-mediated platelet activation via PAR4 is required for murine embryonic development. PAR4 deficiency (but not PAR3 deficiency) partially rescues >40% of Tfpi-null (Tfpi−/−) embryos from lethal disseminated intravascular coagulation, demonstrating that TFPI physiologically modulates thrombin-dependent platelet activation in vivo. Adult Tfpi−/−:Par4−/− mice show focal liver fibrin deposition and elevated thrombin-antithrombin complexes, indicating that TFPI dampens intravascular procoagulant stimuli even without thrombin-mediated platelet activation. Genetic epistasis (Tfpi+/−:Par4−/− crosses); survival analysis; immunohistochemistry for fibrin(ogen); plasma thrombin-antithrombin complex measurement; venous electrolytic injury model; TF-induced pulmonary embolism model Blood High 25954015
2016 Conditional knockout of TFPI-1 in vascular smooth muscle cells (VSMCs) of ApoE−/− mice accelerates atherosclerosis with increased VSMC proliferation and migration. By mass spectrometry, immunoprecipitation, and co-localization, TFPI-1 was found to interact with angiomotin (AMOT) in human VSMCs. TFPI-1 deficiency decreases AMOT and YAP phosphorylation, leading to increased expression of SLUG and CTGF (Hippo pathway targets linked to atherosclerosis). Conditional knockout mouse model (Tfpi1fl/fl/Sma-Cre+ApoE−/−); Sudan IV staining; immunohistochemistry; mass spectrometry identification of AMOT as binding partner; Co-IP and co-localization; Western blot for AMOT/YAP phosphorylation; qPCR for target genes International journal of cardiology Medium 27875740
2003 Low TFPI and low antithrombin levels in neonates (~50% of adult values) act synergistically to allow sufficient thrombin generation at low tissue factor concentrations, explaining the clinically excellent hemostasis of neonates despite reduced procoagulant factors. At <10 pmol/L lipidated TF, cord plasma clots faster and generates more free thrombin (~90% of adult value) than adult plasma due to combined low TFPI and antithrombin. In vitro clotting assay with lipidated TF titration; factor Xa generation and thrombin generation assays in neonatal cord plasma vs. adult plasma; TFPI and antithrombin concentration measurements Journal of thrombosis and haemostasis Medium 12871499
2010 Transgenic expression of TFPI on porcine aortic endothelial cells (PAECs) inhibits TF activity induced by anti-nonGal IgG binding via a complement-independent pathway, effectively preventing coagulation dysregulation in a xenotransplantation model. Atorvastatin or anti-IgG Fab antibody similarly inhibits TF expression. PAEC culture from wild-type, GT-KO, CD46-transgenic, and TFPI-transgenic pigs; TF activity assay; incubation with naive and sensitized baboon serum; heat inactivation and antibody blocking controls Journal of thrombosis and haemostasis Medium 20553382
2022 TFPI is identified as the colonic crypt receptor for TcdB variants (TcdB2 and TcdB4) from hypervirulent clade 2 Clostridioides difficile. CRISPR/Cas9 genome-wide screens identified TFPI as the receptor for TcdB4. Cryo-EM structure of full-length TcdB4 in complex with TFPI defined the receptor-binding region. TFPI is highly expressed in intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4 toxin. CRISPR/Cas9 genome-wide loss-of-function screen; cryo-EM structure determination of TcdB4-TFPI complex; TFPI expression analysis in intestinal tissue; recombinant TFPI protection assay of colonic epithelium Cell High 35303428
2022 TFPI serves as a host receptor for multiple TcdB subtypes (TcdB2, 4, 7, 10, 11, 12) from C. difficile that do not recognize Frizzled proteins. A six-residue haplotype within the TcdB receptor-binding region distinguishes TFPI-binding (B4/B7 haplotype) from FZD-binding TcdB variants. Intragenic micro-recombination events drive receptor-specificity switching. TcdB10 recognizes chicken/mouse TFPI but not human TFPI, revealing species selectivity. Introduction of B4/B7-haplotype residues into TcdB1 enables dual recognition of TFPI and FZDs. CRISPR-Cas9 genome-wide screen; receptor binding assays across TcdB subtypes; sequence analysis of 206 TcdB variants; site-directed mutagenesis of receptor-binding residues; species-selectivity binding assays Nature communications High 36351897
2016 A C-terminal peptide (TC24) derived from fish (Cynoglossus semilaevis) TFPI-1 exhibits bactericidal activity against multiple bacterial species (S. aureus, V. vulnificus, M. luteus) by penetrating bacterial cell membranes and inducing degradation of genomic DNA and total RNA. In vivo administration of TC24 reduces pathogen dissemination and viral replication in tongue sole tissues. Antimicrobial assay; membrane integrity assay; intracellular localization by microscopy; genomic DNA/RNA degradation assay; in vivo challenge with bacteria and virus followed by pathogen quantification in tissues Fish & shellfish immunology Medium 27840169

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nature genetics 561 21378988
1988 The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 481 3422166
1989 Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 478 2927510
1991 Spectra of spontaneous and mutagen-induced mutations in the lacI gene in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 459 1832771
1978 Sequence of the lacI gene. Nature 448 355891
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1988 Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thrombosis research 430 3413731
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1990 Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 381 2271516
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
1994 Crystal structure of LacI member, PurR, bound to DNA: minor groove binding by alpha helices. Science (New York, N.Y.) 343 7973627
1988 Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains. The Journal of biological chemistry 334 2452157
2006 Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proceedings of the National Academy of Sciences of the United States of America 261 16488980
2013 Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics 250 23583979
1995 Tissue factor pathway inhibitor and the revised theory of coagulation. Annual review of medicine 233 7598447
2014 Biology of tissue factor pathway inhibitor. Blood 227 24620349
1987 Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 223 3492226
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1989 Purification and characterization of the lipoprotein-associated coagulation inhibitor from human plasma. The Journal of biological chemistry 212 2553722
2001 Structure and biology of tissue factor pathway inhibitor. Thrombosis and haemostasis 200 11686353
1997 Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes & development 195 9271116
2008 Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nature neuroscience 188 19160499
2007 COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nature neuroscience 187 17828260
1991 Spontaneous mutation in the Escherichia coli lacI gene. Genetics 186 1660424
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2015 Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein. Arteriosclerosis, thrombosis, and vascular biology 157 26603155
1999 The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron 155 10624948
2006 Tissue factor pathway inhibitor: structure, biology and involvement in disease. The Journal of pathology 154 16261634
1987 Characterization of the inhibition of tissue factor in serum. Blood 150 3024756
2015 Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef. Cell host & microbe 146 26439863
2006 Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 144 16380494
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2013 Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proceedings of the National Academy of Sciences of the United States of America 136 24127605
2009 Allostery in the LacI/GalR family: variations on a theme. Current opinion in microbiology 130 19269243
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