Affinage

THBD

Thrombomodulin · UniProt P07204

Round 2 corrected
Length
575 aa
Mass
60.3 kDa
Annotated
2026-04-28
99 papers in source corpus 25 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Thrombomodulin is an endothelial transmembrane glycoprotein that redirects thrombin from procoagulant to anticoagulant and anti-inflammatory functions by binding thrombin's anion-binding exosite-I through its EGF-like domains 4–6, thereby blocking fibrinogen and platelet-receptor access while optimally presenting protein C for activation; its chondroitin sulfate moiety enhances thrombin affinity 10–20-fold (PMID:2820710, PMID:10761923, PMID:7615164). The thrombin–thrombomodulin complex also activates TAFI with a 1250-fold increase in catalytic efficiency, coupling coagulation to fibrinolysis inhibition, and accelerates factor I–mediated C3b inactivation to negatively regulate complement—loss-of-function THBD mutations that impair these activities cause approximately 5% of atypical hemolytic-uremic syndrome cases (PMID:8663147, PMID:19625716). Beyond hemostasis, thrombomodulin's N-terminal lectin-like domain mediates Ca²⁺-dependent cell adhesion and sequesters HMGB1, and endothelial thrombomodulin promotes post-ischemic angiogenesis independently of its anticoagulant role (PMID:12951323, PMID:21805323, PMID:33028093). THBD transcription is regulated by CLOCK/BMAL2 via an E-box element (conferring circadian oscillation), repressed by TNF-α through NF-κB/p300 coactivator competition and BRG1/DNMT1-mediated CpG methylation, and induced by statins via KLF2 (PMID:17848551, PMID:15677570, PMID:36162255, PMID:16043642).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1985 High

    The discovery of soluble thrombomodulin in plasma and urine, retaining protein C cofactor activity but with reduced thrombin affinity, established that thrombomodulin functions as a circulating anticoagulant cofactor and that membrane anchorage modulates thrombin interaction.

    Evidence Radioimmunoassay and immunoaffinity purification from human plasma/urine with kinetic protein C activation assays

    PMID:3001144

    Open questions at the time
    • Structural basis for reduced thrombin affinity of soluble TM was unknown
    • Physiological relevance of soluble vs. membrane-bound TM not quantified in vivo
  2. 1987 High

    Cloning the full-length cDNA revealed thrombomodulin's modular architecture—signal peptide, N-terminal (lectin-like) domain, six EGF-like repeats, Ser/Thr-rich region, transmembrane segment, and cytoplasmic tail—encoded by an intronless gene on chromosome 20, providing the structural framework for all subsequent domain-function mapping.

    Evidence Independent cDNA/genomic cloning and sequencing with COS cell expression and functional validation

    PMID:2819876 PMID:2820710 PMID:2822087

    Open questions at the time
    • Individual domain contributions to thrombin binding and protein C activation not yet dissected
    • Post-translational modifications (chondroitin sulfate, glycosylation) not structurally resolved
  3. 1989 High

    Biochemical reconstitution demonstrated that thrombomodulin converts thrombin from a procoagulant enzyme into an anticoagulant one by abolishing fibrinogen clotting and platelet activation while enabling rapid protein C activation, defining the core switch mechanism.

    Evidence In vitro reconstitution with purified components and enzyme kinetics

    PMID:2538457

    Open questions at the time
    • Atomic-level binding interface unresolved
    • Relative contributions of steric blockade vs. allosteric change debated
  4. 1995 High

    Detailed kinetic and competition studies resolved the dual mechanism: chondroitin sulfate enhances thrombin affinity 10–20-fold by engaging a heparin-binding surface, while EGF-like domains sterically occlude procoagulant substrates; together these explain how thrombomodulin simultaneously inhibits procoagulant function and promotes protein C activation.

    Evidence Mutagenesis, competition assays, and structural analysis of thrombin–TM interactions

    PMID:7615164

    Open questions at the time
    • Three-dimensional structure of the complex not yet determined
    • Role of individual EGF domains not fully assigned
  5. 1995 Medium

    Identification of the first THBD coding mutation (Asp468Tyr) in a patient with pulmonary embolism linked THBD genetic variation to venous thromboembolism, opening the question of whether loss-of-function alleles are common thrombophilia risk factors.

    Evidence PCR-SSCP and DNA sequencing in a thromboembolism patient

    PMID:7811989

    Open questions at the time
    • Single case report without family cosegregation data
    • Functional impact of Asp468Tyr on protein C activation not directly measured in this study
  6. 1996 High

    The discovery that thrombomodulin enhances TAFI activation by thrombin 1250-fold expanded thrombomodulin's role beyond anticoagulation into fibrinolysis regulation, establishing the thrombin–TM–TAFI ternary complex model.

    Evidence In vitro reconstitution with purified thrombin, TM, and TAFI; full steady-state kinetics

    PMID:8663147

    Open questions at the time
    • In vivo quantitative contribution of TM-dependent TAFI activation to fibrinolysis control unclear
    • Whether TAFI activation shares or competes with protein C activation for TM binding not resolved
  7. 2000 High

    The 2.3 Å crystal structure of thrombin bound to TM EGF-like domains 4–6 resolved the longstanding question of mechanism: TM binds exosite-I in a Y-shaped configuration, sterically blocking procoagulant substrates without major active-site allosteric changes, and positioning the substrate-presentation surface for protein C docking.

    Evidence X-ray crystallography of thrombin–TME456 complex with molecular modeling

    PMID:10761923

    Open questions at the time
    • No ternary structure with protein C or TAFI
    • Role of chondroitin sulfate not captured in the crystal
  8. 2003 High

    Functional dissection of the lectin-like domain revealed a non-hemostatic role: Ca²⁺-dependent cell adhesion mediated by this domain suppresses monolayer permeability and tumor growth, establishing TM as a multifunctional protein beyond coagulation.

    Evidence Domain-deletion mutants in TM-negative melanoma cells, confocal imaging, permeability assays, in vivo tumor model

    PMID:12951323

    Open questions at the time
    • Endogenous ligand for the lectin-like domain in cell adhesion not identified
    • Structural basis for Ca²⁺-dependent interaction unknown
  9. 2005 High

    Two key transcriptional regulatory mechanisms were defined: TNF-α represses THBD via NF-κB competing for the coactivator p300 away from Ets factors at the TM promoter, while statins induce THBD through KLF2 upregulation via Rho pathway inhibition, explaining how inflammation and pharmacology modulate endothelial anticoagulant phenotype.

    Evidence ChIP, EMSA, promoter analysis, NF-κB inhibition, p300 overexpression, mouse lung injury model; KLF2 siRNA epistasis with statin treatment

    PMID:15677570 PMID:16043642

    Open questions at the time
    • Relative contributions of Ets family members to basal TM transcription not resolved
    • Whether KLF2 binds the TM promoter directly or acts through intermediaries unclear
  10. 2007 High

    CLOCK/BMAL2 heterodimer binding to an E-box in the THBD promoter was shown to drive circadian oscillation of TM mRNA and protein in mouse vasculature, abolished in Clock mutant mice, establishing THBD as a clock-controlled gene and linking circadian biology to hemostatic capacity.

    Evidence ChIP, EMSA, luciferase reporter, Clock mutant mice, temporal feeding restriction

    PMID:17848551

    Open questions at the time
    • Whether circadian TM variation translates to measurable oscillation in protein C activation rate in vivo not tested
    • Contribution of BMAL1 vs. BMAL2 to TM regulation not clarified
  11. 2009 High

    THBD mutations were shown to cause ~5% of atypical HUS by impairing complement regulation: TM binds C3b and factor H, accelerates factor I–mediated C3b inactivation, and promotes TAFI-dependent anaphylatoxin degradation—aHUS-associated mutations reduce both activities, revealing TM as a complement regulator.

    Evidence Patient cohort sequencing, purified protein binding assays, cell-based complement activation assays with mutant TM constructs

    PMID:19625716

    Open questions at the time
    • Structural basis for TM–C3b interaction unknown
    • Whether complement dysregulation alone or combined coagulation defect drives aHUS pathology in THBD mutation carriers unclear
  12. 2017 High

    Conditional Thbd ablation in adult mice demonstrated that complete TM deficiency causes consumptive coagulopathy and sudden death, with APC supplementation rescuing thrombosis but not pregnancy-associated morbidity, revealing essential non-endothelial (placental) TM functions; separately, transmembrane domain truncation mutants showed that domain length governs metalloprotease-dependent shedding, explaining how naturally occurring mutations increase soluble TM.

    Evidence Inducible Cre/loxP Thbd knockout with transgenic PC rescue; site-directed mutagenesis/shedding assays in COS-1 cells

    PMID:28920104 PMID:29145514

    Open questions at the time
    • Identity of the metalloprotease(s) responsible for TM shedding not determined
    • Mechanism of TM function in trophoblast biology uncharacterized
  13. 2020 High

    Brain endothelial–specific Thbd deletion worsened stroke outcome not through coagulopathy or inflammation but by impairing peri-infarct angiogenesis, establishing a coagulation-independent pro-angiogenic function for endothelial thrombomodulin.

    Evidence Inducible Cre/loxP brain endothelial Thbd knockout, MCA occlusion model, vessel morphometry

    PMID:33028093

    Open questions at the time
    • Molecular pathway through which TM promotes angiogenesis (receptor, signaling cascade) not identified
    • Whether the lectin-like domain or EGF-like domains mediate the angiogenic effect unknown
  14. 2022 High

    An epigenetic repression axis was defined: BRG1 upregulates DNMT1 under TNF-α stimulation, increasing CpG methylation of the THBD promoter and silencing expression; endothelial-specific BRG1 knockout restored THBD and reduced DVT in mice, providing a druggable epigenetic mechanism for thrombosis.

    Evidence Conditional endothelial BRG1 knockout mice, DVT ligation model, CpG methylation analysis, pharmacological BRG1 inhibitor PFI-3

    PMID:36162255

    Open questions at the time
    • Whether DNMT1-mediated THBD methylation is reversible with DNMT inhibitors in established DVT not tested
    • Relative contribution of THBD silencing vs. other BRG1 targets to DVT phenotype not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis for TM's complement-regulatory (C3b binding) and angiogenic functions, the identity of the sheddase(s), the signaling mechanism linking TM to angiogenesis independently of APC, and whether circadian TM oscillation measurably affects in vivo hemostatic thresholds.
  • No ternary crystal structure of thrombin–TM–protein C or TM–C3b
  • Sheddase identity unknown
  • Pro-angiogenic signaling pathway downstream of TM uncharacterized
  • In vivo functional consequence of circadian TM oscillation untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 2
Pathway
R-HSA-109582 Hemostasis 7 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1 R-HSA-9909396 Circadian clock 1
Partners
C3CFHCPB2F2HMGB1PROCPROCR
Complex memberships
Thrombin–thrombomodulin complexThrombin–thrombomodulin–TAFI ternary complexThrombin–thrombomodulin–protein C ternary complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 Human thrombomodulin cDNA was cloned and the complete 575-amino acid sequence deduced, revealing a domain structure comprising a signal peptide, N-terminal domain, six EGF-like domains, an O-glycosylation-rich region, a 24-residue transmembrane domain, and a cytoplasmic tail. Transfection of COS cells with the cDNA produced immunoreactive, functionally active thrombomodulin. cDNA cloning, expression in COS cells, functional assay The EMBO journal High 2820710
1987 Complete cDNA sequence of human thrombomodulin confirmed a 575-amino acid protein with six EGF-type repeats, no introns in the coding region, and putative regulatory elements in the promoter. The gene was localized to chromosome 20. cDNA and genomic cloning, Northern blot, chromosomal mapping Biochemistry High 2822087
1987 The thrombomodulin gene contains no introns within its coding region, contains six EGF-type B repeats, has homology to the LDL receptor, and the promoter region contains potential regulatory elements. The intronless coding region was established by comparison of cDNA and genomic sequences. Genomic and cDNA cloning, nucleotide sequencing Proceedings of the National Academy of Sciences of the United States of America High 2819876
1985 Thrombomodulin is present as a soluble form in human plasma and urine. Soluble thrombomodulin retains intrinsic protein C-activating cofactor activity with the same apparent Km for protein C as the cellular form, but requires 3–5-fold higher thrombin concentration for half-maximal activity, suggesting loss of the membrane-anchoring domain alters thrombin affinity. Radioimmunoassay, immunoaffinity chromatography, immunoblot, protein C activation assay The Journal of clinical investigation High 3001144
1989 Thrombomodulin acts as a thrombin receptor on endothelium that functions as a cofactor for protein C activation, converting thrombin from a procoagulant to an anticoagulant enzyme. The thrombin–thrombomodulin complex loses ability to clot fibrinogen and activate platelets while gaining ability to rapidly activate protein C zymogen. Biochemical reconstitution, enzyme kinetics, functional assays The Journal of biological chemistry High 2538457
1995 Thrombomodulin's chondroitin sulfate moiety binds to a basic surface on thrombin also involved in heparin interaction, enhancing thrombin affinity for thrombomodulin 10–20-fold, altering thrombin conformation and specificity, and accelerating thrombin inhibition by antithrombin. The EGF-like domains of thrombomodulin block thrombin's procoagulant substrate binding sites (fibrinogen, platelet receptor), while conformational changes in the thrombin active site facilitate protein C docking. Structural analysis, kinetic studies, competition assays, mutagenesis FASEB journal High 7615164
1995 The first thrombomodulin gene mutation associated with thromboembolism was identified: a heterozygous G1456T substitution predicting Asp468Tyr, located between the transmembrane domain and the sixth EGF-like domain, in a patient with pulmonary embolism. PCR-SSCP, DNA sequencing Blood Medium 7811989
1996 The thrombin–thrombomodulin complex, rather than free thrombin, is the physiologic activator of TAFI (thrombin-activatable fibrinolysis inhibitor/procarboxypeptidase B). Thrombomodulin increases the catalytic efficiency of TAFI activation 1250-fold, primarily by increasing kcat. The reaction follows a ternary complex model: thrombin binds thrombomodulin (Kd = 8.6 nM) or TAFI (Km = 1.0 µM), and the binary complex recruits the third component to form an active ternary complex. Activated TAFI inhibits fibrinolysis half-maximally at ~1 nM. In vitro reconstitution, enzyme kinetics, purified components The Journal of biological chemistry High 8663147
2000 Crystal structure of human α-thrombin bound to TME456 (EGF-like domains 4–5–6 of thrombomodulin, the smallest fragment sufficient for full protein C cofactor activity) at 2.3 Å resolution. Thrombomodulin binds thrombin's anion-binding exosite-I in a Y-shaped configuration, sterically blocking procoagulant substrate binding without inducing marked allosteric rearrangements at the thrombin active site. Modeling indicates TME45 may orient protein C's cleavage site optimally toward the unaltered thrombin active site. X-ray crystallography (2.3 Å), molecular docking Nature High 10761923
2003 Thrombomodulin mediates Ca²⁺-dependent cell-to-cell adhesion via its lectin-like domain. In TM-negative melanoma cells transfected with GFP-tagged TM, cells formed closely clustered colonies with TM localized at intercellular boundaries, reduced monolayer permeability in vitro, and decreased tumor growth in vivo. Deletion of the lectin-like domain abolished these effects. Adhesion was inhibited by anti-lectin-domain antibody and by mannose, chondroitin sulfate A, or chondroitin sulfate C. Transfection of TM-negative cells, domain-deletion mutants, confocal microscopy, permeability assay, in vivo tumor model, antibody inhibition The Journal of biological chemistry High 12951323
2004 Thrombomodulin–protein C–EPCR system is integrated to regulate both coagulation and inflammation. Thrombomodulin serves as a cofactor for thrombin-mediated protein C activation (further amplified by EPCR), and activated protein C exerts anticoagulant, anti-inflammatory, profibrinolytic, and cytoprotective effects. The covalently associated chondroitin sulfate moiety of TM additionally enhances thrombin binding and modulates TAFI activation and complement regulation. Review of biochemical, cell biology, and in vivo experimental data Arteriosclerosis, thrombosis, and vascular biology High 15178554
2005 Inflammatory cytokines (TNF-α) down-regulate endothelial thrombomodulin expression through NF-κB activation. NF-κB does not bind the TM promoter directly but competes for limited pools of the coactivator p300, which is required by Ets transcription factors for TM promoter transactivation. Blocking NF-κB activation prevented cytokine-induced TM down-regulation in vitro and in a mouse TNF-α lung injury model. EMSA, chromatin immunoprecipitation, promoter deletion/mutation analysis, NF-κB inhibition, p300 overexpression, mouse model Blood High 15677570
2005 KLF2 (Krüppel-like factor 2) is required for statin-induced upregulation of thrombomodulin in endothelial cells. Statin treatment induces KLF2 mRNA via Rho pathway inhibition and de novo transcription through a myocyte enhancer factor binding site in the KLF2 promoter. siRNA-mediated KLF2 knockdown strongly attenuated mevastatin-induced thrombomodulin protein accumulation. siRNA knockdown, promoter deletion/mutation analysis, pharmacological inhibition, Western blot Circulation High 16043642
2007 Thrombomodulin expression in vascular endothelial cells is clock-controlled: TM mRNA and protein show circadian oscillation in mouse lung and heart. The CLOCK/BMAL2 heterodimer directly binds an E-box element in the TM promoter to drive transcription, as shown by reporter assays, EMSA, and ChIP. Oscillation was abolished in Clock mutant mice and phase-shifted by temporal feeding restriction. Microarray, reporter assay, EMSA, chromatin immunoprecipitation, Clock mutant mice, temporal feeding restriction The Journal of biological chemistry High 17848551
2007 Endothelial thrombomodulin-dependent activated protein C (APC) formation is reduced in diabetic mice and causally linked to diabetic nephropathy. APC prevents glucose-induced apoptosis in endothelial cells and podocytes via protease-activated receptor PAR-1 and endothelial protein C receptor EPCR, modulating the mitochondrial apoptosis pathway. Loss of thrombomodulin-dependent APC disrupts endothelial–podocyte crosstalk, causing glomerular apoptosis. Diabetic mouse model, endothelial cell and podocyte in vitro assays, PAR-1/EPCR pathway analysis, apoptosis assays Nature medicine High 17982464
2009 THBD mutations cause ~5% of atypical hemolytic-uremic syndrome (aHUS) cases. Mechanistically, thrombomodulin binds C3b and factor H and negatively regulates complement by accelerating factor I-mediated C3b inactivation (requiring cofactors CFH or C4b-binding protein). TM also accelerates inactivation of anaphylatoxins C3a and C5a via procarboxypeptidase B activation. aHUS-associated missense mutations in THBD reduce C3b inactivation and procarboxypeptidase B activation in cell-expression systems. THBD gene sequencing, purified protein binding assays, cell-expression systems, complement activation assays The New England journal of medicine High 19625716
2011 Thrombomodulin exhibits anti-inflammatory properties through multiple mechanisms: (1) cofactor for thrombin-mediated protein C activation; (2) TAFI activation to inhibit fibrinolysis; (3) complement regulation via C3b inactivation; (4) binding and sequestration of the pro-inflammatory cytokine HMGB1 via its lectin-like domain; (5) interaction with Lewis Y antigen. TM expression is tightly regulated by cytokines (down-regulated by TNF-α, IL-1), shear stress, and thrombin. Review integrating published biochemical and in vivo experimental data Seminars in immunopathology High 21805323
2013 Loss of endothelial thrombomodulin (TM) and EPCR at sites of malaria-infected erythrocyte cytoadherence in cerebral malaria is associated with cerebral fibrin clot formation. Using ex vivo subcutaneous microvessels, loss of TM and EPCR was detectable at sites of infected erythrocyte binding in non-fatal cerebral malaria, linking parasite sequestration to disruption of endothelial anticoagulant/anti-inflammatory protection. Autopsy immunostaining, novel ex vivo microvascular assay, coagulation activation assays Blood Medium 23741007
2014 Regulatory sequences from the porcine THBD gene (7.6-kb upstream fragment) drive endothelial-specific expression of human thrombomodulin (hTM) in transgenic pigs. Endothelial cells from hTM transgenic pigs showed 3–4-fold increased clotting time in human whole blood assays compared to wild-type, demonstrating that hTM retains anticoagulant function in a xenograft context and can overcome human–pig coagulation incompatibilities. Transgenic pig generation (somatic cell nuclear transfer), endothelial cell coagulation assay with human whole blood Transplantation Medium 24150517
2017 Tissue-selective Thbd gene ablation in adult mice reveals that complete Thbd deficiency leads to low-grade consumptive coagulopathy and sudden-onset mortality. Supplementation with activated protein C (via a partially Thbd-independent PC transgene) prevented thrombotic pathologies but Thbd-deficient females showed near-complete pregnancy-induced morbidity. This demonstrates that Thbd function in nonendothelial embryonic tissues (placenta, yolk sac) influences the penetrance and severity of postnatal thrombosis through unknown mechanisms. Conditional Cre/loxP Thbd gene ablation, transgenic protein C supplementation, histopathology, coagulation assays Blood advances High 28920104
2017 A THBD c.1611C>A nonsense mutation (p.Cys537X) leads to a truncated thrombomodulin that has lost the last three amino acids of the transmembrane domain and the cytoplasmic tail. This truncated protein is partially membrane-anchored but is shed at ~6× higher levels than wild-type TM. Shedding is ~75% dependent on metalloprotease activity and is not affected by cathepsin G, elastase, reducing agents, or high shear stress. Other truncation mutants with shortened transmembrane domains also show increased shedding, indicating the transmembrane domain length is critical for membrane retention. Site-directed mutagenesis, transient transfection in COS-1 cells, Western blot, immunofluorescence, metalloprotease inhibitor assay, ELISA PloS one High 29145514
2020 Endogenous THBD promotes angiogenesis in the ischemic brain. Following middle cerebral artery occlusion in mice, Thbd expression increased in the peri-infarct area. Inducible, brain endothelial cell-specific Thbd deletion worsened stroke outcome without increasing coagulation, thrombosis, or inflammation, but instead decreased vessel diameters and impaired angiogenesis in the peri-infarct area, reducing overall vessel length 1 week post-stroke. Mouse MCA occlusion model, inducible Cre/loxP brain endothelial-specific Thbd knockout, histology, vessel morphometry Arteriosclerosis, thrombosis, and vascular biology High 33028093
2021 miR-18a-5p negatively regulates THBD expression in endometrial cancer cells. Dual-luciferase assay confirmed direct targeting of THBD 3'UTR by miR-18a-5p. Overexpression of miR-18a-5p enhanced proliferation, migration, and invasion of EC cells, while THBD overexpression inhibited these abilities. Rescue experiments showed THBD overexpression reversed the oncogenic effects of miR-18a-5p, placing THBD downstream of miR-18a-5p in a regulatory axis suppressing EC cell aggressiveness. Dual-luciferase reporter assay, qRT-PCR, Western blot, CCK-8 assay, Transwell assay, rescue experiments Critical reviews in eukaryotic gene expression Medium 34347980
2022 BRG1 (a chromatin remodeling ATPase) epigenetically represses THBD transcription in endothelial cells, contributing to deep vein thrombosis. TNF-α stimulation decreases THBD expression; BRG1 knockdown or inhibition recovers THBD expression. Mechanistically, BRG1 directly upregulates DNMT1 expression after TNF-α treatment, increasing CpG methylation of the THBD promoter. Endothelial-specific BRG1 conditional knockout mice showed substantially decreased DVT susceptibility with decreased thrombus weight/size. Conditional endothelial BRG1 knockout mice (Cdh5-ERT-Cre × Brg1-loxP), siRNA/inhibitor experiments, CpG methylation analysis, DVT ligation model, small-molecule BRG1 inhibitor (PFI-3) Thrombosis research High 36162255
2021 The THBD c.1418C>T (p.Ala473Val) variant reduces protein C activation and impairs endothelial progenitor cell (EPC) migration and angiogenesis. Expression of p.Ala473Val in EPCs decreased VEGFRs, MMP1/2/3, VE-cadherin, Flk-1, eNOS, and TIE-2 expression, weakened wound healing, Transwell migration, and tube formation, mechanistically linking the variant to reduced angiogenic capacity. THBD cDNA transfection in EPCs, ELISA, wound healing, Transwell migration, tube formation, Western blot International angiology Medium 34236150
2025 Adrenomedullin (ADM) signaling through its receptor RAMP2 synergizes with shear stress to increase THBD expression in human pulmonary endothelial cells, enhancing anti-coagulant phenotype (increased THBD, decreased tissue factor F3). This effect was completely abolished by RAMP2 blockade, identifying ADM/RAMP2 as an upstream paracrine regulator of endothelial THBD expression. ECIS, XperT barrier assay, qPCR, pharmacological receptor blockade, shear stress apparatus bioRxiv (preprint)preprint Low
2024 In pristane-induced lupus, MEK1/2-ERK1/2 pathway activation in B6 mice upregulates Thbd (thrombomodulin) gene expression and increases circulating soluble Thbd protein in the lung, contributing to endothelial anticoagulant dysregulation and diffuse alveolar hemorrhage. MEK1/2 inhibition (trametinib) normalized Thbd expression and circulating Thbd levels, and abolished DAH, linking the ERK pathway to Thbd-mediated hemostatic imbalance. MEK/ERK inhibitor treatment in mouse lupus model, qPCR, Western blot, ELISA, tail bleeding assay bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 99 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
2000 BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. Journal of immunology (Baltimore, Md. : 1950) 1003 11086035
1989 The roles of protein C and thrombomodulin in the regulation of blood coagulation. The Journal of biological chemistry 927 2538457
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2010 Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. The Journal of experimental medicine 837 20479116
2016 Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer cell 818 27424807
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2010 Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. The Journal of experimental medicine 654 20479115
2010 Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. The Journal of experimental medicine 552 20479117
1996 TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. The Journal of biological chemistry 537 8663147
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2009 Thrombomodulin mutations in atypical hemolytic-uremic syndrome. The New England journal of medicine 435 19625716
2003 The dynamics of thrombin formation. Arteriosclerosis, thrombosis, and vascular biology 387 12524220
1987 Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. The EMBO journal 357 2820710
1995 Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 328 7615164
2007 Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nature medicine 326 17982464
1985 Thrombomodulin is present in human plasma and urine. The Journal of clinical investigation 311 3001144
2004 Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arteriosclerosis, thrombosis, and vascular biology 298 15178554
2005 Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 290 16043642
2000 Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 270 10761923
2010 Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Human mutation 258 20513133
2011 Thrombomodulin and its role in inflammation. Seminars in immunopathology 253 21805323
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2012 Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. The Journal of experimental medicine 205 22547651
1987 Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. Biochemistry 203 2822087
2013 Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 176 23741007
2015 Circulating precursors of human CD1c+ and CD141+ dendritic cells. The Journal of experimental medicine 169 25687281
2001 The DNA sequence and comparative analysis of human chromosome 20. Nature 168 11780052
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
1987 Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control. Proceedings of the National Academy of Sciences of the United States of America 142 2819876
2003 Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. The Journal of biological chemistry 132 12951323
2019 The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2. Molecular cell 124 30639242
2016 Human dendritic cells (DCs) are derived from distinct circulating precursors that are precommitted to become CD1c+ or CD141+ DCs. The Journal of experimental medicine 109 27864467
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2013 CD141+ dendritic cells produce prominent amounts of IFN-α after dsRNA recognition and can be targeted via DEC-205 in humanized mice. Blood 107 23482932
2007 Thrombomodulin is a clock-controlled gene in vascular endothelial cells. The Journal of biological chemistry 106 17848551
1995 The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood 98 7811989
2005 Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B. Blood 96 15677570
2017 Constitutive resistance to viral infection in human CD141+ dendritic cells. Science immunology 88 28783704
2014 FLT3-ligand treatment of humanized mice results in the generation of large numbers of CD141+ and CD1c+ dendritic cells in vivo. Journal of immunology (Baltimore, Md. : 1950) 85 24453245
2013 CD141⁺ myeloid dendritic cells are enriched in healthy human liver. Journal of hepatology 80 23968887
2022 PD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer. Nature communications 71 36272973
2012 Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells. Blood 69 23093620
2016 Targeting CLEC9A delivers antigen to human CD141+ DC for CD4+ and CD8+T cell recognition. JCI insight 68 27699265
2019 Coexpression of CD163 and CD141 identifies human circulating IL-10-producing dendritic cells (DC-10). Cellular & molecular immunology 67 30842629
2008 Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response. The Journal of allergy and clinical immunology 61 18947863
2014 Regulatory sequences of the porcine THBD gene facilitate endothelial-specific expression of bioactive human thrombomodulin in single- and multitransgenic pigs. Transplantation 60 24150517
2013 Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease. American journal of physiology. Renal physiology 58 24049150
2014 Human CD141+ dendritic cells induce CD4+ T cells to produce type 2 cytokines. Journal of immunology (Baltimore, Md. : 1950) 56 25246496
2011 Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141(+)XCR1+ dendritic cells. Gene therapy 53 22071967
2015 Arming the Melanoma Sentinel Lymph Node through Local Administration of CpG-B and GM-CSF: Recruitment and Activation of BDCA3/CD141(+) Dendritic Cells and Enhanced Cross-Presentation. Cancer immunology research 50 25633713
2018 Directed Differentiation of Human Induced Pluripotent Stem Cells into Dendritic Cells Displaying Tolerogenic Properties and Resembling the CD141+ Subset. Frontiers in immunology 47 29358940
2021 Human CD141+ dendritic cells (cDC1) are impaired in patients with advanced melanoma but can be targeted to enhance anti-PD-1 in a humanized mouse model. Journal for immunotherapy of cancer 45 33737342
2017 Human CD141+ Dendritic Cell and CD1c+ Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice In Vivo. Frontiers in immunology 44 29163495
2014 Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 42 25225421
2014 TLR3-responsive, XCR1+, CD141(BDCA-3)+/CD8α+-equivalent dendritic cells uncovered in healthy and simian immunodeficiency virus-infected rhesus macaques. Journal of immunology (Baltimore, Md. : 1950) 38 24740505
2020 Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells. Journal for immunotherapy of cancer 36 32737142
2018 Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis. JCI insight 36 30518680
2018 Activation of human CD141+ and CD1c+ dendritic cells in vivo with combined TLR3 and TLR7/8 ligation. Immunology and cell biology 35 29344995
2020 Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1-specific CD8+ T cells. Clinical & translational immunology 32 32547743
2022 Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study. Journal of thrombosis and haemostasis : JTH 28 34970867
2022 Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial. Journal for immunotherapy of cancer 28 36113895
2016 Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age. Aging 28 27244900
2020 Endogenous THBD (Thrombomodulin) Mediates Angiogenesis in the Ischemic Brain-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 24 33028093
2016 TLR3 Signaling Promotes the Induction of Unique Human BDCA-3 Dendritic Cell Populations. Frontiers in immunology 23 27014268
2020 Targeted Co-delivery of Tumor Antigen and α-Galactosylceramide to CD141+ Dendritic Cells Induces a Potent Tumor Antigen-Specific Human CD8+ T Cell Response in Human Immune System Mice. Frontiers in immunology 22 32973811
2021 T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A+CD141+ cDC1 and CD14+ antigen-presenting cell recruitment. Journal for immunotherapy of cancer 20 33737341
2013 Differential response of BDCA-1+ and BDCA-3+ myeloid dendritic cells to respiratory syncytial virus infection. Respiratory research 19 23829893
2020 The Superior Ability of Human BDCA3+ (CD141+) Dendritic Cells (DCs) to Cross-Present Antigens Derived From Necrotic Lung Cancer Cells. Frontiers in immunology 16 32655564
2017 Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation. Blood advances 16 28920104
2021 Metabolomic and lipidomic signatures associated with activation of human cDC1 (BDCA3+ /CD141+ ) dendritic cells. Immunology 12 34431087
2021 MiR-18a-5p Promotes Proliferation, Migration, and Invasion of Endometrial Cancer Cells by Targeting THBD. Critical reviews in eukaryotic gene expression 11 34347980
2019 Human CD141+ dendritic cells generated from adult peripheral blood monocytes. Cytotherapy 11 31447319
2017 Why patients with THBD c.1611C>A (p.Cys537X) nonsense mutation have high levels of soluble thrombomodulin? PloS one 10 29145514
2015 Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 10 26159646
2021 STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16+ Monocytes and CD141+ Dendritic Cells. Journal of immunology (Baltimore, Md. : 1950) 9 34654687
2022 The In Vitro Differentiation of Human CD141+CLEC9A+ Dendritic Cells from Mobilized Peripheral Blood CD34+ Hematopoietic Stem Cells. Current protocols 8 35435334
2017 THBD sequence variants potentially related to recurrent pregnancy loss. Reproductive biology and endocrinology : RB&E 8 29195508
2023 WT1 Pulsed Human CD141+ Dendritic Cell Vaccine Has High Potential in Solid Tumor-Targeted Immunotherapy. International journal of molecular sciences 7 36675017
2023 Cardioprotective efficacy of Xin-shu-bao tablet in heart failure with reduced ejection fraction by modulating THBD/ARRB1/FGF1/STIM1 signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 7 37423168
2017 Human Bronchial Epithelial Cells Induce CD141/CD123/DC-SIGN/FLT3 Monocytes That Promote Allogeneic Th17 Differentiation. Frontiers in immunology 7 28487694
2024 A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors. Cancer immunology, immunotherapy : CII 6 38954010
2022 Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis. Thrombosis research 6 36162255
2024 Intratumoral administration of the immunologic adjuvant AS01B in combination with autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma. Journal for immunotherapy of cancer 5 38212127
2023 Human skin CD141+ dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2. iScience 5 37860766
2022 The PDE4 inhibitor tanimilast shows distinct immunomodulatory properties associated with a type 2 endotype and CD141 upregulation. Journal of translational medicine 5 35538539
2014 Paramyxovirus infection regulates T cell responses by BDCA-1+ and BDCA-3+ myeloid dendritic cells. PloS one 5 24918929
2012 Professional cross-presenting CD8α-type CD141(hi) dendritic cells: we have got you in our skin! Immunity 5 22840836
2021 The associations between THBD c.1418C>T polymorphism and lower extremity deep vein thrombosis or endothelial progenitor cell. International angiology : a journal of the International Union of Angiology 4 34236150
2024 Identification of CD141+vasculogenic precursor cells from human bone marrow and their endothelial engagement in the arteriogenesis by co-transplantation with mesenchymal stem cells. Stem cell research & therapy 2 39482744
2023 Novel nucleotide variations in the thrombomodulin (THBD) gene involved in coagulation pathways can increase the risk of recurrent pregnancy loss (RPL). Gene 2 37979949
2017 Juvenile myelomonocytic leukemia with prominent CD141+ myeloid dendritic cell differentiation. Human pathology 2 28414089
2011 [Polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene and association with unfavorable outcomes of coronary atherosclerosis in patients with a history of acute ischemic heart disease]. Genetika 2 22232927
2023 Family Aggregation of Hematological Malignancies Discovered from an Acute Myeloid Leukemia Patient with STK11 and THBD Gene Mutation. Case reports in oncology 1 37900785
2022 Clinical grade adjuvants to mature CD141+ DCs for immunotherapy. Frontiers in bioscience (Elite edition) 1 35320906
2018 Administration of Thrombomodulin (CD141) Could Improve Cardiac Allograft Survival in Mice. Transplantation proceedings 1 30401399
2025 Peripheral HLA-DRhiCD141+ Classical Monocytes Predict Relapse Risk and Worsening in Multiple Sclerosis. Neurology(R) neuroimmunology & neuroinflammation 0 40609052
2025 Plasmacytoid and CD141+ Myeloid Dendritic Cells Cooperation with CD8+ T Cells in Lymph Nodes is Associated with HIV Control. MedComm 0 40949488
2025 A pedigree analysis of deep venous thrombosis caused by rare compound heterozygous PROC mutations combined with a heterozygous THBD mutation. Thrombosis journal 0 41454398