Details for: THBD

Gene ID: 7056

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: THBD

Ensembl ID: ENSG00000178726

Description: thrombomodulin

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • mononuclear phagocyte CL0000113
    CSI 17.79
    rCSI 39.15%
    PRS 84.44
  • pulmonary artery endothelial cell CL1001568
    CSI 10.23
    rCSI 13.92%
    PRS 88.89
  • elicited macrophage CL0000861
    CSI 9.33
    rCSI 8.57%
    PRS 88.03
  • endothelial cell of artery CL1000413
    CSI 7.69
    rCSI 11.26%
    PRS 87.21
  • vascular associated smooth muscle cell CL0000359
    CSI 7.28
    rCSI 23.61%
    PRS 79.05
  • vein endothelial cell of respiratory system CL4033008
    CSI 7.27
    rCSI 49.91%
    PRS 87.23
  • lung interstitial macrophage CL4033043
    CSI 6.02
    rCSI 13.51%
    PRS 91.72
  • endothelial cell of lymphatic vessel CL0002138
    CSI 5.48
    rCSI 10.87%
    PRS 85.76
  • dendritic cell, human CL0001056
    CSI 4.81
    rCSI 7.39%
    PRS 88.84
  • capillary endothelial cell CL0002144
    CSI 4.65
    rCSI 8.53%
    PRS 84.9
  • retinal blood vessel endothelial cell CL0002585
    CSI 4.27
    rCSI 6.83%
    PRS 84.49
  • pulmonary capillary endothelial cell CL4028001
    CSI 4.24
    rCSI 8.09%
    PRS 89.85
  • cardiac endothelial cell CL0010008
    CSI 4.2
    rCSI 16.92%
    PRS 80.68
  • intermediate monocyte CL0002393
    CSI 3.69
    rCSI 5.57%
    PRS 85.83
  • blood vessel endothelial cell CL0000071
    CSI 3.52
    rCSI 7.3%
    PRS 77.57
  • hepatic stellate cell CL0000632
    CSI 3.38
    rCSI 12.65%
    PRS 73.67
  • alveolar macrophage CL0000583
    CSI 3.29
    rCSI 5.41%
    PRS 84.44
  • monocyte CL0000576
    CSI 3.28
    rCSI 5.93%
    PRS 85.54
  • bronchus fibroblast of lung CL2000093
    CSI 3.27
    rCSI 2.66%
    PRS 80.18
  • vein endothelial cell CL0002543
    CSI 3.18
    rCSI 8.68%
    PRS 87.85
  • lung microvascular endothelial cell CL2000016
    CSI 2.99
    rCSI 57.78%
    PRS 88.29
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 2.68
    rCSI 3.51%
    PRS 90.55
  • alveolar adventitial fibroblast CL4028006
    CSI 2.55
    rCSI 4.03%
    PRS 82.31
  • keratinocyte CL0000312
    CSI 2.52
    rCSI 2.11%
    PRS 83.56
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 2.5
    rCSI 3.02%
    PRS 87.87
  • cerebral cortex endothelial cell CL1001602
    CSI 2.47
    rCSI 4.28%
    PRS 72.69
  • respiratory basal cell CL0002633
    CSI 2.42
    rCSI 2.51%
    PRS 84.76
  • endothelial cell of periportal hepatic sinusoid CL0019021
    CSI 2.4
    rCSI 11%
    PRS 85.04
  • fibroblast of lung CL0002553
    CSI 2.4
    rCSI 2.23%
    PRS 81.66
  • conjunctival epithelial cell CL1000432
    CSI 2.26
    rCSI 3.45%
    PRS 81.02
  • prostate gland microvascular endothelial cell CL2000059
    CSI 2.25
    rCSI 53.82%
    PRS 88.82
  • perivascular cell CL4033054
    CSI 2.22
    rCSI 3.04%
    PRS 85.25
  • blood vessel smooth muscle cell CL0019018
    CSI 2.16
    rCSI 17.55%
    PRS 75.35
  • alternatively activated macrophage CL0000890
    CSI 1.92
    rCSI 2.41%
    PRS 89.52
  • adventitial cell CL0002503
    CSI 1.85
    rCSI 4.43%
    PRS 84.72
  • lung endothelial cell CL1001567
    CSI 1.79
    rCSI 4.18%
    PRS 90.68
  • lung macrophage CL1001603
    CSI 1.62
    rCSI 3.61%
    PRS 87.56
  • extravillous trophoblast CL0008036
    CSI 1.6
    rCSI 1.98%
    PRS 79
  • Hofbauer cell CL3000001
    CSI 1.43
    rCSI 2.71%
    PRS 88.24
  • type B pancreatic cell CL0000169
    CSI 1.41
    rCSI 3.12%
    PRS 80.32
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.33
    rCSI 4.11%
    PRS 84.86
  • endothelial cell of uterus CL0009095
    CSI 1.24
    rCSI 9.06%
    PRS 88.58
  • microcirculation associated smooth muscle cell CL0008035
    CSI 1.21
    rCSI 3.52%
    PRS 80.28
  • vasa recta ascending limb cell CL1001131
    CSI 1.19
    rCSI 5.38%
    PRS 88.33
  • endothelial cell of vascular tree CL0002139
    CSI 1.16
    rCSI 6.37%
    PRS 77.31
  • colon macrophage CL0009038
    CSI 0.77
    rCSI 3.58%
    PRS 91.75
  • type EC enteroendocrine cell CL0000577
    CSI 0.68
    rCSI 2.42%
    PRS 84.7
  • myeloid dendritic cell, human CL0001057
    CSI 0.65
    rCSI 3.64%
    PRS 93.06
  • metallothionein-positive alveolar macrophage CL4033042
    CSI 0.64
    rCSI 7.01%
    PRS 90.36
  • endothelial cell of venule CL1000414
    CSI 0.63
    rCSI 5.6%
    PRS 88.54
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 0.57
    rCSI 3.46%
    PRS 90.98
  • pancreatic stellate cell CL0002410
    CSI 0.48
    rCSI 2.81%
    PRS 84.49
  • endothelial cell of placenta CL0009092
    CSI 0.46
    rCSI 2.24%
    PRS 87.96

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [THBD](/details-gene/7056), or thrombomodulin, is a protein-coding gene located on chromosome 20p11.21. It encodes a transmembrane glycoprotein that functions as a critical receptor for thrombin on the surface of endothelial cells. Upon binding thrombin, [THBD](/details-gene/7056) fundamentally alters thrombin's substrate specificity, converting it from a procoagulant enzyme into a potent anticoagulant by activating protein C. This activity is central to the negative regulation of the coagulation cascade. Expression data shows that [THBD](/details-gene/7056) is a defining marker for various endothelial cell types and [mononuclear phagocyte](/details-cell/CL0000113), underscoring its pivotal role in maintaining vascular hemostasis and modulating inflammation at the blood-vessel interface. Dysregulation of [THBD](/details-gene/7056) is associated with thrombotic disorders, as noted in OMIM entry [188040](https://omim.org/entry/188040). ## Cellular Roles and Expression Landscape The expression profile of [THBD](/details-gene/7056) highlights its fundamental role in the vascular and myeloid compartments. **Overall**, the gene exhibits its highest significance in [mononuclear phagocyte](/details-cell/CL0000113) (CSI: 17.79), suggesting a key function in this myeloid cell lineage beyond its canonical endothelial role. The gene is a quintessential marker of the vascular endothelium, with high significance scores across numerous endothelial subtypes. These include [pulmonary artery endothelial cell](/details-cell/CL1001568) (CSI: 10.23), [endothelial cell of artery](/details-cell/CL1000413) (CSI: 7.69), [vein endothelial cell of respiratory system](/details-cell/CL4033008) (CSI: 7.27), [endothelial cell of lymphatic vessel](/details-cell/CL0002138) (CSI: 5.48), and [capillary endothelial cell](/details-cell/CL0002144) (CSI: 4.65). This widespread and robust expression across the endothelial landscape is consistent with its role in maintaining a non-thrombogenic surface throughout the circulatory system ([Link](https://pubmed.ncbi.nlm.nih.gov/33836597/)). Beyond the endothelium, [THBD](/details-gene/7056) is also highly significant in phagocytic cells, including [elicited macrophage](/details-cell/CL0000861) (CSI: 9.33) and [lung interstitial macrophage](/details-cell/CL4033043) (CSI: 6.02), as well as [dendritic cell, human](/details-cell/CL0001056) (CSI: 4.81). This expression pattern suggests that in addition to its anticoagulant functions, [THBD](/details-gene/7056) likely plays important roles in immune surveillance and the regulation of inflammation, potentially by sequestering damage-associated molecular patterns like HMGB1 ([Link](https://pubmed.ncbi.nlm.nih.gov/15841214/)). ## Pathways and Molecular Function The functional annotations for [THBD](/details-gene/7056) are tightly centered on the regulation of blood clotting and vascular homeostasis. It is a key component of the Reactome pathway '[Hemostasis](/details-pathway/R-HSA-109582)', specifically involved in the '[Common pathway of fibrin clot formation](/details-pathway/R-HSA-140875)' and '[Cell surface interactions at the vascular wall](/details-pathway/R-HSA-202733)'. Its primary biological process, as defined by Gene Ontology, is the '[Negative regulation of blood coagulation](/details-ontology/GO:0030195)'. Mechanistically, [THBD](/details-gene/7056) functions as a '[Transmembrane signaling receptor activity](/details-ontology/GO:0004888)' on the '[External side of plasma membrane](/details-ontology/GO:0009897)'. Its molecular function involves binding both thrombin and '[Calcium ion binding](/details-ontology/GO:0005509)', which facilitates the activation of protein C. This process effectively shuts down the coagulation cascade by inactivating Factors Va and VIIIa. The localization of [THBD](/details-gene/7056) to the cell surface of endothelial cells is critical for this function, allowing it to act as a sentinel that prevents inappropriate clot formation on healthy vessel walls ([Link](https://pubmed.ncbi.nlm.nih.gov/2820710/)). Additionally, its role in processes like '[Response to lipopolysaccharide](/details-ontology/GO:0032496)' aligns with its expression in macrophages and its documented anti-inflammatory properties. ## Research Directions Given the dual role of [THBD](/details-gene/7056) in anticoagulation and anti-inflammation, research into its cell-specific functions during pathological states is critical. Its high expression in both endothelial cells and macrophages suggests it acts as a key homeostatic regulator at the intersection of thrombosis and immunity. **Testable Hypotheses:** 1. The expression of [THBD](/details-gene/7056) on macrophages serves as a critical local braking mechanism to prevent excessive inflammation and microthrombosis in response to pathogens or tissue damage. Loss of macrophage-specific [THBD](/details-gene/7056) would lead to an exaggerated pro-inflammatory and pro-thrombotic state during sepsis or sterile injury. 2. Pathological shear stress or inflammatory cytokines associated with atherosclerosis lead to the shedding or downregulation of [THBD](/details-gene/7056) specifically from arterial endothelial cells. This localized loss of [THBD](/details-gene/7056) function is an initiating event that permits leukocyte adhesion, lipid deposition, and focal thrombus formation, thereby promoting plaque development. **Proposed Experiment:** To test the first hypothesis regarding the role of [THBD](/details-gene/7056) on macrophages, a conditional knockout mouse model could be employed. Specifically, mice with a floxed *Thbd* allele could be crossed with Lyz2-Cre mice to generate myeloid-specific knockouts. These knockout mice and littermate controls would be subjected to a model of sepsis, such as cecal ligation and puncture (CLP). The hypothesis would be tested by measuring key outcomes: (1) systemic inflammatory cytokine levels (e.g., IL-6, TNF-alpha) via ELISA, (2) markers of coagulation activation (e.g., D-dimer, thrombin-antithrombin complexes), and (3) histological analysis of microthrombi formation in vital organs like the lungs and kidneys. A significant increase in inflammation and thrombosis in the knockout animals would support the hypothesis. **Therapeutic Potential:** [THBD](/details-gene/7056) represents a promising therapeutic agent rather than a target for inhibition. Its natural anticoagulant and anti-inflammatory properties make it a strong candidate for **activation** or protein replacement therapy. Recombinant soluble [THBD](/details-gene/7056) is already used clinically for disseminated intravascular coagulation (DIC). Its potential could be expanded to other conditions characterized by endotheliopathy and thromboinflammation, such as severe sepsis, acute respiratory distress syndrome (ARDS), or complications from viral infections. The therapeutic strategy would involve administering recombinant [THBD](/details-gene/7056) to restore vascular homeostasis, suppress inflammation, and prevent microvascular thrombosis.

Genular Protein ID: 771984426

Symbol: TRBM_HUMAN

Name: Thrombomodulin

UniProtKB Accession Codes:

P07204 Q8IV29 Q9UC32

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 3 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 3 EMBL 8 EMDB 1 Ensembl 1 EvolutionaryTrace 1 GO 21 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 12 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 MetOSite 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 13 PDBsum 13 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 5 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 5 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 3 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniLectin 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2820710

Title: Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation.

PubMed ID: 2820710

DOI: 10.1002/j.1460-2075.1987.tb02448.x

PubMed ID: 2822087

Title: Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.

PubMed ID: 2822087

DOI: 10.1021/bi00388a025

PubMed ID: 2819876

Title: Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control.

PubMed ID: 2819876

DOI: 10.1073/pnas.84.18.6425

PubMed ID: 2836377

Title: Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C.

PubMed ID: 2836377

DOI: 10.1093/oxfordjournals.jbchem.a122261

PubMed ID: 11780052

Title: The DNA sequence and comparative analysis of human chromosome 20.

PubMed ID: 11780052

DOI: 10.1038/414865a

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8216207

Title: Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine 474.

PubMed ID: 8216207

DOI: 10.1042/bj2950131

PubMed ID: 8390446

Title: Urinary thrombomodulin, its isolation and characterization.

PubMed ID: 8390446

DOI: 10.1093/oxfordjournals.jbchem.a124063

PubMed ID: 9395524

Title: Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C. A potential mechanism for enhancing generation of activated protein C.

PubMed ID: 9395524

DOI: 10.1074/jbc.272.50.31785

PubMed ID: 15841214

Title: The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism.

PubMed ID: 15841214

DOI: 10.1172/jci22782

PubMed ID: 27055590

Title: LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin.

PubMed ID: 27055590

DOI: 10.1016/j.bbrc.2016.04.007

PubMed ID: 26663133

Title: Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells.

PubMed ID: 26663133

DOI: 10.1111/jth.13222

PubMed ID: 29323190

Title: Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor.

PubMed ID: 29323190

DOI: 10.1038/s41598-017-18912-8

PubMed ID: 33836597

Title: Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells.

PubMed ID: 33836597

DOI: 10.1073/pnas.2022248118

PubMed ID: 7559494

Title: The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin.

PubMed ID: 7559494

DOI: 10.1074/jbc.270.40.23366

PubMed ID: 8528067

Title: Synthesis, activity, and preliminary structure of the fourth EGF-like domain of thrombomodulin.

PubMed ID: 8528067

DOI: 10.1002/pro.5560040904

PubMed ID: 7947766

Title: Thrombin-bound structure of an EGF subdomain from human thrombomodulin determined by transferred nuclear Overhauser effects.

PubMed ID: 7947766

DOI: 10.1021/bi00250a007

PubMed ID: 8745396

Title: Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin.

PubMed ID: 8745396

DOI: 10.1002/pro.5560050202

PubMed ID: 10761923

Title: Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.

PubMed ID: 10761923

DOI: 10.1038/35006683

PubMed ID: 9367781

Title: Structure of the fifth EGF-like domain of thrombomodulin: an EGF-like domain with a novel disulfide-bonding pattern.

PubMed ID: 9367781

DOI: 10.1006/jmbi.1997.1356

PubMed ID: 7811989

Title: The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.

PubMed ID: 7811989

PubMed ID: 9198186

Title: Thrombomodulin gene variations and thromboembolic disease.

PubMed ID: 9198186

PubMed ID: 9157575

Title: A common thrombomodulin amino acid dimorphism is associated with myocardial infarction.

PubMed ID: 9157575

PubMed ID: 9843165

Title: A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.

PubMed ID: 9843165

PubMed ID: 11245641

Title: Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease.

PubMed ID: 11245641

DOI: 10.1161/01.cir.103.10.1386

PubMed ID: 12139752

Title: Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.

PubMed ID: 12139752

DOI: 10.1046/j.1365-2141.2002.03644.x

PubMed ID: 19625716

Title: Thrombomodulin mutations in atypical hemolytic-uremic syndrome.

PubMed ID: 19625716

DOI: 10.1056/nejmoa0810739

PubMed ID: 20513133

Title: Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome.

PubMed ID: 20513133

DOI: 10.1002/humu.21256

Sequence Information:

  • Length: 575
  • Mass: 60329
  • Checksum: 9AF03CD151227D52
  • Sequence:
    • MLGVLVLGAL ALAGLGFPAP AEPQPGGSQC VEHDCFALYP GPATFLNASQ ICDGLRGHLM 
TVRSSVAADV ISLLLNGDGG VGRRRLWIGL QLPPGCGDPK RLGPLRGFQW VTGDNNTSYS 
RWARLDLNGA PLCGPLCVAV SAAEATVPSE PIWEEQQCEV KADGFLCEFH FPATCRPLAV 
EPGAAAAAVS ITYGTPFAAR GADFQALPVG SSAAVAPLGL QLMCTAPPGA VQGHWAREAP 
GAWDCSVENG GCEHACNAIP GAPRCQCPAG AALQADGRSC TASATQSCND LCEHFCVPNP 
DQPGSYSCMC ETGYRLAADQ HRCEDVDDCI LEPSPCPQRC VNTQGGFECH CYPNYDLVDG 
ECVEPVDPCF RANCEYQCQP LNQTSYLCVC AEGFAPIPHE PHRCQMFCNQ TACPADCDPN 
TQASCECPEG YILDDGFICT DIDECENGGF CSGVCHNLPG TFECICGPDS ALARHIGTDC 
DSGKVDGGDS GSGEPPPSPT PGSTLTPPAV GLVHSGLLIG ISIASLCLVV ALLALLCHLR 
KKQGAARAKM EYKCAAPSKE VVLQHVRTER TPQRL