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Gene Review

THBD  -  thrombomodulin

Homo sapiens

Synonyms: AHUS6, BDCA3, CD141, Fetomodulin, THPH12, ...
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Disease relevance of THBD


Psychiatry related information on THBD


High impact information on THBD

  • We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions [7].
  • Plasma thrombomodulin levels in the children with meningococcal sepsis (median, 6.4 ng per liter) were higher than those in the controls (median, 3.6 ng per liter; P=0.002) [7].
  • The residues involved in stabilizing the domain linkage are highly conserved in fibrillin, fibulin, thrombomodulin, and the low density lipoprotein receptor [8].
  • Thrombomodulin binding does not seem to induce marked allosteric structural rearrangements at the thrombin active site [9].
  • By means of mutant substrates, it was shown that LY254603 mediates the change in enzymatic substrate specificity through an alteration in thrombin's S3 substrate recognition site, a mechanism that appeared to be independent of allosteric changes induced by either sodium ions or by thrombomodulin [10].

Chemical compound and disease context of THBD


Biological context of THBD

  • Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p) [16].
  • Structural data suggest that the side chain of Arg-35 projects toward the active site pocket of thrombin, but all other residues are poised to interact with thrombomodulin (TM) [17].
  • To study the role of these residues in TM-mediated protein C (PC) activation by thrombin, a charge reversal mutagenesis approach was used to replace these residues with a Glu in separate constructs [17].
  • The present work investigated the mechanism for down-regulation of thrombomodulin (TM), an anticoagulant glycoprotein, on cultured umbilical vein endothelial cells (HUVECs) exposed to lipid extracts from oxidized low-density lipoprotein (ox-LDL) [18].
  • Therefore, in the present study, we have analyzed the entire TM gene, including the promoter region, by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) in normal healthy volunteers and in patients presenting with a thromboembolic disease [19].

Anatomical context of THBD

  • Thrombomodulin (TM), an endothelial cell surface receptor specific for thrombin, has been identified as an essential component for protein C activation [20].
  • We prepared a recombinant TM peptide (rTME1-6, from R214GHWA to DSGK466 of native TM) composed of these six EGF-like structures and investigated the effect of rTME1-6 peptide on the growth of the Swiss 3T3 fibroblast cell line [21].
  • To identify the region responsible for mediating the endocytic process, deletant forms of TM lacking either the lectin-like region (residues 2-155) or the hydrophobic region of the N-terminal domain (residues 161-202) were expressed in COS cells (COSdel.2-155 and COSdel.161-202, respectively) [22].
  • Immunohistochemistry studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque [23].
  • Soluble TM did not effect lysis in the system of purified components lacking TAFI or in plasmas immunodepleted of TAFI [24].

Associations of THBD with chemical compounds

  • The catalytic properties of the Arg-35 mutant were changed so that PC activation by the mutant no longer required Ca2+ in the presence of TM, but, instead, it was accelerated by EDTA [17].
  • HUVECs exposed to phospholipid extracts, but not to free cholesterol, triglyceride, or cholesterol ester, isolated from ox-LDL reduced TM mRNA levels to nearly the same extent as native ox-LDL [18].
  • The inhibition of fibrinolysis by cellular TM was assessed by forming clots in dialyzed, barium citrate-adsorbed, or normal plasma over cultured human umbilical vein endothelial cells (HUVECs) [24].
  • Now we isolate human EPCR and thrombomodulin (TM) and reconstitute them into phosphatidylcholine vesicles [25].
  • There were no associations between the endothelium-dependent hemostatic factors and lipids, except for a negative correlation between HDL cholesterol and thrombomodulin [26].

Physical interactions of THBD


Enzymatic interactions of THBD


Regulatory relationships of THBD

  • Although protein C can be activated directly by the thrombin-TM complex, the conversion is known as a relatively low-affinity reaction [20].
  • Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma [27].
  • The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve [1].
  • A newly developed functional assay demonstrated that HUVECs potentiate the thrombin-catalyzed, TM-dependent formation of activated TAFI [24].
  • Kinetic modeling on the inhibitory effect of TM confirms a mechanism that involves complete steric blocking of the thrombin/PAI-1 interaction [34].

Other interactions of THBD


Analytical, diagnostic and therapeutic context of THBD


  1. Thrombomodulin deficiency in human diabetic nerve microvasculature. Hafer-Macko, C.E., Ivey, F.M., Gyure, K.A., Sorkin, J.D., Macko, R.F. Diabetes (2002) [Pubmed]
  2. Circulating levels of plasminogen activator inhibitor type-1, tissue plasminogen activator, and thrombomodulin in hemodialysis patients: biochemical correlations and role as independent predictors of coronary artery stenosis. Segarra, A., Chacón, P., Martinez-Eyarre, C., Argelaguer, X., Vila, J., Ruiz, P., Fort, J., Bartolomé, J., Camps, J., Moliner, E., Pelegrí, A., Marco, F., Olmos, A., Piera, L. J. Am. Soc. Nephrol. (2001) [Pubmed]
  3. Antithrombotic effects of recombinant human soluble thrombomodulin in a rat model of vascular shunt thrombosis. Ono, M., Nawa, K., Marumoto, Y. Thromb. Haemost. (1994) [Pubmed]
  4. Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells--inhibition of thrombomodulin-dependent protein C activation. Cariou, R., Tobelem, G., Bellucci, S., Soria, J., Soria, C., Maclouf, J., Caen, J. Thromb. Haemost. (1988) [Pubmed]
  5. Erectile and endothelial dysfunction in Type II diabetes: a possible link. De Angelis, L., Marfella, M.A., Siniscalchi, M., Marino, L., Nappo, F., Giugliano, F., De Lucia, D., Giugliano, D. Diabetologia (2001) [Pubmed]
  6. Increased plasma level of vascular endothelial glycoprotein thrombomodulin as an early indicator of endothelial damage in bone marrow transplantation. Testa, S., Manna, A., Porcellini, A., Maffi, F., Morstabilini, G., Denti, N., Macchi, S., Rosti, G., Porcellini, G., Cassi, D., Ferrari, L. Bone Marrow Transplant. (1996) [Pubmed]
  7. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. Faust, S.N., Levin, M., Harrison, O.B., Goldin, R.D., Lockhart, M.S., Kondaveeti, S., Laszik, Z., Esmon, C.T., Heyderman, R.S. N. Engl. J. Med. (2001) [Pubmed]
  8. Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Downing, A.K., Knott, V., Werner, J.M., Cardy, C.M., Campbell, I.D., Handford, P.A. Cell (1996) [Pubmed]
  9. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Fuentes-Prior, P., Iwanaga, Y., Huber, R., Pagila, R., Rumennik, G., Seto, M., Morser, J., Light, D.R., Bode, W. Nature (2000) [Pubmed]
  10. Enhanced protein C activation and inhibition of fibrinogen cleavage by a thrombin modulator. Berg, D.T., Wiley, M.R., Grinnell, B.W. Science (1996) [Pubmed]
  11. Serum levels of thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the acute phase of Plasmodium vivax malaria. Ohnishi, K. Am. J. Trop. Med. Hyg. (1999) [Pubmed]
  12. Thrombomodulin, a receptor for the serine protease thrombin, is decreased in primary tumors and metastases but increased in ascitic fluids of patients with advanced ovarian cancer FIGO IIIc. Wilhelm, S., Schmitt, M., Parkinson, J., Kuhn, W., Graeff, H., Wilhelm, O.G. Int. J. Oncol. (1998) [Pubmed]
  13. Expression of thrombomodulin by smooth muscle cells in culture: different effects of tumor necrosis factor and cyclic adenosine monophosphate on thrombomodulin expression by endothelial cells and smooth muscle cells in culture. Soff, G.A., Jackman, R.W., Rosenberg, R.D. Blood (1991) [Pubmed]
  14. Quantification and modulation of thrombomodulin activity in isolated rat and human glomeruli. He, C.J., Kanfer, A. Kidney Int. (1992) [Pubmed]
  15. Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model. Solis, M.M., Cook, C., Cook, J., Glaser, C., Light, D., Morser, J., Yu, S.C., Fink, L., Eidt, J.F. J. Vasc. Surg. (1991) [Pubmed]
  16. Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Maglott, D.R., Feldblyum, T.V., Durkin, A.S., Nierman, W.C. Mamm. Genome (1996) [Pubmed]
  17. Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin. Rezaie, A.R., Yang, L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  18. Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RARbeta-RXRalpha heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter. Ishii, H., Tezuka, T., Ishikawa, H., Takada, K., Oida, K., Horie, S. Blood (2003) [Pubmed]
  19. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Ohlin, A.K., Marlar, R.A. Blood (1995) [Pubmed]
  20. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. Fukudome, K., Ye, X., Tsuneyoshi, N., Tokunaga, O., Sugawara, K., Mizokami, H., Kimoto, M. J. Exp. Med. (1998) [Pubmed]
  21. The epidermal growth factor-like domain of recombinant human thrombomodulin exhibits mitogenic activity for Swiss 3T3 cells. Hamada, H., Ishii, H., Sakyo, K., Horie, S., Nishiki, K., Kazama, M. Blood (1995) [Pubmed]
  22. The amino terminal lectin-like domain of thrombomodulin is required for constitutive endocytosis. Conway, E.M., Pollefeyt, S., Collen, D., Steiner-Mosonyi, M. Blood (1997) [Pubmed]
  23. Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads. Sandusky, G., Berg, D.T., Richardson, M.A., Myers, L., Grinnell, B.W. J. Biol. Chem. (2002) [Pubmed]
  24. Both cellular and soluble forms of thrombomodulin inhibit fibrinolysis by potentiating the activation of thrombin-activable fibrinolysis inhibitor. Bajzar, L., Nesheim, M., Morser, J., Tracy, P.B. J. Biol. Chem. (1998) [Pubmed]
  25. Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation. Xu, J., Esmon, N.L., Esmon, C.T. J. Biol. Chem. (1999) [Pubmed]
  26. Tissue factor pathway inhibitor and other endothelium-dependent hemostatic factors in elderly individuals with normal or impaired glucose tolerance and type 2 diabetes. Leurs, P.B., Stolk, R.P., Hamulyak, K., Van Oerle, R., Grobbee, D.E., Wolffenbuttel, B.H. Diabetes Care (2002) [Pubmed]
  27. Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma. Elisen, M.G., von dem Borne, P.A., Bouma, B.N., Meijers, J.C. Blood (1998) [Pubmed]
  28. Protein C inhibitor regulates the thrombin-thrombomodulin complex in the up- and down regulation of TAFI activation. Mosnier, L.O., Elisen, M.G., Bouma, B.N., Meijers, J.C. Thromb. Haemost. (2001) [Pubmed]
  29. Probing the activation of protein C by the thrombin-thrombomodulin complex using structural analysis, site-directed mutagenesis, and computer modeling. Knobe, K.E., Berntsdotter, A., Shen, L., Morser, J., Dahlbäck, B., Villoutreix, B.O. Proteins (1999) [Pubmed]
  30. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. Esmon, C.T. FASEB J. (1995) [Pubmed]
  31. Thrombomodulin RNA is destabilized through its 3'-untranslated element in cells exposed to IFN-gamma. Navarro, A., Frevel, M., Gamero, A.M., Williams, B.R., Feldman, G., Larner, A.C. J. Interferon Cytokine Res. (2003) [Pubmed]
  32. Proline at the P2 position in protein C is important for calcium-mediated regulation of protein C activation and secretion. Rezaie, A.R., Esmon, C.T. Blood (1994) [Pubmed]
  33. Clinical importance of thrombomodulin serum levels. Califano, F., Giovanniello, T., Pantone, P., Campana, E., Parlapiano, C., Alegiani, F., Vincentelli, G.M., Turchetti, P. European review for medical and pharmacological sciences. (2000) [Pubmed]
  34. A steady-state competition model describes the modulating effects of thrombomodulin on thrombin inhibition by plasminogen activator inhibitor-1 in the absence and presence of vitronectin. Dekker, R.J., Pannekoek, H., Horrevoets, A.J. Eur. J. Biochem. (2003) [Pubmed]
  35. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. Sakharov, D.V., Plow, E.F., Rijken, D.C. J. Biol. Chem. (1997) [Pubmed]
  36. Plasma thrombomodulin in orthotopic liver transplantation. Boutiere, B., Arnoux, D., Boffa, M.C., Samson, D., Le Treut, Y.P., Sampol, J. Transplantation (1994) [Pubmed]
  37. Thrombomodulin is synthesized by osteoblasts, stimulated by 1,25-(OH)2D3 and activates protein C at their cell membrane. Maillard, C., Berruyer, M., Serre, C.M., Amiral, J., Dechavanne, M., Delmas, P.D. Endocrinology (1993) [Pubmed]
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