Disease relevance of THBD

• We demonstrate a substantial reduction of vascular endothelial TM expression throughout human diabetic neuropathy [1].
• These findings suggest that an impaired native TM-dependent protein C antithrombotic mechanism may contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy [1].
• 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 [2].
• Antithrombotic effects of recombinant human soluble thrombomodulin in a rat model of vascular shunt thrombosis [3].
• Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells--inhibition of thrombomodulin-dependent protein C activation [4].

Psychiatry related information on THBD

• The decrease in blood pressure and platelet aggregation in response to L-arginine was lower (p < 0.05-0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05-0.02) [5].
• In 45 patients, we evaluated the coagulation parameters, naturally occurring anticoagulants and thrombomodulin at days +15 and +22 after conditioning therapy [6].

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

• Serum TM, ICAM-1, VCAM-1, E-selectin, and creatinine levels were determined in six Japanese patients in the acute phase of vivax malaria and in seven healthy Japanese controls [11].
• 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 [12].
• We postulate that following acute or chronic EC injury, luminal SMC can express TM, and are therefore able to protect the damaged blood vessel from thrombosis [13].
• Incubation of glomeruli with tumor necrosis factor-alpha (TNF) or E. coli lipopolysaccharide depressed their TM-like activity in a dose and time dependent manner [14].
• Results showed that thrombus was detected in the vena cava in six of the six rats treated with saline solution, in zero of the six rats treated with recombinant thrombomodulin (p less than 0.05), in one of six rats treated with recombinant hirudin (p less than 0.05), and in zero of six rats treated with heparin (p less than 0.05) [15].

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

• Recently it was found, using purified proteins, that the anticoagulant thrombin-thrombomodulin complex was also inhibited by PCI [27].
• Protein C inhibitor regulates the thrombin-thrombomodulin complex in the up- and down regulation of TAFI activation [28].
• Molecular models for PC and thrombin bound to a segment of TM were developed [29].
• Structural, kinetic, and competition studies suggest that thrombomodulin blocks these clotting reactions by masking the binding sites for fibrinogen and the platelet thrombin receptor [30].
• Thrombomodulin RNA is destabilized through its 3'-untranslated element in cells exposed to IFN-gamma [31].

Enzymatic interactions of THBD

• Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM) [32].
• Thrombomodulin is cleaved to its soluble form by neutrophil elastase and by other substances produced during acute and chronic inflammatory responses, immunologic reactions and complement activation [33].

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

• EPCR decreased the dissociation constant and increased the maximum velocity for protein C activation mediated by the thrombin-TM complex [20].
• We conclude that TM alters PCI from an anticoagulant into a procoagulant during tissue factor-induced coagulation [27].
• TM mRNA levels were regulated by transcriptional activation via a retinoid receptor beta (RARbeta) [18].
• Sural nerve biopsies from 7 patients with diabetic neuropathy and 10 with axonal neuropathy without vasculopathy were immunostained with anti-TM and anti-von Willebrand factor (vWF; an endothelial cell marker) antibodies [1].
• In the presence of TM (and a concomitant pro-pCPB activation), lysis was slow and was not accompanied by accumulation of plasminogen on the fibers [35].

Analytical, diagnostic and therapeutic context of THBD

• Clotting was induced by addition of tissue factor to recalcified plasma in the absence or presence of TM, and clot formation was monitored using turbidimetry [27].
• This neuropathologic case-control study investigated whether vascular endothelial TM expression is deficient in peripheral nerve microvessels in diabetic neuropathy [1].
• Plasma thrombomodulin in orthotopic liver transplantation [36].
• The TM level, which was already elevated preoperatively, remained unchanged during OLT, except for an acute and transitory spike at the time of graft reperfusion [36].
• We have shown by enzyme-linked immunoassay, immunocytochemistry, and immunoprecipitation of labeled proteins that thrombomodulin, a transmembrane glycoprotein involved with thrombin in the activation of protein C, is present at the cell surface of osteoblasts [37].

References