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PubMed1998

A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone--thrombomodulin as a possible candidate for an adhesion molecule of squamous cell carcinoma.

Thrombomodulin (TM) is an endothelial cell surface glycoprotein which converts thrombin from a procoagulant protease to an anticoagulant. We have previously reported that TM is a useful marker for immunohistochemical diagnosis of angiogenic tumors and also have reported that TM is expressed on squamous cell carcinoma (SCC) of the human esophagus. In addition, the expression of TM is significantly decreased in metastatic foci in lymph nodes compared with that in primary lesions. In order to reveal the biological significance of TM in SCC, we subcloned and established two different cell lines, i.e. TM-high-expressing (TE3HTM) cells and TM-low-expressing (TE3LTM) cells, from a human SCC cell line, TE3, using fluorescence-activated cell sorter (FACS) and examined the biological characteristics of these variant cell lines. These tumor cells revealed very similar morphological figures in ordinary cultured conditions and showed almost equal growth rates under various cultured conditions. By the invasion assay of these tumor cells using matrigel, we found that TE3LTM cells showed significantly increased invasive ability compared with that of TE3HTM cells. Characteristic intercellular localization of TM and a different manner of invasiveness between TE3LTM cells and TE3HTM cells suggest that TM may act as a cell-to-cell interaction molecule.

Carcinoma, Squamous Cell↗

PubMed1992

An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells.

Thrombomodulin plays a role as a cofactor for thrombin-catalyzed activation of protein C on endothelial cells. We examined the effect of homocysteine, a stimulant of atherosclerosis and thrombotic disease, on the cofactor activity and protein level of thrombomodulin and also on the expression of thrombomodulin in endothelial cells. Homocysteine inhibited the cofactor activity of thrombomodulin both on the surface of endothelial cells and in the whole cells dose- and time-dependently, and maximal inhibition of the cofactor activity occurred after a 3- to 6-hour incubation with 10 mmol/L homocysteine (10% of initial activity). Homocysteine also decreased the amount of intact (unreduced) thrombomodulin in endothelial cells. However, at the same condition the total protein level (reduced and unreduced form) of thrombomodulin, determined by dot immunoblot analysis using the monoclonal antibody that recognized both reduced and unreduced thrombomodulin, decreased slightly, and the mRNA level of thrombomodulin showed a twofold to three-fold increase. After 24 hours of incubation, the cofactor activity and total protein level of thrombomodulin were 60% and 165% of the initial values, respectively. When purified thrombomodulin fixed to a microwell plate was treated with homocysteine, both cofactor activity and thrombin-binding ability to the thrombomodulin were decreased in proportion to the concentration of homocysteine. These findings suggest that homocysteine directly inhibited the cofactor activity of thrombomodulin on endothelial cells by reducing the disulfide-bond rich epidermal growth factor-like structures of thrombomodulin. This would a result in the decrease of the antithrombotic property of endothelium and may also trigger off the synthesis of mRNA and protein of thrombomodulin to maintain the antithrombotic properties of the cells.

Endothelium, Vascular↗

PubMed1988

The structure and function of mouse thrombomodulin. Phorbol myristate acetate stimulates degradation and synthesis of thrombomodulin without affecting mRNA levels in hemangioma cells.

Thrombomodulin is an endothelial membrane anticoagulant protein that is a cofactor for protein C activation. We have evaluated the expression of thrombomodulin in cultured mouse hemangioma cells before and after treatment with phorbol myristate acetate (PMA), an agent that stimulates protein kinase C. We also isolated a cDNA encoding 481 amino acids of mouse thrombomodulin and the entire 3'-untranslated portion of its mRNA. The deduced amino acid sequence of mouse thrombomodulin is similar to those determined for human and bovine thrombomodulin. An S1 nuclease protection assay was used to measure thrombomodulin mRNA in hemangioma cells. The half-life for thrombomodulin mRNA was 8.9 +/- 1.8 h (S.D.) in cells treated with actinomycin D. Treatment with PMA had no effect on thrombomodulin mRNA levels. Thrombomodulin turnover was evaluated by immunoprecipitation of [35S]methionine-labeled thrombomodulin. The t1/2 was 19.8 +/- 3.9 h (S.D.); PMA treatment decreased the t1/2 to 10.9 +/- 1.1 h (S.D.) while increasing the rate of synthesis to a maximum of 190% of control. Protein C cofactor activity on hemangioma cells was reduced 35 +/- 4% by treatment with PMA within 30 min. This decrease was associated with a parallel decline in cell surface thrombomodulin antigen and with enhanced phosphorylation of thrombomodulin on serine residues. We conclude that thrombomodulin is phosphorylated in response to treatment of hemangioma cells with PMA which leads to decreased protein C cofactor activity and both increased degradation and synthesis of thrombomodulin.

Amino Acid Sequence↗

PubMed1999

Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds.

Thrombomodulin is a cell surface anticoagulant that is expressed by endothelial cells and epidermal keratinocytes. Using immunohistochemistry, we examined thrombomodulin expression during healing of partial-thickness wounds in human skin and full-thickness wounds in mouse skin. We also examined thrombomodulin expression and wound healing in heterozygous thrombomodulin-deficient mice, compound heterozygous mice that have <1% of normal thrombomodulin anticoagulant activity, and chimeric mice derived from homozygous thrombomodulin-deficient embryonic stem cells. In both human and murine wounds, thrombomodulin was absent in keratinocytes at the leading edge of the neoepidermis, but it was expressed strongly by stratifying keratinocytes within the neoepidermis. No differences in rate or extent of reepithelialization were observed between wild-type and thrombomodulin-deficient mice. In chimeric mice, both thrombomodulin-positive and thrombomodulin-negative keratinocytes were detected within the neoepidermis. Compared with wild-type mice, heterozygous and compound heterozygous thrombomodulin-deficient mice exhibited foci of increased collagen deposition in the wound matrix. These findings demonstrate that expression of thrombomodulin in keratinocytes is regulated during cutaneous wound healing. Severe deficiency of thrombomodulin anticoagulant activity does not appear to alter reepithelialization but may influence collagen production by fibroblasts in the wound matrix.

Animals↗

PubMed1992

Ligand specificity of human thrombomodulin. Equilibrium binding of human thrombin, meizothrombin, and factor Xa to recombinant thrombomodulin.

Thrombomodulin is an endothelial glycoprotein that serves as a cofactor for protein C activation. To examine the ligand specificity of human thrombomodulin, we performed equilibrium binding assays with human thrombin, thrombin S205A (wherein the active site serine is replaced by alanine), meizothrombin S205A, and human factor Xa. In competition binding assays with CV-1(18A) cells expressing cell surface recombinant human thrombomodulin, recombinant wild type thrombin and thrombin S205A inhibited 125I-diisopropyl fluorophosphate-thrombin binding with similar affinity (Kd = 6.4 +/- 0.5 and 5.3 +/- 0.3 nM, respectively). However, no binding inhibition was detected for meizothrombin S205A or human factor Xa (Kd greater than 500 nM). In direct binding assays, 125I-labeled plasma thrombin and thrombin S205A bound to thrombomodulin with Kd values of 4.0 +/- 1.9 and 6.9 +/- 1.2 nM, respectively. 125I-Labeled meizothrombin S205A and human factor Xa did not bind to thrombomodulin (Kd greater than 500 nM). We also compared the ability of thrombin and factor Xa to activate human recombinant protein C. The activation of recombinant protein C by thrombin was greatly enhanced in the presence of thrombomodulin, whereas no significant activation by factor Xa was detected with or without thrombomodulin. Similar results were obtained with thrombin and factor Xa when human umbilical vein endothelial cells were used as the source of thrombomodulin. These results suggest that human meizothrombin and factor Xa are unlikely to be important thrombomodulin-dependent protein C activators and that thrombin is the physiological ligand for human endothelial cell thrombomodulin.

Cells, Cultured↗

PubMed2000

G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels.

Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p <0.001), and smoking (OR 2.15, p <0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p <0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.

Asian People↗

PubMed1994

Enhancement of thrombin-thrombomodulin-catalysed protein C activation by phosphatidylethanolamine containing unsaturated fatty acids: possible physiological significance of phosphatidylethanolamine in anticoagulant activity of thrombomodulin.

The effects of phospholipid vesicles and their fatty acid compositions on the acceleration of Protein C activation by thrombin-thrombomodulin was studied in vitro. Four main phospholipid fractions were prepared from cultured human umbilical vein endothelial cells, and purified thrombomodulin from human placenta was reconstituted into vesicles consisting of phosphatidylcholine (PtdCho) alone, PtdCho plus phosphatidylethanolamine (PtdEtn), PtdCho plus phosphatidylserine (PtdSer) and PtdCho plus PtdIns (1:1, w/w in each case). Vesicles of PtdCho, PtdIns/PtdCho, PtdSer/PtdCho and PtdEtn/PtdCho increased thrombin-thrombomodulin-catalysed protein C activation by 1.2-, 1.9-, 4.3- and 8.4-fold respectively compared with that in the absence of phospholipid. This Protein C activation was not affected by distearoyl PtdEtn/distearoyl PtdCho, whereas it was markedly increased with increasing content of unsaturated fatty acid in PtdEtn. The thrombin-dependent Protein C activation by thrombomodulin reconstituted into dilinolenoyl PtdEtn/distearoyl PtdCho was 14.6 times that by thrombomodulin reconstituted into distearoyl PtdEtn/distearoyl PtdCho, as a result of a decrease in the dissociation constant (Kd) for thrombin and the Michaelis constant (Km) for Protein C of thrombomodulin. Binding of Protein C to PtdEtn/PtdCho fixed to a microwell plate required the presence of CaCl2 and increased with increasing degree of unsaturation of fatty acid in PtdEtn. As PtdEtn appeared on the outside of the plasma membrane in cultured human umbilical vein endothelial cells after thrombin stimulation, it was presumed that Protein C activation could be elevated by PtdEtn at the outer surface of the plasma membrane via an increased affinity between thrombomodulin, thrombin and Protein C, resulting from both increased formation of the thrombin-thrombomodulin complex via a conformational change in thrombomodulin and increased binding of Protein C to the membrane phospholipid in a Ca(2+)-dependent manner.

Calcium Chloride↗

PubMed1987

[Effect of rabbit thrombomodulin on the inhibition of thrombin by the antithrombin-heparin complex: role of the acid domain of thrombomodulin].

Acidic and non-acidic forms of rabbit thrombomodulin were studied with regard to their effects on the inhibition of thrombin by antithrombin in the presence of exogenous heparin. The non acidic form was obtained by proteolytic cleavage of a polyanionic component (presumably a sulfated polysaccharide) from the parent acidic form of thrombomodulin, and purified by ion-exchange chromatography. It was previously found that the acidic form of thrombomodulin increases the rate of thrombin inactivation by antithrombin. The present study showed that thrombin bound to acidic thrombomodulin was inactivated at a lower rate by antithrombin in the presence of exogenous heparin than was free thrombin or thrombin bound to the non-acidic form of thrombomodulin. The data suggest that the acidic component of thrombomodulin is primarily responsible for the retardation of thrombin-antithrombin complex formation in the presence of exogenous heparin. It is proposed that the polyanionic component of thrombomodulin blocks a site on thrombin required for heparin binding, thus rendering the antithrombin-heparin complex ineffective.

Animals↗

PubMed1993

Sequences required for thrombomodulin cofactor activity within the fourth epidermal growth factor-like domain of human thrombomodulin.

Activation of protein C by thrombin is stimulated by the endothelial cell cofactor thrombomodulin. The structural regions of thrombomodulin necessary for cofactor activity have been localized to the fourth through sixth epidermal growth factor (EGF)-like domains. The fourth EGF-like domain is unnecessary for high affinity thrombin binding, but is required for cofactor activity. To identify essential sequences within the fourth EGF-like domain, a series of recombinant human thrombomodulins consisting of EGF-like domains four through six were expressed in human kidney cells. These mutants contain replacements of disulfide loops within the fourth EGF-like domain, thereby conserving overall disulfide bond structure. All of the mutants bound to thrombin with high affinity, and inhibited the fibrinogen-clotting activity of thrombin to a similar extent. Two regions of the fourth EGF-like domain were identified to be essential for cofactor activity: 1) the sequence consisting of amino acids Glu-357, Tyr-358, and Gln-359 shared by the overlapping first and second disulfide loops, and 2) the amino-terminal region of the third disulfide loop containing amino acids Glu-374, Gly-375, and Phe-376. These results suggest that amino acids critical for thrombomodulin cofactor activity are located near the junction between the two subdomains of the fourth EGF-like domain.

Amino Acid Sequence↗

PubMed2003

Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study.

Plasma thrombomodulin (soluble TM; sTM) is considered to be a marker of endothelial injury, but a recent report indicated that the relationship of sTM with thrombosis is complex. Venous thromboembolic events were identified in adults in two longitudinal cohort studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, totaling 21 690 participants. After 8 years of follow-up, sTM was measured in baseline plasma of 305 participants who developed venous thrombosis and 607 who did not. Thrombomodulin A455V genotype was determined in 302 cases and 626 controls. There was no difference in the prevalence of the three TM genotypes between cases and controls and no difference in age-adjusted mean values of sTM by genotype. There were no associations of age-adjusted sTM or TMA455V genotype with overall venous thromboembolism or with thrombosis in any subtype of venous thromboembolism.

Age Factors↗

PubMed1994

Immobilization of human thrombomodulin on biomaterials: evaluation of the activity of immobilized human thrombomodulin.

Thrombomodulin (TM) is a newly described endothelial cell associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. In this study, the immobilization of hTM was investigated in detail using surface modified polymers. As the basis of immobilization, poly(acrylic acid) (PAAc) surface-grafted poly(ethylene) (PAAc-g-PE) film was used with the expectation of increasing the immobilization amount of hTM. The effect of the immobilization reaction on the hTM activities, and the comparison of the activities of the immobilized hTM with the free hTM, were studied.

Acrylic Resins↗

PubMed2006

Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population.

INTRODUCTION: Thrombomodulin (TM) is an essential cofactor in protein C activation by thrombin. Here, we evaluated the contribution of genetic variations in the TM gene to soluble TM (sTM) level and deep vein thrombosis (DVT) in Japanese. PATIENTS AND METHODS: We sequenced the TM putative promoter, exon, and 3'-untranslated region in DVT patients (n=118). Among 17 genetic variations we identified, two missense mutations (R385K, D468Y) and three common single nucleotide polymorphisms (-202G>A, 2487A>T, 2729A>C) were genotyped in a general population of 2247 subjects (1032 men and 1215 women) whose sTM levels were measured. We then compared the frequency of these mutations in DVT patients with that in the age, body mass index-adjusted population-based controls. RESULTS: We identified one neutral mutation (H381) and three missense mutations (R385K; n=2, A455V; n=53 heterozygous, n=14 homozygous, D468Y; n=2) of TM in the DVT patients. Age-adjusted mean values of sTM were lower in C-allele carriers of 2729A>C than in noncarriers in the Japanese general population (women: 16.7+/-0.3 U/ml vs. 17.9+/-0.2 U/ml, p<0.01, men: 19.4+/-0.3 U/ml vs. 20.4+/-0.3 U/ml, p=0.03). Additionally, the CC genotype of this mutation was more common in the male DVT patients than in the male individuals of the general population (odds ratio=2.76, 95% confidence interval=1.14-6.67; p=0.02). This mutation was in linkage disequilibrium (r-square>0.9) with A455V mutation. CONCLUSIONS: TM mutations, especially those with a haplotype consisting of 2729A>C and A455V missense mutation, affect sTM levels, and may be associated with DVT in Japanese.

3' Untranslated Regions↗

PubMed2003

Statins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation.

Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. TM maintains thrombohemorrhagic homeostasis by forming a complex with thrombin, which subsequently loses its procoagulant properties and instead activates protein C. Acquired deficiency of endothelial TM is of particular pathophysiological significance in sepsis and related disorders. We show here that two different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), atorvastatin and simvastatin, strongly increase the expression and functional activity of TM in human umbilical vein endothelial cells, human coronary artery endothelial cells, and EA.hy926 endothelial cells. The increase in endothelial TM conferred by statin was prevented by the addition of mevalonic acid, geranylgeranyl-pyrophosphate, and nitric oxide scavenger, and was mimicked by the addition of a specific inhibitor of geranylgeranyl transferase, as well as by nitric oxide donors. Moreover, statin counteracted tumor necrosis factor alpha-induced downregulation of endothelial cell TM. The increase in endothelial cell TM activity in response to statin constitutes a novel pleiotropic (non-lipid-related) effect of these commonly used compounds, and may be of clinical significance in disorders where deficient endothelial TM and protein C activation play a pathophysiological role.

Anticholesteremic Agents↗

PubMed2005

Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma.

Endothelial cell membrane-bound thrombomodulin (TM) plays a critical role as a cofactor in the protein C pathway, important in regulating coagulation as well as inflammation. Heterogeneous soluble TM fragments circulate in the plasma and are found at increased levels in various diseases such as cardiovascular disease and diabetes, and in ischemic and/or inflammatory endothelial injuries. The anticoagulant function of these soluble fragments has not been measured in healthy individuals or in patients. Using an immobilized monoclonal antibody against TM and a microtiter plate format, an assay was designed to capture the soluble TM fragments in plasma and measure their cofactor activity in the thrombin-mediated activation of protein C. In addition, soluble TM antigen levels were measured by enzyme-linked immunosorbent assay. Both assays were used to investigate a group of healthy blood donors. TM fragments released into plasma were shown to retain significant cofactor activity, and reference intervals for healthy men and women were established. Furthermore, a statistically significant correlation was observed between soluble TM antigen levels and soluble TM cofactor activity. This notwithstanding, soluble TM activity only accounted for a minor part of all variation in soluble TM antigen levels (R2 = 22% in men and R2 = 16% in women).

Adolescent↗

PubMed2006

Amplified anticoagulant activity of tissue factor-targeted thrombomodulin: in-vivo validation of a tissue factor-neutralizing antibody fused to soluble thrombomodulin.

Tissue factor (TF) exposure is a potent pro-thrombotic trigger that initiates activation of the coagulation cascade, while thrombomodulin (TM) is a potent anticoagulant protein that limits the extent of activation. Both TF neutralizing antibodies and soluble TM (sTM) are effective anticoagulants. We have developed a novel anticoagulant fusion protein, Ab(TF)-TM, by fusing a TFneutralizing single-chain antibody, Ab(TF), to an active fragment of TM. Ab(TF)-TM is a novel anticoagulant targeting to sites of TF exposure with a dual mechanism of action. The Ab(TF) portion of the molecule inhibitsTF/factorVIIa mediated activation of FIX and FX, and the TM portion of the molecule acts as a cofactor for activation of protein C. In-vitro coagulation assays show that Ab(TF)-TM more potently inhibits TF-initiated coagulation (prothrombin time) than can its individual components, Ab(TF) (20-fold) and sTM (80-fold) alone, or in combination (10-fold). In contrast, the potency of Ab(TF)-TM in the activated partial thromboplastin and thrombin clotting time assays was similar to sTM alone. In a rat model of disseminated intravascular coagulation (DIC), intravenous injection of a human TF-containing thromboplastin reagent (0.5 ml/kg) resulted in an immediate death in approximately 60% of the animals and a clinical score of approximately 2.5. Pre-injection of Ab(TF)-TM or Ab(TF) and sTM, given alone or in combination, showed dose-dependent efficacy. At a dose of 0.7 nmol/kg, Ab(TF)-TM completely prevented death and reduced clinical scores by 79%, while neitherAb(TF) nor sTM, given alone or in combination, showed significant therapeutic effects. Calculated effective doses that reduced mortality by 50% relative to that in the control group (ED(50), nmol/kg) were 0.21 for Ab(TF)-TM, 3.2 for an equimolar mixture of Ab(TF) and sTM, 4.3 for sTM and 20 for Ab(TF). Thus, Ab(TF)-TM presented 10- to 100-fold enhancement of the anticoagulant potency, relative to the ED(50) in Ab(TF) and sTM given either alone or in combination, in a rat DIC model.

Animals↗

PubMed1998

Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells.

Thrombomodulin (TM), a thrombin receptor protein found on the endothelial cell surface, contains 6 tandem epidermal growth factor (EGF)-like structures. Recombinant human TM peptide containing these 6 EGF-like domains (rTME1-6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localization of TM in atherosclerotic lesions and the effects of rTME1-6 on the growth of cultured rat vascular smooth muscle cells (SMCs). Immunohistochemical analysis demonstrated that TM antigen was localized on monocytes, macrophages, and vascular SMCs. In cultured vascular SMCs, rTME1-6 accelerated [3H]thymidine uptake into DNA in a dose-dependent manner up to 3.4 times the control level. This mitogenic activity was abolished by addition of polyclonal anti-human TM antibody. The rTME1-6-induced mitogenesis was enhanced by EGF. However, a neutralizing monoclonal antibody against the EGF receptor (monoclonal antibody 225) did not inhibit the mitogenic activity of rTME1-6. Calphostin C, a specific protein kinase C inhibitor, and lavendustin-A, an inhibitor of EGF receptor-specific protein tyrosine kinase, inhibited the mitogenic activities of both rTME1-6 and EGF. Finally, rTME1-6 treatment increased the level of phosphorylated mitogen-activated protein kinase in SMCs. Together, these results suggest that TM expression in atherosclerotic lesions may be associated with promotion of atherosclerosis through its mitogenic activity in vascular SMCs.

Aged↗

PubMed2001

Tissue-restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block.

The endothelial cell surface receptor thrombomodulin (TM) inhibits blood coagulation by forming a complex with thrombin, which then converts protein C into the natural anticoagulant, activated protein C. In mice, a loss of TM function causes embryonic lethality at day 8.5 p.c. (post coitum) before establishment of a functional cardiovascular system. At this developmental stage, TM is expressed in the developing vasculature of the embryo proper, as well as in non-endothelial cells of the early placenta, giant trophoblast and parietal endoderm. Here, we show that reconstitution of TM expression in extraembryonic tissue by aggregation of tetraploid wild-type embryos with TM-null embryonic stem cells rescues TM-null embryos from early lethality. TM-null tetraploid embryos develop normally during midgestation, but encounter a secondary developmental block between days 12.5 and 16.5 p.c. Embryos lacking TM develop lethal consumptive coagulopathy during this period, and no live embryos are retrieved at term. Morphogenesis of embryonic blood vessels and other organs appears normal before E15. These findings demonstrate a dual role of TM in development, and that a loss of TM function disrupts mouse embryogenesis at two different stages. These two functions of TM are exerted in two distinct tissues: expression of TM in non-endothelial extraembryonic tissues is required for proper function of the early placenta, while the absence of TM from embryonic blood vessel endothelium causes lethal consumptive coagulopathy.

Animals↗

PubMed1996

Increased endothelial and epidermal thrombomodulin expression and plasma thrombomodulin level in progressive systemic sclerosis.

To clarify the relation between systemic and cutaneous vascular endothelial injury in progressive systemic sclerosis (PSS), we examined thrombomodulin (TM) expression in PSS skin lesions immuno-histopathologically and compared it with plasma soluble TM levels measured by specific enzyme-linked immunosorbent assay. The plasma soluble TM level in PSS patients was significantly higher than that of normal controls and was as high as the levels of SLE patients. In relation to disease activities, the plasma TM levels of sclerotic phase PSS patients were significantly higher than that of atrophic phase PSS patients. The plasma samples with anti-Scl-70 antibody showed a high TM level than samples with anti-centromere antibody or anti-RNP antibody. Barnett's types or systemic corticosteroid treatment did not affect the TM level. Histopathologically, the dermal endothelial TM expression significantly increased in the sclerotic skin and moderately increased in the non-sclerotic skin of PSS compared with that of normal control skin. In addition, immunoreactive TM expression in the epidermis also increased in PSS. Disease activity-dependent elevation of plasma TM levels and immuno-histopathological expression of TM suggested generalized endothelial and epidermal cell involvement in PSS, and compensation in part by overproduction of TM by endothelial cells.

Adult↗