Thrombomodulin as a regulator of the anticoagulant pathway

Anastasiou, Georgia; Gialeraki, Argyri; Merkouri, Efrossyni; Politou, Marianna; Travlou, Αnthi

doi:10.1097/mbc.0b013e32834cb271

Cited by 67 publications

(61 citation statements)

References 124 publications

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“…However the specific THBD SNPs associated with VTE risk have not been definitively identified. 32,33 The functional implication that the minor alleles of rs2144940 (C), rs2567614 (G), and rs1998081 (T) are associated with lower THBD gene expression, combined with lower THBD gene expression in VTE cases compared with controls, supports our findings that carriers of the minor alleles for rs2144940, rs2567617, and rs1998081 have an increased risk of VTE ( Figure 2; Table 2). …”

supporting

confidence: 78%

“…31 THBD acts as an intrinsic anticoagulant by forming a 1:1 complex with the coagulation factor thrombin (F2) and altering F2 specificity for several substrates, ultimately acting as an antithrombotic factor. 32 In addition, the F2:THBD complex activates protein C, leading to degradation of factors V and VIII. 30 Consequently, THBD is an important candidate gene in VTE risk.…”

mentioning

confidence: 99%

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Novel genetic predictors of venous thromboembolism risk in African Americans

Hernandez

Gamazon

Smithberger

et al. 2016

Blood

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• Our study has identified common genetic risk factors for VTE among AAs.• These risk factors are associated with decreased thrombomodulin gene expression, suggesting a mechanistic link.Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P < 6 3 10 27). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P 5 9.87 3 10 26 ). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease. (Blood. 2016;127(15):1923-1929

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supporting

confidence: 78%

mentioning

confidence: 99%

Novel genetic predictors of venous thromboembolism risk in African Americans

Hernandez

Gamazon

Smithberger

et al. 2016

Blood

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“…In the 3.3-Mb DNA fragment of sSMC (20), 35 genes were mapped. Among them, the THBD gene codes for thrombomodulin, an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds [Anastasiou et al, 2012]. This protein is also a cofactor of the protein C anticoagulant pathway which is expressed mainly on the endothelial surface of blood vessels and in placental syncytiotrophoblast cells [Stortoni et al, 2012] and therefore could be involved in the pathogenesis of pregnancy loss in this case.…”

Section: Genetic Content Of Ssmc In Infertile Patientsmentioning

confidence: 99%

Small Supernumerary Marker Chromosomes in Human Infertility

Armanet

Tosca

Brisset

et al. 2015

Cytogenet Genome Res

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Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by banding cytogenetics. The objective of this study was to provide an overview of sSMC frequency and characterization in a context of infertility and to review the literature describing sSMC in relation with male and female infertility. Therefore, a systematic literature review on sSMC associated with infertility was conducted by means of a PubMed literature and a sSMC database (http://ssmc-tl.com/sSMC.html) search. A total of 234 patients with infertility were identified as carriers of sSMC. All chromosomes, except chromosomes 10, 19 and the X, were involved in sSMC, and in 72% the sSMC originated from acrocentric chromosomes. Euchromatic imbalances were caused by the presence of sSMC in 30% of the cases. Putative genes have been identified in only 1.2% of sSMC associated with infertility. The implication of sSMC in infertility could be due to a partial trisomy of some genes but also to mechanical effects perturbing meiosis. Further precise molecular and interphase-architecture studies on sSMC are needed in the future to characterize the relationship between this chromosomal anomaly and human infertility.

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“…15 The formation of the thrombin-TM complex is important for initiating the activation of the protein C anticoagulant pathway, wherein thrombin converts into a protein whose procoagulant activity is blocked. 16,17 At the same time, it acquires a number of important qualities such as the ability to activate protein C, to inhibit protein C inhibitor, and others. 18 The soluble form of TM (sTM), resulting from the enzyme cleavage of the membrane form, circulates freely in the plasma.…”

Section: Introductionmentioning

confidence: 99%

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Negreva

Georgiev

Vitlianova

2016

Clin Appl Thromb Hemost

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Background: Increased coagulation activity has been established in paroxysmal atrial fibrillation (PAF), but data on the anticoagulant system are scarce. Purpose: To examine the protein C anticoagulant pathway in the early hours of the disease. Materials and Methods: Fifty-one patients (26 men and 25 women; mean age 59.84 + 1.60 years) and 52 controls (26 men and 26 women; mean age 59.50 + 1.46 years) were selected for the study. Protein C antigen and its activity, total protein S, free protein S and its activity, soluble forms of endothelial protein C receptor (sEPCR), and thrombomodulin (sTM) were examined in the plasma. Results: The indicators were studied in patients between the 2nd and the 24th hour after the onset of arrhythmia. Levels of protein C were significantly elevated in patients compared to controls (111.40% + 6.66% vs 94.83% + 4.47%; P ¼ .039). Protein C activity showed significant reduction in PAF (73.13% + 5.80% vs 103.3% + 3.80%; P < .001). Total protein S levels did not differ significantly (108.20% + 4.07% vs 102.40% + 3.65%; P ¼ .30). Free protein S (76.81% + 6.01% vs 122.10% + 3.97%; P < .001) and its activity (71.39% + 6.27% vs 119.50% + 6.54%; P < .001) were reduced in patients. Higher levels of sEPCR (203.10 + 10.33 vs 133.10 + 7.37 ng/mL; P < .001) and sTM (6.50+0.40 vs 4.48+0.28 ng/mL; P < .001) were measured in PAF. Conclusion: Protein C activity is reduced still in the first hours (until the 24th hour) of PAF clinical manifestation, determining reduced activity of the anticoagulant pathway as a whole. The established low levels of free protein S and its activity as well as low sEPCR and sTM levels are a possible explanation of the changes in protein C activity.

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Thrombomodulin as a regulator of the anticoagulant pathway

Cited by 67 publications

References 124 publications

Novel genetic predictors of venous thromboembolism risk in African Americans

Novel genetic predictors of venous thromboembolism risk in African Americans

Small Supernumerary Marker Chromosomes in Human Infertility

Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

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