Soluble thrombomodulin as a predictor of type 2 diabetes: results from the MONICA/KORA Augsburg case–cohort study, 1984–1998

Thorand, Barbara; Baumert, Jens; Herder, Christian; Meisinger, Christa; Köenig, Wolfgang

doi:10.1007/s00125-006-0568-x

Cited by 15 publications

(15 citation statements)

References 11 publications

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“…While sTM was not predictive for CHD in the present study, in a previous report a 1 SD increase in sTM was associated with a 27% decrease in the risk of type 2 diabetes (HR 0.73; 95%CI 0.58-0.91) in the same population [5].…”

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confidence: 88%

“…Therefore, we sought to further elucidate whether sTM is a predictor of CHD in a large prospective population-based cohort study of middle-aged men and women.We conducted a case-cohort study using data from the population-based MONICA/KORA Augsburg cohort study. The study design has been described previously [4,5]. Briefly, three independent surveys, with a total number of 13 427 participants aged 25-74 years, were conducted.…”

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confidence: 99%

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Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case–cohort study

Karakas

Baumert

Herder

et al. 2011

Journal of Thrombosis and Haemostasis

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There is increasing experimental evidence that endothelial dysfunction represents an important component of atherosclerotic cardiovascular disease (CVD).Thrombomodulin (TM) is an endothelial cell surface receptor for thrombin and exerts anti-coagulatory effects through thrombin-mediated activation of protein C which, in the presence of protein S, degrades factor (F)Va and FVIIIa, thereby restraining the coagulation reactions and restricting fibrin formation [1]. In spite of being mostly located on endothelial cells of arteries, there is, however, a small amount of circulating, soluble TM (sTM). The physiological role of sTM is not fully known, but it is thought to indicate endothelial damage [2]. Data from epidemiological studies, aiming to evaluate the potential association between circulating levels of sTM and incident CHD, are sparse and controversial [3]. Therefore, we sought to further elucidate whether sTM is a predictor of CHD in a large prospective population-based cohort study of middle-aged men and women.We conducted a case-cohort study using data from the population-based MONICA/KORA Augsburg cohort study. The study design has been described previously [4,5]. Briefly, three independent surveys, with a total number of 13 427 participants aged 25-74 years, were conducted. A combined endpoint that included incident fatal/non-fatal myocardial infarction (MI) and sudden cardiac death occurring before the age of 75 years was used as the outcome variable. Until 2000, the diagnosis of a major non-fatal MI event was based on the MONICA algorithm taking into account symptoms, cardiac enzymes and electrocardiograph (ECG) changes. Since 2001 MI was diagnosed according to European Society of Cardiology (ESC) and American College of Cardiology (ACC) criteria. Deaths from MI were validated by autopsy reports, death certificates, chart review and information from the last treating physician. As a result of the low incidence of CHD under 35 years, the present study was limited to 10 718 persons (5382 men and 5336 women) between 35-74 years at baseline. After exclusion of participants with self-reported prevalent CHD, the source population for the present study comprised 9300 subjects. For the case-cohort study, a random sample of the source population was selected stratifying by sex and survey. Participants with missing values for sTM or any of the covariables used in the present analysis were excluded. The present analysis comprised 1378 participants (197 men and 49 women with CHD, and 602 men and 530 women without CHD). The follow-up time (mean ± SD) was 7.2 ± 4.0 years.Levels of sTM were measured in plasma using ELISA (Diaclone, Besanc¸on, France). The intra-and inter-assay CVs were 10.3% and 16.8%, respectively, which may have attenuated the association between sTM concentration and CHD slightly.All statistical analyses have been described in detail elsewhere [4]. Cox proportional hazards analysis was used to assess the association between sTM and incident CHD using different adjustments for classic cardiovascular...

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confidence: 99%

Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case–cohort study

Karakas

Baumert

Herder

et al. 2011

Journal of Thrombosis and Haemostasis

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“…Soluble TM fragments in plasma and urine are proposed to be released from the cell surface by 14 proteases and may serve as diagnostic biomarkers of blood circulation disorders such as coronary heart disease, or diabetes (Blann and Yip, 1998;Gabat et al, 1996;Ishii and Majerus, 1985;Nakano et al, 1998;Salomaa et al, 1999;Salomaa et al, 1998;Thorand et al, 2007). In this study, reduction of sTM and decreased TM levels were observed in primary cultured skin from TM lox/lox ; K5-Cre mice, and these mice exhibited delayed cutaneous wound healing.…”

Section: Discussionmentioning

confidence: 98%

Thrombomodulin Regulates Keratinocyte Differentiation and Promotes Wound Healing

Cheng

Lai

et al. 2013

Journal of Investigative Dermatology

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The membrane glycoprotein thrombomodulin (TM) has been implicated in keratinocyte differentiation and wound healing, but its specific function remains undetermined. The epidermis-specific TM knockout mice were generated to investigate the function of TM in these biological processes. Primary cultured keratinocytes obtained from TM(lox/lox); K5-Cre mice, in which TM expression was abrogated, underwent abnormal differentiation in response to calcium induction. Poor epidermal differentiation, as evidenced by downregulation of the terminal differentiation markers loricrin and filaggrin, was observed in TM(lox/lox); K5-Cre mice. Silencing TM expression in human epithelial cells impaired calcium-induced extracellular signal-regulated kinase pathway activation and subsequent keratinocyte differentiation. Compared with wild-type mice, the cell spreading area and wound closure rate were lower in keratinocytes from TM(lox/lox); K5-Cre mice. In addition, the lower density of neovascularization and smaller area of hyperproliferative epithelium contributed to slower wound healing in TM(lox/lox); K5-Cre mice than in wild-type mice. Local administration of recombinant TM (rTM) accelerated healing rates in the TM-null skin. These data suggest that TM has a critical role in skin differentiation and wound healing. Furthermore, rTM may hold therapeutic potential for the treatment of nonhealing chronic wounds.

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“…Also, we found an increased plasma concentration of TM as a result of endothelial damage in our hypertensive patient. Paradoxically, higher plasma TM concentrations at inception were associated with a lower incidence of coronary heart disease and diabetes in a cohort of presumed healthy people, implying that its soluble form may be vasculoprotective [17,18]. Instead, young patients with diabetes have increased plasma TM concentrations compared to patients without diabetes, reflecting endothelial damage [19].…”

Section: Tm and Endothelial Dysfunctionmentioning

confidence: 99%

Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome

Demeulenaere

Devreese

Vanbelleghem

et al. 2018

Nephron

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Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.

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Soluble thrombomodulin as a predictor of type 2 diabetes: results from the MONICA/KORA Augsburg case–cohort study, 1984–1998

Cited by 15 publications

References 11 publications

Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case–cohort study

Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case–cohort study

Thrombomodulin Regulates Keratinocyte Differentiation and Promotes Wound Healing

Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome

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