Circulating Thrombomodulin: Release Mechanisms, Measurements, and Levels in Diseases and Medical Procedures

Abstract

Thrombomodulin (TM) is a type I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM, which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood, but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with coronavirus disease-2019 (COVID-19) recently. In addition, microvesicles that contain membrane TM (microvesicle-TM) have been found to be released from activated cells, which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and microvesicle-TM have been reported, including enzymatic, chemical and TM mutation mechanisms. Measurements of sTM and microvesicle-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories: (i) release mechanisms of circulating TM, (ii) methods for measuring circulating TM in biological samples, and (iii) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease.

Prognostic value of an automated thrombin generation assay in COVID-19 patients entering hospital: A multicentric, prospective observational study

“…This new putative marker for clinical worsening may help for risk stratification on admission. TM is a type-I transmembrane protein that is mainly expressed on endothelial cells, but also on macrophages, monocytes, neutrophils and platelets, and that has multiple biological functions, among which anti-inflammatory, anticoagulant and fibrinolysis functions: it can be released in the circulation [13] . Elevated plasma levels of soluble TM is a component of the so-called COVID-19 coagulopathy and two recent findings suggest that soluble TM is highly correlated with survival among COVID-19 patient [14] , [15] , soluble TM levels being considered as a surrogate marker for the degree of endothelial injury.…”

Association and predictive value of soluble thrombomodulin with mortality in patients with acute respiratory distress syndrome: systematic review and meta-analysis

“…The mechanism for TM shedding has been reported on. The sTM is formed due to the proteolytic cleavage of proteases, including neutrophil-derived proteases, rhomboids, and metalloproteinases, which are released during vascular damage-related diseases, including inflammation, infection, and sepsis (9). Furthermore, oxygen radicals can rapidly induce endothelial cells to chemically release sTM.…”

“…When TM interacts with thrombin, a TM-thrombin complex is formed to activate protein C, thereby exerting anticoagulatory, antiinflammatory, and profibrinolytic effects (8). As a major form of circulating TM, soluble TM (sTM) is produced when an intact protein is cleaved under pathologic conditions like cardiovascular diseases, inflammation, infection, and metabolic disorders (9). Hence, elevated sTM levels are associated with endothelial injury, impaired anticoagulation and fibrinolysis, and inflammatory status.…”

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

“…Thrombomodulin (TM), also known as CD141, is a type I transmembrane glycoprotein expressed on the surface of ECs that functions as a cofactor in the thrombin-catalyzed activation of protein C in the anticoagulant pathway by forming a 1:1 stoichiometric complex with thrombin [ 229 ]. Circulating fragments of TM lacking the transmembrane domain and known as soluble TM (sTM) are also found in blood, urine, and other biofluids [ 229 ]. In healthy humans, sTM levels are low, while high sTM levels are common in patients suffering from various diseases.…”

“…In healthy humans, sTM levels are low, while high sTM levels are common in patients suffering from various diseases. In particular, a consistent increase in sTM levels is now widely regarded as an important biomarker for EC dysfunction and vascular risk assessment [ 229 ]. As far as SSc is concerned, sTM was found to be elevated in SSc patients respect to healthy controls [ 230 , 231 ], and to be significantly associated with PAH [ 232 ].…”