Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure

Abstract

The fact that thrombomodulin (TM) is released into the bloodstream from damaged vascular endothelial cells led us to hypothesize that plasma levels of soluble TM could be an indicator of the development of organ failure. In this study, we examined the changes in plasma levels of TM in 60 septic patients and 13 postsurgical patients, and investigated the circulating levels of interleukin 6 (IL-6) and polymorphonuclear leukocyte elastase (PMN-E) to determine the mechanism causing the excess liberation of TM. The arterial ketone body ratio (AKBR) was also measured as an indicator of the hepatocyte energy state. Of the 60 septic patients, 26 developed organ failure, 10 of whom died. In contrast, none of the postsurgical patients developed organ failure. The mean plasma level of TM was significantly higher in the septic patients who developed organ failure compared to those without organ failure (P < 0.001) or the postsurgical patients (P < 0.001). Furthermore, those patients whose plasma TM values became elevated over 6.0 ng/ml frequently developed complications. A positive correlation was also observed between the plasma TM levels and the IL-6 (P < 0.01) and PMN-E levels (P < 0.01). In contrast, a negative correlation was seen between the plasma TM levels and the AKBR (P < 0.01). These findings show that plasma TM could be a useful indicator of impending organ failure during sepsis.

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

“…Distinct phosphorylation of ERK by CLEC14A modulation upon stimula-deletion of Clec14a, increased vessel density following severe hemorrhaging appears more reliable. While the greater hemorrhagic potential of tumors in CLEC14A-KO mice is a possible cause of early death, we cannot exclude other potential causes, such as the inflammatory response to hemorrhagic shock or B16BL6 cell infiltration of the lungs (Figure 5Q), particularly since both VEGFR-3 and the CLEC14A paralog thrombomodulin regulate sepsis (52)(53)(54). Further immunological analysis of CLEC14A-deficient mice is required to determine the precise cause of early death.…”

Recombinant Thrombomodulin Inhibits Lipopolysaccharide-Induced Inflammatory Response by Blocking the Functions of CD14

“…Soluble TM is increased significantly in the plasma of septic patients (16); however, its functions in sepsis remain unclear. Our earlier work demonstrated that rTMD1 inhibits LPS-induced inflammation by binding to the Lewis Y Ag on LPS (18), but the function of rTMD23 in LPS-induced inflammation is largely unknown.…”

“…TM consists of a C-type lectinlike domain (domain 1), a domain with six epidermal growth factor (EGF)-like structures (domain 2), a serine/threonine-rich domain (domain 3 [D3]), a transmembrane domain (domain 4), and a cytoplasmic domain (domain 5) (15). Soluble forms of TM are also reportedly high in the plasma of septic patients (16). Because TM is a natural anticoagulant protein, recombinant human soluble TM protein (ART-123) effectively reduces disseminated intravascular coagulation (17).…”

Soluble Thrombomodulin Levels are Related to Inflammation after Coronary Bypass Surgery

“…Soluble TM is released from the surface of endothelial cells secondary to increased proteolytic cleavage when endothelial damage occurs [7]. Increased sTM level has been associated with mortality in patients with trauma, acute respiratory distress syndrome, major surgery and sepsis, expressing a correlation with multiple organ failure [5][6][7]. Moreover, increased sTM in patients with atherosclerosis is a predictor of poor cardiovascular outcome and increased levels of sTM, C-reactive protein (CRP) and another inflammatory markers have been reported after percutaneous coronary interventions [15] and have been found to be a predictor of poor outcome in patients surviving acute coronary syndromes [4].…”

“…Clinically, elevated sTM has been found to predict events in patients surviving an acute coronary syndrome [4], and increased sTM level has been reported in patients with multiple organ dysfunction syndrome (MODS), disseminated intravascular coagulation induced by sepsis or blunt trauma. In all these conditions, sTM has been associated with increased mortality [5][6][7]. Therefore, it has been suggested that the elevation of sTM levels might be associated with a higher inflammatory state [4,8,9].…”