Effects Of Recombinant Soluble Thrombomodulin Research Articles

Recombinant soluble thrombomodulin attenuates cisplatin-induced intestinal injury by inhibiting intestinal epithelial cell-derived cytokine secretion.

Intestinal injury is one of the main side-effects of cisplatin chemotherapy, impairing the quality of life in patients with cancer. In this study, we investigated the protective effects of recombinant soluble thrombomodulin (rsTM), which is a potent anti-inflammatory agent, on cisplatin-induced intestinal injury. We first evaluated the effects of rsTM on intestinal injury caused by cisplatin in mice in vivo. Disease progression was monitored by analyzing loss of body weight and histological changes in intestinal tissue. We then investigated the effects of rsTM on mouse intestinal organoid formation and growth in vitro. Gene expression levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. rsTM treatment significantly attenuated the loss of body weight, histological damage and gene expression levels of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and high-mobility group box-1 in a cisplatin-treated mouse model. Furthermore, rsTM alleviated the inflammatory response and apoptosis in a cisplatin-treated intestinal epithelial organoid model. rsTM suppresses cisplatin-induced intestinal epithelial cell-derived cytokine production and alleviates intestinal mucositis.

Associations between acute GVHD-related biomarkers and endothelial cell activation after allogeneic hematopoietic stem cell transplantation

BackgroundHematopoietic stem cell transplantation (HSCT) can cause serious transplant-related complications such as graft-versus-host disease (GVHD). Acute GVHD (aGVHD) has been diagnosed by clinical manifestations, laboratory data and pathological effects until now, but recently the discovery of specific biomarkers such as suppression of tumorigenicity 2 (ST2), elafin and regenerating islet-derived 3α (REG3α) is challenging this approach. MethodsWe investigated the expression of aGVHD-related markers (regulated on activation normal T-cell expressed and secretes: RANTES, elafin, REG3α and ST2) and endothelial cell activation markers (soluble vascular cell adhesion molecule: sVCAM-1 and plasminogen activator inhibitor: PAI-1) in patients undergoing allogeneic HSCT. Additionally, we studied the effects of recombinant soluble thrombomodulin (rTM) on the expression of these markers. Our study cohort included 225 patients who underwent allogeneic HSCT at several institutions in Japan. ResultsRANTES, sVCAM-1, PAI-1, elafin, REG3α and ST2 exhibited significant increases in patients not receiving rTM after HSCT. When we examined patients with confirmed complications, the frequencies of aGVHD and VOD were significantly lower in the rTM-treated group. In addition, aGVHD-related biomarkers such as elafin, REG3α, and ST2 were elevated significantly in patients with aGVHD. ConclusionOur findings suggest that endothelial cell activation might be linked to aGVHD, and that rTM might act to prevent aGVHD, at least in part, through its effect on endothelial cells.

急性GVHDとリコンビナント トロンボモジュリン

Hematopoietic stem cell transplantation (HSCT) involves the potential for certain serious transplant-related complications such as graft-versus-host disease (GVHD), and recovery from such complications is vital for a successful HSCT outcome. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. Authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1 and microparticle (MP) in patients undergoing allogeneic HSCT. Additionally, authors studied the effects of recombinant soluble thrombomodulin (rTM) on the expression of these markers. This study cohort included 312 patients who underwent allo HSCT at 25 institutions in Japan. In the 143 patients who developed aGVHD, levels of endothelial cell activation markers were significantly higher compared to patients who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to aGVHD, and that rTM might at least in part act to prevent aGVHD by its effect on endothelial cells.

Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation

IntroductionWe assessed the safety and effectiveness of recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) in the treatment of disseminated intravascular coagulation (DIC) in a post-marketing surveillance. MethodsThe cases of 3548 patients with DIC caused by infection (n=2516, Infection-DIC) or hematological malignancy (n=1032, Hemat-DIC) were analyzed and compared to the results of a phase III (P-III) study. ResultsThe DIC scores were significantly decreased in the Infection-DIC and Hemat-DIC groups with TM-α treatment (both P<0.001). The incidences of critical bleeding adverse drug reactions (ADRs) in the Infection-DIC and Hemat-DIC groups were 2.6% and 2.4%, and the survival rates were 64.1% and 70.7%, respectively. Patients with DIC were subcategorized into three groups (Infection-DIC-1 or Hemat-DIC-1, P-III criteria-matched patients; Infection-DIC-2 or Hemat-DIC-2, P-III criteria-non-matched patients treated solely with TM-α; and Infection-DIC-3 or Hemat-DIC-3, P-III criteria-non-matched patients treated with TM-α and other concomitant anticoagulants). Subcategory analysis revealed that the incidences of critical bleeding ADRs of Hemat-DIC-2 and Hemat-DIC-3 were significantly higher and their survival rates were significantly lower than those of Hemat-DIC-1. By multivariate analysis in Hemat-DIC, younger age (odds ratio: 2.629, P=0.0033) and pre-existing bleeding (odds ratio: 2.044, P=0.019) were found to affect bleeding ADRs and the severity of underlying disease was the most important factor for survival rate (odds ratio: 0.288, P<0.001). ConclusionsThis surveillance provided real-world data for the safety and effectiveness of TM-α in the treatment of Infection-DIC and Hemat-DIC in general practice settings.