Effect of recombinant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation

Abstract

From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n = 23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n = 11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment for coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (P = 0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy.

The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model

“…Our previous clinical observations showed that the use of rTM successfully rescues individuals with endothelial syndrome [8][9][10] and significantly prolongs overall survival of transplant patients with coagulopathy complicated by endothelial syndrome. 12 These observations indicate the cytoprotective roles of rTM in the context of HSCT. Indeed, a recent in vitro study found that TME45 protects endothelial cells from cytokines and calcineurin inhibitor-induced apoptosis, 7 supporting the clinical benefit of rTM for transplant patients.…”

Recombinant human thrombomodulin in the treatment of acute myeloid leukemia patients complicated by disseminated intravascular coagulation: retrospective analysis of outcomes between patients treated with heparin and recombinant human thrombomodulin therapy

“…In addition, 28-day mortality was significantly lower in patients treated with rTM than in non-rTM treated patients [31]. On the other hand, in patients undergoing hematopoietic stem cell transplantation, the administration of rTM improved the clinical outcomes of recipients with coagulopathy [32]. However, according to the ISTH guidelines, therapeutic doses of LMWH should be considered in cases of DIC in which thrombosis predominates (low quality) because of insufficient randomized controlled trials on the survival benefits of rTM [23].…”

“…A randomized controlled study reported that rTM therapy improved DIC and relieved bleeding complications in DIC patients more significantly than UFH therapy [18]. Furthermore, the administration of rTM reduced coagulation abnormally, and increased survival associated with several causes [30][31][32]. The SOFA score was lower in sepsis cases treated with rTM than in the controls [31].…”

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

“…In fact, clinical use of rTM for the treatment of DIC that develops after HSCT does not significantly increase the incidence of relapserelated mortality. 10 Surprisingly, the use of rTM significantly augmented the engraftment of CD34 + human hematopoietic stem/progenitor cells in severe immunodeficient mice ( Figure 6). Other investigators have also demonstrated that recombinant TM rescues mice from radiation-induced lethality in an APC-dependent manner.…”

“…[7][8][9] We have recently performed the retrospective cohort study that showed that the use of rTM significantly decreases the mortality rate at day 100 of HSCT and improves the OS of transplant patients who developed DIC within 28 days of HSCT compared with those who did not receive rTM. 10 We thus expected that the use of rTM would decrease the incidence of acute GVHD (aGVHD) owing to its anti-inflammatory activity. Contrary to our expectation, a decrease in the incidence of either aGVD or chronic GVHD (cGVHD) was not noted.…”