Prophylaxis Against Endothelial Damage Using Recombinant Human Soluble Thrombomodulin (rTM) In Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT).

Abstract 4523

Thrombomodulin (TM) is a vascular endothelial cell protein which controls coagulation. Recombinant human soluble thrombomodulin (rTM) is a new agent for treatment of disseminated intravascular coagulation. rTM also exhibited anti-inflammatory effects and ameliorated endothelial injuries in our pilot study where rTM was administered to a patient during cord blood transplantation (CBT) as a prophylaxis against veno-occulsive disease (VOD). Major complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) triggered by endothelial damage not only include VOD, but also thrombotic microangiopathy (TMA). Two case reports showed that rTM dramatically ameliorated VOD and TMA (Bone Marrow Transplant. 2010;45:783 and 803, respectively) following allo-peripheral blood stem cell transplantation (PBSCT). In the present study, we examined the effectiveness of rTM as a prophylaxis against endothelial damage in patients receiving allo-HSCT.

We evaluated seven patients (age range 50–72 y; median 61 y) with hematological malignancies receiving allo-HSCT at our institute from July 2009 to February 2010. Each patient provided written informed consent prior to inclusion in the study. One patient received conventional SCT, and the others received reduced-intensity SCT using a fludarabine-based conditioning regimen. Two patients were transplanted from related PBSC and the others were transplanted from unrelated CB using rabbit anti-thymoglobulin (rATG) before transplantation as a prophylaxis against graft-versus-host disease (GVHD). Four patients received rTM as a prophylaxis against endothelial damage from day −6 to day 30 (long period) based on the day they received transplantation, and three patients received rTM from day 6 to day 19 (short period) and heparin on the other days. IL-1β, IL-6, IL-8, TNFα, HMGB1, RANTES, SDF-1, E-selectin, and VCAM-1 levels were measured using ELISA before and after rTM administration, and changes were evaluated using a two-tailed Wilcoxon test.

IL-1β (p=0.018), IL-6 (p=0.018), IL-8 (p=0.018), TNFα (p=0.017), RANTES (p=0.017), HMGB1 (p=0.018) decreased significantly following rTM administration. No significant change in CRP level, considered to affect cytokine measurements, was observed (p=0.063), and neither E-selectin nor VCAM-1 level increased. No significant differences were observed between changes in these parameters among patients treated with rTM during the long and short periods. All patients achieved engraftment by the mean post-transplantation day as previously reported (range 16–29 days; median 22 days). Of the seven patients, only one developed VOD, and no patients developed TMA or acute GVHD. Pre-engraftment immune reaction was not observed in any patients who underwent CBT. Four patients were alive and three patients were deceased as of July 30, 2010, with main causes of death being cerebral hemorrhage, VOD and relapse of primary disease, respectively. Median event-free survival and overall survival after transplantation were 54 days (26–283 days) and 168 days (55–283 days), respectively.

rTM showed potent inhibitory effects on inflammatory cytokines, including TNFα, IL-1β, IL-6, IL-8, and prevented the release of HMGB1 through absorption of alarmin. It has been reported that rATG contributes to an increase in inflammatory cytokines; however, rTM treatment prohibited these increases among patients receiving CBT. We previously observed increased levels of E-selectin and VCAM-1 after allo-HSCT (Biol Blood Marrow Transplant. 2008;14:766); however, rTM prohibited these increases in the present study, indicating that it prevents allo-HSCT-induced endothelial injuries. One patient died of cerebral hemorrhage 26 days after the end of prophylactic administration of rTM. An association between this major bleeding event and rTM administration is unlikely because the t1/2 of rTM is approximately 20 h. One patient developed fatal VOD, despite controlled cytokine levels. This patient underwent CBT on primary disease progression. We speculated that disease progression in this case contributed to the development of VOD in spite of prophylactic administration of rTM. Although this study involved a small number patients and median follow-up was relatively short, given the present findings, rTM may prevent VOD and TMA following allo-HSCT.