Efficacy and Safety of Recombinant Thrombombomodulin for the Prophylaxis of Vaso-Occlusive Complications in Allogenic Hematopoietic Stem Cell Transplantation : A Systematic Review and Meta-Analysis
Authors: Kashyap Richi , Ali Muhammad Ashar , Mirza Taaha Muddassir , Javaid Anum , Raheem Aniqa , Gul Rohail , Tayyeb Muhammad , Anwar Muhammad Yasir , Dar Abdul Jabbar , Khurshid Qasim , Neupane Karun , Anwer Faiz 
Published: November 2020

Background:
Hepatic veno-occlusive disease (VOD) also termed as sinusoidal obstruction syndrome (SOS) is a lethal complication seen after haematopoietic stem cell transplantation (HSCT). There are a limited number of options for prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, has been shown to help prevent veno-occlusive complications after stem cell transplantation. Various trials have shown safety and efficacy of recombinant thrombomodulin in preventing SOS.
Methods:
A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "thrombomodulin" AND "stem cell transplantation" from the inception of literature till June 2020. Out of 239 articles, we screened and included nine trials (N=850) in the systematic review and meta-analysis. We extracted the data for VOD episodes, graft vs host disease (GVHD) episodes and survival after stem cell transplantation. We excluded case reports, preclinical trials, review articles, meta-analysis, and trials not providing any information about the above-mentioned. We used the R programming language (version 4.0.2) to conduct a meta-analysis.
Results:
Total number of patients tested was 356 in thrombomodulin group and 494 in control group. The age range was 16 to 74 years. Thrombomodulin group had 254 males and control group had 190 (Table 1.). For VOD, risk ratio (RR) was 0.53 (I2= 0%, 95% CI=0.32-0.89) in favor of rTM vs heparin or no therapy for prevention of VOD after stem cell transplantation (Fig 1.). rTM was effective in prevention of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT. RR was 0.48 (I2= 62%, 95% CI=0.20-1.17) with significant lower incidence of TMA in rTM group (Fig 2.). In a trial, seven of nine patients recovered from TA-TMA in the rTM group, but none recovered in the control group who received various therapies including fresh frozen plasma, therapeutic plasma exchange(TPE) or others (p=0.003) (Fujiwara et al). The risk of GVHD was also significantly lower in rTM group and RR was 0.48 (I2= 64%, 95% CI=0.32-0.72) which again favours rTM vs heparin or no therapy (Fig 3.). Ishii et al showed that stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM was an independent risk factor for aGVHD (p=0.000, odds ratio=3.006) and VOD (p=0.015, odds ratio=2.65). Yakushijin et al compared rTM with Defibrotide and found similar complete remission (CR) rate and the overall survival (OS) at day 100 in both the groups. Therefore, rhTM could be one of the potential novel candidate for SOS treatment. Use of rTM improved the survival rate of patients with disseminated intravascular coagulation (DIC), diagnosed according to the criteria established by the Ministry of Health, Labor and Welfare of Japan, at day 100 (83% vs. 50%, P = 0.026) and significantly prolonged the OS of these patients (P = 0.044). The Kaplan-Meier curves clearly showed the improved non-relapse-related mortality of patients who received rTM after HSCT (Ikezoe et al). Mean DIC scores improved significantly with the use of rhTM (p = 0.003; DIC withdrawal rate 91.7%). FDP and CRP levels were also significantly decreased (p = 0.042 and p = 0.001). The recovery rate from DIC at 28 days was significantly better in rTM than in antithrombin or heparin group (p = 0.011) (Inoue et al). The mean peak plasminogen activator inhibitor type one (PAI- 1) level was significantly lower in the rTM group vs heparin and ursodiol group (P = 0.04), and the mean peak activated protein C (APC) level was significantly higher in the rTM group (P = 0.01) (Yamamoto et al). No serious grade 3 or 4 adverse events were reported by trials.
Conclusion:
This systematic review and meta-analysis shows that prophylactic rTM (380 units/kg) has a beneficial role in the prevention of post- HSCT SOS complication in patients that are at high risk of developing the condition. It appears to help improve treatment-related mortality and overcome the poor survival rates. Additional randomized clinical trials are needed to establish efficacy and safety of rTM to prevent VOD and to confirm these results.

Disclosures
Anwer: Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau.