Infusion-related thrombogenesis by liver-derived mesenchymal stem cells controlled by anticoagulant drugs in 11 patients with liver-based metabolic disorders

摘要

Mesenchymal stem cell (MSC) transplantation is a fast-developing therapy in regenerative medicine. However, some concerns have been raised regarding their safety and the infusion-related pro-coagulant activity. The aim of this study is to analyze the induced thrombogenic risk and the safety of adding anticoagulants during intraportal infusions of liver-derived MSCs (HepaStem), in patients with Crigler-Najjar (CN) and urea cycle disorders (UCD). Eleven patients (6 CN and 5 UCD patients) were included in this partially randomized phase 1/2 study. Three cell doses of HepaStem were investigated: low (12.5?×?106 cells/kg), intermediate (50?×?106 cells/kg), and high doses (200?×?106 cells/kg). A combination of anticoagulants, heparin (10 I.U./5?×?106cells), and bivalirudin (1.75?mg/kg/h) were added during cell infusions. The infusion-related thrombogenic risk and anticoagulation were evaluated by clinical monitoring, blood sampling (platelet and D-dimer levels, activated clotting time, etc.) and liver Doppler ultrasound. Mixed effects linear regression models were used to assess statistically significant differences. One patient presented a thrombogenic event such as a partial portal vein thrombus after 6 infusions. Minor adverse effects such as petechiae, epistaxis, and cutaneous hemorrhage at the site of catheter placement were observed in four patients. A significant decrease in platelet and increase in D-dimer levels were observed at the end of the infusion cycle, normalizing spontaneously after 7?days. No significant and clinically relevant increase in portal vein pressure could be observed once the infusion cycle was completed. The safety- and the infusion-related pro-coagulant activity remains a concern in MSC transplantation. In our study, a combination of heparin and bivalirudin was added to prevent the thrombogenic risk induced by HepaStem infusions in 11 patients. A significant decrease in platelet and increase in D-dimer levels were observed, suggesting the activation of coagulation in these patients; however, this was spontaneously reversible in time. We can conclude that adding this combination of anticoagulants is safe and limits infusion-related thrombogenesis to subclinical signs in most of the patients.