Abstract
BackgroundMesenchymal 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).MethodsEleven 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.ResultsOne 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.ConclusionsThe 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.Trial registrationClinicalTrials.gov identifier: NCT01765283—January 10, 2013
Highlights
Mesenchymal stem cell (MSC) transplantation is a fast-developing therapy in regenerative medicine
Study population Eleven patients were treated with HepaStem infusions, of which five urea cycle disorders (UCD) and six CN
Two UCD and two CN patients were assigned to low dose (12.5 × 106 cells/kg), one UCD and one CN to medium dose (50 × 106 cells/kg), and three UCD and two CN to high dose
Summary
Mesenchymal stem cell (MSC) transplantation is a fast-developing therapy in regenerative medicine. Hepatocyte transplantation can be an alternative treatment for liver-based metabolic conditions [1,2,3,4,5,6,7] This treatment is limited due to the inability of hepatocytes to proliferate in vitro, due to the metabolic damages induced by cryopreservation and to organ shortage as well [8,9,10]. Other cell sources, such as mesenchymal stem cells (MSCs), are currently under evaluation in numerous clinical trials. Patients presenting urea cycle disorders (UCDs) and Crigler-Najjar (CN) syndrome are good candidates for MSC transplantation, because their current treatments are heavy, only supportive, and impose a real burden on the patients and their family
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