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

Louise C F Coppin, Françoise Smets, Jérome Ambroise, Etienne E M Sokal, Xavier Stéphenne, Louise C F Coppin, Françoise Smets, Jérome Ambroise, Etienne E M Sokal, Xavier Stéphenne

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov identifier: NCT01765283-January 10, 2013.

Keywords: Blood coagulation; Cell therapy; Clinical trial; Liver diseases; Mesenchymal stem cells.

Conflict of interest statement

E.S is a founder and scientific advisor for the Promethera Biosciences and has founding shares and/or stock options. F.S. is the principal Investigator for the Promethera Biosciences. X.S. has a consultancy agreement with the Promethera Biosciences. This study was supported in part by research funding from the Promethera Biosciences. Other authors declare that they have no competing financial interests. All authors declare to have no non-financial conflict of interests.

Figures

Fig. 1
Fig. 1
Monitoring of portal vein pressure before and after intraportal infusion of HepaStem in patients (n = 11). Portal vein pressure was monitored through a portal catheter before and every 15 min during and after the infusions until normalization. a Portal vein pressure is represented for each patient during 1, 2, or 3 days of HepaStem infusions. The horizontal dotted line is the maximum normal value. b 95% CI (confidence interval) whiskers representing portal vein pressure for all patients at different time points. Statistical analysis: Wilcoxon signed-rank test. The horizontal dotted line represents the mean before infusion. *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 2
Fig. 2
Monitoring of blood parameters before and after intraportal infusion of HepaStem in patients (n = 11). Blood samples were performed before, at the end, and 1, 3, and 7 days after, the infusion cycle was completed. Blood samples included the following: hemoglobin (normal values 11–14.5 g/dl), platelets (normal values 150–350 × 103/μl), white blood count (normal values 4–10 × 103/μL), polymorphonuclear (PMN) (normal values 5.6–17 and D-dimer levels (normal values < 500 ng/ml), and 95% CI (confidence interval) whiskers. The horizontal dotted line represents mean before infusion. *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 3
Fig. 3
Monitoring of anticoagulation by measuring activated clotting time (ACT) levels during and after intraportal infusion of HepaStem in patients (n = 11). ACT levels (targeted values 200–350 s; dotted horizontal lines) are represented for each patient during cell infusions (1–10)

References

    1. Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82(4):441–449. doi: 10.1097/.
    1. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338(20):1422–1426. doi: 10.1056/NEJM199805143382004.
    1. Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, et al. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet. 2002;359(9303):317–318. doi: 10.1016/S0140-6736(02)07529-3.
    1. Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, et al. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation. 2003;76(4):735–738. doi: 10.1097/01.TP.0000077420.81365.53.
    1. Stephenne X, Najimi M, Smets F, Reding R, de Ville de Goyet J, Sokal EM. Cryopreserved liver cell transplantation controls ornithine transcarbamylase deficient patient while awaiting liver transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2005;5(8):2058–2061. doi: 10.1111/j.1600-6143.2005.00935.x.
    1. Schneider A, Attaran M, Meier PN, Strassburg C, Manns MP, Ott M, et al. Hepatocyte transplantation in an acute liver failure due to mushroom poisoning. Transplantation. 2006;82(8):1115–1116. doi: 10.1097/01.tp.0000232451.93703.ab.
    1. Dhawan A, Strom SC, Sokal E, Fox IJ. Human hepatocyte transplantation. Methods Mol Biol. 2010;640:525–534. doi: 10.1007/978-1-60761-688-7_29.
    1. Stephenne X, Najimi M, Ngoc DK, Smets F, Hue L, Guigas B, et al. Cryopreservation of human hepatocytes alters the mitochondrial respiratory chain complex 1. Cell Transplant. 2007;16(4):409–419. doi: 10.3727/000000007783464821.
    1. Stephenne X, Najimi M, Sokal EM. Hepatocyte cryopreservation: is it time to change the strategy? World J Gastroenterol. 2010;16(1):1–14.
    1. Sokal EM. From hepatocytes to stem and progenitor cells for liver regenerative medicine: advances and clinical perspectives. Cell Prolif. 2011;44(Suppl 1):39–43. doi: 10.1111/j.1365-2184.2010.00730.x.
    1. Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36(4):568–584. doi: 10.1016/j.biocel.2003.11.001.
    1. Stephenne X, Nicastro E, Eeckhoudt S, Hermans C, Nyabi O, Lombard C, et al. Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity. PLoS One. 2012;7(8):e42819. doi: 10.1371/journal.pone.0042819.
    1. Moll G, Ignatowicz L, Catar R, Luecht C, Sadeghi B, Hamad O, et al. Different procoagulant activity of therapeutic mesenchymal stromal cells derived from bone marrow and placental decidua. Stem Cells Dev. 2015;24(19):2269–2279. doi: 10.1089/scd.2015.0120.
    1. Gleeson BM, Martin K, Ali MT, Kumar AH, Pillai MG, Kumar SP, et al. Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by antithrombin therapy. Stem Cells. 2015;33(9):2726–2737. doi: 10.1002/stem.2050.
    1. Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun. 2013;431(2):203–209. doi: 10.1016/j.bbrc.2012.12.134.
    1. Christy BA, Herzig MC, Montgomery RK, Delavan C, Bynum JA, Reddoch KM, et al. Procoagulant activity of human mesenchymal stem cells. J Trauma Acute Care Surgery. 2017;83(1 Suppl 1):S164–S1s9. doi: 10.1097/TA.0000000000001485.
    1. Sokal EM, Stephenne X, Ottolenghi C, Jazouli N, Clapuyt P, Lacaille F, et al. Liver engraftment and repopulation by in vitro expanded adult derived human liver stem cells in a child with ornithine carbamoyltransferase deficiency. JIMD reports. 2014;13:65–72. doi: 10.1007/8904_2013_257.
    1. Jung JW, Kwon M, Choi JC, Shin JW, Park IW, Choi BW, et al. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 2013;54(5):1293–1296. doi: 10.3349/ymj.2013.54.5.1293.
    1. Wu Z, Zhang S, Zhou L, Cai J, Tan J, Gao X, et al. Thromboembolism induced by umbilical cord mesenchymal stem cell infusion: a report of two cases and literature review. Transplant Proc. 2017;49(7):1656–1658. doi: 10.1016/j.transproceed.2017.03.078.
    1. Melmed GY, Pandak WM, Casey K, Abraham B, Valentine J, Schwartz D, et al. Human placenta-derived cells (PDA-001) for the treatment of moderate-to-severe Crohn’s disease: a phase 1b/2a study. Inflamm Bowel Dis. 2015;21(8):1809–1816. doi: 10.1097/MIB.0000000000000441.
    1. Wang H, Strange C, Nietert PJ, Wang J, Turnbull TL, Cloud C, et al. Autologous mesenchymal stem cell and islet motransplantation: safety and efficacy. Stem Cells Transl Med. 2018;7(1):11–19. doi: 10.1002/sctm.17-0139.
    1. Perlee D, van Vught LA, Scicluna BP, Maag A, Lutter R, Kemper EM, et al. Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group, placebo controlled Trial. Stem Cells. 2018;36(11):1778–1788. doi: 10.1002/stem.2891.
    1. Bennet W, Groth CG, Larsson R, Nilsson B, Korsgren O. Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci. 2000;105(2):125–133. doi: 10.1517/03009734000000059.
    1. Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Kallen R, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360(9350):2039–2045. doi: 10.1016/S0140-6736(02)12020-4.
    1. Gustafson EK, Elgue G, Hughes RD, Mitry RR, Sanchez J, Haglund U, et al. The instant blood-mediated inflammatory reaction characterized in hepatocyte transplantation. Transplantation. 2011;91(6):632–638. doi: 10.1097/TP.0b013e31820ae459.
    1. Lee CA, Dhawan A, Smith RA, Mitry RR, Fitzpatrick E. Instant blood-mediated inflammatory reaction in hepatocyte transplantation: current status and future perspectives. Cell Transplant. 2016;25(7):1227–1236. doi: 10.3727/096368916X691286.
    1. Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant. 2011;16(6):620–626. doi: 10.1097/MOT.0b013e32834c2393.
    1. Smets Françoise, Dobbelaere Dries, McKiernan Patrick, Dionisi-Vici Carlo, Broué Pierre, Jacquemin Emmanuel, Lopes Ana Isabel, Gonçalves Isabel, Mandel Hanna, Pawlowska Joanna, Kamińska Diana, Shteyer Eyal, Torre Giuliano, Shapiro Riki, Eyskens François, Clapuyt Philippe, Gissen Paul, Pariente Danièle, Grunewald Stephanie, Yudkoff Marc, Binda Maria Mercedes, Najimi Mustapha, Belmonte Nathalie, de Vos Beatrice, Thonnard Joelle, Sokal Etienne. Phase I/II Trial of Liver–derived Mesenchymal Stem Cells in Pediatric Liver–based Metabolic Disorders. Transplantation. 2019;103(9):1903–1915. doi: 10.1097/TP.0000000000002605.
    1. Najimi M, Khuu DN, Lysy PA, Jazouli N, Abarca J, Sempoux C, et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplant. 2007;16(7):717–728. doi: 10.3727/000000007783465154.
    1. Iranpour P, Lall C, Houshyar R, Helmy M, Yang A, Choi JI, et al. Altered Doppler flow patterns in cirrhosis patients: an overview. Ultrasonography. 2016;35(1):3–12. doi: 10.14366/usg.15020.
    1. Armonis A, Patch D, Burroughs A. Hepatic venous pressure measurement: an old test as a new prognostic marker in cirrhosis? Hepatology. 1997;25(1):245–248. doi: 10.1002/hep.510250145.
    1. Johansson H, Lukinius A, Moberg L, Lundgren T, Berne C, Foss A, et al. Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes. 2005;54(6):1755–1762. doi: 10.2337/diabetes.54.6.1755.
    1. Moll G, Rasmusson-Duprez I, von Bahr L, Connolly-Andersen AM, Elgue G, Funke L, et al. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 2012;30(7):1565–1574. doi: 10.1002/stem.1111.
    1. Moll G, Alm JJ, Davies LC, von Bahr L, Heldring N, Stenbeck-Funke L, et al. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014;32(9):2430–2442. doi: 10.1002/stem.1729.
    1. Baygan A, Aronsson-Kurttila W, Moretti G, Tibert B, Dahllof G, Klingspor L, et al. Safety and side effects of using placenta-derived decidual stromal cells for graft-versus-host disease and hemorrhagic cystitis. Front Immunol. 2017;8:795. doi: 10.3389/fimmu.2017.00795.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever