The thrombogenic risk induced by intraportal infusion of Adult Derived Human Liver Stem/ Mesenchymal Cells in Wistar rats can be controlled with a combinaBon of anBcoagulant drugs, heparin and bivalirudin

Coppin, Louise;Rozzi, Milena;Komuta, Mina;Horman, Sandrine;Stephenne, Xavier;et.al.
(2018) AASLD Liver Meeting — Location: San Francisco, USA (9.November.2018)

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Authors
  • Coppin, LouiseUCLouvain
    Author
  • Rozzi, MilenaUCLouvain
    Author
  • Komuta, MinaUCLouvain
    Author
  • Horman, Sandrineorcid-logoUCLouvain
    Author
  • Sokal, EtienneUCLouvain
    Author
  • Stephenne, XavierUCLouvain
    Author
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Abstract
(en) Background: Mesenchymal stem cell (MSC) infusions are currently tested in numerous clinical trials, but therapy-induced thrombi have been described in several patients. Most MSCs, like Adult Derived Human Liver Stem Cells (ADHLSCs), in fact express a procoagulant actvity (PCA) linked to tissue factor (TF) expression, which is the fuse that ignites the coagulation cascade leading to coagulation factors consumption. The aim was to study in vivo, the effect of anticoagulant drugs, combining an antithrombin activator, heparin and a thrombin inhibitor, bivalirudin and the effect of cell doses on the thrombogenic risk induced by intraportal infusion of ADHLSCs. Methods Wistar rats (n=6/group) were infused with 3 different cell dosages (50 (High), 12.5 (High) and 5 (Low) million ADHLSCs/kg), with or without anticoagulant therapy through an intraportal catheter. Control group was infused with PBS. Blood samples were collected before and 1 hour after cell infusion (Total blood count, coagulation factors and thrombin-antithrombin (TAT) complexes). Rats were sacrificed and liver tissue was collected 1 hour after cell infusion. Serial slides were performed to analyze the localization of AHDLSCs and fibrin. Results ADHLSCS intraportal infusion influences after 1h platelet count levels and coagulation factors in a cell dose dependant manner (Fig.1). Infusion of high cell dosage of ADHSLCs, 12.5 - 50x106 cells/kg, induced a significant decrease in platelets (p<0.01) without inducing a drop in haemoglobin levels. When 50x106 cells/kg are infused, fibrinogen (p<0.001), coagulation factors II, V and VIII (p<0.01) levels decrease and Thrombin-Antithrombin (TAT) complex levels increase significantly (p<0.05). Adding anticoagulants prevented significantly the decrease in platelet counts (p<0.01, Fig.2) and factor II, V and VIII (p<0.05).Fibrin production around the infused cells localized in Portal Veins (PV) was significantly (p < 0.001) reduced, from 86.6% ± 6.4 to 26.4% ± 13.8 in the anticoagulated group. Nevertheless, TAT complex levels increased significantly (p<0.01) showing the activation of coagulation is limited but not completely prevented. Conclusion: Infusion of low doses, such as 5x106cells/kg is safe, and infusion of high doses, such as 50x106cells/kg can be controlled when anticoagulant drugs, heparin and bivalirudin are added.
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Coppin, L., Rozzi, M., Komuta, M., Horman, S., Sokal, E., & Stephenne, X. (2018). The thrombogenic risk induced by intraportal infusion of Adult Derived Human Liver Stem/ Mesenchymal Cells in Wistar rats can be controlled with a combinaBon of anBcoagulant drugs, heparin and bivalirudin. AASLD Liver Meeting, San Francisco, USA. https://hdl.handle.net/2078.5/62446