Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity.
Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.
Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Unité de Recherche PEDI, Brussels, Belgium. xavier.stephenne@uclouvain.be
Xavier
X
Stephenne
Emanuele
E
Nicastro
Stephane
S
Eeckhoudt
Cedric
C
Hermans
Omar
O
Nyabi
Catherine
C
Lombard
Mustapha
M
Najimi
Etienne
E
Sokal
D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D002648:Child; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000378:metabolism; D055815:Young Adult
D000925:Anticoagulants; D006629:Hirudins; D008074:Lipoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D013925:Thromboplastin; C074619:bivalirudin