A pilot, two-center, sequential dose escalation safety study of alteplase with fresh frozen plasma during normothermic liver perfusion.

Donor livers may contain occult fibrin, which is associated with adverse transplant outcomes in livers donated after brain death (DBD) and circulatory death (DCD). Ex situ normothermic machine perfusion (NMP) may allow fibrinolytic therapy before transplantation. Before undertaking a large efficacy study for the prophylaxis of cholangiopathy, we wished to assess the safety of a protocol comprising alteplase and fresh frozen plasma (FFP), the latter as a source of plasminogen, and also to ascertain which of the 4 possible treatment strategies was associated with the greatest fibrin breakdown, as judged by D-dimer release. Eighty livers, 40 DBD and 40 DCD, were randomized to 1 of 5 groups of 16 each, receiving 10 mg or 20 mg alteplase, 1 or 2 units (250 mL) of FFP, with alteplase and FFP being delivered into either the hepatic artery cannula or portal reservoir at the start of NMP. The primary endpoint was bleeding post-transplant. Forty-four of 64 treated livers were transplanted, as were 12 of the 16 control livers receiving FFP alone. There was no increase in post-implant bleeding or blood transfusion requirement of any alteplase-treated liver compared with the FFP alone control group. All 4 alteplase groups were associated with more D-dimer release than the FFP alone control group; 10 mg alteplase was as effective as 20 mg, and delivery into the portal reservoir was as effective as delivery into the hepatic artery cannula. The protocol achieving release of most D-dimers involved 10 mg alteplase being delivered directly into the portal reservoir containing 2 units of FFP. Portal delivery was found to be more straightforward than infusion into the hepatic artery cannula. The combination of alteplase with FFP appeared safe, with no bleeding complications.