Evolution of Urokinase-Type Plasminogen Activator (u-PA) and Tissue-Type Plasminogen Activator (t-PA) in Orthotopic Liver Transplantation (OLT)

Summary

In orthotopic liver transplantation (OLT) hyperfibrinolysis seems to be of causative importance for intra- and postoperative bleeding. Although recently hyperfibrinolysis has been successfully reduced by intraoperative aprotinin treatment, small increases of fibrinolysis still remain during OLT. Originally, tissue-type plasminogen activator (t-PA) was considered to be responsible for the increases, but the efficacy of aprotinin which inhibits besides plasmin also kallikrein and urokinase-type plasminogen activator (u-PA) suggested also a role for the intrinsic and contact system-dependent plasminogen activators. We investigated the role of u-PA. From 29 patients undergoing OLT with intraoperative aprotinin infusion arterial blood samples were taken at 7 different time points. The preoperative median values for u-PA antigen (u-PA Ag) and plasmin-activatable single-chain u-PA (scu-PA) levels, which were more than 2-fold above normal (both: p <0.01), decreased slightly during the preanhepatic phase and remained unchanged during the anhepatic phase. With reperfusion of the graft liver the two levels decreased significantly (p = 0.0003 and p = 0.006, respectively) to almost normal values, probably due to clearance by the graft liver. Active two-chain u-PA (tcu-PA) was preoperatively 2-fold above the detection limit, remained stable during the preanhepatic phase and increased 2-fold in the anhepatic phase (p = 0.0018). As expected tcu-PA also relapsed upon reperfusion, but to the preoperatively enhanced level, possibly caused by sustained activation of scu-PA by cathepsin B. t-PA activity levels were at the upper end of the normal range preoperatively, slightly increased during preanhepatic and anhepatic phases and decreased significantly with reperfusion. The increases in tcu-PA and t-PA activities during the anhepatic phase coincided with greatly increased fibrinolysis as demonstrated by thrombelastography, indicating that both u-PA and t-PA are involved in the development of fibrinolysis during OLT.

One patient was excluded from statistical evaluations because preoperative u-PA Ag, scu-PA, tcu-PA and t-PA activity levels were much higher than in the other 28 patients. In the investigated group this patient was the only one with diffuse peritonitis intraoperatively and severe bleeding complications postoperatively which made retransplantation mandatory.

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