Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model

Abstract

We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (WBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1:2 with Ringer's acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5 degrees C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline = 4 (3.5-7.7), 3 h = 17.3* (12.5-27), 12h = 31* (17.7-63.6), HC: baseline = 4.9 (3.2-6.8), 3h = 9* (6-14.4), 12h = 13.7* (7.4-18.1). TCC: NC: baseline = 0.4 (0.2-0.6), 3h = 5*(0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline = 0.5 (0.1-0.6), 3 h = 0.6* (0.1-0.8), 12 h = 1.2* (0.3-2) AU/ml; median and range (*: p < 0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h, p < 0.001; 12 h, p < 0.001. TCC (NC vs. HC group): 3h, p < 0.001; 12 h, p < 0.001. Significant increases in the values of thrombin-antithrombin complexes (p = 0.003), prothrombin fragment 1 + 2 (p = 0.006) and plasmin-alpha2-antiplasmin complexes (p = 0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for WBP reduces activation of the plasma cascade systems in a closed venous system in vitro.

Right lobe living donor liver transplantation with or without venovenous bypass

“…A phenomenon observed in this study was that there was severe spontaneous bleeding from the wound and retroperitoneum after reperfusion of the liver graft in patients with venovenous bypass, possibly because of fibrinolysis 4 , depletion of platelets 6 and platelet dysfunction in the presence of hypothermia 23 . Haemostasis of the retroperitoneum after graft implantation could be difficult and at the expense of prolonged rotation and hence ischaemic injury of the liver graft.…”

“…It allows time for the surgeon to perform faultless venous anastomoses, and was considered to play a major role in the improvement of results of liver transplantation in the 1980s and dissemination of the transplant technique to the new generation of surgeons 1,2 . However, apart from the cost of the equipment and personnel required to monitor the procedure, complications such as air embolism 3 , massive bleeding, activation of complement factors, fibrinolysis 4 , haemolysis 5 , entrapment of platelets in the tubing 6 , hypothermia 7 , injury to brachial plexus and artery 8 , and lymphatic leakage 9 contribute to patients' morbidity and mortality 10 . Thus, some surgeons have not advocated its routine use 11 -13 .…”

The significance of heparin-coated veno-venous bypass circuits in liver transplantation

“…19,20 Factors responsible for complement system activation could be reperfusion injury, immunological reactions and the use of other devices such as the cell saver. However, based on the results of in vitro studies by our group, where we found significant reduction of complement activation in HC systems compared to NC systems, 18 it is reasonable to believe that the VVBP circuit may also contribute to activation of the complement system in the in vivo situation, as the experimental conditions used in the in vitro study were comparable with respect to key factors such as flow rate and temperature. However, it seems that the significance of complement activation during OLT as a result of the contact with foreign surfaces in the VVBP circuit and the role of heparin in this context is minor compared to other factors.…”

Early Results of the “Clamp and Sew” Fontan Procedure Without the Use of Circulatory Support

“…A variety of early outcome measures improved in the no-oxygenator group, but there was no difference between the active and passive IVC decompression groups, suggesting that elimination of the oxygenator might be more important than elimination of the pump. It is known that veno-venous bypass is not immune from activation of the inflammatory cascades [16]. Contact between the patient’s blood and the perfusion tubing may result in activation of the complement systems independently from the presence or absence of an oxygenator.…”