Synthesis of coagulation factors during long‐term ex situ liver perfusion

Abstract

Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with bloodbased, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate.

Observations and findings during the development of a subnormothermic/normothermic long‐term ex vivo liver perfusion machine

“…Prior to perfusion, it is impossible to predict which liver can be categorized as a “good” one (Group 1). Further information on parameters that could indicate a “good” liver due to liver specifications/details prior perfusion and due to the performance of the machine can be found in Tables 1 and 2 and the literature 15,21 …”

“…By means of the described perfusion technology, a discarded liver was preserved and evaluated on the perfusion machine and finally successfully transplanted to a patient on the fourth day 25 . For detailed information, we refer to our previous publications 15,20–24,26,27 . For the first time in this manuscript, we show how monitoring of perfusate parameters supports research and development of a liver perfusion machine based on three scenarios.…”

“…Over the last 6 years, our multidisciplinary team has developed a blood‐based perfusion technology in a stepwise fashion, starting with pig livers and finally proving the technology with human livers 18–24 . With this perfusion machine (PM), it is possible to perfuse and observe livers prior to transplantation for the desired/required time (up to 10 days) at close to physiological conditions in a metabolically active state.…”

“…4,[15][16][17] Over the last 6 years, our multidisciplinary team has developed a blood-based perfusion technology in a stepwise fashion, starting with pig livers and finally proving the technology with human livers. [18][19][20][21][22][23][24] With this perfusion machine (PM), it is possible to perfuse and observe livers prior to transplantation for the desired/required time (up to 10 days) at close to physiological conditions in a metabolically active state. By means of the described perfusion technology, a discarded liver was preserved and evaluated on the perfusion machine and finally successfully transplanted to a patient on the fourth day.…”

Long-term normothermic machine preservation of human livers: what is needed to succeed?

“…In one study, factor V, fibrinogen, and factor VII appear to have reached a plateau when measured for several days, which may indicate that an equilibrium between synthesis and clearance of coagulation factors by the liver has been established. However, antithrombin exceeded the maximum measuring limit after only 3 days of perfusion (73). Evidence has been provided that regulation of the plasma levels of coagulation factors does not appear to be controlled by the liver (74).…”