The Synthesis Of Coagulation Factors During Normothermic Machine Perfusion Of Livers Is Impaired By Ischemia In Pigs And Might Predict Graft Viability


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Abstract

IntroductionNormothermic Machine Perfusion (NMP) of livers is a promising tool to test graft viability during preservation. Coagulation factors are synthetized by the liver, hence are candidate markers of function. We evaluated the production of coagulation factors during NMP, tested if ischemia alters their synthesis, and correlated their levels with markers of hepatocyte damage (AST) and sinusoidal endothelial injury {Hyaluronic acid (HAc)}.MethodPorcine livers exposed to 60 min Warm Ischemia (WI60, n=5) or not (WI0, n=5) were NMP perfused for 6 h. The concentration of Factors V (FV), VIII (FVIII), and X (FX) in the perfusate was measured at 15, 30min, 1, 2, 3, and 6h of NMP and compared within and between groups (between-within ANOVA). Levels of AST and HAc were correlated to FV and FVIII. Mean ±SD is given.ResultsFV increased significantly over time in both groups, although with a different kinetics, as a plateau was reached at 2h of NMP in WI0 only. FV concentration was inferior in WI60 vs. WI0 (p<0.0001) (Figure 1A). Similarly, FVIII raised over time significantly in both WI0 and WI60, reaching a plateau at 3h of NMP only in WI0. The production of FVIII was inferior in WI60 vs. WI0 (p=0.006) (Figure 1B). FX raised steadily without a plateau in WI0, while no significant increase was observed in WI60, in which the concentration of FX was inferior (p=0.001) (Figure 1C). The area under the curve of AST was greater in WI60 (3077) vs WI0 (405.3, p=0.0006). FV was inversely correlated to AST release at all time points except 6h. HAc levels increased over time [11.3 ±5.3 ng/mL at 15min to 101.8 ±75.5 ng/mL at 6h in WI0 (p=0.045), and from 51.5 ±6.9 ng/mL at 15min to 303.2 ±107.7 ng/mL at 6h in WI60 (p=0.01)] and were higher in WI60 vs WI0 (p=0.004). FVIII was inversely correlated to HAc levels at 1h (r:-0.58, p=0.02) and 2h (r:-0.59, p=0.03) of NMP.DiscussionCoagulation factors are actively produced during NMP and their synthesis was impaired during NMP of severely WI damaged porcine livers. In particular, FV and FVIII, produced by hepatocytes and sinusoidal cells, respectively, can be used as markers of function of the hepatocellular and endothelial compartment, since they were inversely related to markers of hepatocellular injury (AST) and sinusoidal cell damage (HAc). FX synthesis during NMP should be further investigated, since its production is dependent on vitamin K, which was not supplemented in the perfusion system. The correlation of our findings to post-transplant outcomes warrants further investigations.ConclusionThe production of coagulation factors during NMP of human livers and their role in the assessment of viability deserve to be explored.

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