Perfusate Enzymes and Platelets Indicate Early Allograft Dysfunction After Transplantation of Normothermically Preserved Livers : Transplantation

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Perfusate Enzymes and Platelets Indicate Early Allograft Dysfunction After Transplantation of Normothermically Preserved Livers

Melandro, Fabio MD, PhD1; Ghinolfi, Davide MD, PhD1; Lai, Quirino MD, PhD2

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doi: 10.1097/TP.0000000000004309
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We read with great interest the recent article by Weissenbacher et al on the predictive value of perfusate parameters during normothermic machine perfusion (NMP) in grafts coming from extended criteria donors (ECDs) used for liver transplantation (LT).1 Apart from the molecules typically tested for liver viability during NMP (ie, lactates and transaminases), the authors identified different factors connected with a higher risk of early allograft dysfunction. In detail, the median platelet count and the Von Willebrand factor antigen rose over time in perfusate and postoperatively when early allograft dysfunction occurred.

We think some considerations about platelets’ role need to be discussed.

Platelets play a crucial role in several settings of inflammation, such as the tumor progression or the liver damage after ischemia–reperfusion injury (IRI), creating interconnections with leukocytes and endothelial cells and releasing mediators able to trigger inflammation.2 IRI causes necrosis and apoptosis of sinusoid epithelial cells with the consequent intrasinusoidal microthrombus formation and liver damage. ECD grafts preserved by cold storage are characterized by intrasinusoidal platelet aggregation after reperfusion with disruption of the microcirculatory bed.3

On the other hand, platelets play a critical role in the repair and regeneration of the liver, releasing several biologically active mediators in the injury sites, which initiate or modulate angiogenesis and regenerate the damaged tissue. The mediators are primarily stored in α-granules of resting platelets, including several growth factors, such as serotonin, hepatocyte growth factor (HGF), vascular endothelial growth factor, and insulin-like growth factor-1. Serotonin and HGF are also the most important contributors to the initiation of hepatocyte proliferation.4

Platelets are also involved in the prevention of hepatic fibrosis. Platelets inhibit the activation of hepatic stellate cells (HSC) and the production of type I collagen in HSC. Furthermore, platelet-derived growth factor inhibits the expression of type I collagen genes in HSC and the expression of the transforming growth factor β. Studies from patients with NAFLD showed that inflammatory mediators such as interleukin-6 (IL-6) stimulate the production of greater, reticulated platelets into the bloodstream.5

In light of the significant number of mechanisms connected with platelets, we suggest also adding the mean platelet volume (MPV) and the platelet distribution width (PDW) to the median number of platelets. MPV and PDW are simple-to-use platelet indices that typically increase during platelet activation. MPV was found significantly elevated in the presence of liver disease.6 The PDW characterizes the changeability in thrombocyte size, delivering more information than median platelet count concerning platelet reactivity.7

Several parameters have been proposed in recent years for viability testing in NMP and LT.8 The need to find viability tests with high specificity and sensibility is urgent because of the high availability of marginal grafts. Although the role of liver injury markers (ie, lactate, transaminases) is still controversial and not widely accepted for their clinical use, many studies focused on synthetic and excretory function markers. As Weissenbacher et al have shown, the platelets could be evaluated to test the quality of the liver.1 Another recent study reporting the use for LT of a 3-d normothermically perfused graft reported the absence of relevant IRI after LT, also thanks to the inclusion of platelets into the NMP system.9

The exact mechanism of platelets should be clarified in the setting of NMP: a double effect should be driven, on the one side favoring inflammation-related damage, and on the other side, consenting a repair of the damage itself. Adding the 2 platelet-related parameters, MPV and PDW, during graft evaluation in NMP could be used, in our opinion, to optimize the decision on the graft viability and prevent postoperative complications.

REFERENCES

1. Weissenbacher A, Bogensperger C, Oberhuber R, et al. Perfusate enzymes and platelets indicate early allograft dysfunction after transplantation of normothermically preserved livers. Transplantation. 2022;106:792–805.
2. Lai Q, Melandro F, Larghi Laureiro Z, et al. Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer: a systematic review and meta-analysis. World J Gastroenterol. 2018;24:1658–1665.
3. Kanazawa H, Obara H, Yoshikawa R, et al. Impact of machine perfusion on sinusoid microcirculation of liver graft donated after cardiac death. J Surg Res. 2020;245:410–419.
4. Han S, Park HW, Song JH, et al. Association between intraoperative platelet transfusion and early graft regeneration in living donor liver transplantation. Ann Surg. 2016;264:1065–1072.
5. Kumari B, Sharma S, Kumar R, et al. Efficacy of lipid ratios and platelet distribution width for assessment of liver fibrosis in patients with non-alcoholic fatty liver disease. Cureus. 2022;14:e21110.
6. Tahtaci M, Yurekli OT, Bolat AD, et al. Increased mean platelet volume is related to histologic severity of primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2015;27:1382–1385.
7. Vagdatli E, Gounari E, Lazaridou E, et al. Platelet distribution width: a simple, practical and specific marker of activation of coagulation. Hippokratia. 2010;14:28–32.
8. Panconesi R, Flores Carvalho M, Mueller M, et al. Viability assessment in liver transplantation-what is the impact of dynamic organ preservation? Biomedicines. 2021;9:161.
9. Clavien PA, Dutkowski P, Mueller M, et al. Transplantation of a human liver following 3 days of ex situ normothermic preservation. Nat Biotechnol. In press.
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