Anticoagulant Management and Synthesis of Hemostatic Proteins during Machine Preservation of Livers for Transplantation

Abstract

Liver transplantation remains the only curative treatment for patients with end-stage liver disease. Despite a steadily increasing demand for suitable donor livers, the current pool of donor organs fails to meet this demand. To resolve this discrepancy, livers traditionally considered to be of suboptimal quality and function are increasingly utilized. These marginal livers, however, are less tolerant to the current standard cold preservation of donor organs. Therefore, alternative preservation methods have been sought and are progressively applied into clinical practice. Ex situ machine perfusion is a promising alternative preservation modality particularly for suboptimal donor livers as it provides the ability to resuscitate, recondition, and test the viability of an organ prior to transplantation. This review addresses the modalities of machine perfusion currently being applied, and particularly focuses on the hemostatic management employed during machine perfusion. We discuss the anticoagulant agents used, the variation in dosage, and administration, as well as the implications of perfusion for extended periods of time in terms of coagulation activation associated with production of coagulation factors during perfusion. Furthermore, in regard to viability testing of an organ prior to transplantation, we discuss the possibilities and limitations of utilizing the synthesis of liver-derived coagulation factors as potential viability markers.

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

“…[26][27][28] Despite the prominent clinical role of coagulation parameters in liver transplantation, they are not included in any of the viability criteria currently used during ex situ perfusion outside of the body. 4,18,29,30 In this study, we quantified coagulation parameters applying clinically established assays in injured livers that were maintained in a metabolically active state using our normothermic machine perfusion technology. On the first day of perfusion, the measured INR values were below the cut off for primary non-function as proposed by NHS and UNOS.…”

“…Previously, we presented viability assessment criteria during long-term normothermic perfusion, where coagulation parameters were not included. [14][15][16][17][18][19] Coagulation parameters constitute additional markers that are used commonly for liver function assessment after liver transplantation. However, to the best of our knowledge, coagulation factors are not yet included in liver viability assessment during long-term ex situ perfusion.…”

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

“…To prevent this activation, anticoagulation strategies are used in medical devices, such as ECMO, but also in organ perfusion machines it is common to use an anticoagulant. Most often, anticoagulation is achieved by the addition of high doses of unfractionated heparin (67,69). Although most groups performing liver MP use unfractionated heparin, there is still no consensus on the correct dosage (69).…”

“…Most often, anticoagulation is achieved by the addition of high doses of unfractionated heparin (67,69). Although most groups performing liver MP use unfractionated heparin, there is still no consensus on the correct dosage (69). One drawback of heparin is that it requires binding to antithrombin or heparin cofactor II to function, and it induces release of tissue factor pathway inhibitor (70).…”

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“…In a subsequent study, Karangwa et al discuss challenges in hemostatic management during ex-vivo perfusion of human donor liver prior to transplantation. 17 Historically, donor organs are kept on ice from procurement until transplantation. However, in recent years, machine perfusion of donor organs with the aims to assess graft quality and to resuscitate the organ has been introduced in clinical practice.…”