Patients with liver disease frequently acquire a complex disorder of hemostasis secondary to their disease. Routine laboratory tests such as the prothrombin time and the platelet count are frequently ...abnormal and point to a hypocoagulable state. With more sophisticated laboratory tests it has been shown that patients with liver disease may be in hemostatic balance as a result of concomitant changes in both pro- and antihemostatic pathways. Clinically, this rebalanced hemostatic system is reflected by the large proportion of patients with liver disease who can undergo major surgery without any requirement for blood product transfusion. However, the hemostatic balance in the patient with liver disease is relatively unstable as evidenced by the occurrence of both bleeding and thrombotic complications in a significant proportion of patients. Although it is still common practice to prophylactically correct hemostatic abnormalities in patients with liver disease before invasive procedures by administration of blood products guided by the prothrombin time and platelet count, we believe that this policy is not evidence-based. In this article, we will provide arguments against the traditional concept that patients with liver failure have a hemostasis-related bleeding tendency. Consequences of these new insights for hemostatic management will be discussed.
The development of cholangiopathies after liver transplantation impacts on the quality and duration of graft and patient survival, contributing to higher costs as numerous interventions are required ...to treat strictures and infections at the biliary tree. Prolonged donor warm ischaemia time in combination with additional cold storage are key risk factors for the development of biliary strictures. Based on this, the clinical implementation of dynamic preservation strategies is a current hot topic in the field of donation after circulatory death (DCD) liver transplantation. Despite various retrospective studies reporting promising results, also regarding biliary complications, there are only a few randomised-controlled trials on machine perfusion. Recently, the group from Groningen has published the first randomised-controlled trial on hypothermic oxygenated perfusion (HOPE), demonstrating a significant reduction of symptomatic ischaemic cholangiopathies with the use of a short period of HOPE before DCD liver implantation. The most likely mechanism for this important effect, also shown in several experimental studies, is based on mitochondrial reprogramming under hypothermic aerobic conditions, e.g. exposure to oxygen in the cold, with a controlled and slow metabolism of ischaemically accumulated succinate and simultaneous ATP replenishment. This unique feature prevents mitochondrial oxidative injury and further downstream tissue inflammation. HOPE treatment therefore supports livers by protecting them from ischaemia-reperfusion injury (IRI), and thereby also prevents the development of post-transplant biliary injury. With reduced IRI-associated inflammation, recipients are also protected from activation of the innate immune system, with less acute rejections seen after HOPE.
...organ transplant following DCD is associated with worse outcomes than with DBD. The OrganEx system uses some components that are already used in ex situ machine perfusion of donor organs8, such as ...antioxidants and Hemopure, alongside several innovations. Because the investigators used a multimodal approach to test this multifaceted system, it remains to be determined whether all of its components contribute to the benefits they observed. ...inclusion of a haemodialysis unit has already proved beneficial in the prolonged ex situ machine perfusion of isolated livers10.
Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft ...viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.
Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. ...Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses.
Liver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended ...criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. To further increase the availability of donor livers suitable for transplantation, new strategies are required that make it possible to use organs that are initially too damaged to be transplanted. With the current progress in experimental liver transplantation research, (long-term) normothermic machine perfusion may be used in the future as a dynamic platform for regenerative medicine approaches, enabling repair and regeneration of injured donor livers. Currently explored therapeutics such as defatting cocktails, RNA interference, senolytics, and stem cell therapy may assist in the repair and/or regeneration of injured livers before transplantation. This review will provide a forecast of the future utility of normothermic machine perfusion in decreasing the imbalance between donor liver demand and supply by enabling the repair and regeneration of damaged donor livers.
Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more ...biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model.
After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system.
After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024).
Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts.
Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE ...resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.
This clinical cohort study indicates that a combination of hypo‐ and normothermic machine perfusion, using a preservation fluid containing an hemoglobin‐based oxygen carrier, is feasible and provides a tool to resuscitate and select initially declined high‐risk donor livers that can be transplanted successfully.
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