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The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience., (© 2018 Steunstichting ESOT.)

Background: Non-anastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) have a negative influence on graft survival. Expert opinion suggests a negative effect of NAS on other important aspects of post-transplant care, although its impact is largely unknown as data are scarce., Methods: This retrospective single center study analyzed data on healthcare consumption, use of ionizing radiation, infectious complications and development of highly resistant microorganisms (HRMO) in adult patients with NAS. A comparison with a matched control group was made., Results: Forty-three liver recipients with NAS and 43 controls were included. Hospital admissions were higher in patients with NAS. Most common reason for admission was bacterial cholangitis (BC), with 70% of the patients having at least one episode compared to 9% in the control group. In patients with NAS, 67% received at least one ERCP compared to 21% in the control group (p = 0.001). This resulted in a larger yearly received radiation dose for patients with NAS (p = 0.001). Frequency of intravenous antibiotic therapy was higher (p = 0.001) for patients with NAS, consistently resulting in a higher number of cultures found with HRMO (p = 0.012)., Conclusion: NAS after OLT have a negative effect on post-transplant care, increasing readmission rates, interventional procedures, exposure to ionizing radiation, use of antibiotics, and development of HRMO., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Liver transplantation with livers grafts from elderly donors has been associated with a higher risk of biliary complications. The aim of this study was to examine whether our national protocol could contribute to a lower incidence of biliary complications., Methods: All adult recipients in the Netherlands transplanted with a liver from an elderly donor (≥ 65 yrs; n = 68) in the period January 2000-July 2011 were matched with recipients of a liver from a donor <65 yr (n = 136). Outcome parameters were 90-d, one-yr, and three-yr patient/graft survival rates, biliary complications (non-anastomotic stricture, anastomotic stricture, biliary leakage, and post-transplant cholangitis), and postoperative hepatic ischemic injury serum markers (AST/ALT)., Results: The median cold ischemia time (CIT) was 7:25 (h:min) in the group recipients of an elderly donor liver graft. Ninety-day, one-yr, and three-yr patient/graft survival rates were similar between the group with an elderly donor liver and their younger controls. Moreover, no differences were found in the incidence of biliary complications and postoperative levels of AST/ALT between the two groups., Conclusion: Transplantation of livers from elderly donors (≥ 65 yr) is not associated with a higher incidence of biliary complications, in a national policy wherein the CIT is kept short., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent advances in the understanding of the coagulopathy in chronic liver disease have provided a strong support for anticoagulation as a new therapeutic paradigm for patients with cirrhosis. Laboratory studies indicate that the net effect of changes in hemostasis in many patients with chronic liver disease is a hypercoagulable status. In turn, clinical thrombosis is increasingly recognized as a complication of liver disease. When occurring within the liver, thrombosis may even progress the disease course. Exciting preliminary data regarding the potential of low-molecular-weight heparin to slow down the progression of liver disease indicate that this class of drugs may improve outcome without a major increase in bleeding risk. However, this new era for antithrombotic therapy in chronic liver disease is still hindered by a persistent false notion that patients with cirrhosis are "auto-anticoagulated" by their underlying liver disease. In addition, there is insufficient clinical evidence on safety and efficacy of anticoagulant therapy in cirrhosis and the studies conducted so far are limited by small sample sizes, uncontrolled treatment arms, or by their retrospective nature. Finally, a lack of knowledge on how or when to monitor antithrombotic treatment to optimize the risk-benefit ratio has restricted a widespread application of anticoagulant treatment in clinical management algorithms. Nonetheless, by systematically covering possibilities and pitfalls, this review highlights the potential of antithrombotic therapy to improve the quality of life and the clinical outcome of patients with chronic liver disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Liver disease is characterized by changes in all phases of hemostasis. These hemostatic alterations were long considered to predispose patients with liver disease towards a bleeding tendency, as they are associated with prolonged conventional coagulation tests. However, these patients may also suffer from thrombotic complications, and we now know that the hemostatic system in patient with liver disease is, in fact, in a rebalanced state. In this review we discuss the concept of rebalanced hemostasis and its implications for clinical management of patients with liver disease. For instance, there is no evidence that the use of prophylactic blood product transfusion prior to invasive procedures reduces bleeding risk. Clinicians should also be aware of the possibility of thrombosis occurring in patients with a liver disease, and regular thrombosis prophylaxis should not be withheld in these patients.

The hemostatic profile of patients with liver diseases is frequently profoundly different from that of healthy individuals. These complex alterations lead to abnormal results from routine laboratory tests, but because of the nature of these assays, they fail to accurately represent the patient's hemostatic state. Nevertheless, based on abnormal laboratory coagulation values, it has long been assumed that patients with liver disease have a natural bleeding tendency and are protected from thrombosis. This assumption is false; the average patient with liver disease is actually in a state of "rebalanced hemostasis" that can relatively easily be tipped toward both bleeding and thrombosis. The new paradigm of rebalanced hemostasis has strong implications for the clinic, which are presented in this review. There is no evidence that prophylactic transfusion of plasma helps to prevent procedure-related bleeding. In addition, the presence of independent risk factors such as poor kidney status or infections should be carefully assessed before invasive procedures. Furthermore, central venous pressure plays an important role in the risk of bleeding in patients with liver diseases, so during procedures, a restrictive infusion policy should be applied. Finally, thrombosis prophylaxis should not be withheld from patients with cirrhosis or acute liver failure, and clinicians should be alert to the possibility of thrombosis occurring in these patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In Eurotransplant, more than 50% of liver allografts come from extended criteria donors (ECDs). However, not every ECD is the same. The limits of their use are being explored. A continuous scoring system for analyzing donor risk has been developed within the Organ Procurement and Transplantation Network (OPTN), the Donor Risk Index (DRI). The objective of this study was the validation of this donor risk index (DRI) in Eurotransplant. The study was a database analysis of all 5939 liver transplants involving deceased donors and adult recipients from January 1, 2003 to December 31, 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. Follow-up data were available for 5723 patients with a median follow up of 2.5 years. The mean DRI was remarkably higher in the Eurotransplant region versus OPTN (1.71 versus 1.45), and this indicated different donor populations. Nevertheless, we were able to validate the DRI for the Eurotransplant region. Kaplan-Meier curves per DRI category showed a significant correlation between the DRI and outcomes (P < 0.001). A multivariate analysis demonstrated that the DRI was the most significant factor influencing outcomes (P < 0.001). Among all donor, transplant, and recipient variables, the DRI was the strongest predictor of outcomes., (Copyright © 2011 American Association for the Study of Liver Diseases.)

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.

Hepatitis E virus (HEV) infections are known to run a self-limiting course. Recently, chronic hepatitis E has been described in immunosuppressed patients after solid-organ transplantation. Besides the general recommendation to lower the immunosuppressive medication in these patients, there is currently no specific treatment. We here describe the successful use of pegylated interferon alpha-2b in the treatment of 2 liver transplant recipients who suffered a chronic HEV infection for 9 years (case A) or 9 months (case B). After 4 weeks of therapy, a 2-log decrease (case A) and a 3-log decrease (case B) in the viral load were observed. In case A, who received treatment for 1 year, serum viral RNA became undetectable from week 20 onward, and serum liver enzymes normalized completely. In case B, interferon was discontinued at week 16 because of a lack of a further decline in the viral load. However, 4 weeks after the cessation of therapy, viral RNA was no longer detectable in the serum, and this was probably related to a further decline in the immunosuppressive medication. Liver tests normalized completely. In both cases, no relapse has been noted so far. We conclude that pegylated interferon alpha-2b may be useful in the treatment of chronic HEV infections in patients in whom the reduction of the immunosuppressive medication alone is not sufficient., ((c) 2010 AASLD.)

Background & Aims: Patients with liver disease often show substantial changes in their hemostatic system, which may aggravate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indistinguishable from controls provided thrombomodulin, the natural activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic balance is preserved in patients with liver disease, despite conventional coagulation tests suggest otherwise., Methods: Here we examined thrombin generation profiles in serial plasma samples taken from ten consecutive patients undergoing liver transplantation., Results: At all time points, the endogenous thrombin potential (ETP) was slightly lower compared to healthy volunteers, despite substantially prolonged PT and APTT values. However, when thrombin generation was tested in the presence of thrombomodulin, the ETP was equal to or even higher than that in healthy subjects. In fact, thrombin generation was hardly affected by thrombomodulin, while thrombin generation in healthy subjects decreased profoundly upon the addition of thrombomodulin. In patients undergoing liver transplantation, efficient thrombin generation in the presence of thrombomodulin may be explained by decreased levels of protein C, S, and antithrombin, and by elevated levels of FVIII., Conclusions: Thrombin generation in patients undergoing liver transplantation is equal or even superior to thrombin generation in healthy volunteers when tested in the presence of exogenous thrombomodulin. These results support the recently advocated restrictive use of plasma during liver transplantation and warrants further study of the prophylactic use of anticoagulants to reduce thromboembolic complications after transplantation., (Copyright (c) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low., (Copyright 2009 AASLD)

Intraoperative blood loss and transfusion of blood products are negatively associated with postoperative outcome after liver surgery. Blood loss can be minimized by surgical methods, including vascular clamping techniques, the use of dissection devices, and the use of topical hemostatic agents. Preoperative correction of coagulation tests with blood products has not been shown to reduce intraoperative bleeding and it may, in fact, enhance the bleeding risk. Maintaining a low central venous pressure has been shown to be effective in reducing blood loss during partial liver resections, and volume contraction rather than prophylactic transfusion blood products seems justified in patients undergoing major liver surgery. Although antifibrinolytic drugs have proved to be effective in reducing blood loss during liver transplantation, systemic hemostatic drugs are of limited value in reducing blood loss in patients undergoing partial liver resections.

Patients who have liver disease commonly present with alterations in platelet number and function. Recent data have questioned the contribution of these changes to bleeding complications in these patients. Modern tests of platelet function revealed compensatory mechanisms for the decreased platelet number and function, the most prominent compensatory mechanism being substantially elevated levels of the adhesive protein von Willebrand's factor. Consequently, standard diagnostic tests of platelet functions seem to be of little use to predict bleeding complication in patients who have liver disease. This article outlines the role of platelet abnormalities and possibilities for platelet function testing in patients who have liver disease.

Apart from the well-known role of blood platelets in hemostasis, there is emerging evidence that platelets have various nonhemostatic properties that play a critical role in inflammation, angiogenesis, tissue repair and regeneration, and ischemia/reperfusion (I/R) injury. All these processes may be involved in the (patho)physiological alterations occurring in patients undergoing liver transplantation. Experimental and clinical research points toward a dualistic role of platelets in patients undergoing liver transplantation, resulting in both beneficial and detrimental effects. Although a low platelet count is generally considered a risk factor for perioperative bleeding, recent studies have indicated that platelet function in patients with cirrhosis may not be as abnormal as previously assumed. Platelet transfusions are frequently considered in liver transplant recipients to correct low platelet counts and to prevent bleeding; however, evidence-based transfusion thresholds are lacking, and the other detrimental and nonhemostatic properties of platelets are generally not weighed in this respect. First, platelets have been shown to contribute to I/R injury of the liver graft via induction of sinusoidal endothelial cell apoptosis. Second, platelet transfusion has been identified as an independent risk factor for reduced survival via mechanisms that are not completely understood yet. On the other hand, recent studies indicate that platelets are critically involved in restoration after liver injury and in liver regeneration via serotonin-mediated mechanisms. These findings make platelets both friend and foe in liver transplantation. The scientific challenge will be to further dissect the mechanisms and clinical relevance of these contrasting roles of platelets in liver transplantation.

Background: Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after orthotopic liver transplantation (OLT). Although experimental studies have shown that platelets contribute to reperfusion injury of the liver, the influence of allogeneic platelet transfusion on outcome has not been studied in detail. In this study, we evaluate the impact of various blood products on outcome after OLT., Methods: Twenty-nine variables, including blood product transfusions, were studied in relation to outcome in 433 adult patients undergoing a first OLT between 1989 and 2004. Data were analyzed using uni- and multivariate stepwise Cox's proportional hazards analyses, as well as propensity score-adjusted analyses for platelet transfusion to control for selection bias in the use of blood products., Results: The proportion of patients receiving transfusion of any blood component decreased from 100% in the period 1989-1996 to 74% in the period 1997-2004. In uni- and multivariate analyses, the indication for transplantation, transfusion of platelets and RBC were highly dominant in predicting 1-yr patient survival. These risk factors were independent from well-accepted indices of disease, such as the Model for End-Stage Liver Disease score and Karnofsky score. The effect on 1-yr survival was dose-related with a hazard ratio of 1.377 per unit of platelets (P = 0.01) and 1.057 per unit of RBC (P = 0.001). The negative impact of platelet transfusion on survival was confirmed by propensity-adjusted analysis., Conclusion: This retrospective study indicates that, in addition to RBC, platelet transfusions are an independent risk factor for survival after OLT. These findings have important implications for transfusion practice in liver transplant recipients.

Summary: Studies from the USA and Nordic countries indicate primary sclerosing cholangitis (PSC) patients have low mortality on the liver transplantation (LTx) waiting list. However, this may vary among geographical areas. Therefore, we compared waiting list mortality and post‐transplant survival between laboratory model for end‐stage liver disease (LM) and MELD exception (ME)‐prioritized PSC and non‐PSC candidates in a nationwide study in the Netherlands. A retrospective analysis of patients waitlisted from 2006 to 2013 was conducted. A total of 852 candidates (146 PSC) were waitlisted of whom 609 (71.5%) underwent LTx and 159 (18.7%) died before transplantation. None of the ME PSC patients died, and they had a higher probability of LTx than LM PSC [HR obtained by considering ME as a time‐dependent covariate (HRME 9.86; 95% CI 6.14–15.85)] and ME non‐PSC patients (HRME 4.60; 95% CI 3.78–5.61). After liver transplantation, PSC patients alive at 3 years of follow‐up had a higher probability of relisting than non‐PSC patients (HR 7.94; 95% CI 1.98–31.85) but a significantly lower mortality (HR 0.51; 95% CI 0.27–0.95). In conclusion, current LTx prioritization advantages PSC patients on the LTx waiting list. Receiving ME points is strongly associated with timely LTx. [ABSTRACT FROM AUTHOR]

Background & Aims In addition to their function in thrombosis and haemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver has been demonstrated. We studied kinetics of platelet influx in the regenerating liver and investigated the signal that initiates platelet influx. Methods We visualized platelets in the liver remnant after partial hepatectomy in mice using intravital microscopy and assessed liver regeneration by examination of liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. Results We demonstrated rapid but transient platelet influx into the liver remnant after a partial liver resection. Liver regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, liver regeneration was only mildly impaired when thrombocytopaenia was induced 2 hours after partial liver resection. Platelet influx into the liver remnant was virtually absent in the presence of an antibody to von Willebrand factor ( VWF) suggesting that VWF release from liver sinusoidal endothelial cells mediates platelet influx. Additionally, liver regeneration in mice deficient in VWF was markedly impaired. Conclusions A rapid but transient VWF-dependent platelet influx into the liver remnant drives platelet-mediated liver regeneration. [ABSTRACT FROM AUTHOR]

Objectives: To explore whether distinct trajectories of anxiety and depression exist among liver transplant candidates, and to gain insight into demographic, clinical, and individual characteristics related with these trajectories.Design: A multicentre, prospective cohort study among 216 liver transplant candidates. Respondents filled out a questionnaire at study entrance and subsequently every 6 months until transplantation or removal from the waiting list.Methods: Anxiety (STAI6), depression (CES-D), demographic, and individual variables were assessed by questionnaire. Clinical variables were retrieved by medical record review. The SAS PROC TRAJ procedure was used to identify distinct trajectories. Univariate and multiple ordinal logistic regression analyses were used to explore related variables.Results: Regarding anxiety, three stable trajectories were identified as follows: below clinical level (51%), slightly above clinical level (34%), and high above clinical level (15%). Regarding depression, four stable trajectories were identified as follows: below clinical level (23%), slightly below clinical level (34%), slightly above clinical level (28%), and high above clinical level (6%). For anxiety as well as for depression, experiencing more liver disease symptoms, a lower level of personal control, making more use of emotional coping, and making less use of task-oriented coping increased the likelihood of membership in those trajectories with higher symptom levels.Conclusion: Distinct, but stable, trajectories of anxiety and depression were present in liver transplant candidates. The trajectories with symptom levels above clinical relevant levels for anxiety or depression comprised, respectively, 49% and 34% of the respondents. Therefore, psychological screening and subsequently providing appropriate interventions are warranted early in the transplant process. Statement of contribution What is already known on this subject For transplant candidates, the waiting-list period is a period of uncertainty and unpredictability. Psychological problems, such as anxiety and depression, are common among liver transplant candidates. Several demographic, clinical, and individual characteristics are associated with anxiety and depression, but these results remain inconclusive. What does this study add Distinct trajectories of symptoms of anxiety and depression are present among liver transplant candidates. Given the stability of the trajectories over time, the symptom level at baseline is indicative of the symptom level during the waiting-list period. Experiencing more liver disease symptoms, low mastery, more use of emotional coping, and less use of task-oriented coping are associated with trajectories of high symptom levels. [ABSTRACT FROM AUTHOR]

Background & Aims Cirrhosis frequently affects multiple components of hemostasis. Reversal of the coagulopathy of these patients is frequently required in case of bleeding episodes, or as prophylaxis before invasive procedures. Although 1-deamino-8-D-arginine vasopressin ( DDAVP) is widely used as a pro-hemostatic agent in patients with cirrhosis, it is unclear whether DDAVP truly enhances hemostasis in these patients. Here we investigated the hemostatic effects of a single bolus of DDAVP in patients with cirrhosis. Methods Ten patients with cirrhosis (child B or C) and ten patients with mild haemophilia A received an intravenous single bolus of 0.3 microgram/kg DDAVP. Plasma was collected prior to and at 1, 3, 6, and 24 h after DDAVP administration. Levels of Von Willebrand factor ( VWF), VWF propeptide, factor VIII ( FVIII), and ADAMTS13 were measured in all plasma samples, whereas VWF multimers and functional VWF-dependent platelet adhesion were determined in the samples pre- and 1 h after DDAVP administration. Results Following DDAVP administration, VWF, FVIII, and VWF propeptide levels increased in patients with haemophilia, while patients with cirrhosis only showed an increase in VWF propeptide and FVIII levels. High molecular weight VWF multimers and VWF-dependent platelet adhesion increased in patients with haemophilia one hour after DDAVP administration, but did not change in the patients with cirrhosis. Levels of ADAMTS13 were unaffected in both patient groups after DDAVP. Conclusion The lack of relevant effects of DDAVP on laboratory indices of primary hemostasis in patients with cirrhosis is in line with previous clinical study results in these patients. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known. Objectives: We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis. Patients/Methods: Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs. Results: Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma. Conclusions: The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aim Experimental studies in animals have suggested that liver regeneration is impaired in steatotic livers. However, few studies have focused on the impact of steatosis in patients undergoing partial hepatectomy ( PH). This study aims to determine the role of steatosis on liver regeneration in humans following PH. Methods Eighty-eight patients undergoing PH were included in this study. All patients underwent CT-scanning of the liver preoperatively and 7 days after surgery. Additional CT-scans were performed 6 months post-operatively. Preoperative and post-operative volumes of the total liver ( TLV), future liver remnant ( FLR) and liver remnant ( LR) were measured on CT-scans. Regeneration indices ( RI) were calculated at 7 days and 6 months using the formula: (Volume LR−Volume FLR)/Volume FLR × 100%. Based on histological examination of the resected part of the liver, patients were classified into three groups: (1) no steatosis, (2) mild steatosis (1-29%) and (3) moderate-to-severe steatosis (≥30%). Results The early RI (at day 7) was 40%, 24% and 20% for patients in group 1, 2 and 3 respectively. Late RI (at 6 months) was 81% for group 1, 44% for group 2 and 22% for group 3 ( P = 0.019). At 7 days, the LR represented 79%, 80% and 79% of the TLV for groups 1-3. At 6 months, this was 93%, 92% and 79% respectively. Conclusion Although early RI after PH did not differ in patients with or without steatosis, the late RI in patients with moderate-to-severe steatosis was lower, suggesting that late liver regeneration is impaired in these patients. [ABSTRACT FROM AUTHOR]

Summary Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver was extremely difficult in 38% of patients, because of presence of adhesions from prior therapy (17%). Karnofsky score following LT was 90%. The 1- and 5-year graft survival rate was 94.3% and 87.5%, while patient survival rate was 94.8% and 92.3%, respectively. Survival rates after LT for PCLD are good. [ABSTRACT FROM AUTHOR]

Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT. Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS. Methods: MMP-2 (−1306 C/T) and MMP-9 (−1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra- or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures. Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype ( P=0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P=0.02) and MMP-2 CT genotype (hazard ratio 3.5, P=0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs. Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT. [ABSTRACT FROM AUTHOR]

Background: The model of end-stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation. Aims: To assess the contribution of the individual components of the MELD score in interlaboratory variability. Methods: We sent 15 samples from patients listed for liver transplantation to seven different European laboratories who were asked to measure all three variables. In addition, 10 samples from patients on oral anticoagulant treatment were sent to the same labs for the international normalised ratio (INR) measurement. Results and Conclusions: In all 15 samples, a substantial and clinically relevant variation in the calculated MELD score was observed between laboratories. The mean difference in the MELD score between the highest- and the lowest-scoring laboratory was 4.8. The variation in creatinine measurements resulted in differences of up to three MELD points in a single patient when comparing the highest and the lowest scoring lab. The variation in bilirubin measurements only accounted for a difference of one point between the highest- and the lowest-scoring laboratory, but the variation in INRs resulted in differences of 2 to 12 MELD points. MELD scores or INR values were not substantially different in laboratories that used the Owren instead of the more widely used Quick methodology for INR measurements. The variability in the INR in patients on oral anticoagulants was substantially less as compared with the variability in patients with liver disease. In conclusion, we observed a large interlaboratory variation in the MELD score. This variation in the MELD score is primarily caused by the INR. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the status of platelet activation in patients with liver disease in the 2011 issue.

Patients with liver disease frequently have substantial changes in their haemostatic system. This is reflected in abnormal test results on routine coagulation screening assays such as the prothrombin time (PT), activated thromboplastin time (APTT) and platelet count. Traditionally, attempts were made to correct abnormalities in the haemostatic system as measured by routine coagulation assays prior to invasive procedures by infusion of platelets or fresh frozen plasma (FFP). Recent laboratory and clinical data have indicated that the haemostatic reserve in cirrhotic patients is relatively well maintained although the coagulation screening assays suggest otherwise. Pre-procedural correction of coagulation tests with blood products may therefore not be necessary, and may even have harmful side-effects. In particular, fluid overload resulting in exacerbation of portal hypertension by infusion of blood products may in fact promote bleeding. In recent years, it has become clear that reduction of the central and portal venous pressure by fluid restriction and avoidance of blood product transfusion is a beneficial strategy in minimizing bleeding during liver surgery in cirrhotic patients. Some investigators have even taken this a step further and suggested pre-procedural phlebotomy in liver transplant recipients. The aim of this review is to provide an overview of recent studies and developments which have changed our understanding of the clinical relevance of abnormal coagulation tests in patients with cirrhosis, and which have contributed to a reduction in blood loss and transfusion requirements when liver surgery is needed in these patients. [ABSTRACT FROM AUTHOR]