Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

Patients with liver diseases may develop alterations in all components of the hemostatic system. Thrombocytopenia, low levels of coagulation factors and inhibitors, low levels of fibrinolytic proteins, and increased levels of endothelial-derived proteins such as von Willebrand factor are all part of the coagulopathy of liver disease. Due to concomitant changes in pro- and antihemostatic drivers, the net effects of these complex hemostatic changes have long been unclear. According to current concepts, the hemostatic system of patients with liver disease is in an unstable balance, which explains the occurrence of both bleeding and thrombotic complications. This review will discuss etiology and management of bleeding and thrombosis in liver disease and will outline unsolved clinical questions. In addition, we will discuss the role of intrahepatic activation of coagulation for progression of liver disease, a novel paradigm with potential consequences for the general management of patients with liver disease.</p

Protective mechanisms and current clinical evidence of hypothermic oxygenated machine perfusion (HOPE) in preventing post-transplant cholangiopathy

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

Laparoscopic Versus Open Cholecystectomy: A Prospective Matched-Cohort Study

To compare the results of laparoscopic cholecystectomy (LC) and open cholecystectomy (OC) for symptomatic cholelithiasis in elective surgery we performed a prospective matched-cohort study. Hundred consecutive patients who underwent LC in the period Sept. 1990-June 1992, and 100 patients who were age and sex matched and underwent an elective OC in the foregoing two years (1989-1990) were studied. The median operation time for LC (75, 40-180 min) was significantly longer than for OC (55, 20-155 min; p < 0.001). Postoperative hospitalization was significantly shorter after LC (3, 1-16 days), compared with OC (7, 4-22 days; p<0.001). Conversion of LC to OC occurred in 12 (12%) patients initially scheduled to undergo LC. Complications occurred in 5 patients (5%) after LC and in 5 patients (5%) after OC. The calculated expenses (operation and postoperative hospitalization, 3rd class) were approximately fl. 3740,- for LC (excl. investments for pieces of apparatus) and fl. 6725,- for OC. This study demonstrates that LC can be performed safely with the number of complications comparable to those for OC. Bile duct injury is a serious potential threat. The main advantages ofLC are the minimal trauma, with more rapid recovery. Insurers seem to benefit from reduced postoperative disability and earlier discharge

Blood Markers of Portal Hypertension Are Associated with Blood Loss and Transfusion Requirements during Orthotopic Liver Transplantation

There is increasing evidence that portal hypertension plays a major role in bleeding risk during orthotopic liver transplantation (OLT). We investigated the association between preoperative blood levels of von Willebrand factor (VWF) and soluble CD163 (sCD163), which are established markers of portal hypertension, and blood loss and transfusion requirements during OLT. We measured levels of VWF and sCD163 in preoperative serum samples of 168 adult patients undergoing a primary OLT between 1998 and 2012. Preoperative levels of VWF and sCD163 correlated with the model of end-stage liver disease (MELD) score (r = 0.414, p < 0.001 and r = 0.382, p < 0.001, respectively). Patients with high VWF or sCD163 levels (VWF and sCD163 levels above the median) had a substantially increased risk of needing red blood cell transfusion compared with patients with low VWF or sCD163 levels (VWF and sCD163 levels below the median) (odds ratio 3.5 [95% confidence interval, CI 1.7-7.0] and 2.3 [95% CI 1.1-4.5], respectively). Blood loss was highest in patients with both high VWF or sCD163 levels and a high preoperative international normalized ratio. Elevated blood levels of markers of portal hypertension are associated with increased blood loss and transfusion requirements during OLT and support the notion that portal hypertension is an important contributor to perioperative blood loss

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

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

Hemostatic disorders in orthotopic and auxiliary liver transplantation : clinical and experimental studies

In patients with severe liver disease, hepatic dysfunction may deteriorate to such an extent that conservative medical treatments are no longer sufficient to maintain the, for life essential, liver functions. For these patients the transplantation of a donor liver represents the only hope for survival. Livers can be transplanted in two different manners: either in the orthotopic position after removal of the diseased native liver, or in a heterotopic position as an auxiliary liver

Normothermic liver machine perfusion as a dynamic platform for regenerative purposes. What does the future have in store for us?

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 utilization by resuscitation and 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, ribonucleic acid 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 for repair and regeneration of damaged donor livers to ultimately decrease the imbalance between donor liver demand and supply

Topical haemostatic agents in liver surgery: do we need them?

AbstractBackgroundWorldwide, partial liver resections are increasingly being performed for primary or secondary hepatic malignancies. There are various techniques to reduce blood loss druing liver surgery. Several topical haemostatic agents have been developed to improve haemostasis of the resection surface and these agents are used more and more, even although the true effects remain unclear.MethodsThe present literature about the use of topical haemostatic agents in liver surgery was reviewed. Furthermore we conducted a Dutch national survey to explore the use of and belief in these agents in liver surgery.ResultsThe Dutch national survey among surgeons showed that topical haemostatic agents are frequently used not only to lower intra-operative blood loss or shorten time to haemostasis, but even more importantly, to reduce resection surface related complications such as bile leakage, postoperative haemorrhage and abscess formation. Although various topical haemostatic agents have been shown to reduce intra-operative time to haemostasis at the resection surface after liver resections, there is no scientific proof that these topical haemostatic agents really reduce resection surface related complications.ConclusionThis review highlights the need for more randomized clinical trials to investigate the efficacy of topical haemostatic agents in reducing resection surface related complications

Outflow obstruction after living donor liver transplantation managed with a temporary vena cava filter:A case report

Introduction: Outflow obstruction is a rare but critical vascular complication in liver transplantation, which may lead to graft loss and mortality. We report a case of caval vein outflow obstruction due to retrohepatic compression after living donor liver transplantation (LDLT), which was managed by temporary implantation of a vena cava filter. Presentation of case: A 63-year-old male with end stage liver disease presented with caval vein outflow obstruction and massive ascites 12 days after right lobe LDLT. We opted for a minimally invasive approach and implanted a vena cava filter at the compressed site through transjugular route. The patient's ascites drainage significantly decreased and graft function maintained stable after the intervention. On day 50 posttransplant, the filter was successfully removed and the patient was discharged without complications. Discussion: Outflow obstruction after liver transplantation can result from anastomotic stenosis, graft size mismatch, thrombosis or compression of the outflow tract. Various management strategies have been employed both peri- and posttransplant, ranging from surgical interventions to minimally-invasive techniques. The treatment strategy should be tailored to the individual case, considering the timing of presentation and the specific cause for the obstruction. Conclusion: We successfully managed a case of compressive outflow obstruction by temporary implantation of a vena cava filter after LDLT. The vena cava filter was safely removed under angiography.</p