Robert J. Porte

Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences

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.

Chronic hepatitis E virus infection in liver transplant recipients

Hepatitis E virus (HEV) infection is known to run a self‐limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze‐stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse‐transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long‐term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients. Liver Transpl 14:547–553, 2008.

Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation : A pilot study

Background. Large transfusion requirements, i.e., excessive blood loss, during orthotopic liver transplantation (OLT) are correlated with increased morbidity and mortality. Recombinant factor VIIa (rFVIIa) has been shown to improve hemostasis in a variety of conditions, but has never been studied in liver transplantation. Methods. We performed a single-center, open-label, pilot study in adult patients undergoing OLT for cirrhosis Child-Pugh B or C, to assess efficacy and safety of rFVIIa. rFVIIa (80 &mgr;g/kg) was administered at the start of the operation, to be repeated according to predefined criteria. Packed red blood cells (RBC), fresh-frozen plasma, and platelet concentrates were administered according to predefined criteria. Perioperative transfusion requirements in study patients were compared with matched controls. Results. Six patients were enrolled in the study. All received a single dose of rFVIIa. Transfusion requirements (given as median, with range in parentheses) were lower in the study group than in matched controls: 1.5 (0–5) vs. 7 (2–18) units of allogeneic RBC (P =0.006), 0 (0–2) vs. 3.5 (0–23) units of autologous RBC (P =0.043), total amount of RBC 3 (0–5) vs. 9 (4–40) units (P =0.002). Transfused fresh-frozen plasma was 1 (0–7) vs. 8 (2–35) units (P =0.011). Blood loss was 3.5 L (1.4–5.3) vs. 9.8 L (3.7–35.0) (P =0.004). One study patient developed a hepatic artery thrombosis at day 1 postoperatively. Conclusions. A single dose of 80 &mgr;g/kg rFVIIa significantly reduced transfusion requirements during OLT. Further study is needed to establish the optimally effective and safe dose of rFVIIa in orthotopic liver transplantation.

The Impact of Intraoperative Transfusion of Platelets and Red Blood Cells on Survival After 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.

Hemostasis and thrombosis in patients with liver disease: The ups and downs

Patients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. However, this balance may easily tip towards a hypo- or hypercoagulable situation. Indeed, patients with liver disease may encounter both hemostasis-related bleeding episodes as well as thrombotic events. During the 3rd International Symposium on Coagulopathy and Liver disease, held in Groningen, The Netherlands (18-19 September 2009), a multidisciplinary panel of experts critically reviewed the current data concerning pathophysiology and clinical consequences of hemostatic disorders in patients with liver disease. Highlights of this symposium are summarized in this review.

Report of the Paris consensus meeting on expanded criteria donors in liver transplantation.

Because of organ shortage and a constant imbalance between available organs and candidates for liver transplantation, expanded criteria donors are needed. Experience shows that there are wide variations in the definitions, selection criteria, and use of expanded criteria donors according to different geographic areas and different centers. Overall, selection criteria for donors have tended to be relaxed in recent years. Consensus recommendations are needed. This article reports the conclusions of a consensus meeting held in Paris in March 2007 with the contribution of experts from Europe, the United States, and Asia. Definitions of expanded criteria donors with respect to donor variables (including age, liver function tests, steatosis, infections, malignancies, and heart‐beating versus non–heart‐beating, among others) are proposed. It is emphasized that donor quality represents a continuum of risk rather than “good or bad.” A distinction is made between donor factors that generate increased risk of graft failure and factors independent of graft function, such as transmissible infectious disease or donor‐derived malignancy, that may preclude a good outcome. Updated data concerning the risks associated with different donor variables in different recipient populations are given. Recommendations on how to safely expand donor selection criteria are proposed. Liver Transpl 14:1694–1707, 2008.

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose‐finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double‐blind trial, patients with end‐stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty‐three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Anastomotic biliary strictures after liver transplantation: Causes and consequences

We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re‐evaluated. Twenty‐one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty‐seven grafts showed an anastomotic stricture: 42 in duct‐to‐duct anastomoses, and 5 in hepaticojejunal Roux‐en‐Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%, 10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, endoscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long‐term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS. Liver Transpl 12:726–735, 2006.

Biliary complications after liver transplantation : A review

After liver transplantation, the prevalence of complications related to the biliary system is 6–35%. In recent years, the diagnosis and treatment of biliary problems has changed markedly. The two standard methods of biliary reconstruction in liver transplant recipients are the duct-to-duct choledochocholedochostomy and the Roux-en-Y-hepaticojejunostomy. Biliary leakage occurs in approximately 5–7% of transplant cases. Leakage from the site of anastomosis, the T-tube exit site and donor or recipient remnant cystic duct is well described. Symptomatic bile leakage should be treated by stenting of the duct by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTCD). Biliary strictures can occur at the site of the anastomosis (anastomotic stricture; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). AS occur in 5–10% of cases and are due to fibrotic healing. Treatment by ERCP or PTCD with dilatation and progressive stenting is successful in the majority of cases. NAS can occur in the context of a hepatic artery thrombosis, or with an open hepatic artery (ischaemic type biliary lesions or ITBL). The incidence is 5–10%. NAS has been associated with various types of injury, e.g. macrovascular, microvascular, immunological and cytotoxic injury by bile salts. Treatment can be attempted with multiple sessions of dilatation and stenting of stenotic areas by ERCP or PTCD. In cases of localized diseased and good graft function, biliary reconstructive surgery is useful. However, a significant number of patients will need a re-transplant. When biliary strictures or ischaemia of the graft are present, stones, casts and sludge can develop.

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).