Coagulopathy and transfusion therapy in pediatric liver transplantation

Bleeding and coagulopathy are critical issues complicating pediatric liver transplantation and contributing to morbidity and mortality in the cirrhotic child. The complexity of coagulopathy in the pediatric patient is illustrated by the interaction between three basic models. The first model, developmental hemostasis, demonstrates how a different balance between pro- and anticoagulation factors leads to a normal hemostatic capacity in the pediatric patient at various ages. The second, the cell based model of coagulation, takes into account the interaction between plasma proteins and cells. In the last, the concept of rebalanced coagulation highlights how the reduction of both pro- and anticoagulation factors leads to a normal, although unstable, coagulation profile. This new concept has led to the development of novel techniques used to analyze the coagulation capacity of whole blood for all patients. For example, viscoelastic methodologies are increasingly used on adult patients to test hemostatic capacity and to guide transfusion protocols. However, results are often confounding or have limited impact on morbidity and mortality. Moreover, data from pediatric patients remain inadequate. In addition, several interventions have been proposed to limit blood loss during transplantation, including the use of antifibrinolytic drugs and surgical techniques, such as the piggyback and lowering the central venous pressure during the hepatic dissection phase. The rationale for the use of these interventions is quite solid and has led to their incorporation into clinical practice; yet few of them have been rigorously tested in adults, let alone in children. Finally, the postoperative period in pediatric cohorts of patients has been characterized by an enhanced risk of hepatic vessel thrombosis. Thrombosis in fact remains the primary cause of early graft failure and re-transplantation within the first 30 d following surgery, and it occurs despite prolongation of standard coagulation assays. Data, however, are currently lacking regarding the use of anti-aggregation/anticoagulation therapies and how to best monitor for thrombosis in the early postoperative period in pediatric patients. Therefore, further studies are necessary to elucidate the interaction between the development of the coagulation system and cirrhosis in children. Moreover, strategies to optimize blood transfusion and anticoagulation must be tested specifically in pediatric patients. In conclusion, data from the adult world can be translated with difficulty into the pediatric field as indication for transplantation, baseline pathologies and levels of pro- and anticoagulation factors are not comparable between the two populations.     

Development of Graves' disease in a patient under immunosuppressive therapy after liver transplantation

Susceptibility to Graves' disease (GD) is determined by multiple environmental and genetic factors, which are not fully understood. Because of the autoimmune etiology of the disease, recent reports describing the development of GD during long-term immunosuppressive treatment seem quite surprising. We report a second case of GD in a 17-yr old patient, treated with cyclosporin A and prednisone, after liver transplantation. The development of GD despite adequate immunosuppressive therapy may suggest that this patient had a genetic predisposition to autoimmunity and severe immunoregulatory defects. We analyzed the HLA-DRB1 alleles and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene polymorphism (A/G) at position 49 in exon 1. The patient had the HLA-DRB1*03 allele which is known to confer susceptibility to GD. Further studies are necessary to identify genes that may predispose patients specifically to GD during immunosuppressive therapies.     

Multimodal therapy for hepatocellular carcinoma: A complementary approach to liver transplantation

Objective. To evaluate the survival benefit of multimodal therapy for the treatment of HCC.Background. Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT.Methods. A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 - 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods.Results. Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease.Conclusion. Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.     

Thrombosis prophylaxis in pediatric liver transplantation: A systematic review

AIM To review current literature of thrombosis prophylaxis in pediatric liver transplantation(PLT) as thrombosis remains a critical complication.METHODS Studies were identified by electronic search of MEDLINE, EMBASE and Cochrane Library(CENTRAL) databases until March 2018. The search was supplemented by manually reviewing the references of included studies and the references of the main published systematic reviews on thrombosis and PLT. We excluded from this review case report, small case series, commentaries, conference abstracts, papers which describing less than 10 pediatric liver transplants/year and articles published before 1990. Two reviewers performed study selection independently, with disagreements solved through discussion and by the opinion of a third reviewer when necessary.RESULTS Nine retrospective studies were included in this review. The overall quality of studies was poor. A pooled analysis of results from studies was not possible due to the retrospective design and heterogeneity of included studies. We found an incidence of portal vein thrombosis(PVT) ranging from 2% to 10% in pediatric living donorliver transplantation(LDLT) and from 4% to 33% in pediatric deceased donor liver transplantation(DDLT). Hepatic artery thrombosis(HAT) was observed mostly in mixed LDLT and DDLT pediatric population with an incidence ranging from 0% to 29%. In most of the studies Doppler ultrasonography was used as a first line diagnostic screening for thrombosis. Four different surgical techniques for portal vein anastomosis were reported with similar efficacy in terms of PVT reduction. Reduced size liver transplant was associated with a low risk of both PVT(incidence 4%) and HAT(incidence 0%, P 0.05). Similarly, aortic arterial anastomosis without graft interposition and microsurgical hepatic arterial reconstruction were associated with a significant reduced HAT incidence(6% and 0%, respectively). According to our inclusion and exclusion criteria, we did not find eligible studies that evaluated pharmacological prevention of thrombosis. CONCLUSION Poor quality retrospective studies show the use of tailored surgical strategies might be useful to reduce HAT and PVT after PLT; prospective studies are urgently needed.     

Efficacy of augmented immunosuppressive therapy for early vasculopathy in heart transplantation

Objectives. The present study was undertaken to prospectively and comparatively evaluate the role of serial myocardial perfusion imaging and coronary angiography for the detection of early vasculopathy in a large patient population and also to determine the short- and long-term efficacy of augmented immunosuppressive therapy in the potential reversal of the early vasculopathy.Background. Allograft vasculopathy is the commonest cause of death after the first year of heart transplantation. Anecdotal studies have reported the efficacy of augmented immunosuppressive therapy after early detection of vascular involvement. However, no prospective study has evaluated the feasibility of early detection and treatment of allograft vasculopathy.Methods. In 76 cardiac allograft recipients, 230 coronary angiographic and 376 scintigraphic studies were performed in a follow-up period of 8 years. Angiography was performed at 1 month and every year after transplantation, and thallium-201 scintigraphy at 1, 3, 6 and 12 months after transplantation and twice a year thereafter. Prospective follow-up of 76 patients showed that 18 developed either angiographic or scintigraphic evidence of coronary vasculopathy. All episodes were treated with 3-day methylprednisolone pulse and antithymocyte globulin.Results. Twenty-two episodes of vasculopathy were diagnosed and treated in these 18 patients. Of these 22 episodes, two were detected only by angiography, seven by both angiography and scintigraphy, four by scintigraphy and histologic evidence of vasculitis and nine episodes only by thallium-201 scintigraphy studies. Angiographic and/or scintigraphic resolution was observed in 15 of the 22 episodes (68%) with augmented immunosuppression. The likelihood of regression was higher when treatment was instituted within the first year of transplantation (92%) than after the first year (40%) (p = 0.033). Eighty percent of patients who responded to follow-up.Conclusions. The present study suggests that early detection of allograft coronary vasculopathy is feasible with surveillance myocardial perfusion or coronary angiographic studies. When identified early after transplantation, immunosuppressive treatment may result in regression of coronary disease.     

Withdrawal of immunosuppression in liver transplantation and the mechanism of tolerance

BACKGROUND: Immunosuppression reagents have side effects and cause considerable long-term morbidity and mortality in patients after liver transplantation. Sufficient evidences showed that minimization or withdrawal of immunosuppression reagents does not deteriorate the recipient's immune response and physiological function and therefore, is feasible in some recipients of liver transplantation. However, the mechanisms are not clear. The present review was to update the current status of immunosuppression in liver transplantation and the mechanism of minimization or withdrawal of immunosuppression in liver recipients.DATA SOURCES: We searched articles in English on minimization or withdrawal of immunosuppression in liver transplantation in Pub Med. We focused on the basic mechanisms of immune tolerance in liver transplantation. Studies on immunosuppression minimization or withdrawal protocols and biomarker in tolerant recipients were also analyzed.RESULTS: Minimization or withdrawal of immunosuppression can be achieved by the induction of immune tolerance, which may not be permanent and can be affected by various factors. However, accurately evaluating immune status post-transplant is a prerequisite to achieve individualized immunosuppression. Numerous mechanisms for immune tolerance have been found, including immunophenotypic shift of memory CD8+ T cells and CD4+ T cell subsets. Activation of the inflammasome through apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain(ASC) in dendritic cells is associated with rejection after liver transplantation. CONCLUSIONS: Minimization or withdrawal of immunosuppression can be achieved by the induction of immune toler-ance via different mechanisms. This process could be affected by immunophenotypic shift of memory CD8+ T cells and CD4+ T cell subsets, which may be correlated with activation of the inflammasome through ASC in dendritic cells.     

Withdrawal of immunosuppressive therapy in allogeneic bone marrow transplantation reactivates chronic viral hepatitis C.

A 28-year-old female patient with acute myelogenous leukemia and post-transfusion chronic viral hepatitis C received an allogeneic bone marrow transplantation (BMT) in first complete remission. The inflammatory activity of chronic hepatitis C decreased dramatically with the start of BMT and during the whole course of cyclosporin A treatment. After the immunosuppressive therapy was stopped, however, the chronic hepatitis C activity increased and the serum alanine amino-transferase levels thereafter remained as high as before BMT. Hepatitis C virus RNA was detected by polymerase chain reaction in serum drawn 60 days and 52 months after BMT. Since fulminant viral hepatitis B may take place after tapering of immunosuppressive therapy following BMT due to an excessive response of recovering immunity to the actively replicating virus during immune suppression, careful monitoring of liver function for patients with chronic viral hepatitis C in BMT is suggested.     

肝脏移植耐受及其抗原递呈细胞相关作用的研究进展

免疫排斥反应是移植器官组织最终能否成活的最大障碍．解决此问题最理想的方法是诱导特异性免疫耐受．肝脏除了有代谢消化功能外,还能够处理外来抗原并诱导机体对其产生特异性免疫耐受反应,尤其是在移植耐受中表现出了独特作用．目前相关机制研究发现,除了特殊的微环境外,肝脏还拥有大量的驻留和非驻留型抗原提呈细胞参与内部免疫反应．肝脏抗原递呈细胞在移植耐受诱导过程中占有重要地位．     

Delayed introduction of immunosuppressive regimens in critically ill patients after liver transplantation

BACKGROUND: The manipulation of immunosuppression therapy remains challenging in patients who develop infectious diseases or multiple organ dysfunction after liver transplantation.We evaluated the outcomes of delayed introduction of immunosuppression in the patients after liver transplantation under immune monitoring with Immu Know assay.METHODS: From March 2009 to February 2014, 225 consecutive liver recipients in our institute were included. The delayed administration of immunosuppressive regimens was attempted in 11 liver recipients with multiple severe comorbidities.RESULTS: The median duration of non-immunosuppression was 12 days(range 5-58). Due to the infectious complications,the serial Immu Know assay showed a significantly low ATP level of 64±35 ng/mL in the early period after transplantation. With the development of comorbidities, the Immu Know value significantly increased. However, the acute allograft rejection developed when a continuous distinct elevation of both ATP and glutamyltranspeptidase levels was detected.The average ATP level measured just before the development of acute rejection was 271±115 ng/mL.CONCLUSIONS: The delayed introduction of immunosuppressive regimens is safe and effective in management of critically ill patients after liver transplantation. The serial Immu Know assay could provide a reliable depiction of the dynamics of functional immunity throughout the clinical course of a given patient.     

Successful rapid discontinuation of immunosuppressive therapy at molecular relapse after allogeneic bone marrow transplantation in a pediatric patient with myelodysplastic syndrome

The success of allogeneic bone marrow transplantation (allo-BMT) in children with myelodysplastic syndrome (MDS) is mainly affected by relapse. The role of additional immunotherapy for pediatric patients with MDS relapsing after allo-BMT remains to be established. Because immunotherapy is generally more effective for patients who bear a low tumor burden, monitoring of minimal residual diseases (MRD) is essential for early diagnosis at molecular relapse. We report here that a patient with relapsed MDS after allo-BMT was successfully treated by the rapid discontinuation of immunosuppressive therapy at molecular relapse while monitoring Wilms tumor (WT1) gene expression levels. Quantitative analysis of WT1 gene expression appeared to be a useful tool to monitor MRD in the present case.