Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation.

BACKGROUND: PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. METHODS: Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy. RESULTS: The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. CONCLUSION: It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation.

Evidence for a rebalanced hemostatic system in pediatric liver transplantation: A prospective cohort study.

In adults with end-stage liver disease concurrent changes in pro- and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017-October 2018). Routine hemostasis tests, thrombomodulin-modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age-matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end-stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin-dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis.

Motor development in children 0-2 years pre- and post-LTX, a prospective study.

To determine prospectively gross and fine motor development of children <2 years of age, who undergo LTX. In this prospective study, children aged <2 years who undergo LTX were tested using the motor scale of the Bayley Scales of infant and toddler development, 3rd edition Dutch version. Testing was done during screening pre- and post-LTX: at the time of hospital discharge (2-6 weeks), at 3 months, 6 months, and 1 year. Z-scores were calculated. Twenty-nine children participated in this study, 14 boys, median age 6 months, at screening for LTX. Gross motor skills were delayed pre-LTX (Z-score -1.3). Fine motor skills were normal (Z-score 0.3). Immediately post-LTX, both skills reduced, and at 1 year post-LTX, gross motor skills Z-score was -1.0 and fine motor skills Z-score 0.0. Both gross and fine motor skills Z-scores decline post-LTX and tend to recover after 1 year, gross motor skills to low normal and fine motor skills to normal levels. Monitoring of gross motor development and attention on stimulating gross motor development post-LTX remains important, to enable participation in physical activity and sport for health benefits later in life.

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency.

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

Time-to-reach Target Calprotectin Level in Newly Diagnosed Patients With Inflammatory Bowel Disease.

OBJECTIVES: Treatment targets in inflammatory bowel disease (IBD) move away from controlling symptoms towards complete recovery of the intestinal mucosa. Currently, the most frequently used noninvasive surrogate marker of mucosal healing is a faecal calprotectin concentration in the target range. This study tested if there was a relation between time-to-reach target calprotectin and first flare. METHODS: We prospectively included new-onset IBD patients ages 17 and younger in a cloud-based registry (FastForwardCare) and followed them for at least 52 weeks. They were treated according to Dutch national guidelines that advocate a step-up approach. Time-to-reach target was defined as the first calprotectin measurement below 250 µg/g after the start of induction therapy. Time-to-first flare was the time from the first calprotectin measurement below 250 µg/g until reappearance of symptoms with calprotectin values above 250 µg/g. RESULTS: We included 76 patients (luminal Crohn disease [CD] 43); ulcerative colitis [UC] 33). Median age at diagnosis was, respectively 14.5 and 14.1 years. Median time-to-reach target calprotectin was 37 weeks in CD and 11 weeks in UC patients (Log-rank test, P = 0.001). Once the calprotectin target was reached, time-to-first flare was significantly longer in CD than in UC patients (Log-rank test, P = 0.001). CD patients with time-to-reach target calprotectin ≤12 weeks after conventional induction therapy (ie, exclusive enteral nutrition or steroids) had a more favorable disease course in the first year than those with time-to-reach target calprotectin >12 weeks (Log-rank test, P = 0.057). In UC patients, time-to-reach target calprotectin ≤12 weeks is not associated with a favorable disease course in the first year. CONCLUSIONS: The findings of this prospective registry suggest that a quick response to conventional therapy predicts a favorable disease course in new-onset paediatric CD, but not in UC. The concept "time-to-reach target calprotectin level" rationalizes the indefinite term "response to treatment" and is well suited for studying treatment effectiveness in real-world practices.

Physical activity and aerobic fitness in children after liver transplantation.

To determine physical activity (PA), aerobic fitness, muscle strength, health-related quality of life (HRQOL), fatigue, and participation in children after liver transplantation. Children, 6-12 years, at least one year after liver transplantation, participated in this cross-sectional study. Measurements: Time spent in moderate to vigorous PA (MVPA) was measured using an accelerometer, and aerobic fitness (VO2 peak ) was measured by cardiopulmonary exercise testing. Muscle strength was measured by hand-held dynamometry. Fatigue was measured using the multidimensional fatigue scale, and HRQOL with the Pediatric Quality of life Core scales and leisure activities was measured using the Children's Assessment of Participation and Enjoyment. Outcomes (medians and interquartile range (IQR)) were compared to norm values. Twenty-six children participated in this study (14 boys, age 9.7 years, IQR 7.7;11.4). Children spent 0.8 hours/d (IQR 0.6;1.1) on MVPA. One child met the recommendation of at least 1 hour of MVPA every day of the week. Aerobic fitness was similar to norms (VO2 peak 1.4 L/min , IQR 1.1;1.7, Z-score -0.3). Z-scores of muscle strength ranged between -1.4 and -0.4 and HRQOL and fatigue between -2.3 and -0.4. Participation was similar to published norms (Z-scores between -0.6 and 0.6). Young children after liver transplantation have similar MVPA patterns and aerobic fitness compared to published norms. Despite lower HRQOL, more fatigue, and less muscle strength, these children have similar participation in daily activities. Although children do well, it remains important to stimulate PA in children after liver transplantation in the context of long-term management.

First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion.

One of the main limiting factors in pediatric liver transplantation is donor availability. For adults, DCD liver grafts are increasingly used to expand the donor pool. To improve outcome after DCD liver transplantation, ex situ machine perfusion is used as an alternative organ preservation strategy, with the supplemental value of providing oxygen to the graft during preservation. We here report the first successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion. The full-size liver graft was derived from a 13-year-old, female DCD donor and was end-ischemic pretreated with dual hypothermic oxygenated machine perfusion. Arterial and portal pressures were set at 18 and 4 mm Hg, slightly lower than protocolized settings for adult livers. During 2 hours of machine perfusion, portal and arterial flows increased from 100 to 210 mL/min and 30 to 63 mL/min, respectively. The pretreated liver graft was implanted in a 16-year-old girl with progressive familial intrahepatic cholestasis type 2. Postoperative AST, ALT, and prothrombin time normalized within a week. The recipient quickly recovered and was discharged from the hospital after 18 days. One year after transplantation, she is in excellent condition with a completely normal liver function and histology. This case is the first report of successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion and illustrates the potential role of ex situ machine perfusion in expanding the donor pool and improving outcome after pediatric liver transplantation.

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome.

BACKGROUND & AIMS: Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10-20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome. METHODS: Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. RESULTS: Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792. CONCLUSIONS: The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12-24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.

Oral Tocofersolan Corrects or Prevents Vitamin E Deficiency in Children With Chronic Cholestasis.

OBJECTIVES: D-Alpha-tocopheryl polyethylene glycol 1000 succinate (Tocofersolan, Vedrop), has been developed in Europe to provide an orally bioavailable source of vitamin E in children with cholestasis. The aim was to analyze the safety/efficacy of Vedrop in a large group of children with chronic cholestasis. METHODS: Two hundred seventy-four children receiving Vedrop for vitamin E deficiency or for its prophylaxis were included from 7 European centers. Median age at treatment onset was 2 months and median follow-up was 11 months. Vedrop was prescribed at a daily dose of 0.34 mL/kg (25 IU/kg) of body weight. Three methods were used to determine a sufficient serum vitamin E status: vitamin E, vitamin E/(total cholesterol), vitamin E/(total cholesterol + triglycerides). RESULTS: Before Vedrop therapy, 51% of children had proven vitamin E deficiency, 30% had normal vitamin E status and 19% had an unknown vitamin E status. During the first months of treatment, vitamin E status was restored in the majority of children with insufficient levels at baseline (89% had a normal status at 6 months). All children with a normal baseline vitamin E status had a normal vitamin E status at 6 months. Among children with an unknown vitamin E status at baseline, 93% had a normal vitamin E status at 6 months. A sufficient vitamin E status was observed in 80% of children with significant cholestasis (serum total bilirubin >34.2 µmol/L). No serious adverse reaction was reported. CONCLUSIONS: Vedrop seems a safe and effective oral formulation of vitamin E that restores and/or maintains sufficient serum vitamin E level in the majority of children with cholestasis, avoiding the need for intramuscular vitamin E injections.

Experience with molecular adsorbent recirculating system treatment in 20 children listed for high-urgency liver transplantation.

For more than 10 years, children at our national center for pediatric liver transplantation (LT) have been treated with Molecular Adsorbent Recirculating System (MARS) liver dialysis as a bridging therapy to high-urgency LT. Treatment was reserved for 20 patients with the highest degrees of hepatic encephalopathy (HE; median grade = 3.5). Death from neurological sequelae was considered imminent for these patients, and this was further reflected in significantly higher international normalized ratios and ammonia levels and worse prognostic liver indices (Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores and liver injury units) in comparison with 32 wait-listed patients who did not receive MARS dialysis. MARS therapy was generally well tolerated, with a reduction in thrombocytes and hemorrhaging as the most common side effects. HE improvement was documented in 30% of the treated patients, but progression to grade IV encephalopathy occurred in 45% of the patients despite the treatment. Serum ammonia, bilirubin, bile acid, and creatinine levels significantly decreased during treatment. Eighty percent of MARS-treated patients survived to undergo LT, and their survival was equivalent to that of non-MARS-treated patients with severe liver failure (69%, P = 0.52). The heterogeneity between MARS-treated patients and non-MARS-treated patients in our cohort precluded a statistical evaluation of a benefit from MARS for patient survival. Our data demonstrate the safety of MARS even in the most severely ill patients awaiting LT, but strategies that promote the more rapid and widespread availability of high-quality donor organs remain of critical importance for improving patient survival in cases of severe acute liver failure.

Achievement of developmental milestones in young adults after liver transplantation in childhood.

Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood.

Long-term Outcome of Asymptomatic Patients With Graft Fibrosis in Protocol Biopsies After Pediatric Liver Transplantation.

BACKGROUND: The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. METHODS: We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. RESULTS: In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027). CONCLUSIONS: At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.

Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008.

OBJECTIVE: To examine the outcome of biliary atresia (BA) and to identify prognostic factors using a national database. STUDY DESIGN: All children born between January 1987 and December 2008 who underwent the Kasai surgical procedure for BA were retrieved from the Netherlands Study Group on Biliary Atresia Registry database. Outcomes were measured in terms of clearance of jaundice (bilirubin <1.17 g/dL, or 20 µmol/L, within 6 months after surgery) and 4-year transplant-free survival. Two cohorts, one from 1987-1997 and the other from 1998-2008, were compared. Survival rates were determined using Kaplan-Meier analysis, and prognostic factors were tested with univariate and multivariate analyses. RESULTS: Between January 1987 and December 2008, 214 patients underwent Kasai surgery for BA. In this series, the 4-year transplant-free survival was 46%±4%, and 4-year overall survival was 73%±3%. Clearance of jaundice, surgery within 60 days, and postoperative antibiotic prophylaxis use were independently associated with increased transplant-free survival. The yearly caseload per center (range, 0.5-2.1) was not correlated with transplant-free survival (r=0.024; P=.73). CONCLUSION: During the past 2 decades, outcome parameters have remained constant and are comparable with those reported from other Western countries, despite a relatively low annual caseload per center. Timely surgical correction and postoperative antibiotic therapy were associated with a higher transplant-free survival rate.

Indeterminate pediatric acute liver failure: Clinical characteristics of a temporal cluster of five children in the Netherlands in the spring of 2022.

There is increasing global concern of severe acute hepatitis of unknown etiology in young children. In early 2022, our center for liver transplantation in the Netherlands treated five children who presented in short succession with indeterminate acute liver failure. Four children underwent liver transplantation, one spontaneously recovered. Here we delineate the clinical course and comprehensive diagnostic workup of these patients. Three of five patients showed a gradual decline of liver synthetic function and had mild neurological symptoms. Their clinical and histological findings were consistent with hepatitis. These three patients all had a past SARS-CoV-2 infection and two of them were positive for adenovirus DNA. The other two patients presented with advanced liver failure and encephalopathy and underwent dialysis as a bridge to transplantation. One of these children spontaneously recovered. We discuss this cluster of patients in the context of the currently elevated incidence of severe acute hepatitis in children.

Honoring the contract with our patients: outcome after repeated re-transplantation of the liver.

The aim of this study was to describe the outcome after repeated orthotopic liver re-transplantations (re-OLT) in a population of adults and children, and to determine whether such repeated re-transplantations are an effective treatment or should be considered futile. In a consecutive series of 867 patients, 628 adults and 239 children, who underwent OLT at the University Medical Center Groningen, 23 patients (2.7%), 10 adults and 13 children, underwent more than two re-transplantations of the liver between March 1979 and October 2008. All 23 patients had a second re-transplantation, and seven of them received a third transplant. The overall actuarial patient survival at 1, 5, and 10 yr after primary OLT was 96%, 87%, and 71%, respectively. The overall actuarial patient survival after the second re-OLT was 78%, 73%, and 67%, respectively. Sixteen patients (70%) survived long term. However, for the 23 repeated re-transplantation patients, 76 grafts were used. In a simulation calculation, it was shown that honoring the initial commitment to the 23 patients ultimately led to more surviving patients and less death than if treatment of the original patients was stopped after the first re-transplantation and the remaining grafts were allocated to other primary graft recipients.

Graft fibrosis after pediatric liver transplantation: ten years of follow-up.

UNLABELLED: Previously we reported the presence of portal fibrosis in 31% (n = 84) of the grafts in protocol biopsies 1 year after pediatric liver transplantation (LTx). To assess the natural history of graft fibrosis after pediatric liver transplantation, we extended the analysis of graft histology in follow-up protocol biopsy specimens obtained 5 and 10 years after transplantation. We correlated histological results with clinical parameters at the time of LTx and during follow-up, to allow identification of risk factors for the development of fibrosis. From 1 year to 5 years after LTx, the prevalence of fibrosis increased from 31% to 65% (n = 66) but remained stable thereafter (at 10 years, 69%, n = 55). At 10 years after LTx, however, the percentage of patients with severe fibrosis had increased from 10% (at 5 years) to 29%. Of the 69% of children without fibrosis at 1 year post-transplantation, 64% (n = 39) had developed some degree of fibrosis at 10 years. Fibrosis was strongly related to transplant-related factors such as prolonged cold ischemia time, young age at the time of transplantation, high donor/recipient age ratio, and the use of partial grafts (P < 0.05). Fibrosis was not significantly related to rejection, chronic hepatitis, or the nature of the immunosuppressive therapy. CONCLUSION: Biopsies after pediatric LTx show that most grafts developed fibrosis within 5 years. At 10 years after LTx, the graft fibrosis had progressed to severe fibrosis in at least 25% of the patients. Development of fibrosis, starting either before or after the first year post-LTx, was strongly related to transplant-related factors, indicating the importance of these factors to long-term graft prognosis.

Routine Postoperative Antithrombotic Therapy in Pediatric Liver Transplantation: Impact on Bleeding and Thrombotic Complications.

BACKGROUND: Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) are serious causes of morbidity and mortality after pediatric liver transplantation. To reduce thrombotic complications, routine antithrombotic therapy consisting of 1 week heparin followed by 3 months acetylsalicylic acid, was implemented in our pediatric liver transplant program in 2003. This study aimed to evaluate incidences of bleeding and thrombotic complications since the implementation of routine antithrombotic therapy and to identify risk factors for these complications. METHODS: This retrospective cohort study includes 200 consecutive pediatric primary liver transplantations performed between 2003 and 2016. Uni- and multivariate logistic regression analysis, Kaplan-Meier method, and Cox regression analysis were used to evaluate recipient outcome. RESULTS: HAT occurred in 15 (7.5%), PVT in 4 (2.0%), and venous outflow tract thrombosis in 2 (1.0%) recipients. Intraoperative vascular interventions (odds ratio [OR] 14.45 [95% confidence interval [CI] 3.75-55.67]), low recipient age (OR 0.81 [0.69-0.95]), and donor age (OR 0.96 [0.93-0.99]) were associated with posttransplant thrombosis. Clinically relevant bleeding occurred in 37%. Risk factors were high recipient age (OR 1.08 [1.02-1.15]), high Child-Pugh scores (OR 1.14 [1.02-1.28]), and intraoperative blood loss in mL/kg (OR 1.003 [1.001-1.006]). Both posttransplant thrombotic (hazard ratio [HR] 3.38 [1.36-8.45]; p = 0.009) and bleeding complications (HR 2.50 [1.19-5.24]; p = 0.015) significantly increased mortality. CONCLUSION: In 200 consecutive pediatric liver transplant recipients receiving routine postoperative antithrombotic therapy, we report low incidences of posttransplant vascular complications. Posttransplant antithrombotic therapy seems to be a valuable strategy in pediatric liver transplantation. Identified risk factors for bleeding and thrombotic complications might facilitate a more personalized approach in antithrombotic therapy.

In Vitro Evaluation of Pro- and Anticoagulant Drugs in Children with End-Stage Liver Disease Undergoing Liver Transplantation.

BACKGROUND: Pro- and anticoagulant drugs are commonly used in pediatric liver transplantation to prevent and treat thrombotic and bleeding complications. However, the combination of baseline hemostatic changes in children with liver disease and additional changes induced by transplantation makes this very challenging. This study aimed to analyze the efficacy of clinically available pro- and anticoagulant drugs in plasma from children undergoing liver transplantation. METHODS: In vitro effects of pro- and anticoagulant drugs on thrombin generation capacity were tested in plasma samples of 20 children (≤ 16 years) with end-stage liver disease undergoing liver transplantation, and compared with 30 age-matched healthy controls. RESULTS: Addition of pooled normal plasma had no effect in patients or controls, while 4-factor prothrombin complex concentrate increased thrombin generation in both patients and controls, with enhanced activity in patients. At start of transplantation, dabigatran and unfractionated heparin had a higher anticoagulant potency in patients, whereas 30 days after transplantation low molecular weight heparin was slightly less effective in patients. Effects of rivaroxaban were comparable between patients and controls. CONCLUSION: This study revealed important differences in efficacy of commonly used pro- and anticoagulant drugs in children with end-stage liver disease undergoing liver transplantation. Therefore, dose adjustments of these drugs may be required. The results of this study may be helpful in the development of urgently needed protocols for strategies to prevent and treat bleeding and thrombotic complications in pediatric liver transplantation.

Growth and final height after liver transplantation during childhood.

OBJECTIVE: To evaluate the effect of end-stage pediatric liver disease and liver transplantation on growth and final height. PATIENTS AND METHODS: We evaluated growth at 2 years (n = 101) and 5 years (n = 63) after pediatric liver transplantation (LTx). Twenty-three children reached final height. Height was expressed as a standard deviation score of the target height (zTH score) of each patient. RESULTS: At the first 2 years after LTx, the zTH score was significantly increased from -1.7 to -1.3 SD (P < 0.05). Growth at 2 or 5 years after LTx, expressed as DeltazTH score, was positively correlated with pretransplant growth retardation (P < 0.05). In comparison with patients with noncholestatic primary liver disease, patients with cholestatic primary liver disease were more severely growth retarded before LTx (zTH score -2.0 vs -1.2 SD, P < 0.05) and had better growth in the first 2 years after LTx (DeltazTH score +0.6 vs -0.1 SD, P < 0.05). Twelve of the 23 patients had a final height below -1.3 SD of their target height. CONCLUSIONS: Growth retardation is common in children before LTx, particularly in children with an underlying cholestatic disease. After LTx, catch-up growth was partial and was prominent only in cholestatic children who had been severely growth retarded before LTx. After LTx during childhood, approximately 50% of patients reach a final height lower than -1.3 SD of their genetic potential.