Comprehensive and innovative techniques for livertransplantation in rats: A surgical guide

AIM: To investigate our learning curves of orthotopic liver transplantation (OLT) in rats and the most important factor for successful surgery. METHODS: We describe the surgical procedures for our rat OLT model, and determined the operator learning curves. The various factors that contributed to successful surgery were determined. The most important surgical factors were evaluated between successful and unsuccessful surgeries.RESULTS: Learning curve data indicated that 50 cases were required for operator training to start a study. Operative time, blood loss, warm ischemic time, anhepatic phase, unstable systemic hemodynamic state, and body temperature after surgery significantly affected surgery success by univariate analysis, while the anhepatic phase was the most critical factor for success by multivariate analysis. CONCLUSION: OLT in rats is the only liver transplantation model that provides clinically relevant and reliable results. Shortened anhepatic phase is key to success in this model.

Impact of lymph node micrometastasis in hilar bile duct carcinoma patients

AIM- To immunohistochemicaUy examine micrometastasis and VEGF-C expression in hilar bile duct carcinoma （HBDC） and to evaluate the clinical significance of the results. METHODS： A total of 361 regional lymph nodes from 25 patients with node-negative HBDC were immunostained with an antibody against cytokeratins 8 and 18 （CAM 5.2）, and immunohistochemical staining of VEGF-C was performed in 34 primary resected tumors. RESULTS： Lymph node micrometastasis was detected in 6 （24%） of the 25 patients and 10 （2.8%） of the 361 lymph nodes. Patients with micrometastasis showed significantly poorer survival rates than those without （P= 0.025）. VEGF-C expression was positive in 17 （50%） of 34 HBDC, and significantly correlated with lymph node metastasis （P=0.042） and microscopic venous invasion （P=0.035）. CONCLUSIONS： It is suggested that immunohistochemically detected lymph node micrometastasis has an impact on the outcome of HBDC. VEGF-C expression is highly correlated with lymph node metastasis in HBDC and might therefore be a useful predictor.

Progressive familial intrahepatic cholestasis

BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic cholestasis'and'PFIC'was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

AIM:To investigate oxidative stress(OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage.METHODS: Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant(60% hepatectomy); orthotopic liver transplantation(OLT) with whole liver graft(100% OLT); and split OLT(SOLT) with 40% graft(40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OSinduced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase(PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase(MMP)-9, MMP-2, tissue inhibitor of metalloproteinase(TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography. RESULTS: Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT. CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage via the Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery.

Laparoscopic liver resection: Toward a truly minimally invasive approach

In the surgical treatment of hepatocellular carcinoma and colorectal liver metastasis, it is important to preserve sufficient liver volume after resection in order to avoid post-hepatectomy liver sufficiency and to increase the feasibility of repeated hepatectomyin case of intrahepatic recurrence. Parenchymasparing approach, which minimizes the extent of resection while obtaining sufficient surgical margins, has been developed in open hepatectomy. Although this approach can possibly have positive impacts on morbidity and mortality, it is not popular in laparoscopic approach because parenchyma-sparing resection is technically demanding especially by laparoscopy due to its intricate curved transection planes. "Small incision, big resection" is the words to caution laparoscopic surgeons against an easygoing trend to seek for a superficial minimal-invasiveness rather than substantial patient-benefits. Minimal parenchyma excision is often more important than minimal incision. Recently, several reports have shown that technical evolution and accumulation of experience allow surgeons to overcome the hurdle in laparoscopic parenchymasparing resection of difficult-to-access liver lesions in posterosuperior segments, paracaval portion, and central liver. Laparoscopic surgeons should now seek for the possibility of laparoscopic parenchyma-sparing hepatectomy as open approach can, which we believe is beneficial for patients rather than just a small incision and lead laparoscopic hepatectomy toward a truly minimally-invasive approach.

Stability of cirrhotic systemic hemodynamics ensures sufficient splanchnic blood flow after living-donor liver transplantation in adult recipients with liver cirrhosis

AIM： To investigate the correlation between systemic hemodynamics and splanchnic circulation in recipients with cirrhosis undergoing living-donor liver transplantation （LDLT）, and to clarify how systemic hemodynamics impact on local graft circulation after LDLT.METHODS： Systemic hemodynamics, indocyanine green （ICG） elimination rate （K,cG） and splanchnic circulation were simultaneously and non-invasively investigated by pulse dye densitometry （PDD） and ultrasound. Accurate estimators of optimal systemic hyperdynamics after LDLT [i.e., balance of cardiac output （CO） to blood volume （BV） and mean transit time （MTT）, defined as the time required for half the administered ICG to pass through an attached PDD sensor in the first circulation] were also measured. Thirty recipients with cirrhosis were divided into two groups based on clinical outcomes corresponding to postoperative graft function.RESULTS： Cirrhotic systemic hyperdynamics characterized by high CO, expanded BV and low total peripheral resistance （TPR） were observed before LDLT. TPR reflecting cirrhotic vascular alterations was slowly restored after LDLT in both groups. Although no significant temporal differences in TPR were detected between the two groups, CO/BV and M＇IT differed significantly. Recipients with good outcomes showed persistent cirrhotic systemic hyperdynamics after LDLT, whereas recipients with poor outcomes presented with unstable cirrhotic systemic hyperdynamics and severely decreased KICG. Systemic hyperdynamic disorders after LDLT impacted on portal venous flow but not hepatic arterial flow.CONCLUSION： We conclude that subtle systemic hyperdynamics disorders impact on splanchnic circulation, and that an imbalance between CO and BV decreases portal venous flow, which results in critical outcomes.

Unexpected metastasis of intraductal papillary neoplasm of the bile duct without an invasive component to the brain and lungs:A case report

BACKGROUND Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct(IPNB),distant metastasis remains unexplained especially in cases of carcinoma in situ.In the present study,we report a rare and interesting case of IPNB without invasive components that later metastasized to lungs and brain.CASE SUMMARY A 69-year-old male was referred to our hospital due to suspected cholangiocarcinoma.Laboratory tests on admission reported a mild elevation of alkaline phosphatase,γ-glutamyl transpeptidase,and total bilirubin in serum.Endoscopic retrograde cholangiography revealed a filling defect in the common bile duct(CBD)extending to the left hepatic duct.Peroral cholangioscopy delineated a tumor in the CBD that had a papillary pattern.Multidetector computed tomography and magnetic resonance cholangiopancreatography detected partial blockage ot interlude in the CBD leading to cholestasis without evidence of metastasis.Therefore,a diagnosis of IPNB cT1N0M0 was established.Left hepatectomy with bile duct reconstruction was performed.Pathological examination confirmed an intraepithelial neoplasia pattern without an invasive component and an R0 resection achievement.The patient was monitored carefully by regular examinations.However,at 32 mo after the operation,a 26 mm tumor in the lungs and a 12 mm lesion in the brain were detected following a suspicious elevated CA 19-9 level.Video-assisted thoracoscopic surgery of left upper lobectomy and stereotactic radiotherapy are indicated.In addition to histopathological results,a genomic profiling analysis using whole exome sequencing subsequently confirmed lung metastasis originating from bile duct cancer.CONCLUSION This case highlights the important role of genomic profiling analysis using whole exome sequencing in identifying the origin of metastasis in patients with IPNB.

Simple and reproducible hepatectomy in the mouse using the clip technique

AIM: To investigate the reliability of massive hepatectomy models by using clip techniques. METHODS: We analyzed anatomical findings in 100 mice following massive hepatectomy induced by liver reduction > 70%. The impact of various factors in the different models was also analyzed, including learning curves, operative time, survival curves, and histopathological findings.RESULTS: According to anatomical results, models with 75%, 80%, and 90% hepatectomy produced massive hepatectomy. Learning curves and operative times were most optimal with the clip technique. Each hepatectomy performed using the clip technique produced a reasonable survival curve, and there were no differences in histopathological findings between the suture and clip techniques. CONCLUSION: Massive hepatectomy by the clip technique is simple and can provide reliable and relevant data.

Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice

AIM： To investigate the effect of matrix metallopro- teinase-9 （MMP-9） on the remnant liver after massivehepatectomy in the mouse.METHODS： Age-matched, C57BL/6 wild-type （WT）, MMP-9（-/-）, and tissue inhibitors of metalloprotein- ases （TIMP）-1（-/-） mice were used. The mice received 80%-partial hepatectomy （PH）. Samples were obtained at 6 h after 80%-PH, and we used histology, immuno- histochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor.RESULTS： We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and ne- crotic lesions in MMP-9（-/-） remnant livers compared with WT and TIMP-1（-/-） livers （P 〈 0.01）, with no dif- ference between WT and TIMP-1（-/-） mice. Serum ala- nine aminotransaminase levels were significantly lower in MMP-9（-/-） mice compared with those in TIMP-I（-/-） mice （WT： 476± 83 IU/L, MMP-9（-/-）： 392 ± 30 IU/L, TIMP-I（-/-）： 673 ± 73 IU/L, P 〈 0.01）. Western blot- ting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9（-/-） mice, which was in contrast to WT and TIMP-1（-/-） mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9（-/-） mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice （P 〈 0.05）. These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver.CONCLUSION： Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and mightbe a potential therapy to ameliorate liver injury after massive hepatectomy.

Small-for-size syndrome in living donor liver transplantation

When the graft volume is too small to satisfy the recipient’s metabolic demand, the recipient may thus experience small-for-size syndrome (SFSS). Because the occurrence of SFSS is determined by not only the liver graft volume but also a combination of multiple negative factors, the definitions of small-for-size graft (SFSG) and SFSS are different in each institute and at each time. In the clinical setting, surgical inflow modulation and maximizing the graft outflow are keys to overcoming SFSS. Accordingly, relatively smaller-sized grafts can be used with surgical modification and pharmacological manipulation targeting portal circulation and liver graft quality. Therefore, the focus of the SFSG issue is now shifting from how to obtain a larger graft from the living donor to how to manage the use of a smaller graft to save the recipient, considering donor safety to be a priority.

Protocol for laparoscopic cholecystectomy: Is it rocket science?

Laparoscopic cholecystectomy(LC) does not require advanced techniques, and its performance has therefore rapidly spread worldwide. However, the rate of biliary injuries has not decreased. The concept of the critical view of safety(CVS) was first documented two decades ago. Unexpected injuries are principally due to misidentification of human factors. The surgeon's assumption is a major cause of misidentification, and a high level of experience alone is not sufficient for successful LC. We herein describe tips and pitfalls of LC in detail and discuss various technical considerations.Finally, based on a review of important papers and our own experience, we summarize the following mandatory protocol for safe LC:(1) consideration that a high level of experience alone is not enough;(2) recognition of the plateau involving the common hepatic duct and hepatic hilum;(3) blunt dissection until CVS exposure;(4) Calot's triangle clearance in the overhead view;(5) Calot's triangle clearance in the view from underneath;(6) dissection of the posterior right side of Calot's triangle;(7) removal of the gallbladder body; and(8) positive CVS exposure. We believe that adherence to this protocol will ensure successful and beneficial LC worldwide, even in patients with inflammatory changes and rare anatomies.

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

Advanced liver cirrhosis is usually accompanied by portal hypertension. Long-term portal hypertension results in various vascular alterations. The systemic hemodynamic state in patients with cirrhosis is termed a hyperdynamic state. This peculiar hemodynamic state is characterized by an expanded blood volume, high cardiac output, and low total peripheral resistance. Vascular alterations do not disappear even long after liver transplantation(LT), and recipients with cirrhosis exhibit a persistent systemic hyperdynamic state even after LT. Stability of optimal systemic hemodynamics is indispensable for adequate portal venous flow(PVF) and successful LT, and reliable parameters for optimal systemic hemodynamics and adequate PVF are required. Even a subtle disorder in systemic hemodynamics is precisely indicated by the balance between cardiac output and blood volume. The indocyanine green(ICG) kinetics reflect the patient's functional hepatocytes and effective PVF, and PVF is a major determinant of the ICG elimination constant(kICG) in the well-preserved allograft. The kICG value is useful to set the optimal PVF during living-donor LT and to evaluate adequate PVF after LT. Perioperative management has a large influence on the postoperative course and outcome; therefore, key points and unexpected pitfalls for intensive management are herein summarized. Transplant physicians should fully understand the peculiar systemic hemodynamic behavior in LT recipients with cirrhosis and recognize the critical importance of PVF after LT.

Effect of ONO-4057 and tacrolimus on ischemia-reperfusion injury of the liver

AIM: To investigate the effects of a novel Leukotriene B4 receptor antagonist and/or tacrolimus on ischemia-reperfusion in a rat liver model. METHODS: Male Lewis rats were pretreated with ONO-4057 (100 mg/kg) and/or tacrolimus (1 mg/kg) orally, and divided into four experimental groups; group 1 (control), group 2 (ONO-4057), group 3 (tacrolimus), group 4 (ONO-4057 + tacrolimus). RESULTS: There was a tendency for long survival in the groups treated with tacrolimus alone and ONO-4057 plus tacrolimus. Post-reperfusion serum aspartate aminotransferase levels decreased more signif icantly in ONO-4057 plus tacrolimus group (P < 0.01), than in the tacrolimus alone group (P < 0.05), compared to controls. CONCLUSION: This study demonstrated that pretreat-ment with ONO-4057 in combination with tacrolimus produced additive effects in a rat model of liver isch-emia-reperfusion injury.

Is biliary bile acid a good predictor for acute cellular rejection in living donor liver transplantation?

BACKGROUND:In liver transplantation,acute cellular rejection(ACR)is still a major complication that can lead to mortality.Bile secretion has been considered as a marker of early graft function. METHODS:The study included 41 adults who received living donor liver transplantation(LDLT)at Kyoto University Hospital between April 2007 and February 2008. The patients were stratified according to the presence or absence of ACR.Bile samples were collected from donors once and from recipients every other day for the first 2 weeks after transplantation.Total bile acid(BA)and taurine-conjugated bile acid(TCBA)in bile were measured by magnetic resonance spectroscopy.The recipient/donor (R/D)BA ratio and R/D TCBA ratio were calculated. RESULTS:The ACR group(n=12)showed a greater decrease in BA post-transplantation than the non-ACR group,but this difference was not statistically significant. On both day 7 and day 9 post-transplantation the R/D TCBA was significantly different between the two groups (P=0.038 on day 7 and P=0.036 on day 9).The R/D TCBA ratio≥0.5 on days 7 and 9,and≥0.38 on day 11 post- transplantation were associated with better ACR-free survival. CONCLUSION:The recipient/donor TCBA ratio can be a predictor for ACR after LDLT as early as post- transplantation day 7.

Laparoscopic approach for choledochojejunostomy

Laparoscopic hepatobiliary and pancreatic (HBP) surgery has been developed slowly because of technical challenges and a protracted learning curve with the exception of laparoscopic cholecystectomy [1]. Surgical treatments for benign diseases of the extrahepatic bile duct (EHBD) are classified according to their therapeutic purpose as lithotomy (i.e., choledocholithotomy) or diversion (i.e., choledochojejunostomy)[2].

Assessment of cardiac output in liver transplantation recipients

BACKGROUND:Liver cirrhosis causes peculiar systemic hemodynamics,and accurate evaluation of systemic hemodynamic state is important for cirrhotic recipients who underwent living donor liver transplantation(LDLT). We investigated the clinical advantages of a novel non- invasive method for measuring systemic hemodynamic parameters using indocyanine green(ICG). METHODS:Twenty-eight LDLT recipients were evaluated. Simultaneous measurements of cardiac output(CO)using Swan-Ganz catheters and pulse dye densitometry(PDD) were performed every 12 hours after LDLT.A total of 155 sets of simultaneous CO measurements were obtained. RESULTS:The CO values obtained by PDD correlated well with those obtained by the invasive catheter technique.In addition,none of the recipients developed any side-effects, and we verified the safety of repeated ICG injections.ICG is safe,even for repeated use over time in the same recipient. Moreover,PDD can measure the blood volume(BV).CONCLUSIONS:Since the cirrhotic systemic hemody- namics characterized by high CO and large BV remains, even after LDLT,the ability to measure CO and BV in a non-invasive,simple and real-time manner using PDD has advantages for cirrhotic LDLT recipients.

Living-related liver transplantation in patients with variceal bleeding:outcome and prognostic factors

BACKGROUND:Liver transplantation currently represents the ultimate therapy for bleeding esophageal varices in patients with liver cirrhosis.It is the only therapy that cures both portal hypertension and the underlying liver disease.The outcome of liver transplantation is thought to be correlated with several factors.In this study,the clinical outcome of living-related liver transplantation(LRLT) was evaluated in patients with variceal bleeding,and the prognostic indicators of short-term survival in these patients were identified. METHODS:We reviewed retrospectively 121 patients with a history of variceal bleeding who had received LRLT from 1998 to 2006.The clinical outcomes were analyzed,and the risk factors for short-term survival were defined. RESULTS:The 3-month survival rate of patients with variceal bleeding was 83.4%,while that of non-bleeders was 87%.Sepsis was the commonest cause of death in both groups.Portal vein diameter and blood transfusion were the only independent prognostic factors for short-term survival among variceal bleeders. CONCLUSION:The outcome of LRLT in recipients with variceal bleeding is based on the improvement of portal hemodynamics,by minimizing intraoperative blood loss and subsequent blood transfusion.

Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity

After the first observation of the immunosuppressive effects of ultraviolet(UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells(Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery.

Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice

AIM:To investigate the role of matrix metalloproteinase(MMP)-9 in the pathogenesis of postoperative liver failure(PLF) after extended hepatectomy(EH).METHODS:An insufficient volume of the remnant liver(RL) results in higher morbidity and mortality,and a murine model with 80%-hepatectomy was used.All investigations were performed 6 h after EH.Mice were first divided into two groups based on the postoperative course(i.e.,the PLF caused or did not),and MMP-9 expression was measured by Western blotting.The source of MMP-9 was then determined by immunohistological stainings.Tissue inhibitor of metalloproteinase(TIMP)-1 is the endogenous inhibitor of MMP-9,and MMP-9 behavior was assessed by the experiments in wild-type,MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography.The behavior of neutrophils was also assessed by immunohistological stainings.An anti-MMP-9 monoclonal antibody and a broadspectrum MMP inhibitor were used to examine the role of MMP-9.RESULTS:Symptomatic mice showed more severe PLF(histopathological assessments:2.97 ± 0.92 vs 0.11 ± 0.08,P < 0.05) and a higher expression of MMP-9(71085 ± 18274 vs 192856 ± 22263,P < 0.01).Nonnative leukocytes appeared to be the main source of MMP-9,because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings.In the histopathological findings,the PLF was improved in MMP-9(-/-) mice(1.65% ± 0.23% vs 0.65% ± 0.19%,P < 0.01) and it was worse in TIMP-1(-/-) mice(1.65% ± 0.23% vs 1.78% ± 0.31%,P < 0.01).Moreover,neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings.Two methods of MMP-9 inhibition revealed reduced PLF,and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments(9.6 ± 1.9 vs 4.2 ± 1.2,P < 0.05,and 9.9 ± 1.5 vs 5.7 ± 1.1,P < 0.05).CONCLUSION:MMP-9 is important for the process of PLF.The initial injury is associated with MMP-9 derived from neutrophils,and MMP-9 blockade reduces PLF.MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

Thrombotic microangiopathy-like disorder after living-donor liver transplantation:A single-center experience in Japan

AIM:To investigate thrombotic microangiopathy (TMA)in liver transplantion,because TMA is an infrequent but life-threatening complication in the transplantation field. METHODS:A total of 206 patients who underwent living-donor liver transplantation (LDLT) were evaluated,and the TMA-like disorder (TMALD) occurred in seven recipients. RESULTS:These TMALD recipients showed poor outcomes in comparison with other 199 recipients. Although two TMALD recipients successfully recovered,the other five recipients finally died despite intensive treatments including repeated plasma exchange (PE) and re-transplantation. Histopathological analysis of liver biopsies after LDLT revealed obvious differences according to the outcomes. Qualitative analysis of antibodies against a disintegrin-like domain and metalloproteinase with thrombospondin type 1 motifs (ADAMTS-13) were negative in all patients. The fragmentation of red cells,the microhemorrhagic macules and the platelet counts were early markers for the suspicion of TMALD after LDLT. Although the absolute values of von Willebrand factor (vWF) and ADAMTS-13 did not necessarily reflect TMALD,the vWF/ADAMTS-13 ratio had a clear diagnostic value in all cases. The establishment of adequate treatments for TMALD,such as PE for ADAMTS-13 replenishment or treatments against inhibitory antibodies,must be decided according to each case. CONCLUSION:The optimal induction of adequate therapies based on early recognition of TMALD by the reliable markers may confer a large advantage for TMALD after LDLT.