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Transient elastography of liver: Could it be a guide for diagnosis and management strategy in hepatic veno-occlusive disease (sinusoidal obstruction syndrome)?
Corresponding author at: Yeditepe University Faculty of Medicine, Department of Internal Medicine Division of Hematology, Koşuyolu Mah. Koşuyolu Cad. No: 168 Kadıköy, Istanbul, Turkey.
Hepatic veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS), is a rare and life threatening complication of hematopoetic stem cell transplantation (HSCT). Many conditions can mimic the clinical signs of VOD/SOS. Differential diagnosis and diagnosis of the disease at an early stage is important, since the severe form of the disease has higher mortality rates and early-initiated specific treatment has better response rates. A sensitive and specific non-invasive imaging technique that can diagnose the disease at an early stage is still an unmet need today. We aimed to determine the role of liver stiffness measurement (LSM) with transient elastograph (TE) for the diagnosis of VOD/SOS after allogeneic HSCT. Between January 2019 and October 2021, a total of 49 patients underwent allogeneic HSCT and were retrospectively analyzed. Thirty-one adult patients who had a two or more LSM value were included in the study. Revised European Society for Blood and Marrow Transplantation (EBMT) was the criteria used for the diagnosis of VOD/SOS. Two of 31 patients developed VOD/SOS (6.4 %). Very high LSM values were detected in all patients who developed VOD/SOS. Early and specific VOD/SOS treatment resulted in improvement of LSM values together with other related features. However, LSM values did not increase significantly in patients with high a bilirubin level (≥2 mg/dl) without VOD/SOS. This study demonstrates that TE might be a promising non-invasive imaging method for diagnosis, follow-up and differential diagnosis of this dismal complication of HSCT. Yet, these results need to be supported by prospective studies.
Hepatic veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS), is a rare and life threatening complication of hematopoetic stem cell transplantation (HSCT) particularly caused by toxic damage of the conditioning regimen [
]. VOD/SOS is diagnosed using different diagnostic criteria including clinical findings such as painful hepatomegaly, weight gain, jaundice, and right upper quadrant pain [
Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group.
Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group.
]. The incidence of VOD/SOS is variable according to the use of different diagnostic criteria, differences in patient and transplant related risk factors in various studies; ranging from 0 to 60 %, with an overall of 15 % [
Hepatic veno-occlusive disease development in the hematopoietic stem cell transplantation patients: incidence and associated risk factors, a meta-analysis.
Many conditions can mimic the clinical signs of VOD/SOS, and, not so infrequently, histopathological confirmation or hepatic vein pressure gradient (HVPG) measurement is required to confirm the diagnosis, even though these are invasive procedures with a high risk of bleeding. Though it is a challenging diagnosis, early detection of VOD/SOS is crucial. It is important to diagnose the disease at an early stage, because the severe form of the disease has higher mortality rates and the early-stage diagnosis and early-initiated treatment have better response rates [
], all have limited sensitivity and specificity, and they are able to identify severe forms only when serious organ damage or multiorgan dysfunction has already occurred.
Many studies have been reported to evaluate the early diagnosing ability of different noninvasive imaging techniques, but currently a highly sensitive and specific imaging technique is still not widely accepted for the diagnosis of VOD/SOS [
Shear wave elastography in the detection of sinusoidal obstruction syndrome in adult patients undergoing allogenic hematopoietic stem cell transplantation.
]. In the last decade, promising results of a limited number of studies have been reported on the diagnosis of VOD/SOS with liver stiffness measurement(LSM) with transient elastography (TE) point shear wave with acoustic radiation force impulse (ARFI), and two-dimensional real-time shear wave (2D-SWE) [
Liver stiffness measurement allows early diagnosis of veno-occlusive Disease/Sinusoidal obstruction syndrome in adult patients who undergo hematopoietic stem cell transplantation: results from a monocentric prospective study.
].The aim of this study was to determine the role of LSM with TE for the diagnosis, follow-up and differential diagnosis of VOD/SOS after allogeneic HSCT.
2. Patients and methods
Between January 2019 and October 2021, a total of 49 patients underwent allogeneic HSCT at Yeditepe University Hospital, Istanbul, Turkey. The data of the patients were accessed from the hospital operating system, retrospectively. Thirty-one adult patients with at least two LSM with TE (performed at different times in the pre- and post-transplantation period or two times after transplantation) were included in the study, regardless of donor type, conditioning regimen and stem cell source. This study was conducted in compliance with the Declaration of Helsinki and was approved by Institutional Ethics Committee of Yeditepe University (ethics committee approval number: 202111109) All patients gave their written informed consent.
Since 2019, as part of our pre-transplant routine work-up program, pre-transplant TE was performed for every patient. LSM values were assessed at the patients’ bedside by transient elastography by the same gastroenterogist using the Fibroscan® (Echosens, Paris, France) apparatus with an “M-probe” or “XL-probe” after an overnight fast. Normal values of LSM with TE range from 3.9 to 7.1 kPa [
]. Valid and reliable TE measurements were defined by ten valid single shots and an interquartile range < 30 % of the median value in cases with LS > 7.1 kPa. An LS > 7.1 kPa was regarded as a pathological measurement indicating an increased risk of hepatic inflammation or fibrosis [
]. Results higher than 20 kPa of LSM by TE have been accepted as clinically significant of portal hypertension, according to the Baveno VI consensus criteria [
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
]. The diagnosis of VOD/SOS was based on the EBMT criteria comprising unexplained weight gain or ascites, hepatomegaly associated with tenderness of the right upper abdomen and jaundice [
Defibrotide (DF) prophylaxis was used in variable doses (10–25/mg/kg/day, 4 divided doses) for the patients who have one or more risk factors for VOD/SOS according to the criteria described by Health Practice Statement of Ministry of Health of Turkey. Those are the patients who; i) have received abdominal radiotherapy, including liver, ii) were histologically diagnosed with liver cirrhosis, fibrosis or hemochromatosis, iii) were serologically diagnosed with hepatitis B or C iv) have received myeloablative conditioning regimens in a previous HSCT, v) received or planned to receive busulphan in their conditioning regimen vi) received or planned to receive hematopoietic stem cells from an unrelated donor.
All patients received ursodeoxycholic acid (UDCA) (15 mg/kg/day) which was commenced with the conditioning regimen. All patients also received low molecular weight heparin (LMWH) (enoxaparin) until the platelet count decreased lower than 50.000 /mm³. Graft versus host disease (GVHD) prophylaxis comprised post-transplant cyclophosphamide (Cy) and cyclosporine A (CsA) in patients who underwent HSCT from a matched related donor and mycophenolate mofetil was added in patients who underwent HSCT from an unrelated donor or haploidentical donor.
3. Statistical analysis
All analyses were performed on SPSS v21 (SPSS Inc., Chicago, IL, USA). Data are given as median (1 st quartile - 3rd quartile) for continuous variables and as frequency (percentage) for categorical variables. Between groups, analysis of the continuous variables was performed with the Mann Whitney U test Categorical variables were analyzed with the chi-square test or Fisher’s exact test. VOD prediction performance of the transient elastography was evaluated by using the Receiver Operating Characteristic (ROC) curve analysis. Logistic regression analyses were performed to determine significant risk factors for development of VOD/SOS. p < 0.05 values were accepted as statistically significant results.
4. Results
Eighteen of 49 patients were excluded from the study because they did not meet all of the inclusion criteria. We included 31 patients (21 males and 10 females) in our study, the mean age was 50.13 ± 14.14 (range 22–69). The most common diagnosis was AML (54.28 %). Three (9.68 %) patients had hepatitis B surface antigen positivity but none of them had viral replication at the time of HSCT. Two patient had splenomegaly, one of them was associated with Non-Hodgkin Lymphoma (NHL) and the other one was associated with primary myelofibrosis at the time of HSCT. All patients underwent HSCT with peripheral blood-derived stem cells. The most commonly used conditioning regimen was Fludarabine (40 mg/m2/day between day -7 and -4)/Busulphan (3,2 mg/kg/day, day -7 and -6) (16.13 %). Eleven patients (35.5 %) received a myeloablative conditioning (MAC) regimen and a reduced intensity conditioning (RIC) regimen was used in 20 patients (645%). Twenty-three (74.19 %) patients received defibrotide prophylaxis and all patients received UDCA prophylaxis. The bilirubin levels in 9 (30.00 %) patients were higher than 2 mg/dl. Two (6.45 %) patients were diagnosed with VOD/SOS according to the EBMT criteria. Four cases (12.90 %) of 31 patients who underwent HSCT have died, one of them had VOD/SOS (+90th day).
Transient elastography at the time of VOD/SOS diagnosis (p = 0.020) and TE in patients with a high bilirubin level (≥2 mg/dl) (p = 0.040) were significantly higher in the patients with VOD/SOS than in the patients without VOD/SOS (Fig. 1). There were no significant differences between groups with regard to age, gender, hepatitis B positivity, hepatitis C positivity, donor type, conditioning regimen, ferritin level, VOD/SOS risk score, defibrotide prophylaxis, UDCA prophylaxis, pre-transplant TE and mortality (Table 1).
Fig. 1a Pre-transplant TE with regard to the presence of VOD/SOS. b TE at the time of VOD/SOS diagnosis with regard to the presence of VOD/SOS. cTE in patients with total bilirubin ≥2 mg/dl with regard to presence of VOD/SOS.
Pre transplant TE had 100.00 % sensitivity, 55.17 % specificity, 56.67 % accuracy, 7.14 % positive predictive value and 100.00 % negative predictive value for 5.20 cut-off point to predict VOD/SOS (AUC: 0.569, 95 % CI: 0.388−0.750, p = 0.817). Transient elastography at the time of VOD/SOS diagnosis and TE in patients with high bilirubin level (≥2 mg/dl) perfectly discriminated patients with VOD/SOS and without VOD/SOS (Table 3).
Table 3VOD/SOS prediction performance of Transient Elastography.
Pre-transplant TE (n = 30)
TE at the time of VOD/SOS diagnosis (n = 31)
TE in patients with Total bilirubin ≥2 mg/dl (n = 9)
Cut-off
5.20
23.35
29.05
Sensitivity
100.00 %
100.00 %
100.00 %
Specificity
55.17 %
100.00 %
100.00 %
Accuracy
56.67 %
100.00 %
100.00 %
PPV
7.14 %
100.00 %
100.00 %
NPV
100.00 %
100.00 %
100.00 %
AUC (95.0 % CI)
0.569 (0.388−0.750)
1.000 (1.000−1.000)
1.000 (1.000−1.000)
p
0.817
0.020
0.040
PPV: Positive Predictive Value, NPV: Negative Predictive Value, AUC: Area Under ROC Curve, CI: Confidence Intervals.
We performed logistic regression analysis to determine significant risk factors for the development of VOD/SOS. Age (p = 0.260), gender (p = 0.587), primary disease (p = 0.146), hepatitis B surface antigen positivity (p = 0.102), donor type (p = 0.663) and ferritin level (p = 0.062) were not found to be significant variables (Table 4.).
Table 4Risk factors of VOD/SOS, simple logistic regression analysis.
Details of a patient who was diagnosed with VOD/SOS are summarized below;
Patient 1: 61-year-old female patient was diagnosed with acute myeloid leukemia in association with Langerhans cell histiocytosis. After a first complete remission, she underwent allogeneic HSCT from an HLA-A, -B, -C and -DR phenotypically matched, but one locus DRB1 genotypically mismatched unrelated donor. She received fludarabine (30 mg/m2, between day -7 and -3) and melphalan (140 mg/m2, day -2) conditioning regimen. Post-transplant cyclophosphamide, cyclosporine and mycophenolate mofetil were used for GVHD prophylaxis. Pre-transplant LSM was not performed because LSM with TE were not yet established at the time as a part of our pre-transplant routine work-up program. Defibrotide (4 × 100 mg/day) and UDCA (2 × 250 mg) was used for VOD/SOS prophylaxis. She was complicated with gram negative sepsis on day +7 and treated with appropriate antibiotics. On day +8, deep palpation of the right upper abdominal quadrant caused discomfort and pain accompanied by weight gain and hyperbilirubinemia. Ultrasonography revealed no specific abdominal pathology. The LSM value with TE was detected as 55 kPa. In light of these clinical and laboratory findings, VOD/SOS was diagnosed according to the EBMT criteria. The defibrotide dose was increased to the treatment dose (25 mg/kg/day) based upon the clinical signs and LSM value. On day +14, due to incomplete regression of laboratory findings and addition of ascites to the clinical findings, methylprednisolone and n-acetyl cysteine was started alongside defibrotide. Due to the negative blood culture result on day +21, antibiotics were stopped. On day +25, two weeks after the defibrotide and one week after steroid treatment, her LSM value with TE was measured as 33 kPa but the clinical signs had not resolved completely. By day +50, clinical and laboratory findings of VOD/SOS had resolved with the treatment and the LSM value with TE declined to 9,1 kPa. She was then discharged from the hospital without any complaints on day +60.
Details of a patient who was suspected with early VOD/SOS with TE;
Patient 2: A 65-year-old female patient was diagnosed with primary myelofibrosis with a high risk MIPSS70 score. She underwent haploidentical stem cell transplantation from her son. The pre-transplant LSM value with TE was 8.2 kPa. She had hepatosplenomegaly (liver size 165 mm, spleen size 215 mm) despite the use of ruxolitinib at the time of the conditioning regimen. She received fludarabine (40 mg/m2/day, between day -5 and -2), busulphan (3,2 mg/kg/day, between day -3 and -2) and anti-thymocyte globulin (rabbit) (5 mg/kg/day, between day -3 and -1) and splenic radiation (day -1) in the conditioning regimen. Post-transplant cyclophosphamide, cyclosporine and mycophenolate mofetil was used for GVHD prophylaxis. Defibrotide (4 × 100 mg/day) and UDCA (2 × 250 mg) were used for VOD/SOS prophylaxis. During weekly routine follow-up with TE, a liver stiffness value of 17.7 kPa was measured on day -2, accompanied by weight gain and a bilirubin level of 1,2 mg/dl. Although she was not diagnosed with VOD/SOS according to EBMT criteria, the increased LSM value was thought to be a predictor of early VOD/SOS, and the dose of defibrotide was increased to 25 mg/kg/day. Due to severe thrombocytopenia, liver biopsy and measurement of HVPG could not be performed to prove the diagnosis. At the end of the first week of defibrotide treatment, the patient’s case was complicated with gram-negative sepsis and appropriate antibiotics were started. Although the patient's bilirubin level increased during this period, the LS value was measured as 8.1 kPa on day +7. Hyperbilirubinemia was thought to be primarily related to sepsis. Despite all efforts, the patient died on the third week after transplantation due to gram-negative sepsis.
5. Discussion
Hepatic VOD/SOS is one of the causes of early transplant related mortality. Early diagnosis may be helpful to start specific treatment at an early phase and is associated with better outcomes. Our retrospective study, in which we aimed to investigate the role of TE for the diagnosis, follow-up and differential diagnosis of VOD/SOS, showed that the use of TE for the diagnosis, differential diagnosis and follow-up of VOD/SOS, was beneficial. According to our data, TE at the time of VOD/SOS diagnosis and TE in patients with total bilirubin ≥2 mg/dl perfectly discriminated patients with and without VOD/SOS. Our data showed that the VOD/SOS risk calculator by CIBMTR did not accurately predict VOD/SOS development alone. In addition, contrary to many studies, age, gender, primary disease, hepatitis B surface antigen positivity, donor type and ferritin level were not found to be significant risk factors for development of VOD/SOS.
In our study, the incidence of VOD/SOS was found to be 6.4 % (2/31). While this result is similar to many studies published in the literature in recent years, it is higher when compared to the studies using prophylaxis for VOD/SOS [
Incidence and risk factors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation in adults with prophylactic ursodiol and intravenous heparin or prostaglandin E1..
Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.
]. This result can be explained by our use of lower doses of defibrotide for prophylaxis than those in the other studies.
In the last decade, many studies and meta-analyses have detected a significant positive relationship between liver stiffness values and histological fibrosis in chronic liver diseases. Regarding the pathophysiology of VOD/SOS, noninvasive imaging methods such as ultrasound elastography with transient elastography (TE, Fibroscan), point shear wave with acoustic radiation force impulse (ARFI), and two-dimensional real-time shear wave (2D-SWE) have been investigated to detect hepatic fibrosis and portal hypertension [
Shear wave elastography in the detection of sinusoidal obstruction syndrome in adult patients undergoing allogenic hematopoietic stem cell transplantation.
Liver stiffness measurement allows early diagnosis of veno-occlusive Disease/Sinusoidal obstruction syndrome in adult patients who undergo hematopoietic stem cell transplantation: results from a monocentric prospective study.
]. In a review, Chan et al. claim that LSM with ultrasound elastography could be used as a method to confirm diagnosis and to monitor the treatment response of VOD/SOS [
According to Auberger et al., maximal total serum bilirubin after HSCT was found to be significantly higher in patients with pre-transplant LSM values >8.0 kPa than with values <8.0 kPa. Therefore, the authors claimed that TE could potentially be useful before conditioning for risk stratification and in identifying patients at high risk of developing liver complications including VOD/SOS following HSCT [
]. On the contrary, Karlas et al. showed that baseline evaluations of liver and spleen with TE did not differ significantly between patients with and without severe hepatic VOD/SOS [
]. Karlas et al., in their other study with a larger patient group, found that liver elastography before conditioning therapy is predictive of liver events [
]. Our study was designed only to investigate the role of TE in the diagnosis, differential diagnosis and follow-up of VOD/SOS. Although there was no significant difference between the baseline LSM value in patients with and without VOD/SOS, we modified conditioning regimens in patients with higher pre-transplant LSM value >7.1 kPa aiming to reduce the risk of VOD/SOS development; as an example, melphalan was preferred instead of busulfan. Similar to the study by Karlas et al. [
]. The availability of a predictive diagnostic tool for VOD/SOS diagnosis is important because a delay in treatment administration of only 2 days results in a worse clinical outcome, which has already been documented [
Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.
Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT)..
]. In studies performed with LSM techniques, important data were obtained for the early diagnosis of VOD/SOS. Two recent studies have evaluated the role of TE in the early diagnosis of VOD/SOS. The first study found that a sudden increase in LS preceded the clinical appearance of VOD/SOS by 2–6 days [
]. The second study conducted by the same author found that LSM by TE increases occurred 2–12 days before clinical VOD/SOS appearance and gradually decreased following successful VOD/SOS specific treatment. LSM values did not significantly increase in patients without VOD/SOS. According to a doctoral thesis from Alma Dl University (monocentric proof of the ELASTOVOD study in Bologna), the incidence of VOD/SOS was found to be 4.4 % (20/456); a sudden increase in LSM value, compared to the previous assessment and pre-transplant measurement, was found in all patients who developed VOD/SOS. The VOD/SOS diagnostic performance of increased LSM values over pre-transplant assessment showed an AUROC of 0.997 (Sens.75 %Spec.98.7 %). LSM values did not significantly increase in patients with hepatobiliary complications other than VOD/SOS [
Liver stiffness measurement allows early diagnosis of veno-occlusive Disease/Sinusoidal obstruction syndrome in adult patients who undergo hematopoietic stem cell transplantation: results from a monocentric prospective study.
]. In our study, which was designed retrospectively, TE was not performed on each patient on the same post-transplant day. Therefore, it could not be determined how long before there was an increase in LSM value for the diagnosis of VOD/SOS. However, similar to the second study of Colecchia et al., our result showed that the LSM value decreased with defibrotide treatment.
The development of jaundice after HSCT is an often encountered complication and it has many causes such as cholestasis, drug related liver injury, sepsis, parenteral nutrition and, hepatic GVHD. Histological confirmation is often needed to accurately discriminate between multiple differential diagnoses [
]. The first study in the literature, in which TE was analyzed as a predictor of VOD/SOS, showed that bilirubin elevation (≥ 2 mg/dl) was quite common in patients during allogeneic HSCT period (84 with the MAC regimen, 50 % with the RIC regimen) [
]. In our study, we found that bilirubin levels increased (≥ 2 mg/dl) in 9 (29 %) patients within first 21 days post-transplantation, but only 2 (6.4 %) of patients were diagnosed with VOD/SOS. In patients with hyperbilirubinemia, the LSM value was found to be significantly higher in all patients diagnosed with VOD/SOS. Ravaioli F. similarly showed, in his doctoral thesis, that LSM values did not increase in patients without a diagnosis of VOD/SOS [
Ravaioli F. ELASTOVOD PROJECT: Prospective studies to evaluate the preclinical diagnostic potential of hepatic ultrasound-based elastography measurement for predicting the development of Sinusoidal Obstruction Syndrome (SOS/VOD) and hepatic complications in patients undergoing hematopoietic stem cell transplantation (HSCT). 25 March 2020http://amsdottorato.unibo.it/9268/.
]. Also, an increased LSM without hyperbilirubinemia was detected in one of our patients. However, a diagnosis of VOD/SOS could not be given according to the EBMT diagnostic criteria. In this patient, early stage anicteric VOD/SOS was considered, but the diagnosis could not be supported by invasive techniques due to severe thrombocytopenia. The dose of defibrotide was adjusted to a treatment dose. Although there was a significant decrease in the LSM value after two weeks of defibrotide treatment, the patient developed hyperbilirubinemia. This hyperbilirubinemia was primarily linked to the concurrent gram-negative sepsis at that time, instead of VOD/SOS, due to a normal LSM value. Elevated bilirubin levels caused by infection without a rise in LSM value were found to be associated with CsA, GVHD and engraftment syndrome in 6 patients. Although details of these patients were not described in this article, we state that TE is a highly effective non-invasive imaging technique which can be used for the differential diagnosis of VOD/SOS in patients with elevated bilirubin levels. The results of the prospective multicenter study conducted by Festi et al., currently recruiting patients, will, perhaps, provide us with more detailed knowledge about the role of TE in VOD/SOS (https://clinicaltrials.gov/ct2/show/NCT03426358) [
The limitations of our study were that it was retrospective and included a small number of patients. VOD/SOS was diagnosed using only EBMT criteria and TE, and invasive diagnostic methods were not used to confirm the diagnosis in any of the patients. In addition, TE was not performed on the same day post-transplantation.
In conclusion, we believe that LSM with TE would be an important part of the criterias for the diagnosis of VOD/SOS and also for differential diagnosis of other etiologies which can mimic laboratory and clinical features of VOD/SOS. Its' incorporation into the pre-transplantation work-up process may lead to a decrease in the incidence of VOD/SOS by managing risk factors like conditioning regimen and planning prophylactic strategies to prevent this dismal complication at the beginning of HSCT.
Declaration of Competing Interest
The authors of this study declare no conflict of interest.
Acknowledgements
We would like to express our gratitude and appreciation for Hasan Atilla Özkan, whose guidance, support and encouragement has been invaluable throughout this study. We would also like to thank the gastroenterology team, who have been a great source of support.
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Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors.
Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group.
Hepatic veno-occlusive disease development in the hematopoietic stem cell transplantation patients: incidence and associated risk factors, a meta-analysis.
Shear wave elastography in the detection of sinusoidal obstruction syndrome in adult patients undergoing allogenic hematopoietic stem cell transplantation.
Liver stiffness measurement allows early diagnosis of veno-occlusive Disease/Sinusoidal obstruction syndrome in adult patients who undergo hematopoietic stem cell transplantation: results from a monocentric prospective study.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Incidence and risk factors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation in adults with prophylactic ursodiol and intravenous heparin or prostaglandin E1..
Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.
Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT)..
Ravaioli F. ELASTOVOD PROJECT: Prospective studies to evaluate the preclinical diagnostic potential of hepatic ultrasound-based elastography measurement for predicting the development of Sinusoidal Obstruction Syndrome (SOS/VOD) and hepatic complications in patients undergoing hematopoietic stem cell transplantation (HSCT). 25 March 2020http://amsdottorato.unibo.it/9268/.
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