Abstract
Purpose
Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication following hematopoietic stem cell transplantation (HSCT) in which early diagnosis improves patient outcome. The aim of our study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS.
Methods
This retrospective study included 182 children, adolescents, and young adults who underwent allogeneic or autologous HSCT for the first time (median age 7.2 years). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation (EBMT). We investigated 15 laboratory parameters after HSCT before the onset of SOS.
Results
The overall incidence of SOS was 14.8%. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients at a median time of 13 days after HSCT. We observed a low SOS mortality rate of 11.1% within 100 days after HSCT. International normalized ratio (INR) ≥ 1.3, activated partial thromboplastin time (aPTT) ≥ 40 s, reptilase time ≥ 18.3 s, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L showed significant associations with the onset of SOS in the univariate analyses. In the multivariate analysis, INR ≥ 1.3 [odds ratio (OR) = 8.104, p = 0.006], aPTT ≥ 40 s (OR = 10.174, p = 0.001), protein C ≤ 48% (OR = 5.215, p = 0.014), and ferritin ≥ 3100 µg/L (OR = 7.472, p = 0.004) could be confirmed as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), protein S, fibrinogen, and alanine aminotransferase (ALT) were not relevant for the occurrence of SOS.
Conclusion
In summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a serious complication after hematopoietic stem cell transplantation (HSCT), especially in children. The incidence of SOS following HSCT depends on diagnostic criteria, type of HSCT and patient age. Therefore the incidence varies in several publications. The median incidence of SOS is 14% and ranges from 0 to 60% in the published reports (Coppell et al. 2010; Xia et al. 2021). Following allogeneic HSCT the frequency of SOS is higher (12.9%) than after autologous HSCT (8.7%) (Coppell et al. 2010). A recent study by Coutsouvelis et al. (2023) reported an incidence of 11.5% in pediatric patients and 4.1% in adults. Further studies confirmed higher incidences in children (20%) than in adults (10%) (Barker et al. 2003; Cesaro et al. 2005; Corbacioglu et al. 2012, 2018).
Most patients with SOS suffer from hepatomegaly, ascites, and weight gain (Corbacioglu et al. 2018). There are several clinical diagnostic criteria used for SOS. Diagnostic standards are based on the Baltimore criteria (Jones et al. 1987) or the Seattle criteria (McDonald et al. 1984). In addition, new pediatric diagnostic criteria were published on behalf of the European Society for Blood and Marrow Transplantation (EBMT), stating that hyperbilirubinemia is a non-mandatory criterion and there is no time limit for the diagnosis of SOS (Corbacioglu et al. 2018). Furthermore, the pediatric EBMT criteria can be used for grading the severity of SOS, which consists of mild, moderate, severe, and very severe SOS (Corbacioglu et al. 2018).
Yoon et al. (2019) concluded an increased mortality of 36.7% within 100 days after HSCT in very severe SOS. Furthermore, Coppell et al. (2010) reported a mortality rate more than 80% in patients with the most severe SOS. Defibrotide is an effective therapy for SOS, which can improve survival (Mohty et al. 2022; Richardson et al. 2016). Mohty et al. (2022) reported better outcomes in patients with severe versus very severe SOS, suggesting early diagnosis and treatment is important before patients develop very severe SOS. In addition, defibrotide prophylaxis can reduce the incidence of SOS and is well tolerated by patients (Corbacioglu et al. 2012).
Different factors, such as conditioning therapy, endotoxins, cytokines, and certain drugs lead to endothelial imbalance. This results in a loss of sinusoidal endothelial cell fenestration and destruction of endothelial barrier. Erythrocytes penetrate into the space of Disse and damaged sinusoids induce vascular obstruction downstream (Carreras and Diaz-Ricart 2011; DeLeve et al. 2002). The reduced blood flow to the liver leads to liver damage (DeLeve et al. 2002). In addition, fibrinogen and factor VIII within the subendothelial zones can also lead to thrombosis of the vessels (Shulmann et al. 1987). Moreover, an exposure of tissue factors and initiation of the coagulation cascade, which is followed by reduced synthesis of coagulation factors, causes hemostatic imbalance (DeLeve et al. 2002; Nürnberger et al. 1997). Due to the pathogenesis, it is obvious that laboratory parameters, such as coagulation, fibrinolytic, and liver parameters are changed. An increase of D-dimer, bilirubin, and alanine aminotransferase (ALT) as well as a decrease of antithrombin III and protein C were observed in patients with SOS (Jevtić et al. 2011; Lee et al. 1998; Sartori et al. 2012).
The purpose of our retrospective study was to investigate laboratory parameters that can predict the development of SOS. Therefore, we analyzed coagulation, fibrinolytic, and liver parameters following HSCT before SOS.
Methods
Patients
Our study population consisted of 182 children, adolescents, and young adults who underwent HSCT at the Department of Pediatrics, Jena University Hospital, Germany between 2007 and 2022. The patients received allogeneic or autologous HSCT for the first time. We excluded patients with defibrotide prophylaxis and more than one HSCT, respectively. The conditioning therapy was always myeloablative and dependent on the type of HSCT and underlying disease. In addition, the transplanted patients underwent an infection prophylaxis and were isolated in rooms with special laminar airflow filtration systems.
SOS
The pediatric EBMT criteria were used to diagnose SOS (Corbacioglu et al. 2018).
Accordingly, there is no time limit of onset and SOS is diagnosed if two or more of the following criteria are present: transfusion-refractory thrombocytopenia, unexplained weight gain > 5%, or weight gain on three consecutive days despite diuretics, ascites, hepatomegaly, bilirubin ≥ 34 µmol/L within 72 h, or an increase in bilirubin on three consecutive days. The classification of the severity of SOS was also based on the pediatric severity EBMT criteria (Corbacioglu et al. 2018). The patients with SOS received 25 mg/kg/day defibrotide in four single doses for 30 days.
Risk factors
In our study, we considered the following 15 laboratory parameters: international normalized ratio (INR), activated partial thromboplastin time (aPTT), reptilase time, factor VIII, factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), fibrinogen, antithrombin III, protein C, protein S, D-dimer, ALT, bilirubin, and ferritin. Laboratory parameters were measured weekly following HSCT. In the SOS patient group, the last laboratory values within one week before the onset of SOS were analyzed. We investigated the parameters for four weeks after transplantation in the non-SOS patient group and calculated the median.
Statistical analysis
A retrospective analysis of potential risk factors was performed. We always considered results with p values less than 0.05 as statistical significant. Differences in the laboratory values between the SOS and the non-SOS patient group were analyzed using the Mann–Whitney U test. We performed univariate and multivariate analyses to find significant associations between the values of laboratory parameters and the occurrence of SOS. The results were presented with corresponding p value (p), odds ratio (OR), and 95% confidence interval (CI). Cut-off values were selected for the continuous parameters based on existing reference values and receiver operating characteristic (ROC) curves analyses. We divided the values according to the corresponding cut-off values and performed the univariate analyses by Fisher's exact test for nominal parameters. The significant variables were entered as independent variables into multivariate analysis, which carried out by binary logistic regression and backward elimination. Using the significant independent variables, we calculated the probability of developing SOS. All calculations were performed using the software IBM SPSS Statistics 27.
Results
Patient characteristics
This retrospective analysis included 182 patients (109 males and 73 females) with a median age of 7.2 years (ranged from 2 months to 26 years). Our study population consisted of 126 patients who underwent allogeneic HSCT (69.2%) and 56 patients who received autologous HSCT (30.8%). The most frequent underlying diseases were solid tumors (34.1%), genetic diseases (19.2%), acute lymphoblastic leukemia (18.1%), and acute myeloid leukemia (13.7%). Peripheral blood (50.5%) or bone marrow (49.5%) was used as stem cell source. Table 1 summarizes the characteristics of the patients.
A total of 27 patients (14.8%) developed SOS. In the allogeneic patient group, SOS was diagnosed in 24 of 126 patients, which corresponds to a frequency of 19.1%. The SOS frequency was lower in the autologous patient group, 3 of 56 patients developed SOS (5.4%). The time period between HSCT and the onset of SOS ranged from 1 to 28 days (median 13 days). Two patients (7.4%) showed a mild SOS and 7 patients (25.9%) a moderate SOS. Furthermore, a severe SOS occurred in 8 patients (29.6%). The remaining 10 patients (37.1%) developed a very severe SOS. Only 3 out of 27 patients, who suffered from very severe SOS, died within 100 days after HSCT (11.1%). Six out of 155 patients without SOS died in this time period (3.9%).
Analysis of risk factors
Table 2 shows the medians and interquartile ranges of the investigated laboratory parameters as well as the results of the Mann–Whitney U test. The coagulation parameters INR, aPTT, and reptilase time demonstrated significantly higher values in the SOS group than in the non-SOS group. In Mann–Whitney U test, we detected that antithrombin III, protein C, and factor VIII were significantly lower in the SOS group than in the non-SOS group. Patients with SOS also had significantly higher levels of D-dimer, bilirubin, and ferritin. We observed no significant differences of factor XIII, vWF, vWF activity, fibrinogen, protein S, and ALT between the SOS group and the non-SOS group by using Mann–Whitney U test.
We selected cut-off values, which were defined by reference values and ROC curve analyses. Figure 1 demonstrates the ROC curves of INR, aPTT, protein C, and ferritin with the cut-off values. The results of the univariate anlyses are presented in Table 3 with the corresponding p value, odds ratio, and 95% CI. For the values of factor XIII, vWF, VWF activity, fibrinogen, protein S, and ALT we could not find any significant results. If the coagulation parameters exceeded a certain value, such as INR ≥ 1.3, aPTT ≥ 40 s, and reptilase time ≥ 18.3 s, the SOS was diagnosed significantly more often. In addition, patients with factor VIII ≤ 80%, antithrombin III ≤ 75%, and protein C ≤ 48% showed a significantly higher incidence of SOS. We detected a significant association between the onset of SOS and the serum levels of D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L after HSCT.
We investigated nine laboratory parameters in the multivariate analysis, which were significant in the univariate analyses. After binary logistic regression and backward elimination, we identified four laboratory parameters as significant independent variables. The significant correlation between INR ≥ 1.3 after HSCT and SOS could be confirmed (OR = 8.104, 95% CI = 1.847–35.554, p = 0.006). In addition, aPTT ≥ 40 s before SOS was significantly associated with the onset of SOS (OR = 10.174, 95% CI = 2.722–38.020, p = 0.001). Protein C ≤ 48% (OR = 5.215, 95% CI = 1.390–19.562, p = 0.014) and ferritin ≥ 3100 µg/L (OR = 7.472, 95% CI = 1.912–29.202, p = 0.004) could be affirmed as significant predictive variables. Table 4 displays the significant results of the multivariate analysis.
The four significant laboratory parameters can be used to predict the probability of SOS, which depends on the regression coefficients of the parameters. We calculated the probability of SOS for each combination of the existing cut-off values using logistic regression. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. Additionally, if all four laboratory parameters were changed according to the cut-off values, the probability of SOS was 96%.
Discussion
In this retrospective analysis, 27 out of 182 patients (14.8%) developed SOS after HSCT. Following allogeneic HSCT, the incidence was higher (19.1%) than in the autologous patient group (5.4%). Therefore, our study is in line with other publications, which report comparable incidence rates of 14–20% (Xia et al. 2021; Coppell et al. 2010). Additionally, the published lower incidence rate following autologous HSCT (8.7%) in comparison to allogeneic HSCT (12.9%) by Coppell et al. (2010), agrees with our findings. In our study, SOS was diagnosed within 1 to 28 days after HSCT (median 13 days). This is comparable to a study by Coutsouvelis et al. (2023), in which a median of 14 days after HSCT was reported. We observed a low overall mortality of 11.1% in SOS patients within 100 days following HSCT. Coutsouvelis et al. (2023) reported a similar mortality rate of 9.4%. An early treatment with defibrotide is associated with a better outcome and could be the reason for the low mortality rate in our study (Corbacioglu et al. 2004).
We found significantly higher INR values in the SOS group than in the non-SOS patient group after HSCT before diagnosis. Moreover, our study demonstrated in the univariate and the multivariate analysis (OR = 8.104, p = 0.006), that INR ≥ 1.3 after HSCT was significantly associated with the occurrence of SOS. A study by Roeker et al. (2019) showed that the INR values in SOS patient group were significantly higher than in non-SOS group on the day of diagnosis. In addition, a high INR ≥ 1.3 before HSCT was considered as a risk factor for the occurrence of SOS (Kloehn et al. 2022). To our knowledge, we report the association between SOS and high INR after HSCT before SOS for the first time. The INR is a blood coagulation screening test, which is particularly dependent on the coagulation factors II, V, VII, and X. Increased INR values are an indication of a bleeding tendency (Bonar et al. 2017; Favaloro and Adcock 2008). Reasons for the increased INR values before the SOS onset could be a reduced synthesis of the coagulation factors due to liver damage or a vitamin K deficiency. Activated coagulation in SOS could also lead to depletion of coagulation factors (Favaloro and Adcock 2008). In addition, an increased bleeding tendency could influence the pathogenesis of SOS, consequently hemorrhage into the Disse space is reported (Carreras and Diaz-Ricart 2011).
Coagulation parameters, such as aPTT and reptilase time were significantly prolonged in the SOS group compared to the non-SOS group. In the univariate analysis, an association between the occurrence of SOS and prolonged aPTT ≥ 40 s or reptilase time ≥ 18.3 s after HSCT could be demonstrated. Reptilase time showed no significant results in the multivariate analysis. In the multivariate analysis, we confirmed aPTT ≥ 40 s as a predictive factor for the development of SOS (OR = 10.174, p = 0.001). To our knowledge, there are no studies in the literature that reported a significant association between aPTT and SOS after HSCT before SOS. However, aPTT is also prolonged after the diagnosis of SOS (Jevtić et al. 2010; Sartori et al. 2005). The aPTT is a screening test to assess intrinsic blood coagulation. A prolonged aPTT is often associated with a deficiency of coagulation factors such as factor VIII, IX, XI or XII (Kershaw 2017). Therefore, the prolonged aPTT could be caused by a decrease of factor VIII, which was reduced in our study.
The median factor VIII activity was significantly lower in the SOS group than in the non-SOS group. We detected factor VIII activity ≤ 80% as a significant variable in the univariate analysis. This, however, could not be confirmed in the multivariate analysis, which agrees with Lee et al. (1998) who reported no significant differences of factor VIII activity in the groups. Nevertheless, factor VIII appears to be an important parameter in the pathogenesis of SOS. Some studies reported that factor VIII and fibrinogen are reasons for the occlusion of the sinusoidal vessels (DeLeve et al. 2002; Shulmann et al. 1987). The reduced factor VIII activity could be the result of liver damage in the context of SOS.
Antithrombin III and protein C are important anticoagulants and showed significant lower values before diagnosis in patients with SOS. In the multivariate analysis, we observed that only protein C ≤ 48% was significantly associated with the development of SOS (OR = 5.215, p = 0.014) and identified protein C as an independent risk factor. Iguchi et al. (2010) reported similar results in a prospective study. The deficiency of protein C can be associated with thrombotic processes, which have an influence on the pathogenesis of SOS. Protein C is synthesized in the liver and therefore it could be decreased by the liver damage (Iguchi et al. 2010; Lee et al. 1998). Thrombotic processes are also associated with increased D-dimer levels. Our study showed that patients after HSCT before SOS had significantly higher D-dimer levels than in the non-SOS patient group. Other studies were able to show similar results (Jevtic et al. 2011; Sartori et al. 2012). We observed a significant association between elevated D-dimer levels ≥ 315 µg/L and SOS in univariate analysis, but this could not be confirmed in multivariate analysis.
In the univariate analysis, bilirubin ≥ 9 µmol/L was significant associated with the occurrence of SOS. Sartori et al. (2012) also found a significantly elevated bilirubin level before diagnosis of SOS. Bilirubin is one of the pediatric EBMT criteria for diagnosing SOS. However, the presence of hyperbilirubinemia is a non-mandatory criterion (Corbacioglu et al. 2018). In a study by Corbacioglu et al. (2020), 29% of pediatric patients did not have a bilirubin level > 34 µmol/L despite SOS. This fits with the non-significant result of bilirubin ≥ 9 µmol/L in the multivariate analysis. High bilirubin levels are often a late finding in patients with SOS (Corbacioglu et al. 2018).
We could find significant increased serum levels of ferritin in the SOS patient group after HSCT before SOS. The multivariate analysis confirmed ferritin ≥ 3100 µg/L after HSCT before SOS as an independent risk factor (OR = 7.472, p = 0.004). High ferritin plasma concentrations after HSCT before the onset of SOS are also reported by Döring et al. (2016). The increased ferritin could be caused by iron overload, which leads to various liver diseases such as SOS (Evens et al. 2004). Additionally, ferritin is an acute-phase protein and is increased in various inflammations in the body and thus can demonstrated inflammatory processes (Armand et al. 2012). High ferritin levels before HSCT are considered as a risk factor for developing SOS (Kloehn et al. 2022; Lee et al. 2010). Therefore, increased ferritin levels are important for the occurrence of SOS before as well as after HSCT.
Factor XIII, vWF, vWF activity, fibrinogen, protein S, and ALT did not show significant p values in Mann–Whitney U test and univariate analyses. However, there are various reports on the association of these parameters with SOS in the published literature (Jevtic et al. 2011; Lee et al. 1998; Park et al. 1997; Sartori et al. 2012).
The laboratory parameters INR, aPTT, protein C, and ferritin are independent risk factors for onset of SOS and the probability of SOS can be calculated with the combination of these parameters. Patients can present different combinations of the certain cut-off values. For each combination, there is a different probability of the SOS development. If at least three of the cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters are changed according to the cut-off values. To our knowledge, this is the first report in which the probability of SOS was calculated with laboratory parameters.
In conclusion, our study confirmed INR ≥ 1.3, aPTT ≥ 40 s, protein C ≤ 48%, and ferritin ≥ 3100 µg/L as predictive factors for the development of SOS and independent risk factors. To our knowledge, the significant association between the onset of SOS with increased INR (≥ 1.3) and aPTT (≥ 40 s) after HSCT is here demonstrated for the first time.
The regular measurement of INR, aPTT, protein C, and ferritin is a useful tool to predict the occurence of SOS after HSCT before SOS. These four parameters can enable earlier diagnosis and treatment, leading to an improved outcome. Other studies are necessary to validate our results, so these results can be used in clinical practice.
References
Armand P, Sainvil MM, Kim HT, Rhodes J, Cutler C, Ho VT, Koreth J, Alyea EP, Neufeld EJ, Kwong RY, Soiffer RJ, Antin JH (2012) Does iron overload really matter in stem cell transplantation? Am J Hematol 87(6):569–572. https://doi.org/10.1002/ajh.23188
Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS (2003) Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant 32(1):79–87. https://doi.org/10.1038/sj.bmt.1704069
Bonar RA, Lippi G, Favaloro EJ (2017) Overview of hemostasis and thrombosis and contribution of laboratory testing to diagnosis and management of hemostasis and thrombosis disorders. Methods Mol Biol 1646:3–27. https://doi.org/10.1007/978-1-4939-7196-1_1
Carreras E, Diaz-Ricart M (2011) The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 46(12):1495–1502. https://doi.org/10.1038/bmt.2011.65
Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, Strugo L, Destro R, Gazzola MV, Varotto S, Errigo G, Carli M, Zanesco L, Messina C (2005) A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 90(10):1396–1404
Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, Guinan E, Vogelsang G, Krishnan A, Giralt S, Revta C, Carreau NA, Iacobelli M, Carreras E, Ruutu T, Barbui T, Antin JH, Niederwieser D (2010) Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 16(2):157–168. https://doi.org/10.1016/j.bbmt.2009.08.024
Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, Straham B, Gross-Wieltsch U, Sykora KW, Ridolfi-Lüthy A, Basu O, Gruhn B, Güngör T, Mihatsch W, Schulz AS (2004) Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 33(2):189–195. https://doi.org/10.1038/sj.bmt.1704329
Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS (2012) Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 379(9823):1301–1309. https://doi.org/10.1016/S0140-6736(11)61938-7
Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P (2018) Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant 53(2):138–145. https://doi.org/10.1038/bmt.2017.161
Corbacioglu S, Kernan NA, Pagliuca A, Ryan RJ, Tappe W, Richardson PG (2020) Incidence of anicteric veno-occlusive disease/sinusoidal obstruction syndrome and outcomes with defibrotide following hematopoietic cell transplantation in adult and pediatric patients. Biol Blood Marrow Transplant 26(7):1342–1349. https://doi.org/10.1016/j.bbmt.2020.03.011
Coutsouvelis J, Kirkpatrick CM, Dooley M, Spencer A, Kennedy G, Chau M, Huang G, Doocey R, Copeland TS, Do L, Bardy P, Kerridge I, Cole T, Fraser C, Perera T, Larsen SR, Mason K, O’Brien TA, Shaw PJ, Teague L, Butler A, Watson AM, Ramachandran S, Marsh J, Khan Z, Hamad N (2023) Incidence of sinusoidal obstruction syndrome/veno-occlusive disease and treatment with defibrotide in allogeneic transplant: a multicentre Australasian registry study. Transplant Cell Ther 29(6):383.e1-383.e10. https://doi.org/10.1016/j.jtct.2023.03.014
DeLeve LD, Shulman HM, McDonald GB (2002) Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 22(1):27–42. https://doi.org/10.1055/s-2002-23204
Döring M, Cabanillas Stanchi KM, Feucht J, Queudeville M, Teltschik HM, Lang P, Feuchtinger T, Handgretinger R, Müller I (2016) Ferritin as an early marker of graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients. Ann Hematol 95(2):311–323. https://doi.org/10.1007/s00277-015-2560-3
Evens AM, Mehta J, Gordon LI (2004) Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress. Bone Marrow Transplant 34(7):561–571. https://doi.org/10.1038/sj.bmt.1704591
Favaloro EJ, Adcock DM (2008) Standardization of the INR: how good is your laboratory’s INR and can it be improved? Semin Thromb Hemost 34(7):593–603. https://doi.org/10.1055/s-0028-1104538
Iguchi A, Kobayashi R, Kaneda M, Kobayashi K (2010) Plasma protein C is a useful clinical marker for hepatic veno-occlusive disease (VOD) in stem cell transplantation. Pediatr Blood Cancer 54(3):437–443. https://doi.org/10.1002/pbc.22314
Jevtić D, Vujić D, Zecević Z, Veljković D, Gazikalović S, Elezović I (2010) Coagulation disturbances in paediatric patients with hepatic veno-occlusive disease after stem cells transplantation. Srp Arh Celok Lek 138:33–38. https://doi.org/10.2298/sarh10s1033j
Jevtic D, Zecevic Z, Veljkovic D, Dopsaj V, Radojicic Z, Elezovic I (2011) Veno-occlusive disease in pediatric patients after hematopoietic stem cell transplantation: relevance of activated coagulation and fibrinolysis markers and natural anticoagulants. J Pediatr Hematol Oncol 33(3):227–234. https://doi.org/10.1097/mph.0b013e31820539fd
Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, Vogelsang GB, Sensenbrenner LL, Santos GW, Saral R (1987) Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 44(6):778–783. https://doi.org/10.1097/00007890-198712000-00011
Kershaw G (2017) Performance of activated partial thromboplastin time (APTT): determining reagent sensitivity to factor deficiencies, heparin, and lupus anticoagulants. Methods Mol Biol 1646:75–83. https://doi.org/10.1007/978-1-4939-7196-1_5
Kloehn J, Brodt G, Ernst J, Gruhn B (2022) Analysis of risk factors for hepatic sinusoidal obstruction syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients. J Cancer Res Clin Oncol 148(6):1447–1455. https://doi.org/10.1007/s00432-021-03732-1
Lee JH, Lee KH, Kim S, Lee JS, Kim WK, Park CJ, Chi HS, Kim SH (1998) Relevance of proteins C and S, antithrombin III, von Willebrand factor, and factor VIII for the development of hepatic veno-occlusive disease in patients undergoing allogeneic bone marrow transplantation: a prospective study. Bone Marrow Transplant 22(9):883–888. https://doi.org/10.1038/sj.bmt.1701445
Lee SH, Yoo KH, Sung KW, Koo HH, Kwon YJ, Kwon MM, Park HJ, Park BK, Kim YY, Park JA, Im HJ, Seo JJ, Kang HJ, Shin HY, Ahn HS (2010) Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant 45(8):1287–1293. https://doi.org/10.1038/bmt.2009.349
McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED (1984) Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 4:116–122. https://doi.org/10.1002/hep.1840040121
Mohty M, Blaise D, Peffault de Latour R, Labopin M, Bourhis JH, Bruno B, Ceballos P, Detrait M, Gandemer V, Huynh A, Izadifar-Legrand F, Jubert C, Labussière-Wallet H, Lebon D, Maury S, Paillard C, Pochon C, Renard C, Rialland F, Schneider P, Sirvent A, Asubonteng K, Guindeuil G, Yakoub-Agha I, Dalle JH (2022) Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance registry study. Bone Marrow Transplant 58:367–376. https://doi.org/10.1038/s41409-022-01900-6
Nürnberger W, Kruck H, Mauz-Körholz C, Burdach S, Göbel U (1997) Humoral coagulation and early complications after allogeneic bone marrow transplantation. Klin Padiatr 209(4):209–215. https://doi.org/10.1055/s-2008-1043952
Park YD, Yasui M, Yoshimoto T, Chayama K, Shimono T, Okamura T, Inoue M, Yumura-Yagi K, Kawa-Ha K (1997) Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation. Bone Marrow Transplant 19(9):915–920. https://doi.org/10.1038/sj.bmt.1700760
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D’Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ (2016) Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 127(13):1656–1665. https://doi.org/10.1182/blood-2015-10-676924
Roeker LE, Kim HT, Glotzbecker B, Nageshwar P, Nikiforow S, Koreth J, Armand P, Cutler C, Alyea EP, Antin JH, Richardson PG, Soiffer RJ, Ho VT (2019) Early clinical predictors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after myeloablative stem cell transplantation. Biol Blood Marrow Transplant 25:137–144. https://doi.org/10.1016/j.bbmt.2018.07.039
Sartori MT, Spiezia L, Cesaro S, Messina C, Paris M, Pillon M, Saggiorato G, Pagnan A, Girolami A, Zanesco L, Cella G (2005) Role of fibrinolytic and clotting parameters in the diagnosis of liver veno-occlusive disease after hematopoietic stem cell transplantation in a pediatric population. Thromb Haemost 93(4):682–689. https://doi.org/10.1160/th04-09-0621
Sartori MT, Cesaro S, Peruzzo M, Messina C, Saggiorato G, Calore E, Pillon M, Varotto S, Spiezia L, Cella G (2012) Contribution of fibrinolytic tests to the differential diagnosis of veno-occlusive disease complicating pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer 58(5):791–797. https://doi.org/10.1002/pbc.23213
Shulman HM, Gown AM, Nugent DJ (1987) Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol 127(3):549–558
Xia Y, Qin H, Yang J (2021) Hepatic veno-occlusive disease development in the hematopoietic stem cell transplantation patients: incidence and associated risk factors, a meta-analysis. Eur J Gastroenterol Hepatol 33(6):872–884. https://doi.org/10.1097/meg.0000000000001802
Yoon JH, Yoo KH, Sung KW, Jung CW, Kim JS, Hahn SM, Kang HJ, Lee JH, Im HJ, Ahn JS, Kook H, Cho B, Lee JW (2019) Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). Bone Marrow Transplant 54(8):1361–1368. https://doi.org/10.1038/s41409-019-0492-6
Funding
Open Access funding enabled and organized by Projekt DEAL. No funding has been received for this work.
Author information
Authors and Affiliations
Contributions
LJ and BG: wrote the main manuscript text and LJ: prepared Fig. 1. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
There is no potential conflict of interest for the authors.
Ethical approval
All procedures complied with ethical standards. The study was accepted by the ethics committee of the University Hospital Jena (2023–2890). Informed consent was obtained from all responsible persons.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Johann, L., Gruhn, B. Analysis of laboratory parameters before the occurrence of hepatic sinusoidal obstruction syndrome in children, adolescents, and young adults after hematopoietic stem cell transplantation. J Cancer Res Clin Oncol 150, 9 (2024). https://doi.org/10.1007/s00432-023-05561-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00432-023-05561-w