Clinical Diagnosis And Treatment Of Endothelial Cell Injury Syndrome(SOS/TA-TMA) After Hematpoietic Stem Cell Transplantation

Part ? Clinical study of low dose recombinant human tissue plasminogen activator(rh-tPA)in the treatment of Sinusoidal obstruction syndrome(SOS)after hematopoietic stem cell transplantationObjective:Sinusoidal obstruction syndrome(SOS)is one of the most serious complications after hematopoietic stem cell transplantation(HSCT)and an important form of endothelial cell injury syndrome after transplantation.This part is a prospective,single-arm,open clinical trial to study the efficacy and safety of SOS after HSCT treatment with a low-dose rh-tPA regimen(a real-world study).Methods:from December 2014 to June 2019,a total of 16 SOS patients with HSCT who met the inclusion/exclusion criteria were enrolled in the first affiliated hospital of Soochow university and treated with the designed low-dose rh-tPA integrated regimen.The core of the program was rh-tPA(alteplase,10mg/d)at a low daily dose and continued administration.The duration of use was determined based on the response to treatment and the assessment of bleeding risk.Other measures included:withdrawal of calmodulin inhibitors(CNI),fluid balance management,glucocorticoids,albumin and blood product support,prostaglandin E1,ursodeoxycholic acid,etc.The main observational indicators included:complete treatment response(CR),overall treatment response(ORR),treatment+100d survival rate,1-year overall survival rate(OS),and adverse events(including severe bleeding).Results:sixteen patients(12 males and 4 females)were enrolled,including 12(75%)patients with severe SOS and 4(25%)patients with extremely severe SOS.The median time from HSCT to SOS was+39.5(17?615)days.In the low-dose rh-tPA trial regimen,12(75%)patients received CR and survived,while 4(NR)patients died.Compared with severe SOS,extremely severe patients had a higher proportion of multiple organ failure(0%,100%)and mortality(8.3%,75%,P<0.05),but no statistical difference was found between the two severe bleeding events(25%,50%,P=0.547).The CR rate was higher(100%,42.9%,P=0.01)and the incidence of severe bleeding was lower(0%,85.7%,P=0.005)in patients with infusion time?10d than in patients with infusion time<10d.Conclusion:low dose rh-tPA based comprehensive regimen of SOS after HSCT has a high therapeutic response and good safety.Part ? the study of predictors of transplant-related thrombotic microvascular disease(TA-TMA)in the peri-diagnosis periodObjective:to investigate whether the clinical and laboratory parameters of transplantation-related thrombotic microvascular disease(TA-TMA)in the peri-diagnosis period have diagnostic and predictive effects,and to screen the basic parameters for the establishment of a "smoldering type" TA-TMA diagnostic model based on the risk scoring system.Methods:107 patients who received allogeneic transplantation in the first affiliated hospital of Soochow university from April 2016 to October 2019 were retrospectively analyzed.Among them,53 patients with TA-TMA were in the experimental observation group,while 54 patients with severe aGVHD were in the control observation group.The clinical and laboratory parameters of the two groups were collected and counted 7 days before diagnosis(peri-diagnosis period).The data differences between the two groups were compared,and the parameters were analyzed by ROC curve to evaluate the accuracy of prediction.The overall survival rate(OS),non-recurrent mortality(NRM)and cumulative recurrence rate(CIR)were analyzed.Results:the serum LDH level of TA-TMA group was significantly higher than that of control group(P<0.001).PLT and HB count were lower than those of the control group from 5 days and 3 days before diagnosis to the time of diagnosis respectively(P<0.05).The ratio of TA-TMA complicated with hypertension requiring ?2 antihypertensive drugs was higher than that of the control group(18.9%vs1.9%,P<0.001).Schizocytosis?2%was more common in the TA-TMA group(64.2%vs16.7%,P=0.001).There was no significant difference in baseline serum creatinine(Scr)levels between the two groups,with a median of 59.4mol/L and 56.2mol/L respectively(P=0.695).There also was no statistical difference in Scr levels between 7 days before diagnosis and the day of diagnosis(P>0.05).However,the incidence of acute kidney injury(AKI)after diagnosis in TA-TMA group was higher than that in the control group(39.6%vs11.1%,P=0.001).Soluble membrane attack complex(sc5b-9)was detected in 37 patients of TA-TMA group and 21 patients of the control group,respectively,and there was no significant statistical difference in the level of sc5b-9 between the two groups(P=0.859).ROC curve analysis further confirmed that LDH,HB,PLT counts,Schizocytosis,and hypertension had higher accuracy in predicting the diagnosis of TA-TMA(P<0.05),while Scr and sc5b-9 levels were less accurate(P>0.05).The 1-year OS,NRM and CIR of the two groups were 31.8%vs 44.3%,64.5%vs 52.0%,3.77%vs3.96%(P>0.05),respectively.However,the+200 days OS was lower and NRM was higher of the TA-TMA group after transplantation(37.7%vs 59.3%(P=0.021),and 57.1%vs 34.1%(P=0.021),respectively.COX univariate analysis showed that severe aGVHD was not a prognostic risk factor for TA-TMA[HR=1.669,95%CI(0.890,3.130),P=0.110].Conclusion:increased serum LDH level,decreased HB and PLT counts,Schizocytosis,and hypertension are the peri-diagnostic dynamic parameters that distinguish TA-TMA from severe aGVHD and can better predict TA-TMA in the early stage.They are expected to be included as the basic elements of the "smoldering type"TA-TMA diagnostic model based on the risk scoring system.