| Background:Hematopoetic stem cell transplantation(HSCT)is an important method to cure hematologic malignancies,non-malignant refractory hematopathy,hereditary diseases and some solid tumors,and is widely used.The prevention and control of post-transplant complications has always been an urgent task for transplant doctors.Transplant associated thrombotic microangiopathy(TA-TMA)is a serious complication of HSCT,with an incidence of 0.5-76%and a mortality of 60-90%.The exact pathophysiological mechanism of TA-TMA is still unclear,it is closely related to small artery endothelial cell injury and thrombosis in small arteries caused by radiotherapy and chemotherapy,immunosuppressive agents,GVHD,infection,and complement disorders,and can cause clinical syndrome of multiple organ failure.The secretion and release of von willebrand factor(vWF),which is mainly synthesized in endothelial cells,is considered as a marker of endothelial cell injury,as a key marker for the initiation of TA-TMA,what is the correlation between plasma vWF level and the occurrence and prognosis of TA-TMA?Can plasma vWF level be used as a diagnostic marker for ta-tma?It's not clear.Therefore,we conducted a study on the correlation between plasma vWF level and TA-TMA in transplant patients.Methods:Patients who received blood stem cell transplants were studied between August 2016 and June 2018.The plasma vWF(vWF:Ag)level was continuously detected once a week by immunoturbidimetry at 0?+100 days after transplantation.To summarize the clinical characteristics of patients with TA-TMA and analyze the related risk factors and prognosis.The difference of plasma vWF level between TA-TMA patients and non-TA-TMA patients was compared,and the determination of the approximate Youden index and the comparison of the area under the curve(AUC)were conducted by MedCalc statistical software,so as to explore the role of vWF in the diagnosis of ta-tma and the threshold value.Results:1)Case overview:among the 79 patients,44 were males and 35 were females,with a median age of 28 years.There were 42 cases of acute myeloid leukemia(AML),22 cases of acute lymphoblastic leukemia(ALL),3 cases of chronic myeloid leukemia(CML),and 12 cases of other blood diseases.According to the diagnostic criteria of TA-TMA,there were 23 cases(29.2%)in the TA-TMA group and 56 cases(70.8%)in the non-TA-TMA group.Transplantation type:29 cases(36.7%)were non-blood transplantation,47 cases(59.5%)were blood transplantation,and 15 cases(18.9%)were haplotype transplantation.HLA?8/10 in 66 cases and HLA<8/10 in 13 cases.35 patients received atg-containing pretreatment regimen.Up to April 15,2019,the incidence of aGVHD was 49.4%,and the median time of diagnosis was+45 days after transplantation(IQR:+32?+58 days),of which 53.8%(21/39)were of grade ii-iv aGVHD.The incidence of cGVHD was 54.4%,the median time of diagnosis was+203 days after transplantation(IQR:+166?+282 days),and the incidence of moderate to severe cGVHD was 69.8%(30/43).There were 23 patients(23/79,29%)who met the diagnostic criteria of TA-TMA(TA-TMA group),and the median diagnosis time was+76 days after transplantation(range:+7?+456 days).Among them,13 patients(13/23,56.6%)were diagnosed with TA-TMA within+100 days after transplantation,9 patients(9/23,39.1%)were diagnosed within+100 days?+200 days after transplantation,and only 1 patient was diagnosed with TA-TMA on 456 days after transplantation.The clinical manifestations of TA-TMA are diverse.In addition to the common clinical manifestations of anemia,platelet decline,and liver and kidney function injury,it can also be manifested as hypertension,pulmonary hypertension and fever.2)Risk factors for the occurrence of TA-TMA:univariate analysis results showed that the TA-TMA group was more likely to be associated with grade ii-iv acute GVHD than the non-ta-tma group(43.5%vs 19.6%;P=0.048),severe gastrointestinal bleeding(73.9%vs 32.1%;P=0.001),liver injury(78.3%vs 48.2%;P=0.023),severe infection(82.6%vs 33.9%;P<0.001)and fungal infections(34.8%vs 5.4%;P=0.002).Hypertension was more common in the TA-TMA group than in the non-TA-TMA group(34.8%vs 8.9%;P=0.008),pulmonary hypertension(39.1%vs 7.1%;P=0.001),increased creatinine(mean±SD,129.2±74.1umol/L vs 83.5±50.3 umol/L;P=0.002),proteinuria(1.0g/L vs 0.3g/L;P=0.015)and other clinical manifestations;The vWF level of ta-tma group was higher than that of non-TA-TMA group(mean±SD,380.7±78.8 vs 284.9±104.5%;P<0.001).Risk factors for the occurrence of TA-TMA were adjusted by Logistic regression,including grade ii-iv aGVHD,fungal infection,PCT,vWF level,liver function injury and severe infection,etc.Multivariate analysis results showed that vWF was an independent predictor of the occurrence of TA-TMA(odds ratio[OR]=1.009;95%[CI]:1.001-1.017;P=0.025).3)The efficacy of vWF in the diagnosis of TA-TMA:the efficacy of vWF in the diagnosis of TA-TMA was represented by the ROC curve,the area under the ROC curve is 0.756(95%[CI]:0.636-0.874).The efficacy of LDH in the diagnosis of TA-TMA was represented by the ROC curve.The area under the curve is 0.816,which is larger than that of vWF.DeLong method was used in MedCalc statistical software to analyze and compare the diagnostic efficacy of LDH and vWF for TA-TMA.It showed that although the area under the curve of LDH-ROC was greater than that of vWF-ROC,there was no statistical difference in the diagnostic efficacy of TA-TMA(P=0.367).Moreover,the rise of vWF was monitored 8 days earlier than that of LDH(IQR:2-22 days).4)vWF prediction threshold vWF?325%:the largest Youden index calculated by MedCalc was 0.542,and the corresponding vWF value had the best diagnostic efficacy.The statistical results showed that the vWF level corresponding to the maximum Youden index was greater than or equal to 325%,and the sensitivity of the diagnosis of TA-TMA was 86.96%(95%[CI]:66.4%-97.2%),while the specificity of the diagnosis of TA-TMA was 67.27%(95%[CI]:53.3%-79.3%).Among the 38 patients who met the criteria of vWF level?325%,20(52.6%)were diagnosed with TA-TMA,while 18(32.1%)of the undiagnosed patients with TA-TMA did not reach the vWF level?325%.5)Patients with vWF?325%had poor prognosis:according to the vWF level corresponding to the maximum approximate index,the patients were divided into groups greater than or equal to 325%and less than 325%.Patients with?325%vWF had a higher two-year cumulative hazard of TA-TMA(53.1%±8.2%vs 7.5%±4.2%;p<0.001)and a lower 32 months survival(32.1%±9.1%vs 83.7%±6.2%;p<0.001)compared with those with<325%vWF.Conclusion:In this study,it was preliminarily confirmed that vWF was an risk factors of the occurrence of TA-TMA,which was increased 8 days earlier than LDH on average.After hematopoietic stem cell transplantation,vWF?325%was a high risk factor for the occurrence of TA-TMA and also a factor affecting the prognosis of patients.Continuous monitoring of vWF levels is conducive to early detection and early intervention of this serious life-threatening complication by clinicians,thus improving the prognosis of patients with TA-TMA. |
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