移植相关的血栓性微血管病的临床观察

Clinical observation of transplant associated thrombotic microangiopathy

目的:了解异基因造血干细胞移植后移植相关血栓性微血管病(TA-TMA)的临床表现、危险因素及预后预测因素。方法:回顾性分析2016年8月—2018年6月期间在广东省人民医院血液科接受异基因造血干细胞移植的76例患者,其中男42例,女34例,中位年龄28岁(范围:12~53岁),基础疾病包括急性髓系白血病42例,急性淋巴细胞白血病22例,慢性粒细胞白血病3例,其他类型血液病9例。临床资料数据采集于住院HIS系统、门诊系统数据记录及电话随访;数据统计采用SPSS分析软件进行分析。结果:76例患者中诊断TA-TMA者23例,非TA-TMA者53例。发生TA-TMA患者的中位年龄为27岁(IQR:20~33岁),中位发病时间为移植后76 d(范围:7~456 d)。对TA-TMA患者的临床症状体征及实验室结果分析表明,与非TA-TMA患者比较,TA-TMA患者的肺动脉高压更加显著(P=0.001),肌酐水平显著升高(P=0.003),尿蛋白明显增多(P=0.024)。单因素分析显示,非血缘供者移植较单倍体移植及同胞全相合移植更容易发生TA-TMA(TA-TMA发生率分别为56.5%、26.1%、17.4%,P=0.015),另外合并Ⅱ~Ⅳ度急性移植物抗宿主病(aGVHD)(P=0.042)、肝功能不全(P=0.026)、严重消化道出血(P=0.001)和重度感染(P<0.001)的患者也更易发生TA-TMA。多因素Logistic回归分析显示,重症感染(P=0.002,OR=7.65,95%CI:2.16~27.10)及消化道出血(P=0.015,OR=4.32,95%CI:1.33~14.06)是TA-TMA的危险因素。TA-TMA患者血管性血友病因子(vWF)水平较非TA-TMA患者明显升高(380%±78%vs 288%±104%,P<0.001),多因素Logistic回归分析中vWF(P=0.006,OR=1.01,95%CI:1.01~1.02)及蛋白尿(P=0.018,OR=1.91,95%CI:1.12~3.25)也是TA-TMA发生的危险因素,且vWF水平的升高较传统早期预测TA-TMA的生物学指标LDH提前8 d(范围:2~22 d)。合并肝功能损伤或重症感染的TA-TMA患者更易发生死亡事件,P值分别为0.048和0.021。结论:TA-TMA患者临床表现具有非特异性、多样性、复杂性等特点,导致早期诊断困难、治疗预后差。本研究发现无关供者移植及合并Ⅱ~Ⅳ度aGVHD、胃肠道aGVHD、肝功能损伤、胃肠道出血、重症感染、真菌感染的患者更易发生TA-TMA。重症感染、消化道出血、vWF水平、尿蛋白水平升高是TA-TMA发生的危险因素,vWF可能成为TA-TMA早期预测因子。TA-TMA患者的死亡率极高,尤其是合并肝功能损伤或重症感染的患者。本研究能够帮助临床医生早期警惕TA-TMA的发生、早期识别及判断TA-TMA患者预后。

Objective: To analyze the risk factors, clinical manifestations and prognosis of allogeneic hematopoietic stem cell transplantation associated thrombotic microangiopathy(TA-TMA). Methods: A retrospective analysis was performed on 76 patients who received allogeneic hematopoietic stem cell transplantation in the hematology department of Guangdong provincial people’s hospital from August 2016 to June 2018, including 42 males and 34 females, with a median age of 28 years(range: 12 to 53 years). The underlying diseases included 42 cases of acute myeloid leukemia, 22 cases of acute lymphocytic leukemia, 3 cases of chronic myelogenous leukemia, and 9 cases of other blood diseases. Clinical data were collected from inpatient HIS system, outpatient system data records and telephone follow-up. The data was analyzed by SPSS. Results: The median age of patients with TA-TMA was 27 years(IQR: 20 to 33), and the median time of onset was 76 days(7 to 456 days) after transplantation. Analysis of the clinical characteristics and laboratory results of TA-TMA patients showed that, compared with the non-TA-TMA group, patients in the TA-TMA group had more significant pulmonary hypertension(P=0.001), significantly increased creatinine level(P=0.003), and significantly increased urinary protein(P=0.024). Single-factor analysis showed that unrelated donor transplantation was more likely to occur TA-TMA than haploid transplantation and sibling full compatibility transplantation(P=0.015), while acute graft versus host disease(Ⅱ-Ⅳ)(P=0.042), liver dysfunction(P=0.026), severe gastrointestinal bleeding(P=0.001) and severe infection(P<0.001) were influence factors for the occurrence of TA-TMA. Multivariate Logistic regression analysis showed that severe infection(P=0.002, OR=7.65, 95%CI: 2.16-27.10) and gastrointestinal bleeding(P=0.015, OR=4.32, 95%CI: 1.33-14.06) were the risk factors of TA-TMA. vWF levels in patients with TA-TMA were significantly higher than those patients without TA-TMA(380%±78% vs 288%±104%, P<0.001). vWF(P=0.006, OR=1.01, 95%CI: 1.01-1.02) and proteinuria(P=0.018, OR=1.91, 95%CI: 1.12-3.25) were also risk factors for TA-TMA in multivariate Logistic regression analysis. In addition, vWF increased 8 days earlier than lactate dehydrogenase(range: 2 to 22 days), and lactate dehydrogenase was widely regarded as an important biological indicator for early prediction of TA-TMA. TA-TMA patients with liver function injury or severe infection were more likely to die, with P values of 0.048 and 0.021, respectively. Conclusion: The clinical manifestations of TA-TMA are characterized by nonspecificity, diversity and complexity, and early diagnosis is difficult. TA-TMA is more likely to occur in patients with independent donor transplantation mode and patients withⅡ-ⅣaGVHD, gastrointestinal aGVHD, liver injury, gastrointestinal bleeding, severe infection, and fungal infection. Severe infection, gastrointestinal bleeding, elevated vWF and urinary protein levels are important risk factors for TA-TMA. The mortality rate of TA-TMA patients is very high, and the second important factor affecting the prognosis of patients is severe infection. This study can help clinicians to alert the risk factors of TA-TMA early, identify TA-TMA early and judge the prognosis of TA-TMA patients.