DataSheet_1_Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy.docx

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.

异基因造血干细胞移植术后移植物相关血栓性微血管病（TA-TMA）是一种致命性并发症。既往研究表明，TA-TMA可能由补体相关基因变异引起的补体激活所致；然而，这一结论尚需进一步验证，尤其是在成人患者中。本研究在一个单一中心对接受异基因造血干细胞移植治疗的成人患者进行了一项嵌套病例对照研究。根据倾向得分匹配，纳入了15名TA-TMA患者和15名非TA-TMA患者。基于先前报道指出补体相关基因与TA-TMA发病之间的关联，我们首先对这些17个基因进行了测序。两组均存在多种罕见等位基因频率的遗传变异；然而，TA-TMA组和非TA-TMA组中罕见变异患者的百分比，以及每位患者罕见变异的平均数量均无显著差异。其次，我们测量了补体蛋白的血浆浓度。值得注意的是，在异基因造血干细胞移植后第7天，TA-TMA组中Ba蛋白的水平异常且显著高于非TA-TMA组，这表明通过替代途径的补体激活可能是TA-TMA发病的促成因素。所有其他参数，包括第7天的可溶性C5b-9，两组之间相似。在第28天之后，TA-TMA组中的C3、C4、CH50以及补体因子H和I的水平显著低于非TA-TMA组。补体相关基因变异并不能预测TA-TMA的发生。相反，第7天Ba水平的异常升高可以预测TA-TMA和非复发死亡的发生。因此，异基因造血干细胞移植后第7天的Ba水平是TA-TMA的一个敏感且具有预后价值的生物标志物。