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Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy
发布于：2013年7月8日 文字：【大】【中】【小】
Blood. 2013 Jun 27. [Epub ahead of print]
Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy.
Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA, Davies SM, Pluthero FG, Lu L, Laskin BL.
Abstract
Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25-35 % of HSCT recipients and shares histomorphological similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation and tissue damage. While significant advances have been made in the understanding of the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-associated thrombotic microangiopathy and may therefore guide the development of targeted treatment interventions
异基因造血干细胞移植（HSCT）相关血栓性微血管病（TA-TMA）通常在HSCT 6-12个月后出现，见于25-35% HSCT患者。内皮细胞损伤是TMA发病及病理改变的核心。既往的研究发现TA-TMA内皮细胞损伤是多因素共同作用引起：化疗、放疗、清髓异基因造血干细胞移植、顺式维甲酸、CNIs、移植物抗宿主病、细胞因子、凝血途径异常、感染、女性受者+男性供者均是发生TA-TMA的危险因素。TA-TMA的确切发病机制认识还是很有限。本文在6例TA-TMA患儿中发现高比例的CFHR1和CFHR3缺失、抗H因子自身抗体阳性；另外18例未出现TMA的HSCT患儿H因子抗体均阴性。因此本文提出补体旁路调节异常可能参与TA-TMA致病。