Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
Pediatr Nephrol. 2018 Aug;33(8):1297-1307. doi: 10.1007/s00467-017-3744-y. Epub 2017 Jul 26.
Thrombotic microangiopathy (TMA) is caused by thrombus formation in the microvasculature. The disease spectrum of TMA includes, amongst others, thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS). TTP is caused by defective cleavage of von Willebrand factor (VWF), whereas aHUS is caused by overshooting complement activation and subsequent endothelial cell (EC) injury. Despite their distinct pathophysiology, the clinical manifestation of TTP and aHUS consisting of microangiopathic haemolytic anaemia and thrombocytopenia is often similar and difficult to distinguish. Recent evidence hints at both a genetic and functional link between TTP and aHUS, especially between VWF and the complement system. There is novel in vitro evidence that complement activation not only results in VWF release from ECs, but that VWF also functions as a negative complement regulator, thus protecting the EC surface from ongoing complement attack. Although contrary to previous experimental work suggesting that complement can be activated on VWF multimers, there may be an explanation in vivo that rationalizes these apparently contradictory findings, whereby a system primarily meant to regulate becomes overwhelmed or pathologic in the disease state. The importance of unravelling these recent findings for our understanding of TMA pathology becomes even more evident considering that glomerular ECs express VWF in a heterogeneous pattern with an overall decreased expression level, thus potentially leaving the glomerular ECs vulnerable to complement-mediated injury. Taken together, these findings support the concept that TTP and aHUS represent two extreme ends of a TMA disease spectrum rather than isolated disease entities.
血栓性微血管病（TMA）是由微血管血栓形成引起的。TMA 的疾病谱包括血栓性血小板减少性紫癜（TTP）和非典型溶血尿毒综合征（aHUS）等。TTP 是由于 von Willebrand 因子（VWF）的缺陷性裂解引起的，而 aHUS 是由于补体过度激活和随后的内皮细胞（EC）损伤引起的。尽管它们具有不同的病理生理学，但 TTP 和 aHUS 的临床表现包括微血管性溶血性贫血和血小板减少，通常相似且难以区分。最近的证据表明 TTP 和 aHUS 之间存在遗传和功能联系，特别是在 VWF 和补体系统之间。有新的体外证据表明，补体激活不仅导致 EC 释放 VWF，而且 VWF 还作为负性补体调节剂发挥作用，从而保护 EC 表面免受持续的补体攻击。尽管与先前的实验工作表明补体可以在 VWF 多聚体上激活相反，但在疾病状态下，可能存在一种解释可以合理化这些明显矛盾的发现，即一个主要用于调节的系统在疾病状态下变得不堪重负或病理性。考虑到肾小球 EC 以异质模式表达 VWF，且总体表达水平降低，因此肾小球 EC 容易受到补体介导的损伤，因此，阐明这些最新发现对于我们理解 TMA 病理学的重要性变得更加明显。综上所述，这些发现支持 TTP 和 aHUS 代表 TMA 疾病谱的两个极端，而不是孤立的疾病实体的概念。
