Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
J Thromb Haemost. 2016 Feb;14(2):340-5. doi: 10.1111/jth.13210. Epub 2016 Feb 1.
ESSENTIALS: The differential diagnosis among thrombotic microangiopathies (TMAs) is challenging. We studied a case of TMA with neurologic symptoms, no renal impairment and normal ADAMTS-13 levels. Two novel mutations in complement factor I and thrombomodulin genes were identified. Complement-regulator genes can be involved in TMAs with normal ADAMTS-13 regardless of renal damage.
Thrombotic microangiopathies (TMAs) often represent a challenge for clinicians, because clinical, laboratory, and even genetic features are not always sufficient to distinguish among different TMAs.
The aim of this study was to investigate the pathogenetic mechanisms underlying an acute case of TMA with features of both thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS).
PATIENTS/METHODS: We report the case of a 49-year-old woman who developed an acute TMA with neurologic involvement and no renal impairment. ADAMTS-13, von Willebrand factor, and complement-system biochemical characterization was performed on acute phase samples. Exome sequencing and direct Sanger sequencing of previously aHUS-associated genes were performed. The functional consequences of the thrombomodulin (THBD) mutation were investigated by in vitro expression studies.
Despite a clinical diagnosis of TTP, the patient had normal ADAMTS-13 levels and increased VWF antigen levels with ultra-large von Willebrand factor multimers. C3, C4, and complement factors H and I (CFI) were normal. Molecular analysis confirmed two novel heterozygous mutations in CFI (c.805G>A, p.G269S) and THBD (c.1103C>T, p.P368L), and in vitro expression studies showed a reduction in the generation of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) caused by mutated THBD. This proinflammatory condition, associated with the p.G269S mutation in CFI, probably leads to a complement-mediated endothelial activation, with a relevant prothrombotic potential in case of transient environmental triggers.
This study identified the first case of acute TMA without renal involvement but with neurological damage carrying two novel mutations in complement-regulator genes, highlighting the possible role of the complement system as a common pathogenetic mechanism in TMAs.
本研究旨在探讨急性 TMA 病例的发病机制，该病例既有血栓性血小板减少性紫癜 (TTP) 的特征，也有非典型溶血尿毒综合征 (aHUS) 的特征。
患者/方法：我们报告了一例 49 岁女性，她出现了急性 TMA，伴有神经系统受累且无肾功能损害。在急性阶段样本中进行 ADAMTS-13、血管性血友病因子和补体系统生化特征分析。进行外显子组测序和先前与 aHUS 相关基因的直接 Sanger 测序。通过体外表达研究研究了血栓调节蛋白 (THBD) 突变的功能后果。
尽管临床诊断为 TTP，但患者的 ADAMTS-13 水平正常，且超大血管性血友病因子多聚体的 VWF 抗原水平升高。C3、C4 和补体因子 H 和 I (CFI) 正常。分子分析证实 CFI（c.805G>A，p.G269S）和 THBD（c.1103C>T，p.P368L）中存在两个新的杂合突变，体外表达研究表明突变的 THBD 导致激活的凝血酶激活的纤溶抑制物 (TAFIa) 的生成减少。这种促炎状态与 CFI 中的 p.G269S 突变相关，可能导致补体介导的内皮激活，在短暂的环境触发因素下具有相关的促血栓形成潜力。
本研究鉴定了首例无肾累及但有神经损伤的急性 TMA 病例，携带补体调节基因中的两个新突变，强调了补体系统作为 TMA 共同发病机制的可能作用。
