Cao Wenjing, Basu Malay K, Staley Elizabeth, Zheng X Long
Departments of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS.
Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS.
Blood Vessel Thromb Hemost. 2024 Jul 16;1(4):100019. doi: 10.1016/j.bvth.2024.100019. eCollection 2024 Dec.
Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13. However, the contribution of genetic variations that may modulate its clinical presentations remains unknown. This study aimed to determine the potential contribution of variants in the genes associated with coagulation, complement activation or regulation, and platelet activation to pathophysiology of iTTP. Multicenter case series, whole-exome sequencing, and bioinformatic approaches were used. We focused on analysis of 20 genes that are involved in regulation of coagulation (eg, , , , , and ), complement activation (eg, , , , , , , , [], , and -), and platelet activation (eg, ) from 40 adult patients with iTTP. Multiple genetic variations were identified in 12 of 20 genes of interest. More than 80% of patients harbored genetic variants in , , , and ; 15% to 55% of patients had variants in , , , and ; and <10% of patients had variants in , , , and . Of these, the variants in are associated with a more favorable renal function, whereas the variants in are associated with more persistently elevated creatinine levels. These results demonstrate that variants in the genes involved in coagulation, complement, and platelet activation are common in patients with iTTP, which may contribute to phenotypical modulations of or predispose to iTTP resulting from severe ADAMTS13 deficiency.
免疫性血栓性血小板减少性紫癜（iTTP）是一种潜在致命的血液疾病，由针对ADAMTS13的自身抗体引起。然而，可能调节其临床表现的基因变异的作用仍不清楚。本研究旨在确定与凝血、补体激活或调节以及血小板激活相关的基因变异对iTTP病理生理学的潜在作用。采用多中心病例系列、全外显子测序和生物信息学方法。我们重点分析了40例成年iTTP患者中涉及凝血调节（如 、 、 、 、 ）、补体激活（如 、 、 、 、 、 、 、 、 、 、 ）和血小板激活（如 ）的20个基因。在20个感兴趣的基因中的12个中鉴定出多个基因变异。超过80%的患者在 、 、 、 中存在基因变异；15%至55%的患者在 、 、 、 中存在变异；<10%的患者在 、 、 、 中存在变异。其中， 中的变异与更有利的肾功能相关，而 中的变异与肌酐水平持续升高相关。这些结果表明，参与凝血、补体和血小板激活的基因变异在iTTP患者中很常见，这可能导致iTTP的表型调节或因严重ADAMTS13缺乏而易患iTTP。
