Abstract
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, ADAMTS13, THBD, MMACHC, INF2, and PLG), complement activation (eg, C3, C3AR1, C5, CFB, CFH, CFI, C4BPA, CD46 [MCP], CD59, and CFHR1-CFHR5), and platelet activation (eg, DGKE) 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 CFI, CFH, C5, and ADAMTS13; 15% to 55% of patients had variants in C3, INF2, CFHR5, and PLG; and <10% of patients had variants in CD46, C3AR1, DGKE, and THBD. Of these, the variants in C5 are associated with a more favorable renal function, whereas the variants in DGKE 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.