Anti-ADAMTS13 Antibodies and a Novel Heterozygous p.R1177Q Mutation in a Case of Pregnancy-Onset Immune-Mediated Thrombotic Thrombocytopenic Purpura

In this study, we investigated a case of pregnancy-onset thrombotic thrombocytopenic purpura (TTP). The patient had severely decreased ADAMTS13 ( isintegrin nd etalloprotease with hrombo pondin type 1 motif, member 13) activity levels during acute phase and the presence of inhibitory anti-ADAMTS13 a...

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Published in:	TH open : companion journal to thrombosis and haemostasis Vol. 2; no. 1; pp. e8 - e15
Main Authors:	Roose, Elien, Tersteeg, Claudia, Demeersseman, Ruth, Schelpe, An-Sofie, Deforche, Louis, Pareyn, Inge, Vandenbulcke, Aline, Vandeputte, Nele, Dierickx, Daan, Voorberg, Jan, Deckmyn, Hans, De Meyer, Simon F, Vanhoorelbeke, Karen
Format:	Journal Article
Language:	English
Published:	Germany Georg Thieme Verlag KG 01-01-2018
Subjects:	anti-adamts13 autoantibodies Original pregnancy-onset ttp snps and mutations thrombotic thrombocytopenic purpura SNPs and mutations thrombotic thrombocytopenic purpura anti-ADAMTS13 autoantibodies pregnancy-onset TTP
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Summary:	In this study, we investigated a case of pregnancy-onset thrombotic thrombocytopenic purpura (TTP). The patient had severely decreased ADAMTS13 ( isintegrin nd etalloprotease with hrombo pondin type 1 motif, member 13) activity levels during acute phase and the presence of inhibitory anti-ADAMTS13 autoantibodies was demonstrated, which led to the diagnosis of immune-mediated TTP. However, ADAMTS13 activity was only mildly restored during remission, although inhibitory anti-ADAMTS13 antibodies were no longer detected. We hypothesized that genetic abnormalities could account for this discrepancy between ADAMTS13 activity and antigen. Genetic analysis revealed the presence of two heterozygous substitutions on the same allele: a single nucleotide polymorphism (SNP) c.2699C > T (p.A900V), located in the beginning of the T5 domain, and a mutation c.3530G > A (p.R1177Q) located in the third linker region of ADAMTS13. In vitro testing of those substitutions by expression of recombinant proteins revealed a normal secretion but a reduced ADAMTS13 activity by the novel p.R1177Q mutation, which could partially explain the subnormal activity levels found during remission. Although changes in the linker region might induce conformational changes in ADAMTS13, the p.R1177Q mutation in the third linker region of ADAMTS13 did not expose a cryptic epitope in the metalloprotease domain. In conclusion, we report on an immune-mediated pregnancy-onset TTP patient who had inhibitory anti-ADAMTS13 autoantibodies during acute phase, but not during remission. Genetic analysis confirmed the diagnosis of immune-mediated TTP and revealed the novel p.R1177Q mutation which mildly impaired ADAMTS13 activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2512-9465 2567-3459 2512-9465
DOI:	10.1055/s-0037-1615252