Multiple B‐cell clones producing antibodies directed to the spacer and disintegrin/thrombospondin type‐1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura

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BackgroundSevere ADAMTS13 deficiency is a critical component of the pathogenesis of idiopathic thrombotic thrombocytopenic purpura but is found only in about 60% of patients clinically diagnosed with this disease. Design and MethodsOver a period of 8 years and six episodes of thrombotic thrombocytopenic purpura we studied the evolution of the anti-ADAMTS13 antibody response in a patient using different ADAMTS13 assays and epitope mapping. ResultsAnti-ADAMTS13 autoantibodies were found in all episodes but were inhibitory only in the last two episodes. In a flow-based assay, normal ADAMTS13 activity was found only during the first disease episode, while ADAMTS13 activity was normal using a static assay in episodes 1 and 3, and severely deficient in the last two episodes. Fluorescence evolution in a modified fluorescence resonance energy transfer assay using a von Willebrand factor A2 domain peptide substrate was linear in episodes 1, 5 and 6, but increased exponentially in episodes 3 and 4. Despite the variable functional characteristics of the anti-ADAMTS13 autoantibodies, their principal epitope was the ADAMTS13 spacer domain in all episodes. ConclusionsThe patient is unique as he displayed features of maturation or shaping of the anti-ADAMTS13 autoantibody response during the course of multiple episodes of thrombotic thrombocytopenic purpura. Anti-ADAMTS13 autoantibodies may be important in vivo despite normal ADAMTS13 activity in routine assays. Consequently, treatment decisions should not be based solely on activity assay results. Haematologica 2012;97(2):297-303. doi:10.3324/haematol.2011 This is an open-access paper.Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura

Section: Discussionmentioning

confidence: 99%

“…19,20 All of the above mentioned recombinant truncated ADAMTS13 proteins contained a C-terminal V5 tag. Normal human plasma served as an autoantibody-negative control and a commercially available mono clonal anti-V5 antibody (Invitrogen, Carlsbad, CA, USA) as a positive control.…”

Section: Epitope Mapping Of Anti-adamts13 Autoantibodiesmentioning

confidence: 99%

Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura

Froehlich-Zahnd¹,

George²,

Vesely³

et al. 2011

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“…Residual ADAMTS13 activity was calculated as described previously. 8 Binding of immunoglobulins to ADAMTS13 was determined using a modification of the Technozym inhibitor ELISA; instead of serial plasma dilutions, several dilutions of IgG in incubation buffer were used.…”

Section: Design and Methodsmentioning

confidence: 99%

Antibodies against the CUB1-2 domains of ADAMTS13 in a patient with benign monoclonal gammopathy: no causal relationship

Riksen¹,

Luken²,

Klasen³

et al. 2007

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Please be advised that this information was generated on 2018-08-28 and may be subject to change. Antibodies against the CUB1-2 domains of ADAMTS13 in a patient with benign monoclonal gammopathy: no causal relationshipWe present a patient with a history of benign monoclonal gammopathy, who developed thrombotic thrombocytopenic purpura (TTP), initially presenting as bilateral serous retinal detachment. Plasma of the patient contained high titers of anti-ADAMTS13 antibodies that were directed towards the disintegrin/TSR1/cysteine-rich/spacer and CUB1-2 domains. ADAMTS13 activity was undetectable. Total IgG purified from plasma of the patient partially inhibited ADAMTS13 activity. In contrast, the isolated M-protein did neither bind to, nor inhibit activity of ADAMTS13. We conclude that in this patient the monoclonal gammopathy and TTP co-existed as distinct pathological entities.

“…25 The two human monoclonal antispacer domain antibodies I-9 and II-1 have been described previously. 18,26 Monoclonal anti-V5 antibody (Invitrogen) coupled to protein G sepharose (GE Healthcare) was used as a positive control. Normal human pooled plasma from 47 healthy donors was included as a negative control.…”

Section: Epitope Mapping Of Anti-adamts13 Antibodiesmentioning

confidence: 99%

Residues Arg568 and Phe592 contribute to an antigenic surface for anti-ADAMTS13 antibodies in the spacer domain

Pos¹,

Sorvillo²,

Fijnheer³

et al. 2011

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118

The online version of this article has a Supplementary Appendix. BackgroundThe majority of patients diagnosed with thrombotic thrombocytopenic purpura have autoantibodies directed towards the spacer domain of ADAMTS13. Design and MethodsIn this study we explored the epitope specificity and immunoglobulin class and immunoglobulin G subclass distribution of anti-ADAMTS13 antibodies. The epitope specificity of antispacer domain antibodies was examined using plasma from 48 patients with acute acquired thrombotic thrombocytopenic purpura by means of immunoprecipitation of ADAMTS13 variants containing single or multiple alanine substitutions. Using similar methods, we also determined the presence of anti-TSP2-8 and CUB1-2 domain antibodies in this cohort of patients.