Abstract Number: OC 53.4
Meeting: ISTH 2021 Congress
Background: TTP is defined by a severe ADAMTS13 deficiency, either acquired due to circulating anti-ADAMTS13 autoantibodies (primarily IgG4) in immune-mediated TTP (iTTP), or as result of bi-allelic ADAMTS13 mutations in hereditary TTP (hTTP). Treatment with exogenous ADAMTS13 (plasma) exposes hTTP patients to the risk of alloantibody formation. In ~10% of hTTP patients, ADAMTS13 IgG antibodies have been documented.
Aims: In this study, we characterize the anti-ADAMTS13 repertoire of hTTP patients with different clinical courses and variable plasma exposure.
Methods: Three hTTP patients (two males; aged 41y (hG), 45y (hP) and one female, aged 49y (hJ); carrying five different ADAMTS13 mutations) donated peripheral blood monocytes to amplify their anti-ADAMTS13 IgG4 Fab κ/λ repertoire by phage display technology. Selected anti-ADAMTS13 Fab clones were analyzed for the IGHV gene usage and the antigen-binding CDR3 sequence. While one patient (hG) received plasma therapy only episodically, two patients were on regular plasma prophylaxis for >15 years. In one of the latter (hP), we documented fluctuating anti-ADAMTS13 IgG antibody titers, which were negative in the other two.
Results: Through five selection rounds on recombinant ADAMTS13 we observed no enrichment of specific phages in patient hG but a 10 to 100-fold enrichment in hJ and hP, however much lower than the enrichment of specific phages (>1000-fold) found in iTTP patients. In total, we obtained 11 anti-ADAMTS13 Fab clones, with seven unique CDR3 sequences. Ten of 11 clones derived from the two patients on regular plasma prophylaxis. The IGHV gene usage was restricted to VH1-8; VH1-46; VH3-15; VH3-30; VH4-4 (n=4) and VH4-34 (n=3) without overlap between patients.
Conclusions: In the immune repertoire of hTTP patients, we found evidence for an antigen-driven ADAMTS13 response with a certain correlation to plasma exposure. The IGHV gene usage differed from that observed in the anti-ADAMTS13 repertoire of iTTP patients. Functional characterization of purified anti-ADAMTS13 Fabs is underway.
To cite this abstract in AMA style:Heeb SR, Schaller M, Tarasco E, Kremer Hovinga JA. Anti-ADAMTS13 Antibodies in Patients with Hereditary Thrombotic Thrombocytopenic Purpura (hTTP) [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/anti-adamts13-antibodies-in-patients-with-hereditary-thrombotic-thrombocytopenic-purpura-http/. Accessed December 7, 2021.
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