Abstract Number: OC 66.2
Meeting: ISTH 2021 Congress
Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency of ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats member 13). Patient autoantibodies have epitopes in all ADAMTS13 domains: Metalloprotease (M) and Disintegrin-like (D) domain, a first Thrombospondin type-1 repeat (T1), a Cysteine-rich (C) and Spacer (S) domain, 7 additional Thrombospondin repeats (T2-T8) and 2 CUB (CUB) domains, and almost all patients have autoantibodies against the CS domains. In healthy individuals, ADAMTS13 circulates in a folded conformation where the central S domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP patients and that patient immunoglobulin G’s (IgGs) can open ADAMTS13. We now hypothesize that the anti-CS and anti-CUB autoantibodies can disrupt the S-CUB interaction in folded ADAMTS13 thereby inducing an open ADAMTS13 conformation.
Aims: To investigate whether patient anti-CS and anti-CUB autoantibodies can induce an open ADAMTS13 conformation.
Methods: Anti-CS and anti-CUB autoantibodies were purified from the total IgGs of 13 acute iTTP patients by CS- or CUB-coupled affinity chromatography and their specificity was evaluated in ELISA. The ability of the affinity purified anti-CS or anti-CUB autoantibodies to open ADAMTS13 was tested in our in-house developed ADAMTS13 conformation ELISA.
Results: Affinity purified anti-CS (10/13 patients, Figure 1A) and anti-CUB (4/13 patients, Figure 1B) autoantibody fractions showed binding to respectively CS or CUB while little to no binding to other ADAMTS13 fragments was observed. Interestingly, all purified anti-CS autoantibody fractions (10/10 patients) were able to induce an open ADAMTS13 conformation (Figure 1C). In contrast, only half of the purified anti-CUB autoantibody fractions (2/4 patients) opened the conformation of ADAMTS13 (Figure 1D).
Conclusions: Our data shows that the presence of anti-CS autoantibodies inducing an open ADAMTS13 conformation is a common feature of the autoantibody response in iTTP patients.
To cite this abstract in AMA style:De Waele L, Curie A, Kangro K, Tellier E, Kaplanski G, Männik A, Tersteeg C, Joly BS, Coppo P, Veyradier A, De Meyer SF, Roose E, Vanhoorelbeke K. Anti-cysteine/Spacer Autoantibodies that Open the Conformation of ADAMTS13 Are a Common Feature of the Autoimmune Response in Immune-mediated Thrombotic Thrombocytopenic Purpura [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/anti-cysteine-spacer-autoantibodies-that-open-the-conformation-of-adamts13-are-a-common-feature-of-the-autoimmune-response-in-immune-mediated-thrombotic-thrombocytopenic-purpura/. Accessed December 7, 2021.
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