VH1‐69 germline encoded antibodies directed towards ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura

Background: Autoantibodies directed towards ADAMTS13 are present in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). Analysis of a set of antibodies derived from two patients with acquired TTP revealed frequent use of the VH1‐69 heavy chain gene segment for the assembly of anti‐ADAMTS13 antibodies. Objective: We explored the ability of two VH1‐69 germline gene‐encoded antibodies to inhibit the von Willebrand factor (VWF)‐processing activity of ADAMTS13 under different experimental conditions. Furthermore, the presence of VH1‐69 encoded anti‐ADAMTS13 antibodies in 40 patients with acquired TTP was monitored using monoclonal antibody G8, which specifically reacts with an idiotype expressed on VH1‐69 encoded antibodies. Methods and Results: Binding of the two VH1‐69 encoded monoclonal antibodies was dependent on the presence of the spacer domain. Both antibodies inhibited ADAMTS13 activity under static conditions, as measured by cleavage of FRETS‐VWF73 substrate and cleavage of VWF multimers. The recombinant antibodies were also capable of inhibiting the processing of UL‐VWF strings on the surface of endothelial cells. G8‐reactive antibodies directed towards ADAMTS13 were present in plasma of all patients containing anti ADAMTS13 antibodies. Conclusions: These results suggest that VH1‐69 derived antibodies directed towards ADAMTS13 develop in the majority of patients with acquired TTP.