Eve of an ADAMTS13 breakthrough

The discovery of deficient activity of the metalloprotease now known as ADAMTS13 was a landmark development in the understanding of thrombotic thrombocytopenic purpura (TTP). For the most common, nonfamilial subtype of TTP, demonstration of inhibitory autoantibodies as the apparent cause of ADAMTS13 deficiency offered the immediate promise of more enlightened therapy. After decades of empirical approaches to treatment, immune modulation might now be used against a demonstrable autoimmune etiology.

However, in the years since the discovery of ADAMTS13 deficiency in TTP, inhibitor studies have left an incomplete picture. Among case series reports, at least one third of patients with nonfamilial TTP had weak or absent ADAMTS13 inhibitor activity, and inhibitor levels often did not correlate well with disease activity. Therefore, a significant subset of patients with nonfamilial TTP was left without a clear cause of ADAMTS13 deficiency. From a treatment standpoint, the inability to reliably identify an autoimmune etiology in a sizable fraction of patients made clinical trials of immunomodulation therapy difficult to design.

The mystery of the missing cause of ADAMTS13 deficiency in nonfamilial TTP may soon be clarified. In this issue, Scheiflinger and colleagues (page 3241) report the discovery of noninhibitory anti-ADAMTS13 antibodies in a patient with nonfamilial TTP. The patient had severely decreased ADAMTS13 activity, but no detectable ADAMTS13-inhibiting antibodies. Using a novel enzyme-linked immunosorbent assay (ELISA) with recombinant human ADAMTS13 as an antibody-binding substrate, they discovered both immunoglobulin G (IgG) and IgM anti-ADAMTS13 antibodies in the patient's plasma in concentrations markedly higher than normal plasma.

Although preliminary, this observation may help fill the current gap in pathogenic models of nonfamilial TTP. It appears that ADAMTS13 deficiency may be caused by different kinds of autoantibodies, not all of which are detected by inhibitor studies. It may be that patients with TTP can develop antibodies with varying degrees of functional inhibition and protein clearance effects, and such variability could account for the sometimes-perplexing results of inhibitor studies. Future studies to determine if ADAMTS13-binding antibodies are prevalent in nonfamilial TTP, and whether levels correlate with disease course, will be of great interest.

An assay that detects a broad range of ADAMTS13-binding antibodies may prove to be the critical tool needed to identify patients and monitor treatment response in ADAMTS13-deficient, nonfamilial TTP. With such a new resource, the promise of significant advances in immune modulation treatment in TTP may be close at hand.