ADAMTS13-RELATED ASSAYS IN ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic disorder, due to the persistence of highly thrombogenic ultra large (UL) von Willebrand factor (VWF) multimers in the microcirculation. TTP is associated with the severe deficiency of ADAMTS13 (activity <10%), the metalloprotease responsible for the proteolytic regulation of VWF multimers size. In the acquired form of the disease, the severe deficiency of ADAMTS13 is caused by anti-ADAMTS13 antibodies that inhibit ADAMTS13 activity (neutralizing anti-ADAMTS13 antibodies or inhibitors) and/or increase its clearance from the circulation (non-neutralizing anti-ADAMTS13 antibodies). In the absence of ADAMTS13, highly adhesive ULVWF, that spontaneously aggregate platelets, accumulates promoting platelet thrombi formation and eventually leading to the clinical features typical of TTP. In the past decade, the increasing knowledge regarding the molecular mechanisms involved in the pathogenesis of TTP, yielded to a proliferation of assays for the measurement of ADAMTS13 and anti-ADAMTS13 antibodies. Despite the numerous studies conducted to assess the clinical utility of ADAMTS13-related markers, their prognostic value is still controversial. The finding that severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 antibody is associated with an increased risk of relapse is rather consistent, but studies on larger cohort of patients are needed. More uncertain is the predictive value of immunoglobulin (Ig) class subtype of anti-ADAMTS13 antibodies, whether or not inhibitory. Controversial results may be partially due to differences in the assays used to measure ADAMTS13 activity and anti-ADAMTS13 antibodies, which require further standardization. With this background, the present research had two main objectives: to evaluate, in a large cohort of acquired TTP patients enrolled in the international Milan TTP Registry (developed and curated at the The Hemophilia and Thrombosis Centre of Milan), the clinical utility of ADAMTS13 related biomarkers and to investigate which ADAMTS13 assay may be more reliable in the management of acquired TTP. In the first part of this study, we analyzed, during both acute and remission phase, all the biomarkers associated with ADAMTS13 (activity, antigen and class, subclass and titre of anti ADAMTS13 autoantibodies) in acquired TTP patients referred to our centre and we correlated them to episode severity and recurrence. We found that both the Ig class and subclass are of predictive value for acute episode severity in patients with TTP. Disease recurrence seemed to be associated with the presence of IgG antibodies during the acute phase, while alterations in several ADAMTS13 related biomarkers (ADAMTS13 activity or antigen levels <10%, presence of ADAMTS13 inhibitor or IgG) could predict recurrence risk when measured during disease remission. The results of this study confirmed and extended previous data on the prognostic value of ADAMTS13 testing, providing valuable information for the…