Individuals with IgG subclasses 4 were found out to be more likely to have disease recurrence than individuals with IgG subclass 1.31 Individuals with high inhibitor titers were found to have worse acute-disease prognosis.31 Consistently, individuals with high levels of IgG (both inhibitory and non-inhibitory) were found to have a higher probability of developing cardiac involvement and, hence, a poorer prognosis in comparison to individuals with low IgG levels.36 All these findings indicate that different antibody features might be Rabbit Polyclonal to PDCD4 (phospho-Ser457) associated with clinical outcomes in TTP, but GSK1292263 more comprehensive studies should be carried out before antibody characterization can be introduced into routine clinical practice of TTP. (congenital TTP)8 or to anti-ADAMTS13 autoantibodies (autoimmune TTP).9C11 The antibody-mediated severe deficiency of ADAMTS13 can be detected in most individuals with idiopathic TTP (i.e. GSK1292263 TTP happening without associated medical conditions/events), whereas its prevalence is much reduced the secondary forms of TTP (i.e. TTP associated with pregnancy, infections, autoimmune diseases and the use of drugs such as ticlopidine and clopidogrel).12,13 It should also be pointed out that there are idiopathic instances of TTP with only slightly deficient and even normal ADAMTS13 levels at demonstration, but these instances are not object of the present article in which idiopathic and autoantibody-mediated TTP are used as synonyms. Epidemiology and medical course of idiopathic thrombotic thrombocytopenic purpura The incidence of idiopathic TTP is definitely estimated to be 4.5/1 million person/years, becoming higher in blacks. The male to female ratio is definitely 1:2, similarly to the percentage for additional autoimmune diseases.14 The acute prognosis of idiopathic, antibody-mediated TTP tends to be less severe, but the risk of recurrent disease is higher than that of secondary forms.15,16 The overall mortality of TTP was higher than 90%, but offers decreased to 8C30% after the introduction of plasma exchange, which is the treatment of choice of acute TTP episodes.17C20 The lower mortality of patients with idiopathic TTP (21% 39% in the frame of the Oklahoma TTP GSK1292263 registry16) is probably due to the higher response to plasma exchange of patients with autoanti-bodies and to the mortality related to associated conditions in secondary cases.21 Up to 40% of individuals with TTP develop recurrent episodes of the disease, with the risk of recurrences being higher in individuals with severe ADAMTS13 deficiency and anti-ADAMTS13 autoanti-bodies during acute episodes.15,16,22C24 The cumulative risk of recurrence at 7.5 years after the first episode in patients with ADAMTS13 activity below 10% at presentation was estimated to be 41%, 10 times that of patients with activity above 10% (4% risk at 7.5 years).16 Persistence of ADAMTS13 deficiency and of autoantibodies during disease remission is also associated with increased risk of recurrence.25,26 Characterization of anti-ADAMTS13 antibodies Anti-ADAMTS13 autoantibodies have been the focus of several research efforts seeking to characterize their immunoglobulin (Ig) subclass, specificity and mechanisms of action. Early studies distinguished two classes of anti-ADAMTS13 autoantibodies: inhibitory and non-inhibitory antibodies. Inhibitory antibodies are present in 50C90% and their mechanism of action is the inhibition of ADAMTS13-mediated proteolysis of VWF.27 When non-inhibitory antibodies will also be measured, anti-ADAMTS13 autoantibodies are detectable in 97C100% of individuals.27,28 The core binding site for VWF, located in the spacer domain of ADAMTS13 and consisting of amino acid residues Tyr572-Asn579 and Arg657-Gly666, signifies the prospective site of the autoantibodies found in the plasma of several TTP individuals.29,30 The mechanism of action of non-inhibitory antibodies has been proposed to be opsonisation and enhanced clearance of ADAMTS13, but this has never been proven.27,28 Studies on the class of anti-ADAMTS13 autoantibodies showed they are usually of IgG type, particularly IgG1 and IgG4 subtypes,10,31 but in a few cases autoantibodies of IgA and/or IgM isotype were also found.28,32 Most anti-ADAMTS13 IgG found in TTP individuals were demonstrated to be directed against the spacer website, but additional antibodies against other ADAMTS13 domains were also detected.33,34 However, these studies were conducted in small cohorts of individuals. In this problem of Haematologica, Zheng em et al. /em 35 present the 1st study of antibody specificity on a relatively large group of individuals with TTP, finding that, although almost all individuals with IgG experienced antibodies directed against the N-terminal ADAMTS13 domains (Cys-rich through spacer), where the catalytic site of ADAMTS13 is located, up to 46% of TTP individuals also experienced antibodies against C-terminal ADAMTS13 domains (TSP1C5 through CUB). Moreover, two individuals had antibodies only against C-terminal domains of ADAMTS13, but not against N-terminal domains. These findings suggest a functional part of C-terminal domains of ADAMTS13 em in vivo /em , also in light of the importance of these domains in the VWF-ADAMTS13 connection under fluid shear stress. Importantly, Zheng em et al. /em 35 correlated antibody specificity with medical data, showing that individuals with antibodies against ADAMTS13 C-terminal domains experienced lower platelet counts at presentation. This is not the first time that anti-ADAMTS13.