Prevalence of the ADAMTS‐13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura

Background: Thrombotic thrombocytopenic purpura (TTP) is most commonly associated with deficiency or inhibition of von Willebrand factor‐cleaving protease (ADAMTS‐13) activity. ADAMTS‐13 mutations and polymorphisms have been reported in childhood congenital TTP, but their significance in adult onset TTP remains unclear. Objectives: We sought to identify common ADAMTS‐13 mutations in adults with late onset TTP and to investigate whether they may predispose acute clinical episodes of the disorder in adulthood. Patients/Methods/Results: We detected a missense mutation (C3178T) in exon 24 of ADAMTS‐13 in 6/53 (11.3%) adult onset TTP patients, but no normal controls (n = 100). Three of the patients had pregnancy‐associated TTP; three had chronic relapsing acute idiopathic TTP. C3178T encodes an arginine to tryptophan (R1060W) substitution in the TSP1‐7 domain of ADAMTS‐13. In vitro expression of mutant and wild‐type ADAMTS‐13 demonstrated that R1060W caused severe intracellular retention of ADAMTS‐13 (