Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura

Background ADAMTS13 adopts an open conformation in immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients in acute phase while being closed in healthy donors. We reported that a substantial number of iTTP patients in remission with restored ADAMTS13 activity (>50%) still had an open ADAMTS13 conformation, although a closed conformation is expected given the extent of remission. Objective To investigate whether open ADAMTS13, represented by conformation index >0.5, is associated with a risk for earlier ADAMTS13 and/or clinical relapse. Patients/Methods We collected follow-up data (ADAMTS13 parameters, ADAMTS13 and clinical relapse and treatment) from 81 iTTP patients in remission with ADAMTS13 activity above 50%. Results During follow-up, 19 ADAMTS13 and 10 clinical relapses were reported (median follow up period: 20 months). First, open or closed ADAMTS13 conformation was dichotomized based on the 0.5 conformation index cut-off. Open ADAMTS13 (conformation index >0.5) was not identified as a risk for ADAMTS13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cut-off for relapse prediction, using classification and regression tree analysis, conformation index >0.645 and >0.835 were shown to be a risk for respectively ADAMTS13 relapse (hazard ratio (HR) 3.3, (95% CI:1.3-8.3), p=0.01) and clinical relapse (HR 4.4, (95% CI:1.3-15.3), p=0.02). Conclusion Patients with open ADAMTS13 with conformation index >0.645 and >0.835, respectively have an over 3- and 4-fold higher risk for earlier ADAMTS13 and clinical relapse. Hence, ADAMTS13 conformation index could be used to complement ADAMTS13 activity monitoring to timely notice ADAMTS13 relapse and prevent clinical relapse.