NET formation contributes to clinical relapses but not ADAMTS13 biomarker relapses in immune-mediated thrombotic thrombocytopenic purpura

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy (TMA) caused by a severe acquired ADAMTS13 deficiency, resulting in persistence of ultra-large von Willebrand Factor (VWF) in circulation [ 1 ]. Treatment rests on three pillars, therapeutic plasma exchange (TPE), immunosuppression, and caplacizumab (limited availability in Switzerland between 2019 and late 2024), a nanobody that prevents platelet binding to VWF [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]. Neutrophil extracellular traps (NETs) contribute to thrombus formation in TMAs [ 7 ] [ 8 ] [ 9 ], yet their role in association with various clinical stages of iTTP and under different treatment modalities remains to be investigated. Method We conducted a retrospective, observational study in eight patients with confirmed iTTP who were followed for 7.4 (range 0.4 – 15.2) years ( [ Fig. 1 ] ) . We studied their first acute episodes (3/8 treated with, 5/8 without caplacizumab), fourteen ADAMTS13 relapses, and six clinical relapses (2 treated with, 4 without caplacizumab). Remission samples were used as patient baselines and controls. Besides clinical and ADAMTS13 parameters, we measured circulating NET markers, i.e. DNA, myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3). Fig. 1 Demographic data, treatments, and outcomes of the study cohort. TPE, therapeutic plasma exchange; FFP, fresh frozen plasma; N/A, not applicable. *Follow-up time: time from first admission to acquirement of last remission sample. §Exacerbation: platelet count