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Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder due to autoantibodies against ADAMTS13. The case of identical twins suffering from acute acquired TTP with severe autoantibody-mediated ADAMTS13 deficiency (Studt JD et al., Blood2004;103:4195) led us to speculate on unknown genetic determinants of acquired TTP and on the immunological basis of ADAMTS13 autoimmunity. We investigated 37 patients (pts) with acute TTP with acquired severe ADAMTS13 deficiency of

The immunosuppressive therapy with everolimus (ERL) after heart transplantation is characterized by a narrow therapeutic window and a substantial variability in dose requirement. Factors explaining this variability are largely unknown. Our aim was to evaluate factors affecting ERL metabolism and to identify novel metabolites associated with the individual ERL dose requirement to elucidate mechanisms underlying ERL dose response variability. We used liquid chromatography coupled with mass spectrometry for quantification of ERL metabolites in 41 heart transplant patients and evaluated the effect of clinical and genetic factors on ERL pharmacokinetics. Non-targeted plasma metabolic profiling by ultra-performance liquid chromatography and high resolution quadrupole-time-of-flight mass spectrometry was used to identify novel metabolites associated with ERL dose requirement. The determination of ERL metabolites revealed differences in metabolite patterns that were independent from clinical or genetic factors. Whereas higher ERL dose requirement was associated with co-administration of sodium-mycophenolic acid and the CYP3A5 expressor genotype, lower dose was required for patients receiving vitamin K antagonists. Global metabolic profiling revealed several novel metabolites associated with ERL dose requirement. One of them was identified as lysophosphatidylcholine (lysoPC) (16:0/0:0). Subsequent targeted analysis revealed that high levels of several lysoPCs were significantly associated with higher ERL dose requirement. For the first time, this study describes distinct ERL metabolite patterns in heart transplant patients and detected potentially new drug–drug interactions. The global metabolic profiling facilitated the discovery of novel metabolites associated with ERL dose requirement that might represent new clinically valuable biomarkers to guide ERL therapy.