Thrombotic microangiopathies comprise different entities, including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and several other conditions. TTP is characterized by hemolytic anemia, thrombocytopenia, and multiorgan failure. TTP is the result of severe von Willebrand factor multimer cleaving protease (ADAMTS13) deficiency that is either inherited or the result of acquired autoantibodies. We report a critically ill 2-year-old girl with invasive pneumococcal disease associated HUS (p-HUS) whose condition was complicated by severe ADAMTS13 deficiency, without detectable inhibitor, in a context of multiple organ failure. The patient recovered with supportive treatment, and ADAMTS13 activity normalized without plasmatherapy. Severe ADAMTS13 deficiency appears to be a manifestation of transient endothelial cell injury in the context of severe sepsis, including invasive p-HUS. The choice of appropriate therapy should not be based on this finding.