Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune 
system activation driven mainly by high levels of interferon gamma. The clinical 
presentation of HLH can have considerable overlap with other inflammatory 
conditions. We present a cohort of patients with therapy refractory HLH referred 
to our center who were found to have a simultaneous presentation of 
complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had 
therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). 
Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal 
replacement therapy, severe hypertension, serositis, and gastrointestinal 
bleeding were documented only in patients with HLH who had concomitant 
complement-mediated TMA. Patients with HLH and without TMA required ventilator 
support mainly due to CNS symptoms, while those with HLH and TMA had respiratory 
failure predominantly associated with pulmonary hypertension, a known 
presentation of pulmonary TMA. Ten patients received eculizumab for 
complement-mediated TMA management while being treated for HLH. All patients who 
received the complement blocker eculizumab in addition to the interferon gamma 
blocker emapalumab had complete resolution of their TMA and survived. Our 
observations suggest co-activation of both interferon and complement pathways as 
a potential culprit in the evolution of thrombotic microangiopathy in patients 
with inflammatory disorders like refractory HLH and may offer novel therapeutic 
approaches for these critically ill patients. TMA should be considered in 
children with HLH and multi-organ failure, as an early institution of a brief 
course of complement blocking therapy in addition to HLH-targeted therapy may 
improve clinical outcomes in these patients.