Despite being the first genetic disease described, sickle cell disease (SCD) continues to afflict patients with immense pain, significant comorbidities and premature death. SCD has only recently benefited from new interventions with L-glutamine (2017), voxelotor (2019) and crizanlizumab (2019) representing the first Food and Drug Administration approved medications for SCD since hydroxyurea in 1997. These interventions have demonstrated some ability to reduce vaso-occlusive pain crisis episodes, improve hemoglobin (HGB), or reduce markers of hemolysis and have largely been used as preventative care measures. While these and additional approaches, such as hematopoietic stem cell transplant and gene therapy, can improve SCD care, many patients with SCD continue to suffer from severe acute SCD complications that can result in organ damage and early death.1,2 Unfortunately, in these situations, supportive care remains the primary approach to alleviate complications. The lack of more targeted approaches in part reflects an incomplete understanding of the pathophysiology and accompanying pharmacological targets that could specifically mitigate acute disease complications. We present a summary of three cases of children with SCD who developed significant acute complications that demonstrate underlying complement-mediated thrombotic microangiopathy (CM-TMA). These cases include a delayed hemolytic transfusion reaction (DHTR), vasoocclusive crisis (VOC) and drug-induced immune hemolytic anemia (DIIHA).